NZ787281A

NZ787281A - Amine-substituted aryl or heteroaryl compounds as ehmt1 and ehmt2 inhibitors

Info

Publication number: NZ787281A
Application number: NZ787281A
Authority: NZ
Inventors: Michael John Munchhof; John Emmerson Campbell; Kenneth William Duncan; Megan Alene Foley; Darren Martin Harvey; Kevin Wayne Kuntz; James Edward John Mills
Original assignee: Epizyme Inc
Filing date: 2017-04-17
Publication date: 2022-04-29

Abstract

The present disclosure relates to amine-substituted aryl or heteroaryl compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anemia) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted aryl or heteroaryl compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.

Description

UBSWTUTEDARYLORFETEROARYLCOMPOUNDSASEHMT1ANDEHMTZIMﬂBWORS RELATED APPLICATIONS This ation claims priority to, and the beneﬁt of, US. Provisional Application Nos. 62/323,602 ﬁled April 15, 2016, 62/348,837 ﬁled June 10, 2016 and ,997 ﬁled September 30, 2016, the entire ts of each of which are incorporated herein by reference.

BACKGROUND Methylation of protein lysine residues is an important signaling mechanism in eukaryotic cells, and the methylation state of histone lysines encodes signals that are recognized by a multitude of proteins and protein complexes in the context of epigenetic gene tion.

Histone methylation is catalyzed by histone transferases (HMTs), and HMTs have been implicated in various human diseases. HMTs can play a role in either activating or repressing gene sion, and certain HMTs (e.g., euchromatic histone-lysine N- methyltransferase 2 or EHMT2, also called G9a) may methylate many nonhistone proteins, such as tumor suppressor proteins (see, e.g., Liu et al, Journal ofMedicinal Chemistry 56:8931-8942, 2013 and Krivega el‘ al, Blood 126(5):665-672, 2015).

Two related HMTs, EHMTl and EHMT2, are overexpressed or play a role in diseases and ers such as sickle cell anemia (see, e.g., Renneville et al, Blood 126(16): 1930—1939, 2015) and proliferative disorders (eg, cancers), and other blood disorders.

SUMMARY In one aspect, the present disclosure features an amine-substituted aryl or heteroaryl compound of Formula (1) below: XZ/X\X34 /X5\ /T\’">/‘R7’ R6 X1 n N :B; or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In Formula (1) above, ring A is phenyl or a 5- or 6-membered heteroaryl, X1 is N, CR2, or NR2’ as y permits, X2 is N; CR3; or NR3’ as y permits; X3 is N; CR4; or NR4’ as valency permits; X4 is N or CR5; or X4 is absent such that ring A is a 5-membered heteroaryl containing at least one N atom; X5 is C or N as valency permits; B is absent or a ring structure selected from the group consisting of C6-C10 aryl; C3- C10 cycloalkyl; 5- to 10-membered aryl; and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; T is a bond or C1-C6 alkylene; C2-C6 alkenylene; or C2-C6 lene linker optionally substituted with one or more of halo; cyano; hydroxyl; oxo; or C1-C6 alkoxy when B is present; or T is H and n is 0 when B is absent; or T is C1-C6 alkyl optionally substituted with (R7)11 when B is absent; or when B is absent; T and R1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl; each of which is optionally substituted with (R7)n; R1 is H or C1-C4 alkyl; each of R2; R3; and R4; independently is selected from the group consisting of H; halo; cyano; C1-C6 alkoxyl; 06-010 aryl; NRaRb; C(O)NRaRb; NRaC(O)Rb; c3—c8 cycloalkyl; 4— to 7- membered heterocycloalkyl; 5- to 6-membered heteroaryl; and C1-C6 alkyl; wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo; ORa; or NRaRb; in which each of Ra and Rb independently is H or C1-C6 alkyl; or R3 is —Q1-T1; in which Q1 is a bond or C1-C6 ne; C2-C6 lene; or C2-C6 lene linker optionally substituted with one or more of halo; cyano; hydroxyl; oxo; or C1-C6 alkoxyl; and T1 is H; halo; cyano; NRSRg; C(O)NR8R9; 0R8; 0R9; or RSI; in which RS1 is C3-C3 cycloalkyl; phenyl; 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms ed from N; O; and S; or a 5- or 6-membered heteroaryl and RSl is optionally substituted with one or more of halo; C1-C6 alkyl; hydroxyl; oxo; -C(O)R9; 60st; -SOZN(R8)2; -NR8C(O)R9; amino; mono- or dialkylamino ; or C1-C6 alkoxyl;; or when ring A is a 5-membered heteroaryl containing at least one N atom; R4 is a fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; each of RZ’; R3’ and R ’ independently is H or C1-C3 alkyl; R5 is selected from the group consisting of H; F; Br; cyano; C1-C6 l; C6-C10 aryl; NRaRb; C(O)NRaRb; NRaC(O)Rb; C3-C3 cycloalkyl; 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; C1-C6 alkyl optionally substituted with one or more of halo; ORa or NRaRb; and C2-C6 l optionally substituted with 4- to 12- membered heterocycloalkyl, wherein said C3-C3 cycloalkyl or 4- to 12-membered cycloalkyl are optionally substituted with one or more of halo, C(O)Ra, ORa, NRaRb, 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, or C1- C4 alkyl optionally tuted with one or more of halo, ORa or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are ed form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, R6 is absent when X5 is N and ring A is a 6-membered aryl, or R6 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 lene, or C2-C6 lene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or RSI, in which R51 is C3-C3 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RSl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, -SOZR8, -SOzN(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and R6 is not NR8C(O)NR12R13, or R6 and one of R2 or R3 together with the atoms to which they are attached form phenyl or a 5- or ered heteroaryl, or R6 and one of Rz’or R3’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered aryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=0), C1-C3 alkoxyl, or -Q1-T1, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, cyano, OR"), OR", C(O)R11, NRIORH, C(O)NR10R11, NR10C(O)R11, 5- to 10-membered heteroaryl, C3-C3 lkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C3-C3 cycloalkyl or 4- to 12-membered cycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, yl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, -SOZRS, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)ORg, or optionally, when B is t, one R7 and R5 together form a C3-C10 alkylene, C2-C10 heteroalkylene, C4-C10 alkenylene, C2-C10 heteroalkenylene, C4-C10 alkynylene or C2- C10 heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB,NR12R13,NR12C(O)R13, C(O)NR12R13, 3, S(O)2R13, S(O)2NR12R13, or R52, in which R52 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more , wherein each Q4 independently is a bond or C1-C3 ne, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting ofH, halo, cyano, C1-C6 alkyl, C3-C3 lkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd ndently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R8 and R9 taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of —Q5-T5, wherein each Q5 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 lkyl, C6-C10 aryl, 4- to ered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered aryl, ORG, C(O)Re, S(O)2Re, S(O)2NReRf, NReRf, C(O)NReRf, and NReC(O)Rf, each of Re and Rf independently being H or C1-C6 alkyl, or —Q5-T5 is oxo, R10 is selected from the group consisting of H and C1-C6 alkyl, R11 is —Q6-T6, in which Q6 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T6 is H, halo, ORg, NRth, NRgC(O)Rh, C(O)NRth, C(O)Rg, g, or RS3, in which each of Rg and Rh independently is H, phenyl, C3-C3 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C3 cycloalkyl, or Rg and Rh together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, and RS3 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O and S, or a 5- to lO-membered heteroaryl, and RS3 is ally substituted with one or more —Q7-T7, wherein each Q7 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T7 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR], C(O)Rj, NRij, C(O)NRij, S(O)2Rj, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl ally substituted with one or more halo, or —Q7-T7 is oxo, or R10 and R11 taken together with the nitrogen atom to which they are ed form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, or C1-C6 alkoxyl, R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 lene linker each optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, and nis 0,1, 2, 3, or4.

In certain embodiments, the nd of a (I) is not 4-(((2-((1-acetylindolin- 6-yl)amino)(triﬂuoromethyl)pyrimidinyl)amino)methyl)benzenesulfonamide, -bromo-N4-(4-ﬂuorophenyl)-N2-(4-methoxy-3 -(2-(pyrrolidin-l - yl)ethoxy)phenyl)pyrimidine-2,4-diamine, N2-(4-methoxy(2-(pyrrolidin- l -yl)ethoxy)phenyl)-N4-(5 -(tert-pentyl)- lH-pyrazol- 3-yl)pyrimidine-2,4-diamine, 4-((2,4-dichloromethoxyphenyl)amino)((3-(2-(pyrrolidin-lyl )ethoxy)phenyl)amino)pyrimidinecarbonitrile, N-(naphthalenyl)(piperidin-l-ylmethoxy)pyrimidinamine, N-(3 ,5 -diﬂuorobenzyl)(3-(pyrrolidin-l -yl)propyl)pyrimidinamine, N—(((4-(3 -(piperidin- l -yl)propyl)pyrimidinyl)amino)methyl)benzamide, N—(2-((2-(3-(dimethylamino)propyl)pyrimidinyl)amino)ethyl)benzamide, 2-(hexahydromethyl- lH-l ,4-diazepin- l -yl)-6,7-dimethoxy-N- [ l -(phenylmethyl) piperidinyl]quinazolinamine, 2-cyclohexylmethoxy-N—[l-(l-methylethyl)piperidinyl][3-(l- pyrrolidinyl)propoxy]quinazolinamine, 3-(1-cyano-l-methylethyl)-N-[3-[(3,4-dihydromethyloxo quinazolinyl)amino]methylphenyl]benzamide, 6-acetylcyclopentylmethyl[(5-piperazin-l-ylpyridinyl)amino]pyrido[2,3- d]pyrimidinone, [4-(Diethylamino)butyl]amino](3,5-dimethoxyphenyl)pyrido[2,3- midinyl]-N'—(1,1-dimethylethyl)urea, or 6-[[2-[[4-(2,4-dichlorophenyl)(5-methyl-lH-imidazolyl) dinyl] amino] ethyl] amino] -3 -pyridinecarbonitrile.

In certain embodiments, when T is a bond, B is substituted phenyl, and R6 is NRSRg, in which R9 is —Q3-RSZ, and RS2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6-membered aryl, then B is substituted with at least one substituent selected from (i) —Q2-OR11 in which R11 is —Q6-RS3 and Q6 is optionally substituted C2-C6 alkylene, 02-06 alkenylene, or C2-C6 alkynylene linker and (ii) —Q2-NR10R11 in which R" is —Q6-RS3.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, then R6 is not OR9 or NRgR9 in which R9 is ally substituted naphthyl.

In certain embodiments, when T is a bond and B is ally substituted phenyl, naphthyl, indanyl or l,2,3,4-tetrahydronaphthyl, then R6 is not NRSR9 in which R9 is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl.

In n embodiments, when T is a bond and B is optionally substituted phenyl or thiazolyl, then R6 is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NRgR9 in which R9 is optionally substituted imidazolyl, pyrazolyl, or 6- to 10-membered heteroaryl.

In certain embodiments, when T is a C1-C6 ne linker and B is absent or optionally substituted C6-C10 aryl or 4- to 12-membered heterocycloalkyl, or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R6 is not )R13.

In certain embodiments, when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are ed form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is , C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain embodiments, when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C1-C6 alkyl, and R6 and R2 together with the atoms to which they are attached form phenyl which is substituted with one or more of ally substituted C1-C3 l, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain embodiments, when T is a bond and B is hydroxyl-substituted phenyl, then ring A is not pyrazinyl.

In certain ments, when ring A is phenyl and B is a 5-membered heteroaryl or phenyl, then T is not C(O), In certain embodiments, when ring A is phenyl, B is absent, and T and R1 er with the atoms to which they are attached form a 4-7 membered heterocycloalkyl, the heterocycloalkyl contains at most one N ring atom or the heterocycloalkyl is not substituted by oxo, In certain embodiments, when one of ring A or B is pyridyl and T is a bond, then the pyridinyl is not substituted at the para-position of N-Rl with —Q1-T1 or —Q2-T2, in which T1 or T2 is phenyl or heteroaryl, or In certain embodiments, when T is a bond or C1-C3 alkylene, ring A is a 6-membered heteroaryl and B is optionally substituted phenyl, l, or piperidinyl, then R6 is not H and at least one of R2, R3, R4 and R5 is not H.

A subset of compounds of Formula (I) includes those of Formula (II): R1 (II), and tautomers thereof, or pharmaceutically able salts of the compounds or the tautomers, wherein ring B is phenyl or pyridyl, one or both of X1 and X2 are N while X3 is CR4 and X4 is CR5 or one or both of X1 and X3 are N while X2 is CR3 and X4 is CR5, and nis 1,2, or3.

Subsets of the compounds of Formula (11) include those of a (Hal), (IIa2), (IIa3), (IIa4) and (IIa5): R5 R5 R3 R3 \ N \ \ N \ I A I /—(R )M7 I A I ZR )M7 R‘8 R‘8 R7 R7 N N N N N N N R9 l1 R9 I (Hal), R1 (11212), R5 R5 3 3 N l x | _1 | X | —(R7)n_1 R8 / / R \8 / / \N R7 R7 N T N N R9 R9 I|\] R1 (IIa3), R1 (IIa4), or \ N \ N l x l —'(R7)n 1 REEN N/ / R7 Fae I R1 (IIaS) and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

Other subsets of the compounds of Formula (11) include those of Formula (IIbl), (IIb2), (IIb3), (IIb4) or (IIbS): R5 R5 R3 R R3 R \ \ \ \ l ' 7 l ' R‘Na / a / R7 Ema-1 N N R‘N R7 N N N IIRQ | #6) | R1 (Hbl), R1 (1112), R5 R5 R3 R R3 R4 N l l —(R7)n_1 l l —(R7)n 1 RN8 N/ / R7 T R"8 N/ / R7 R9 R9 T R1 (IIb3), R1 (IIb4), R3 R4 \ \ N | | —'(R7)n_1 RziN N/ / R7 Fag I1 or R (IIbS) and tautomers thereof, or pharmaceutically acceptable salts of the nds or the tautomers.

Further subsets of the compounds of Formula (11) e those of Formula (IIcl), (IIc2), (IIc3), (IIc4) or (IIc5): R5 R5 R4 R4 N \ \ N \ \ l l 8 )L / /—‘R7)n-1 8 )L / ;‘\R7)n-1 R‘N R7 N Ii] RRN R7 N [I] N R9 R9 R1 (IIcl), R1 (IIc2), R5 R5 R? A / URﬂrH A bRnn-l N N R9 T R9 I R 1 R1 (IIc3), (IIc4), or N \ \ N | —'(R7)n_1 8 A R\N / / R7 N N R9 l R 1 (IIc5), and tautomers f, or pharmaceutically acceptable salts of the compounds or the tautomers.

Yet further subsets of the compounds of Formula (11) include those of Formula , (IId2), (IId3), (IId4) or (IId5): WO 81177 R5 R5 R4 R4 N \ \ N \ \ | | 7%7 | l X"7 R \8 / 8 R7 R s / R7 N N N R9 R2 [I] R9 R2 [I] R1 (Hdl), R1 (11012), R5 R5 R4 R4 N \ N/\ N \ \\ | | —(R7)n_1 | | —eR7)n_1 R \8 / / R \8 R7 / / R7 N N R9 R2 [I] R9 R2 [I] R1 (IId3), R1 (IId4), or N \ \ N | | —'(R7)n_1 R§N / / R7 R9 R2 [L1 (IIdS), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

In another ment, the compounds of Formula (I) include those of Formula (111): XZ—XB < > ’48)" R6 N R2 FL1 (III), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is phenyl or pyridyl, at least one of X2 and X3 is N, and n is l or 2.

A subset of the compounds of Formula (111) includes compounds of Formula (IIIa): N—N’ \ / | _1 R\N8 / / N R7 {29 R2 I R 1 (111a), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

Another subset of the compounds of a (1) includes those of Formula (IV): R20 R5 A R7)" R22 N N R23 I R1 (IV), and tautomers f, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl, each of R20, R21, R22 and R23 independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and n is l or 2.

Another subset of the compounds of Formula (1) includes those of Formula (IVa): R20 R5 / R7)" R22 N N R23 R1 (Na), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl, each of R20, R21, R22 and R23 independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and n is l or 2.

Yet another subset of the compounds of Formula (1) includes those of a (V): Hsc’O \ x3 R9_O NAN/TﬁEB _‘I,_(R7)n R1 (V), and tautomers thereof, and pharmaceutically able salts of the compounds or the tautomers, wherein ring B is absent or C3-C6 cycloalkyl, X3 is N or CR4 in which R4 is H or C1-C4 alkyl, R1 is H or C1-C4 alkyl, or when B is absent, T and R1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered aryl, each of which is optionally tuted with (R7)n, or when B is absent, T is H and n is 0, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, OR"), OR", C(O)R11, NRIORH, C(O)NR10R11, NR10C(O)R11, C3-C3 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, and wherein the C3-C3 cycloalkyl or 4- to 12- membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, , cyano, C1-C6 haloalkyl, -S02R8, or C1-C6 l, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)0Rg, R5 is selected from the group consisting of C1-C6 alkyl, C3-C3 cycloalkyl and 4- to 12- ed heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C3 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, -C(O)C1-C6 alkyl or C1-C6 alkyl optionally substituted with one or more of halo or ORa, R9 is , in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is 4- to 12-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to ered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)RC, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and R(:1 independently being H or C1-C6 alkyl, or — Q4-T4 is oxo, and n is 0, l or 2.

Yet r subset of the compounds of Formula (1) includes those of Formula (Va) or (Vb): WO 81177 R5 R5 H3C’O \ N H3c3’O \ I ‘ R9—o NANA-"(55:}\HR7)n R9—o N/ N/T\(:E;}- Yet another subset of the compounds of Formula (1) includes those of Formula (VI): R3 o \ N \CH3 R6 /\/\ N M o NO (VI), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein R5 and R6 are independently selected from the group consisting of C1-C6 alkyl and NRgRg, or R6 and R3 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl.

Yet another subset of the compounds of Formula (1) includes those of Formula Xz/ \ x3\ 0 | 2L /\/\ 1/ R13 m N X l|\J m e R7)n (VII): R1 (VII), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein mis l or2andnis 0, l,or2.

A further subset of the nds of Formula (1) includes those of Formula (VIIIa): x2 \ x3 / I k I—(R7)n-1I a / R ‘ \ N xl R7 9 I?! R R1 (VIIIa), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo, ORa, or NRaRb, each of R3 and R4 is H, and R5 are independently selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo or ORa, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 l, and wherein at least one of R2 or R5 are not A further subset of the compounds of Formula (1) includes those of Formula x2X\x3 \CH3 RagAXAH (VIIIb): (VIIIb), wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group consisting of H, C3-C3 lkyl, and C1-C6 alkyl each of R3 and R4 is H, and R5 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ er with the atoms to which they are attached form a 5- or 6-membered aryl, in which the phenyl or 5- or 6-membered aryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R5 are not H.

A further subset of the compounds of Formula (1) includes those of Formula (VIIIc): X2’X\\4X3 \R10 3EAA /R11 (VIIIc), wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is ed from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H, and R5 is selected from the group consisting of H, C3-C3 lkyl, and C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or ered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R5 are not H.

In r aspect, the present disclosure es a substituted aryl or heteroaryl compound of Formula (IX-l) below: X\7 \ x3 ( T1_Ql V / / x6 N R158 (IX-1), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, X6 is N or CH, X7 is N or CH, X3 is N or CR4, R4 is selected from the group ting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb ndently is H or C1-C6 alkyl, each Q1 is independently a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, each T1 is independently H, halo, cyano, NRgRg, C(O)NR8R9, C(O)R9, 0R8, 0R9, or RSI, in which RS1 is C3-C3 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is ally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, - sost, -SO2N(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and —Q1—T1 is not NR8C(O)NR12R13, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB,NR12R13,NR12C(O)R13, C(O)NR12R13, C(O)R13, 13, S(O)2NR12R13, or R52, in which R52 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 ne, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally tuted with one or more , wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to ered heteroaryl, or —Q8-T8 is oxo, R15a is CN, C(0)H, C(O)R18, OH, ORIS, C1-C6 alkyl,NHR17, C3-C3 cycloalkyl, C6- C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally tuted with one or more —Q9-T9, wherein each Q9 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T9 independently is selected from the group ting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q9-T9 is oxo, R16a is -Q11-R16 in which Q11 is a bond, 0, NRa, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and R16 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is ally substituted with one or more —Q , wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T10 independently is selected from the group consisting of H, halo, cyano, C(O)H, C(O)R18, S(O)pR18, OH, ORIS, C1-C6 alkyl, C3-C3 lkyl, C6-C10 aryl, 4- to 7-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to ered aryl, or —Q 10 10- -T is oxo, R17 is H or C1-C6 alkyl, each R18 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, p is 0,1, or2, and V is 0, l, or 2.

For example, one subset of compounds of Formula (IX-1) is of Formula (IX) below: (R909—:(V \ \x3 K / / X6 N R15 (IX), or a tautomer thereof, or a pharmaceutically able salt of the compound or the tautomer, wherein X6 is N or CH, X7 is N or CH, X3 is N or CR4, R4 is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, each R9 is independently , in which Q3 is a bond or C1-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which RS2 is C3-C3 cycloalkyl, C6-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 lene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to ered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is ed from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, R15 is C1-C6 alkyl, NHR17, C3-C3 cycloalkyl, C6-C10 aryl, 4- to lZ-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10- membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C3 lkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to lO-membered heteroaryl is optionally substituted with one or more , wherein each Q9 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T9 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl, or —Q9-T9 is oxo, R16 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, C3-C3 cycloalkyl, C6-C10 aryl, 4- to bered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more —Q10- T10, wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 , and each T10 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or — Qlo-T101s oxo, R171s H or C1-C6 alkyl, and V is 0, l, or 2.

A subset of the compounds of Formula (IX) includes those of Formula (X): H CO3 X\ \X3 kl?" (X), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein X3 is N or CR4, n R4 is selected from the group consisting of H, halo, and cyano.

Subsets of the nds of Formula (X) include those of a (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), or (Xg): R16 R16 H CO H CO / A R90 N R15(Xa), R90 N R15 (Xb), R16 R16 H CO3 H CO \ \ N 3 \ \ / A / / R90 N N R15 (Xc) R90 N N R15 (Xd) H300 N\ H3CO F \ \ R90 N/ R15 (Xe), R90 N/ R15 (Xi), or H3CO CN R90 N/ R15 (Xg), wherein R9, R15 and R16 are as deﬁned herein.

In certain embodiments, the compounds of any of Formulae (I)-(Xg) inhibit a kinase with an enzyme inhibition IC50 value of about 100 nM or r, 1 uM or greater, IOuM or greater, 100 uM or greater, or 1000 uM or greater.

In certain embodiments, the compounds of any of Formulae (I)-(Xg) inhibit a kinase with an enzyme tion IC50 value of about 1 mM or greater.

In certain embodiments, the compounds of any of Formulae (I)-(Xg) inhibit a kinase with an enzyme inhibition IC50 value of 1 uM or greater, 2 uM or greater, 5 uM or greater, or uM or greater, wherein the kinase is one or more of the following: AbI, AurA, CHKl, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARKI, MNK2, PKCb2, SIK, and Also provided herein are pharmaceutical compositions comprising one or more ceutically acceptable carriers and one or more compounds of any of the Formulae (I)- (Xg) described .

Another aspect of this disclosure is a method of preventing or treating an EHMT- mediated disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a nd of any of ae (I)—(Xg), or a tautomer thereof, or a pharmaceutically able salt of the compound or the tautomer. The EHMT- mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EHMTI or EHMT2 or both. In one embodiment, the EHMT-mediated disorder is a blood disease or disorder. In certain embodiments, the EHMT-mediated er is selected from proliferative disorders (6. g. Cancers such as leukemia, hepatocellular carcinoma, prostate carcinoma, and lung cancer), addiction (e.g., ***e addiction), and mental retardation.

Unless otherwise stated, any description of a method of ent includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to e a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other e models. Methods described herein may be used to identify suitable candidates for treating or ting EHMT-mediated disorders. For example, the sure also provides s of identifying an inhibitor of EHMTl or EHMT2 or both.

For e, the EHMT-mediated disease or disorder comprises a disorder that is associated with gene ing by EHMTl or EHMT2, e.g., blood diseases or disorders associated with gene silencing by EHMT2.

For example, the method comprises the step of administering to a subject having a disease or disorder associated with gene silencing by EHMTI or EHMT2 a therapeutically effective amount of one or more compounds of the Formulae described herein, wherein the compound(s) inhibits histone methyltransferase ty of EHMTI or EHMT2, thereby treating the disease or disorder.

For example, the blood disease or disorder is selected from the group consisting of sickle cell anemia and beta-thalassemia.

For example, the blood disease or disorder is hematological cancer.

For example, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

For example, the method further ses the steps of performing an assay to detect the degree of histone ation by EHMTI or EHMT2 in a sample comprising blood cells from a t in need thereof In one embodiment, performing the assay to detect methylation of H3-K9 in the histone substrate comprises measuring incorporation of labeled methyl groups.

In one embodiment, the labeled methyl groups are isotopically labeled methyl groups.

In one embodiment, performing the assay to detect methylation of H3-K9 in the histone substrate comprises contacting the e substrate with an antibody that binds specifically to dimethylated H3-K9.

Still another aspect of the disclosure is a method of inhibiting conversion of H3-K9 to dimethylated H3 -K9. The method comprises the step of contacting a mutant EHMT, the wild-type EHMT, or both, with a e substrate comprising H3-K9 and an effective amount of a compound of the present disclosure, n the compound inhibits histone methyltransferase activity of EHMT, thereby inhibiting conversion of H3-K9 to dimethylated H3-K9. r, the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes.

Unless otherwise deﬁned, all cal and scientiﬁc terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the speciﬁcation, the singular forms also include the plural unless the context clearly dictates otherwise. gh methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable s and materials are described below. All publications, patent applications, s and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conﬂict, the t speciﬁcation, including deﬁnitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conﬂict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

Other features and advantages of the disclosure will be apparent from the following ﬁgures, detailed description and .

BRIEF DESCRIPTIONS OF THE GS Figure 1A is a graph indicating the effect of Compound 205 on histone H3K9 ylation (data illustrated by triangles) and on fetal hemoglobin-containing cells (HbF+, data illustrated by squares).

Figure 1B is a graph indicating the effect of Compound 418 on histone H3K9 dimethylation (data illustrated by triangles) and on fetal hemoglobin-containing cells (HbF+, data illustrated by s).

Figure 1C is a graph indicating the effect of Compound 642 on histone H3K9 ylation (data rated by triangles) and on fetal hemoglobin-containing cells (HbF+, data illustrated by squares).

Figure 1D is a graph indicating the effect of Compound 332 on histone H3K9 dimethylation (data rated by triangles) and on fetal hemoglobin-containing cells (HbF+, data illustrated by squares).

Figure 2 is a series of graphs indicating the effect of Compound 205, Compound 642, Compound 332, or Compound 418 on the ratio of be-y to total B globins.

Figure 3 is a series of graphs indicating the effect of Compound 205, Compound 642, Compound 332, or Compound 418 on the ratio of be-y to total B globins as measured by mass spectrometry and PCR.

Figure 4 is a graph indicating the effect of Compound 205 on the rate of growth of MV4-11 cells over 14 days. 0.2% DMSO was used as negative control (containing no compound of the disclosure).

Figure 5 is a graph indicating the effect of Compound 205 on the inhibition of growth of MV4-11 cells over 14 days.

DETAILED DESCRIPTION The present disclosure provides novel substituted aryl or heteroaryl nds, synthetic methods for making the compounds, ceutical compositions containing them and various uses of the compounds.

In one aspect, the compounds disclosed herein may be used to treat a blood disorder, e.g., sickle-cell anemia (i.e., sickle-cell e). Non-limiting examples of sickle-cell anemia forms that may be treated using the contemplated compounds include hemoglobin SS disease, hemoglobin SC disease, hemoglobin SB0 thalassemia disease, hemoglobin SB+ semia disease, hemoglobin SD disease, and obin SE disease.

Without wishing to be bound by any theory, it is believed that sickle-cell anemia describes a group of inherited red blood cell disorders in which at least some of the red blood cells of a subject having sickle-cell anemia n hemoglobin S ("HbS"). Hemoglobin S is a mutated, abnormal form of adult hemoglobin. Without wishing to be bound by any theory, it is believed that the contemplated compounds may treat sickle cell anemia by inducing fetal hemoglobin ("HbF") expression. See, e.g., Renneville et 61]., Blood ): 1930—1939, 2015, the content of which is incorporated herein by reference in its ty.

In some embodiments, one or more complications of sickle-cell anemia may be treated or prevented using the contemplated compounds disclosed herein. Non-limiting examples of cations that may be treated or prevented using the contemplated compounds include anemia (e.g., severe anemia), hand-foot syndrome, splenic sequestration, delayed pmental growth, eye disorders (e.g., vision loss caused by, e.g., blockages in blood vessels supplying the eyes), skin ulcers (e.g., leg ulcers), heart disease, chest syndrome (e.g., acute chest me), priapism, and pain.

The present disclosure provides nds of Formula (I): ®J\N/T\’B)"R7)n R1 (1), and tautomers thereof, and pharmaceutically able salts of the compounds or the tautomers, wherein ring A is phenyl or a 5- or 6-membered heteroaryl, X1 is N, CR2, or NR2’ as valency permits; X2 is N, CR3, or NR3’ as valency permits, X3 is N, CR4, or NR4’ as valency s, X4 is N or CR5, or X4 is absent such that ring A is a 5-membered heteroaryl containing at least one N atom, X5 is C or N as valency permits, B is absent or a ring structure ed from the group consisting of C6-C10 aryl, C3- C10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, T is a bond or C1-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxy when B is present, or T is H and n is 0 when B is absent, or T is C1-C6 alkyl optionally tuted with (R7)Il when B is absent, or when B is absent, T and R1 together with the atoms to which they are ed optionally form a 4-7 ed heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R7)n, R1 is H or C1-C4 alkyl, each of R2, R3, and R4, ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, 06-010 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, c3—c8 cycloalkyl, 4— to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 l and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R3 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, 0R8, 0R9, or RSI, in which RS1 is C3-C3 cycloalkyl, phenyl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RSl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, 0x0, -C(O)R9, -S02R8, -S02N(R8)2, -NR8C(O)R9, amino, mono- or di- alkylamino, or C1-C6 alkoxyl,, or when ring A is a 5-membered aryl containing at least one N atom, R4 is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, each of RZ’, R3’ and R ’ independently is H or C1-C3 alkyl, R5 is selected from the group consisting of H, F, Br, cyano, C1-C6 l, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, C1-C6 alkyl optionally tuted with one or more of halo, ORa or NRaRb, and C2-C6 alkynyl optionally tuted with 4- to 12- ed heterocycloalkyl, wherein said C3-C3 cycloalkyl or 4- to 12-membered cycloalkyl are optionally substituted with one or more of halo, C(O)Ra, ORa, NRaRb, 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, or C1- C4 alkyl optionally substituted with one or more of halo, ORa or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 l, R6 is absent when X5 is N and ring A is a 6-membered heteroaryl, or R6 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or R", in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or ered heteroaryl and RSl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, -S02R8, -S02N(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 l, and R6 is not NR8C(O)NR12R13, or R6 and one of R2 or R3 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R6 and one of Rz’or R3’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered aryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=0), C1-C3 alkoxyl, or -Q1-T1, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, cyano, OR"), OR", C(O)R11, NRIORH, C(O)NR10R11, NR10C(O)R11, 5- to lO-membered heteroaryl, C3-C3 cycloalkyl, or 4- to 12- ed cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to lO-membered heteroaryl, C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, -SO2R8, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)ORg, or optionally, when B is present, one R7 and R5 together form a C3-C10 alkylene, C2-C10 heteroalkylene, C4-C10 alkenylene, C2-C10 heteroalkenylene, C4-C10 alkynylene or C2- C10 heteroalkynylene linker ally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, each R8 independently is H or C1-C6 alkyl, each R9 is independently , in which Q3 is a bond or C1-C6 alkylene, C2-C6 lene, or C2-C6 lene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which RS2 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, n each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, C, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R8 and R9 taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of , wherein each Q5 independently is a bond or C1-C3 alkylene, C2-C3 lene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Re, S(O)2Re, S(O)2NReRf, NReRf, C(O)NReRf, and NReC(O)Rf, each of Re and Rf independently being H or C1-C6 alkyl, or —Q5-T5 is oxo, R10 is selected from the group ting of H and C1-C6 alkyl, R11 is —Q6-T6, in which Q6 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T6 is H, halo, ORg, NRth, NRgC(O)Rh, C(O)NRth, C(O)Rg, S(O)2Rg, or RS3, in which each of Rg and Rh independently is H, phenyl, C3-C3 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C3 cycloalkyl, or Rg and Rh together with the en atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, and RS3 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to lO-membered heteroaryl, and RS3 is optionally substituted with one or more —Q7-T7, wherein each Q7 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T7 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR], C(O)Rj, NRij, C(O)NRij, S(O)2Rj, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl optionally tuted with one or more halo, or —Q7-T7 is oxo, or R10 and R11 taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, or C1-C6 alkoxyl, R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered aryl, each of which is optionally substituted with one or more —Q8-T8, wherein each Q8 independently is a bond or C1-C3 ne, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 lkyl, C6-C10 aryl, 4- to 7-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to ered heteroaryl, or —Q8-T8 is oxo, and nis 0,1,2, 3, or4.

The compounds of Formula (I) can have one or more of the following es when applicable: In n embodiments, the compound of a (I) is not 4-(((2-((1-acetylindolin- 6-yl)amino)(triﬂuoromethyl)pyrimidinyl)amino)methyl)benzenesulfonamide, -bromo-N4-(4-ﬂuorophenyl)-N2-(4-methoxy(2-(pyrrolidin-l- yl)ethoxy)phenyl)pyrimidine-2,4-diamine, N2-(4-methoxy(2-(pyrrolidin- l -yl)ethoxy)phenyl)-N4-(5 -(tert-pentyl)- lH-pyrazol- 3-yl)pyrimidine-2,4-diamine, 4-((2,4-dichloromethoxyphenyl)amino)((3-(2-(pyrrolidin-l- yl)ethoxy)phenyl)amino)pyrimidinecarbonitrile, N—(naphthalenyl)(piperidin-l-ylmethoxy)pyrimidinamine, N—(3 ,5 -diﬂuorobenzyl)(3-(pyrrolidin-l -yl)propyl)pyrimidinamine, N—(((4-(3-(piperidin-l-yl)propyl)pyrimidinyl)amino)methyl)benzamide, N—(2-((2-(3-(dimethylamino)propyl)pyrimidinyl)amino)ethyl)benzamide, ahydromethyl- lH-l ,4-diazepin- l -yl)-6,7-dimethoxy-N- [ l -(phenylmethyl) piperidinyl]quinazolinamine, ohexylmethoxy-N—[l-(l-methylethyl)piperidinyl][3-(lpyrrolidinyl )propoxy]quinazolinamine, 3-(1-cyano-l-methylethyl)-N-[3-[(3,4-dihydromethyloxo quinazolinyl)amino]methylphenyl]benzamide, 6-acetylcyclopentylmethyl[(5-piperazin-l-ylpyridinyl)amino]pyrido[2,3- d]pyrimidinone, N-[2-[[4-(Diethylamino)butyl]amino](3,5-dimethoxyphenyl)pyrido[2,3- d]pyrimidinyl] -N'-(1 , 1 -dimethylethyl)urea, or 6-[[2-[[4-(2,4-dichlorophenyl)(5-methyl-lH-imidazolyl) pyrimidinyl] amino] ethyl] amino] -3 -pyridinecarbonitrile.

In certain embodiments, when T is a bond, B is substituted phenyl, and R6 is NRSRg, in which R9 is Z, and RS2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, then B is substituted with at least one substituent selected from (i) —Q2-OR11 in which R11 is —Q6-RS3 and Q6 is optionally tuted C2-C6 alkylene, 02-06 alkenylene, or C2-C6 alkynylene linker and (ii) —Q2-NR10R11 in which R" is —Q6-RS3.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, then R6 is not OR9 or NRgR9 in which R9 is optionally substituted naphthyl.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, naphthyl, l or l,2,3,4-tetrahydronaphthyl, then R6 is not NRSR9 in which R9 is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl.

In certain embodiments, when T is a bond and B is optionally substituted phenyl or thiazolyl, then R6 is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NRgR9 in which R9 is optionally substituted olyl, pyrazolyl, or 6- to 10-membered heteroaryl.

In certain embodiments, when T is a C1-C6 alkylene linker and B is absent or ally substituted C6-C10 aryl or 4- to 12-membered heterocycloalkyl, or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R6 is not )R13.

In certain embodiments, when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to bered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain ments, when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C3 lkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C1-C6 alkyl, and R6 and R2 er with the atoms to which they are attached form phenyl which is tuted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain embodiments, when ring A is phenyl and B is a 5-membered heteroaryl or phenyl, then T is not C(O), In certain embodiments, when ring A is , B is absent, and T and R1 together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl, the heterocycloalkyl contains at most one N ring atom or the heterocycloalkyl is not substituted by oxo, In certain embodiments, when one of ring A or B is pyridyl and T is a bond, then the pyridinyl is not substituted at the para-position of N-Rl with —Q1-T1 or —Q2-T2, in which T1 or T2 is phenyl or heteroaryl, or In certain embodiments, when T is a bond or C1-C3 ne, ring A is a 6-membered heteroaryl and B is optionally substituted phenyl, pyridyl, or piperidinyl, then R6 is not H and at least one of R2, R3, R4 and R5 is not H.

For example, ring A is a 6-membered heteroaryl, wherein at least one of X1, X2, X3 and x4 is N and x5 is c (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl).

For example, ring A is a 6-membered heteroaryl, wherein two of X1, X2, X3 and X4 is N and X5 are C (e.g., pyrimidinyl, nyl, pyridazinyl, and triazinyl).

For example, R6 and one of R2 or R3 together with the ring A to which they are attached form an optionally substituted 6,5- fused bicyclic heteroaryl, or R6 and one of R2’ or R3’ together the ring A to which they are attached form an optionally substituted 6,5-fused bicyclic heteroaryl. For e, the optionally substituted 6,5- fused ic heteroaryl contains 1-4 N atoms. For example, the 6,5- fused bicyclic heteroaryl is optionally substituted with one or more of halo, C1-C3 alkyl, yl, or C1-C3 alkoxyl.

For example, T is a bond and ring B is .

For example, T is a bond and ring B is pyridyl.

For example, T is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl or C1-C6 alkoxy when B is present.

For example, T is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker when B is present.

For example, 11 is l.

For example, 11 is 2.

For e, 11 is 3.

For example, at least one of R6, R2, R3, and R4 is not H.

For example, when one or more of R2, R3, and R4 are present, at least one of R6, R2, R3, and R4 is not H.

For example, the compounds of a (I) include those of Formula (II): Xz/X\4\x3 k A tmn R6 X1 T R1 (11), wherein ring B is phenyl or pyridyl, one or both of X1 and X2 are N while X3 is CR4 and X4 is CR5 or one or both of X1 and X3 are N while X2 is CR3 and X4 is CR5, and n is 1, 2, or 3.

For example, the compounds of Formula (11) include those of Formula (Hal), (IIa2), (IIa3), (IIa4) or (IIa5): R5 R5 R3 R3 \N \ \N \ al/x '7R’N7 al/x bf"7 Ru" R7 N [I] Rn}! R7 N N R9 R9 T R1 (Hal), R1 (IIa2), R5 R5 N N N N N R9 R9 N R1 (IIa3), R1 , or \ N \ N | X | —'(R7)n_1 REEN N/ / R7 Fae I R1 (IIaS), or tautomers thereof, or pharmaceutically able salts of the compounds or the tautomers.

For example, at most one of R3 and R5 is not H.

For example, neither of R3 and R5 is H.

For example, each of R3 and R5 is H. [0103l For e, the compounds of Formula (11) include those of Formula (IIbl), (IIb2), (IIb3), (IIb4) or (IIbS): R5 R5 R3 R4 R3 R4 \ \ \ \ l l —lR7)n_1 l ‘ R s8 / / R s8 / R7 Jim,"R7 N N T N N T N R9 R9 R 1 (IIbl), R1 , R5 R5 3 4 3 4 N ' URN | | Rim R \3 / / / R7 R e3 / R7 N N T N N R9 R9 T R1 (IIb3), R1 (IIb4), R3 R4 \ \ N | | —'(R7)n_1 R8 / / \N R7 R9 T or R1 (IIbS), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

For example, at most one of R3, R4 and R5 is not H. [0105l For example, at most two of R3, R4 and R5 are not H.

[O 106l For example, none of R3, R4 and R5 is H. [0107l For example, each of R3, R4 and R5 is H. [01081 For e, the compounds of Formula (11) include those of Formula (IIcl), (IIc2), (IIc3), (IIc4) or : R5 R5 R4 R4 N \ \ N \ \ 8A/ '77 1 ;7 R‘N R7 al/ R7 N N R‘N N N N R9 '1 R9 l R (IIcl), R1 (IIc2), R5 R5 R4 N/\ R4 N \ N \ N\\ l Um] I w Rs / / R7 R \8 / / \N N R7 '1] N N R9 R9 '11 R1 (Hc3), R1 (IIc4), or N \ \ N A | —'(R7)n_1 REEN N/ / R7 R9 I R 1 , or tautomers thereof, or pharmaceutically. acceptable salts of the compounds or the ers.

For example, at most one of R4 and R5 is not H.

For e, neither of R4 and R5 is H.

For example, each of R4 and R5 is H. [0112l For example, the nds of Formula (11) include those of Formula (IIdl), (IId2), (IId3), (IId4) or (IId5): R5 R5 R R N \ \ N \ \ l I —(R7)n 1 l I R3 / / R7 R \3 / ;(\R7)n_1 \N R7 N N N N {Q9 R2 I [Q9 R2 I R1 (IIdl), R1 (11012), R5 R5 R R4 N N \ N \ N \ \ | |/\—(R7)n_1 | | :(R7)n_1 R‘EN / / R7 R‘EN / / R7 N N H9 R2 l N9 R2 l R1 (IId3), R1 (IId4), N \ \ N | | —'(R7)n_1 R‘EN / / R7 N9 R2 l or R (IId5), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

For example, at most one of R2, R4 and R5 is not H.

For example, at most two of R2, R4 and R5 are not H.

For example, none of R2, R4 and R5 is H.

For example, each of R2, R4 and R5 is H.

For example, one R7 and R5 together form a C3-C10 alkylene, C2-C10 heteroalkylene, C4-C10 alkenylene, C2-C10 heteroalkenylene, C4-C10 lene or C2-C10 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl.

For example, one R7 and R5 together form an optionally substituted C2-C10 heteroalkylene linker, e.g., -NH(CH2)20(CH2)20-.

For example, ring A is a 5-membered heteroaryl (e.g., pyrrolyl, imidazolyl, triazolyl, olyl, or pyrazolyl).

For example, the compounds of Formula (I) include those of Formula (111): XZ—XB R6 N R2 I R1 (111), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, n ring B is phenyl or pyridyl, at least one of X2 and X3 is N, and nis 1 or2.

For example, the compounds of Formula (111) include those of Formula (IIIa): N—N’ \ / | —(R7)n_1 R§N / / N R7 [29 R2 I R1 (IIIa), or tautomers f, or pharmaceutically acceptable salts of the compounds or the ers.

For example, at most one of R4’ and R2 is not H.

For example, neither of R4’ and R2 is H.

For example, each of R4’ and R2 is H. [0125l For example, the compounds of Formula (I) include those of Formula (IV): R20 R5 A R7)n R22 N N R23 I R1 (IV), or ers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl, each of R20, R21, R22 and R23 independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and n is 1 or 2.

For example, ring B is exyl.

For example, B is absent and T is unsubstituted C1-C6 alkyl or T is C1-C6 alkyl substituted with at least one R7.

For example, B is 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa—6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, icyclo[3.1.0]hexanyl, benzo[d][1,3]dioxolyl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like) and T is unsubstituted C1-C6 alkyl.

For example, the nds of Formula (I) include those of a (IVa): R20 R5 / R7)" R22 N N R23 R1 (Na), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl, each of R20, R21, R22 and R23 independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 l, and nis 1 or2.

For example, ring B is cyclohexyl.

For e, B is 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, l,2,3,6- ydropyridinyl, zinyl, l,4-diazepanyl, l,4-oxazepanyl, 2-oxa azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2-oxaazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3. l .0]hexanyl, benzo[d][l,3]dioxolyl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like) and T is unsubstituted C1-C6 alkyl.

For example, the compounds of a (I) include those of Formula (V): H30 \ x3 R9_O NAN/TNIIT-B _‘;_(R7)n l _ .

R1 (V), wherein ring B is absent or C3-C6 cycloalkyl, X3 is N or CR4 in which R4 is H or C1-C4 alkyl, R1 is H or C1-C4 alkyl, or when B is absent, T and R1 together with the atoms to which they are attached optionally form a 4-7 membered cycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R7)n, or when B is absent, T is H and n is 0, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, yl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, ORIO, OR", C(O)R11, NRIOR", C(O)NR10R11, NR10C(O)R11, C3-C3 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, and wherein the C3-C3 cycloalkyl or 4- to 12- membered heterocycloalkyl is ally substituted with one or more of halo, C1-C6 alkyl ally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 kyl, -SOzR8, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)0Rg, R5 is selected from the group consisting of C1-C6 alkyl, C3-C3 cycloalkyl and 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C3 cycloalkyl and 4- to 12-membered heterocycloalkyl is ally substituted with one or more of 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, -C(O)C1-C6 alkyl or C1-C6 alkyl optionally tuted with one or more of halo or ORa, R9 is —Q3-T3, in which Q3 is a bond or Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more —Q4-T4, n each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)RC, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and R(:1 independently being H or C1-C6 alkyl, or — Q4-T4 is oxo, and n is 0, l or 2.

For e, the compounds of Formula (V) include those of Formula (Va): H30 \ N RQ'O NAN/TﬁBHRUn R1 (Va), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

For example, in Formula (Va), ring B is absent or C3-C6 cycloalkyl, R1 is H or C1-C4 alkyl, or when B is absent, T and R1 er with the atoms to which they are attached ally form a 4-7 membered cycloalkyl or 5-6 ed heteroaryl, each of which is optionally substituted with (R7)n, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 ndently is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, OR"), OR", C(O)R11,NR10R", C(O)NR10R11, NR10C(O)R11, C3-C3 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and n the C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally tuted with NRXRy, hydroxyl, oxo, , cyano, C1-C6 haloalkyl, , or C1-C6 alkoxyl, and R7 is not H or C(O)ORg, each of RX and Ry independently being H or C1-C6 alkyl, or R5 is ed from the group consisting of C3-C3 cycloalkyl and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, optionally substituted with one or more of 1-C6 alkyl or C1-C6 alkyl optionally substituted with one or more of halo or ORa, R9 is —Q3-T3, in which Q3 is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to ered heteroaryl, ORG, C(O)RC, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and R(:1 independently being H or C1-C6 alkyl, or — Q4-T4 is oxo, and n is l or 2.

For example, the compounds of Formula (V) include those of a (Vb): Hsc/O \ R9-O N N/T‘ri—B HRUn R1 (Vb), and tautomers thereof, and pharmaceutically acceptable salts of the nds or the tautomers, wherein ring B is absent or C3-C6 cycloalkyl, R1 is H or C1-C4 alkyl, or when B is absent, T and R1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R7)n, or when B is absent, T is H and n is 0, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 ndently is H, halo, ORIO, OR", C(O)R11, NRIOR", C(O)NR10R11, NR10C(O)R11, C3-C3 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C3-C3 lkyl or 4- to 12- membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl ally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, , or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)0Rg, R5 is selected from the group consisting of C1-C6 alkyl, C3-C3 cycloalkyl and 4- to 12- membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O and S, wherein the C3-C3 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, -C(O)C1-C6 alkyl or C1-C6 alkyl optionally substituted with one or more of halo or ORa, R9 is —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 , and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to ered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)RC, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and R(:1 independently being H or C1-C6 alkyl, or — Q4-T4 is oxo, and n is 0, l or 2.

For example, the compounds of Formula (I) include those of Formula (VI): R3 o \ N \CH3 R6 o/\/\ N M N0 (VI), tautomers thereof, or pharmaceutically able salts of the compounds or the tautomers, wherein R5 and R6 are independently selected from the group consisting of C1-C6 alkyl and NR8R9, or R6 and R3 er with the atoms to which they are attached form phenyl or a 5- or 6- membered heteroaryl.

For example, the compounds of Formula (I) include those of Formula (VII): R13ONMNJLX1J\NIIQ1/H\G_(R7)n (V11), wherein m is l or 2 and n is 0, l, or 2.

For example, the nds of Formula (I) include those of Formula ): x2X\x3 "1%ka —-(R7)n1 (VIIIa), tautomers thereof, or ceutically acceptable salts of the compounds or the ers, wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo, ORa, or NRaRb, each of R3 and R4 is H, and R5 are independently selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo or ORa, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R5 are not H.

For e, the compounds of Formula (I) include those of Formula (VIIIb): x2X\4x3 \CH3 R8 N9)|\X1J\N OMNQ (VIIIb), tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H, and R5 is selected from the group consisting of H, C3-C3 lkyl, and C1-C6 alkyl, or R5 and one of R3 or R4 er with the atoms to which they are ed form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ er with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R5 are not H.

For example, the compounds of Formula (1) includes those of Formula (VIIIc): X2X\4X3 \R10 R8"1%ka /R11 (VIIIc), wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H, and R5 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or ered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R5 are not For example, at least one of X1, X2, X3 and X4 is N.

For example, X2 and X3 is CH, and X1 and X4 is N. [0 144] For example, X2 and X3 is N, X1 is CR2, and X4 is CR5.

For example, R6 is NRgR9 and R5 is C1_6 alkyl or R5 and R3 together with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.

For example, both ole and X3 are N while X2 is CR3 and X4 is CR5.

Further, the compounds of any of Formulae (I)-(VIIIc) above can have one or more of the following features when applicable: For example, R1 is H.

For example, R1 is CH3.

For example, R2 is selected from the group consisting of H, halo, cyano, C1-C4 alkoxyl, phenyl, NRaRb, C(O)NRaRb, NRaC(O)Rb, and C1-C6 alkyl optionally substituted with one or more of halo, ORa or NRaRb.

For example, R3 is selected from the group consisting of H, halo, cyano, C1-C4 alkoxyl, , NRaRb, C(O)NRaRb, NRaC(O)Rb, and C1-C6 alkyl optionally substituted with one or more of halo, ORa or NRaRb.

For example, R4 is selected from the group ting of H, halo, cyano, C1-C4 alkoxyl, phenyl, NRaRb, C(O)NRaRb, NRaC(O)Rb, and C1-C6 alkyl optionally substituted with one or more of halo, ORa or NRaRb.

For example, R5 is ed from the group consisting of H, cyano, C1-C4 alkoxyl, phenyl, NRaRb, C(O)NRaRb, NRaC(O)Rb, and C1-C6 alkyl optionally substituted with one or more of halo, ORa or NRaRb.

For example, R5 is 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, lidinyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa—5- azabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptanyl, 2-oxa—6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexanyl, benzo[d][1,3]dioxolyl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like).

For e, each of Ra and Rb independently is H or C1-C4 alkyl.

For example, R6 is —T1, in which T1 is H, halo, cyano, NR8R9, C(O)NR8R9, 0R8, 0R9, or RSI.

For example, R6 is —Q1-T1, in which Q1 is a C1-C6 alkylene, C2-C6 alkenylene, or C2- C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, 0R8, 0R9, or RSI.

For e, RS1 is C3-C3 cycloalkyl, , 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, idinyl, imidazolidinyl, lidinyl, oxazolidinyl, olidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4- oxazepanyl, 2-oxa—5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa—6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan yl, benzo[d][1,3]dioxolyl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, and the like) or a 5- or 6-membered heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, ne, pyrazine, pyridazine, pyrimidine, and the like), each of which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, -SOzR8, -SOZN(R8)2, O)R9, amino, mono- or di- mino, or C1-C6 alkoxyl.

For e, R6 is NRSRg.

For example, R6 and one of R2 or R3 together with the atoms to which they are attached form phenyl or a 5- or ered heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, le, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like), in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, C1-C3 alkoxyl or —Q1—T1.

For example, R6 and one of Rz’or R3’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, ole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like), in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, C1-C3 alkoxyl or -Q1-T1.

For example, 11 is 1 or 2, and at least one of R7 is —Q2-OR11 in which R11 is —Q6-RS3 and Q6 is optionally substituted C2-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene .

For example, 11 is 1 or 2, and at least one of R7 is —Q2-NR10R11 in which R11 is —Q6- For example, R11 is —Q6-RS3, in which Q6 is a bond or a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker (e.g., C2-C6 alkylene linker) optionally substituted with a hydroxyl and RS3 is 4 to 12-membered heterocycloalkyl (e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12-membered bicyclic cycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, olidinyl, triazolidinyl, tetrahyrofuranyl, dinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4- diazepanyl, 1,4-oxazepanyl, 2-oxa—5-azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa—6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, icyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methylazaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl- piro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methylazaspiro[4.5]decanyl, 2-oxa— ro[3.4]octanyl, 2-oxa—azaspiro[3.4]octanyl, and the like), which is optionally substituted with one or more —Q7-T7.

For example, Q6 is C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl and RS3 is C3-C6 cycloalkyl optionally substituted With one or more —Q7-T7.

For example, each Q7 is independently a bond or a C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 lene linker and each T7 is independently H, halo, C1-C6 alkyl, or phenyl.

For example, —Q7-T7 is 0x0.

For example, Q2 is a bond or a C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene linker.

C1-C4 alkyl For example, at least one of R7 isﬂow $31—04 alkyl 3:, xi, N N—C1-C4 alkyl 3 3 grc /C1-C4 alkyl \ mN—C1_C4 alkyl Hg;\ 9’;‘ 0 GAO "01-04 alkyl 0/1)N OH 3 3 N'C N—C1-C4 alkyl N\ 1.4 alkY I C1-C4 alkyl ~ C3_8 cycloalkyl :"; trio N/ N—C3.e cycloalkyl ;\O/\/\N’C3'8 cycloalkyl ;\O/\/\N’C3'8 cycloalkyl I | H or 01.4 alkyl & i H For example, at least one of R7 is 3 3 /C2-C4 alkyl WWAOMD EMA/\C‘&/:D\CN_C:04 alkyl9’10??NQ m\O/mNfol [Cz—C4 alkyl £10m fiomwfomNCTCNNN gOMNQ m"MW?MN RiomN 3:0m "Ci0 i0"3" fig/\chrm alkyl, Rio/\CN—CM alkyl, reAﬁr\o/\CN-Cs.e cycloalkyl FIND/\CN’? EiO/EN’Q ACACN’O 95:" "A ﬁlo/\C grLOACNK, Elm/\CN’Q *LOACNH H H vaﬁN 3V \3 01- \02-04 alkyl For example, 11 is 2 and the compound r comprises another R7 selected from halo and methoxy.

For example, ring B is selected from phenyl, pyridyl and cyclohexyl, and the halo or methoxy is at the para-position to NR1.

For example, R6 is NRSRg, in which R8 is H or C1-C4 alkyl and R9 is —Q3-T3, or R8 and R9 taken together with the nitrogen atom to which they are ed form a 4 to 12- membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, lidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa—5-azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa—6-azaspiro[3.3]heptanyl, azaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexanyl, benzo[d][1,3]dioxolyl, olinyl, nyl, 2,3-dihydrobenzo[d]oxazolyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, and the like) which is optionally tuted with one or more of —Q5T5.

For example, R9 is —Q3-T3, in which T3 is OK", NR12C(O)R13, C(O)R13, C(O)NR12R13, S(O)2NR12R13, or R52.

For example, Q3 is C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl.

For example, RS2 is C3-C6 cycloalkyl, phenyl, 4 to 12-membered heterocycloalkyl (azetidinyl, idinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, olidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4- oxazepanyl, 2-oxa—5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa—6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan yl, benzo[d][1,3]dioxolyl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, and the like), or a 5 to bered heteroaryl (e.g., triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyiidazinyl, and triazinyl), and RS2 is ally substituted with one or more .

For example, each Q4 is independently a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker optionally substituted with one or more of hydroxyl and halo, and each T4 is independently H, halo, C1-C6 alkyl, or phenyl, or -Q4-T4 is oxo [0178 For example, R6 or NR8R9 is selected from the group consisting of: aH/UNHKN/VO\"\ jg9%P’QN H H HA0] 3 3 3 \3 N gm \H 9‘1 f; H H/\N\( FiN \ O H N\\NH gN in l and F F.

For example, R12 is H.

For example, R12 is C1-C6 alkyl.

For example, R13 is C1-C6 alkyl optionally tuted with one or more —Q8-T8.

For example, R13 is C3-C3 cycloalkyl optionally substituted with one or more —Q8- For example, R13 is C6-C10 aryl (e.g., phenyl) optionally substituted with one or —Q8-T8.

For example, R13 is 4 to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S (e.g., azetidinyl, pyrrolidinyl, olidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, l,2,3,6- tetrahydropyridinyl, zinyl, l,4-diazepanyl, l,4-oxazepanyl, 2-oxa—5- azabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptanyl, 2-oxa—6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3- azabicyclo[3.1.0]hexanyl, benzo[d][l,3]dioxolyl, isoindolinyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, and the like) ally substituted with one or more —Q8-T8.

For example, R13 is 5 to 10-membered heteroaryl (e.g., triazolyl, pyridyl, pyrimidinyl, nyl, pyridazinyl, and triazinyl) optionally substituted with one or more —Q8-T8.

For example, Q8 is a bond.

For example, Q8 is a C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker.

For example, T8 is halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, phenyl, or 4 to 7- membered heterocycloalkyl (e.g., e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, olidinyl, triazolidinyl, tetrahyrofuranyl, dinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro- 2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa yclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and morpholinyl, and the like).

For example, —Q8-T8 is 0x0.

The present disclosure also provides compounds of Formula (IX-1) below: X\7 \ x3 V / /x x6 N R158 (IX-1), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein, X6 is N or CH, X7 is N or CH, X3 is N or CR4, R4 is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally tuted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, each Q1 is independently a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, yl, oxo, or C1-C6 alkoxyl, each T1 is independently H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or RSI, in which RS1 is C3-C3 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, - SOZRS, -S02N(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and —Q1—T1 is not )NR12R13, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which RS2 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 ne, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, CRd, and NRCC(O)Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to bered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, n each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is ed from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered aryl, or —Q8-T8 is oxo, R15a is CN, C(0)H, 8, OH, ORIS, C1-C6 alkyl,NHR17, C3-C3 cycloalkyl, C6- C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to lO-membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to lO-membered heteroaryl is optionally substituted with one or more —Q9-T9, wherein each Q9 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T9 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to ered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, and 5- to ered heteroaryl, or —Q9-T9 is oxo, R16a is -Q11-R16 in which Q11 is a bond, 0, NRa, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and R16 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more —Q 10-T10, wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 lene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T10 independently is selected from the group consisting of H, halo, cyano, C(O)H, C(O)R18, S(O)pR18, OH, ORIS, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q 10 10- -T is oxo, R17 is H or C1-C6 alkyl, each R18 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, p is 0,1, or2, and V is 0, 1, or 2.

For example, R15a is CN or C(O)R18.

For example, R16a is -Q11-R16 in which Q11 is a bond, NRa, or C1-C3 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 .

For example, each Q1 is independently a bond or C1-C6 alkylene or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1- C6 alkoxy.

For example, each T1 is independently NR8R9, 0R9, or RSI, in which RSl is optionally substituted C3-C3 cycloalkyl or optionally substituted 4- to 12-membered heterocycloalkyl.

For example, one subset of compounds of a (IX-1) is of Formula (IX): (mm \ \ x3 V K / /x x6 N R15 (1X), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein X6 is N or CH, X7 is N or CH, X3 is N or CR4, R4 is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C3) aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB,NR12R13,NR12C(O)R13, 12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which R52 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 , and each T4 independently is selected from the group ting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C3) aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, CRd, and NRCC(O)Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, n each Q8 independently is a bond or C1-C3 alkylene, C2-C3 lene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, R15 is C1-C6 alkyl, NHR17, C3-C3 cycloalkyl, C6-C10 aryl, 4- to lZ-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, or 5- to 10- membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted with one or more —Q9-T9, wherein each Q9 ndently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T9 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, and 5- to 6- ed heteroaryl, or —Q9-T9 is oxo, R16 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally tuted with one or more —Q10- T10, wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T10 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or — Qlo-T10 is oxo, R17 is H or C1-C6 alkyl, and V is 0, 1, or 2.

The compounds of Formula (IX) can have one or more of the following features when applicable: For example, each T3 independently is OR12 or ORB.

For example, each Q3 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl.

For example, R15 is C1-C6 alkyl, NHR", or 4- to 12-membered heterocycloalkyl.

For example, R16 is C1-C6 alkyl or 4- to 12-membered cycloalkyl, each optionally substituted with one or more 10.

For e, each T10 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, and 4- to 7-membered heterocycloalkyl.

For example, each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker optionally substituted with a hydroxyl.

For e, the compounds of Formula (IX) include those of Formula (X): XI?" (X), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein X3 is N or CR4, n R4 is selected from the group consisting of H, halo, and cyano.

For example, the compounds of Formula (X) include those of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), or (Xg): R16 R16 H CO3 H CO \ 3 \ N / A R90 N R15 (Xa), R90 N R15 (Xb), H co3 H CO \ \ N 3 \ \ / A / / R O9 9 N N R15 (XC), R O N N R15 (Xd), H co F H 00 N 3 \ \ \ R90 N R15 (Xe), R90 N R15 (Xi), or R90 N R15 (Xg).

For example, X2 and X3 are CH, and X1 and X4 is N.

For example, X2 and X3 are N, X1 is CR2, and X4 is CR5.

For example, R6 is NRgR9 and R5 is C1_6 alkyl or R5 and R3 er with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.

For e, the compound is selected from those in Tables 1-5, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.

The present sure provides compounds which inhibit a kinase with an enzyme inhibition IC50 value of about 100 nM or greater, 1 uM or r, 10 uM or greater, 100 uM or greater, or 1000 uM or r.

The present disclosure provides compounds which inhibit a kinase with an enzyme inhibition IC50 value of about 1 mM or r.

The present disclosure provides compounds which inhibit a kinase with an enzyme inhibition IC50 value of 1 uM or greater, 2 uM or greater, 5 uM or greater, or 10 uM or greater, n the kinase is one or more of the following: AbI, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARKl, MNK2, PKCb2, SIK, and The present sure provides a pharmaceutical composition comprising a compound of any one of the Formulae described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present disclosure provides a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMTl and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of a (I): x2/X\X34 7 Rs/X\X1 N/T\'7£R)n,‘ l \ R1 (1), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein ring A is phenyl or a 5- or 6-membered heteroaryl, X1 is N, CR2, or NR2’ as valency permits, X2 is N, CR3, or NR3’ as valency permits, X3 is N, CR4, or NR4’ as valency permits, X4 is N or CR5, or X4 is absent such that ring A is a 5-membered heteroaryl containing at least one N atom, X5 is C or N as valency permits, B is absent or a ring structure selected from the group consisting of C6-C10 aryl; C3- C10 cycloalkyl; 5- to lO-membered heteroaryl; and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; T is a bond or C1-C6 alkylene; C2-C6 alkenylene; or C2-C6 lene linker optionally substituted with one or more of halo; cyano; hydroxyl; oxo; or C1-C6 alkoxy when B is present; or T is H and n is 0 when B is absent; or T is C1-C6 alkyl optionally substituted with (R7)Il when B is ; or when B is ; T and R1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl; each of which is optionally substituted with (R7)n; R1 is H or C1-C4 alkyl; each of RZ’; R3’ and R4’ ndently is H or C1-C3 alkyl; each of R2; R3; and R4; independently is selected from the group consisting of H; halo; cyano; 01-06 alkoxyl; 06-010 aryl; NRaRb; C(O)NRaRb; NRaC(O)Rb; C3-C8 cycloalkyl; 4—7 membered heterocycloalkyl; 5-6 membered heteroaryl; and C1-C6 alkyl; wherein C1-C6 l and C1-C6 alkyl are optionally substituted with one or more of halo; ORa; or NRaRb; in which each of Ra and Rb independently is H or C1-C6 alkyl; or R3 is —Q1-T1; in which Q1 is a bond or C1-C6 alkylene; C2-C6 alkenylene; or C2-C6 alkynylene linker optionally substituted with one or more of halo; cyano; hydroxyl; oxo; or C1-C6 l; and T1 is H; halo; cyano; NRSRg; C(O)NR8R9; 0R8; 0R9; or RSI; in which RSl is C3-C3 cycloalkyl; phenyl; 4- to 12- ed heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo; C1-C6 alkyl; hydroxyl; oxo; -C(O)R9; 60st; -SOZN(R8)2; -NR8C(O)R9; amino; mono- or di- alkylarnino; or C1-C6 alkoxyl; or when ring A is a 5-membered heteroaryl containing at least one N atom; R4 is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; R5 is ed from the group consisting of H; halo; cyano; C1-C6 alkoxyl; C6-C10 aryl; NRaRb; C(O)NRaRb; NRaC(O)Rb; C3-C3 cycloalkyl; 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; ally substituted with one or more of -C(O)C1-C6 alkyl or C1-C6 alkyl optionally substituted with one or more of halo or ORa; C1-C6 alkyl optionally substituted with one or more of halo; ORa; or NRaRb; and C2-C6 alkynyl ally substituted with 4- to 12-membered heterocycloalkyl; wherein said C3-C3 cycloalkyl and 4- to 12-membered cycloalkyl are optionally substituted with one or more of halo; C(O)Ra; ORa; NRaRb; 4- to 7-membered heterocycloalkyl; -C1-C6 alkylene to 7-membered heterocycloalkyl, or C1-C4 alkyl optionally substituted with one or more of halo, ORa or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or ered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, R6 is absent when X5 is N and ring A is a 6-membered heteroaryl, or R6 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or R", in which RS1 is C3-C8 cycloalkyl, , 4- to 12-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is ally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, -SOZR8, -SOzN(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and R6 is not NR8C(O)NR12R13, or R6 and one of R2 or R3 together with the atoms to which they are ed form phenyl or a 5- or ered heteroaryl, or R6 and one of Rz’or R3’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, yl, oxo (=0), C1-C3 alkoxyl or -Q1-T1, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 ndently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, cyano, ORIO, OR", C(O)R11, NRIOR", C(O)NR10R11, NR10C(O)R11, 5- to 10-membered heteroaryl, C3-C3 cycloalkyl, or 4- to 12- membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, and n the 5- to 10-membered heteroaryl, C3-C3 cycloalkyl, or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, -SOZRS, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)ORg, or optionally, when B is present, one R7 and R5 together form a C3-C10 alkylene, C2-C10 heteroalkylene, C4-C10 alkenylene, C2-C10 heteroalkenylene, C4-C10 alkynylene or C2- C10 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl or C1-C6 alkoxyl, and T3 is H, halo, OR", ORB, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which R52 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is ally substituted with one or more —Q4-T4, wherein each Q4 ndently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, C, RCRd, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and R(:1 independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R8 and R9 taken together with the nitrogen atom to which they are attached form a 4- to bered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of —Q5-T5, wherein each Q5 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Re, S(O)2Re, S(O)2NReRf, NReRf, eRf, and NReC(O)Rf, each of Re and Rf independently being H or C1-C6 alkyl, or —Q5-T5 is oxo, R10 is selected from the group consisting of H and C1-C6 alkyl, R11 is —Q6-T6, in which Q6 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T6 is H, halo, ORg, NRth, )Rh, C(O)NRth, C(O)Rg, S(O)2Rg, or RS3, in which each of Rg and Rh independently is H, phenyl, C3-C3 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C3 cycloalkyl, or Rg and Rh together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, and RS3 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to lO-membered heteroaryl, and RS3 is optionally substituted with one or more —Q7-T7, wherein each Q7 ndently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T7 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR], C(O)Rj, NRij, C(O)NRij, S(O)2Rj, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl optionally substituted with one or more halo, or —Q7-T7 is oxo, or R10 and R11 taken together with the en atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, or C1-C6 alkoxyl, R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally tuted with one or more —Q8-T8, wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, and n is 0, 1, 2, 3, or 4, provided that (l) the compound of Formula (I) is not 2-(hexahydromethyl-1H-1,4-diazepinyl)- 6,7-dimethoxy-N-[ l ylmethyl)piperidinyl] quinazolinamine, or 2-cyclohexylmethoxy-N-[l-(l-methylethyl)piperidinyl][3-(lpyrrolidinyl )propoxy]quinazolinamine, (2) when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5 to -membered heteroaryl, or (3) when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C1-C6 alkyl, and R6 and R2 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

The t sure also provides a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., any compound of any of Formulae (I)-(Xg).

For example, the blood disorder is sickle cell anemia or assemia.

For e, the blood disorder is a hematological cancer.

The present disclosure also provides compounds of Formula (I) which are ive inhibitors of EHMT2.

Representative compounds of the t disclosure include compounds listed in Tables 1-5 or tautomers and salts thereof.

Table 1 WO 81177 Compound 8 2O ZI ZI H \ ZI ZI ,_a ,_a \ 12 a \ \ O\/\/N’3 .-1 . H N N / O\/\/No z / \ 14 AUVO NY" 0WD Compound Structure ,_a m "WOO/""9 N N H "CLH N o OWO UU/N 0/ ,_a \1 "Wm" f" 1:? ,_a 00 N NAN H H or,N ANO\/N | ">{N\©:::/\/© NO VtﬁULWD ’—‘ E? :1 E 2o N U.) Q Q: §0 Compound .l-N4;mNO\ U.) N Compound Structure WO 81177 Compound .l-4;Nw4;4; 1/| /N O/ 46 HNle/H NY" 0WD 4; \l 4; \D WO 81177 Compound Structure Q2 Z]: N 23 H \ 232 m QI I N/2z—< \ Q\§ O\ 2O \l Q; {I 32gm WO 81177 Compound Structure N N Structure f"\ 'A "1/ NH2 N N WO 81177 Compound Structure Structure N N N H H 7 M"n 8 AMWHm "WV/O O NH 2 N F HNN OX0WNH v/ F m \VI WO 81177 Compound Structure WO 81177 Compound Structure *0 H N N O N 104 \ \/\/O H |YU /N O/ /\/N N 09*N 106 QN "K" 0W0 H IYm /N / 107 '3 "/U/N N O N \ \/\/ n o 108 W/ \/\/NO HOVH H 109 W0 NTN O 110 Q N \ \ OWN’3 \O H N N 111 OWN,3 /N O/ 112 ’3 N N N\ OWN I I T / 0/ und Structure H H 1 13 OWN /N N 0WD \ / 114 ONWH n N "VG "Cg " 115 n N n U0/N Kong): N/V\O"1301N/KN 1 17 OW" NY" 0WDIIII'"F 118 O\/H NY" OWD‘F 119 "CuH H N NYN 120 M N M N 0%N "mN/ | 121 @«A HQ compound Structure 0\N NJK 122 W" "Y" HQI 0 U M NW NJK 123 D’NWHUHVJHVQ C‘N Kn 0WD 124 LTUM 0" H N N 125 UCE/N O\/\/NO o / 126 33L ~r" mm @MO MW WO 81177 Compound Congoound ure 140 CAR/V0 NY" "WWI \0 N\ 141 "U"TIL 9M0 ukN N 142 NY" 0WD 0 LN / /O\/\/N 0WD 143 L"I My" 0/ i H "U(I,N N o N 144 N \ W’3 145 \o N/ HN O/V\N \I/ N 202 O NWOD/NH\o O H NWo N N\ NHQ)" Compound U/\N (I0/ "O0 205 | @MO NAN/ N/ H H H H N N 206 / / O\/\/© N\ 0/ H H 207 /N /NTN OWN,3 208 "D P" H H H ZI ’3 \ N 0/ H H 210 /N /NTN\©:O\/\/NLN o CI 0/ 212 /\:\‘/\|Nr\©/\)\/H N N O N Compound 213 0 W HZN 0/ ’d N H 0 214 N/ LNY \/\/NO 215 Y OVH N H 0\/\/NO / 0/ CL 0 n / 217 \/\/ \©:N/\N/ \o 218 "D a "> OMO N \N N H \ / I)g>N/ N \ N\N//N> 220 C‘ /0 /N\N_ 221 \ und Structure 224 o )‘TN OWN \ N O/ 225 Kg" AT" 0WD LN 0/ 226 0V" AT" HWD LN / 227 £10" ‘'1 GM NxN/ N H H 228 11°" \'1 C/NMN N/kN/ N/\O H H H H H /N "TN OWNO‘F 229 LN 0/ N H 230 OWN/j Compound 231 / \iNj/ \/\/ N\ O/ 232 I) "\I @MO N)\N/ N/ H H "D "\ / 233 I @MO NXN/ N/ H H / I) i\ F OMO N N/ N/ H H /D W1/ 9M0 \ F F 236 "D "\FNAN/I CNMO N/ H H 237 K/N\/\o: : ‘N)|\N/ N/ H H /0 N/ 238 k | OMO F N N H F o \ 239 H H /N N WO 81177 Compound Structure 240 x l N\ H OW" HU/ 0/ U 242 OW" H \ 0WD 243 f" 110/05" (DAN NAN O H H n w n o / WD U\N F HN2 N H o\/\/N U\/ N 0/ H H /N / ’3 I NUOWN \N/N 0/ H H OWN'3 247 /N\f\1]/N\N 0/ WO 81177 Compound Structure l N 249 0 I / 0 ONW "x \OUNUUUHN F O N 1 ML W "1 H 05.... H W OWN 252 / O 3 ﬂ O N HAL WO HN HN 254 O Compound Structure 255 o C‘ H / NWO N N 7 / I N\N \o \ / CL 0 n / \O N \ N/ UYNH \ N N 259 H o 0 NJ\ O N— 260 HNQO/ /\/\O A | N \N 0/ H N o 262a / UU/\ \/\/ .2P262b N N OWN/3 263 I T / 0/ H H 265 QWOUNH\o N\ / H H /N N 267 \ /N O/VNO | | /N \ 268 / \ / O/\/ N / \ Compound Structure H N H o D""""’F 271 /\O/ \/\/ \ N O/ 272 / /l \/\/ F 0/ /0I; / r OMO \ H H 274 /N "\er QNH2 \ N 0 n n N/ 275 / )‘T N \ N 0 H H 276 /N "TN OWN’3 277 / "T 278 A" N H 0WD U\N O/ 279 o/VD Compound Structure N N N o N 280 / 1/N/\( \/\/\/ "DN \ 281 N)\NI C/NMO / N/ H H H H 282 /N N gg\H H H N N N o N 283 / L/ \lr \/\/ OWNO\<\FF /H N H 287 /U \ N / (gm/D "9NAN/ / Congoound ure f" O\ 289 \N \NXN H H 0%N 290 / U/\ W H N H 291 / / / N/\ \ N \ N F /O N/\/\O A N N/ N/ H H H N H o / D‘ 293 U/ \/\/ O N— /N /N\|(NH / / N N 295 H \ /N /NTNH H H 296 /N N N UNHz Compound O] o N N N H H N\| / WO 81177 Compound Structure /O \N 6'" 306 | OMO / N NAN/ H H /O \N 307 | hI \ CNMO / / N N/ H H /O \N \N 308 | | CNMO / / N N/ H H /O F \N N \ 309 I I CN/\/\O / / N N/ H H N\ / 310 ON\/\/O NH \O /N /O N \ / \/\o )L N N/ N/ H H /O N \ \o/\/\o i N N/ N/ H H 313 I @MO NAN/ N/ H H 314 I CNMO NAN/ H/ WO 81177 Compound Structure HN N C/NMOF O / N KICK 316 \N \NAN onN/ g | \N \N N o H H / \\\\ \N \N N 0"".

H H /0 F 319 x | 9M0 w C" H CA No 321 \ "K? o\/\/ Structure H H /N / N ’3 322 / O\/\/N \N/N N \ 0/ 323 /N\Kj/Nﬂow©N§NH N\ O/ 324 /W/ / W 325 |\N "1k" cN/\/\O / NMN/ H H V N I N\ / 326 ON\/\/O NH \O /N o F / \ N / 327 | | @MO / N \N /O N/ 328 k | / \\\\N \ \N N o 330 \ \J\ WO 81177 Compound Structure / \\\ \N \Ni g Y N o H H /O N\ N \ 332 l I H H N\ / CNfO ,/N/N To NJ\\N \/N H /N N 335 O \O / N /N N 336 O NWOJCKNHN\O / /OJCL F NxN/I A Table 2 WO 81177 nd Structure WO 81177 WO 81177 WO 81177 WO 81177 I371372 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 WO 81177 Congound Structure WO 81177 Congound Structure WO 81177 Table 3 Strucmre 520 o Strucmre WO 81177 Strucmre Strucmre Strucmre WO 81177 Strucmre Structure Strucmre WO 81177 Strucmre Strucmre Strucmre C0MN n.0 Structure Strucmre Strucmre Strucmre WO 81177 Strucmre WO 81177 Strucmre WO 81177 WO 81177 Strucmre WO 81177 Strucmre Strucmre Strucmre Strucmre Strucmre WO 81177 Compound Structure 611 Q T Compound StFHcmm Strucmre WO 81177 Strucmre WO 81177 Compound Structure 624 J) Compound Structure Compound Structure WO 81177 Strucmre Strucmre Strucmre WO 81177 Strucmre WO 81177 Strucmre WO 81177 Strucmre WO 81177 Strucmre Compound Structure WO 81177 Strucmre WO 81177 Compound Structure Structure WO 81177 Strucmre Strucmre WO 81177 Strucmre Strucmre Strucmre Strucmre Strucmre WO 81177 Compound Structure WO 81177 Compound Structure WO 81177 Strucmre 705 H 0W0 "Y" HV©E>ZO Strucmre Strucmre WO 81177 Strucmre Structure WO 81177 Strucmre Strucmre WO 81177 Strucmre Strucmre Strucmre WO 81177 Strucmre Structure Flumu.Cr/\/\O WO 81177 Strucmre Structure WO 81177 Strucmre WO 81177 Compound Structure Strucmre Strucmre WO 81177 Compound Structure A"Hi/ WO 81177 Table 4 Strucmre 791 N WO 81177 Strucmre Strucmre WO 81177 805 O Strucmre WO 81177 WO 81177 Strucmre WO 81177 Strucmre WO 81177 Strucmre WO 81177 Strucmre WO 81177 Strucmre Compound Structure Compound WO 81177 WO 81177 Strucmre WO 81177 Strucmre Structure WO 81177 Compound Structure WO 81177 Compound Structure WO 81177 C0mNpN0und Structure Strucmre WO 81177 Compound Structure WO 81177 Compound Structure WO 81177 Compound Structure Strucmre Strucmre WO 81177 Compound Structure WO 81177 Compound Structure Strucmre Compound Structure Structure 1011 l Structure WO 81177 Compound Structure Compound Structure WO 81177 Strucmre Tables Structure 104 H C 3 \NH 1044 CH3 1045 CH3 ON \CH3 \N A N N H H o/Y\N 1046 0 ON \CH3 \N )\ N N H @éQQH OMNQ36H IZ Z IZ H30 3o I2 2 I2 Structure 104 0 (A) / f1 I2 z IZ 0 C 1051 o N 0/WI CA7 / 20>’2IZ IZ 3'0 -/l::::> 1052 Hsc—NH 1053 Hsc—NH WO 81177 compound Structure 105 H30——NH OH \x___<:__— /f___j>h__ /pH3 o N( > NH \ >7N 0 NH 1055 H3O LN 23* 0 (3?NH H3O NH 1056 O$;H3 20Y2zI O\"""" (A) z I b 1057 O <:::>N \\CH3 1058 CH3 compound Structure 105 H 1060 O 3 \ )\ N o/$\ 1061 o\\ b) O>72 I2 2 I2 1062 o\\ I2 2 I2 1063 CH3 1064 o\\ compound Structure 106 O\CH3 1066 CH3 1067 O I mr) / zO>_z L;\"2 IZ IZ O 1068 CH3 1069 o\ 1070 0\ H3C\\ IZ Z 0\ IZ L}\ compound Structure 107 CH3 1072 0\\ IZ Z IZ 0 L2I 1073 0 I O \z z2% I I (A) /O 1074 o\\ 1075 o\\ H30\ 2 I2 2 I2 DZ 1076 Hac—NH H30 NW WO 81177 107 Hac—NH H ﬂ)/C"3 HN N NH \ b0 >7N 0 NH 1078 CH3 3 \N)6" {CE W k N N H H o/Y\N\jOH HN—CH3 HN HN47N 0 NH 1081 CH3 N \CH3 N N H H \/\N\j 1082 EN aW0 H c 3 \N X N N H H OMNQg5 WO 81177 108 O\\ ON CH3 \N x N N o N H H 1084 THg CH3 N@NHN uIIlO WO 81177 compound Structure 108 CH3 IZ (9% 0 mm; 1090 H3C—NH CH3 H30 \_< CH3 0 / HN N NH \ >7N O NH 1091 0 O OI I i 2 0 0I—z P2 CA7 OI 1092 o\\ WI G>—2 O I2 2 I2 Oi OIIIIII DZ 1093 o\\ uw4 o—cm Structure 109 HBC—NH H30 \—\ CH3 1 O / HN N NH \ >7N 0 NH 3 VNQQ'O "16>.N/H 0" £1 Hsc\ )\N o N 1098 O N \CH3 H3C )\ 12/ Z IZ Ci 1099 CH3 IZ I2 1100 CH3 I2 2 I2 compound Structure 110 CH3 3 \N 0"1 N N H H 1102 (.ITH3 H c H 1103 (.ITH3 1104 H30\\ I 0 Z (A) I2 1105 H3C\\ 1106 CH3 WO 81177 Com ound 110 OH HBC/ / W / \CH3 H3C \ \N N 0 I\‘\\\OH CH3 CH3 N/\/ A / CH N N N/ H H H N CH3 / \ I HN/CH3 compound Structure 111 0 1112 H3C\\ 1113 CH3 (|:H3 OH Y 1114 CH3 Structure --.TATTTTTT1117 aloof1118 AmlﬁTTTTT OTTTTTTT As used herein, "alkyl", "C1, C2, C3, C4, C3 or C6 alkyl" or "Cl-C 6 alkyl" is intended to include C1, C2, C3, C4, C3 or C6 ht chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C3 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to e C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In n embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for ht chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-Iing (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C3). Examples of cycloalkyl include, but are not limited to, ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. The term "heterocycloalkyl" refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, d, or spiro rings), or 11-14 membered tricyclic ring system , bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., l or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e. g. , 1, 2, 3, 4, 5, or 6 atoms, independently ed from the group consisting of nitrogen, oxygen and sulfur, unless speciﬁed otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, idinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, l,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxaazabicyclo[2.2.l]heptanyl, 2,5-diazabicyclo[2.2. anyl, 2-oxaazaspiro[3.3]heptanyl, azaspiro[3.3]heptanyl, 1,4-dioxa—8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, l-oxaspiro[4.5]decanyl, lazaspiro [4.5]decanyl, 3'H-spiro[cyclohexane-l ,1'—isobenzofuran] -yl, 7'H-spiro[cyclohexanel ,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]—yl, 3- azabicyclo[3. 1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4- zolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, ylazaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl- 2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methylazaspiro[4.5]decanyl, 2-oxaazaspiro [3.4]octanyl, 2-oxa-azaspiro[3.4]octanyl, and the like. In the case of multicyclic non-aromatic rings, only one of the rings needs to be non-aromatic (e.g., 1,2,3,4- tetrahydronaphthalenyl or 2,3-dihydroindole).

The term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, rbonyloxy, carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hiocarbonyl, alkoxyl, phosphate, phosphonato, inato, amino (including alkylamino, lamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, ato, sulfamoyl, sulfonamido, nitro, triﬂuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, "alkyl linker" or "alkylene linker" is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, Cl-C6 alkylene linker is intended to include C1, C2, C3, C4, C5 and C6 alkylene linker groups. es of alkylene linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (-CH2-), ethyl (-CH2CH2-), n-propyl H2CH2-), i-propyl (- CHCH3CH2-), n-butyl (-CH2CH2CH2CH2-), s-butyl (-CHCH3CH2CH2-), i-butyl (-C(CH3) , yl (-CH2CH2CH2CH2CH2-), s-pentyl (-CHCH3CH2CH2CH2-) or n-hexyl (- CH2CH2CH2CH2-).

"Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g., ethenyl, yl, l, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched l groups.

In certain embodiments, a straight chain or ed alkenyl group has six or fewer carbon atoms in its backbone (eg, C2-C6 for straight chain, C3-C6 for branched . The term "C2-C6" es l groups containing two to six carbon atoms. The term "C3-C6" es alkenyl groups containing three to six carbon atoms.

The term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, onato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), ino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, triﬂuoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

"Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, yl, butynyl, yl, hexynyl, heptynyl, octynyl, nonynyl, l), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent rated aliphatic hydrocarbon groups. For example, C2-C6 alkenylene linker is ed to include C2, C3, C4, C5 and C6 alkenylene linker groups.

As used herein, the terms "heteroalkyl", "heteroalkylene linker", "heteroalkenyl", "heteroalkenylene linker", "heteroalkynyl", and "heteroalkynylene linker", are intended to refer to aliphatic hydrocarbon groups that include, e.g., C1 to C10 carbon atoms and one or more heteroatoms, e.g., l or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., l, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and . These tic hydrocarbon groups can either be linear or branched, saturated or unsaturated.

The term "optionally tuted alkynyl" refers to tituted l or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, arbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), o, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, triﬂuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted cycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6- tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

"Aryl" includes groups with aromaticity, ing "conjugated," or yclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. Examples include phenyl, naphthalenyl, etc.

"Heteroaryl" groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as "aryl heterocycles" or "heteroaromatics." As used herein, the term oaryl" is intended to include a stable 5-, 6- or 7-membered clic or 7-, 8-, 9-, 10-, 11- or 12-membered ic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e. g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently ed from the group ting of nitrogen, oxygen and sulfur. The en atom may be substituted or unsubstituted (Le. N or NR wherein R is H or other substituents, as deﬁned).

The nitrogen and sulfur heteroatoms may optionally be oxidized (l'.e., N—>O and S(O)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, ne, pyridazine, pyrimidine, and the like.

Furthermore, the terms "aryl" and "heteroaryl" include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, hiophene, ine, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

The cycloalkyl, heterocycloalkyl, aryl, or aryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, arbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, oyl, amido, nitro, triﬂuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or cyclic rings, which are not ic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as d][1,3]dioxoleyl).

As used herein, "carbocycle" or "carbocyclic ring" is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocycle includes cycloalkyl and aryl. For example, a C3-C14 carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, tyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, ﬂuorenyl, phenyl, yl, indanyl, adamantyl and tetrahydronaphthyl. d rings are also included in the deﬁnition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, and ] bicyclodecane and [2.2.2] bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adj acent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always ts a clic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, ydronaphthyl) and spiro rings are also included.

As used herein, ocycle" or "heterocyclic group" includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O and S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, e, pyran, tetrahydropyran, azetidine, and ydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, idazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, trazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][l,3]dioxole—5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, l,2,4-oxadiazolS(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, lidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, nolizinyl, alinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, l,2,4-thiadiazolyl, thiadiazolyl, l,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, l,2,4-triazolyl, l,2,5-triazolyl, l,3,4-triazolyl and xanthenyl.

The term "substituted," as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.€., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two nt ring atoms (e.g., C=C, C=N or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the nd of a given a, then such substituent may be bonded via any atom in such a. ations of substituents and/or variables are sible, but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other ence. Thus, for e, if a group is shown to be tuted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each ence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O'.

As used herein, "halo" or "halogen" refers to ﬂuoro, chloro, bromo and iodo. The term "perhalogenated" generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

The term "carbonyl" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not d to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term xyl" refers to —COOH or its C1-C6 alkyl ester.

"Acyl" includes moieties that n the acyl radical (R-C(O)-) or a carbonyl group.

"Substituted acyl" es acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, n, yl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, arbonyl, arylcarbonyl, carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, triﬂuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

"Aroyl" includes moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, yl carboxy, etc.

"Alkoxyalkyl," "alkylaminoalkyl," and "thioalkoxyalkyl" include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.

The term y" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, y, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, ylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, ate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, rboxylate, es, alkylsulfinyl, ato, sulfamoyl, sulfonamido, nitro, triﬂuoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups e, but are not limited to, ﬂuoromethoxy, diﬂuoromethoxy, triﬂuoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term "ether" or "alkoxy" includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group ntly bonded to an oxygen atom which is covalently bonded to an alkyl group.

The term "ester" includes compounds or moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as ycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.

The term "thioalkyl" includes compounds or moieties which contain an alkyl group connected with a sulfur atom. The kyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, ylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, laminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), ino (including alkylcarbonylamino, arylcarbonylamino, oyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, triﬂuoromethyl, cyano, azido, heterocyclyl, ryl, or an aromatic or heteroaromatic moieties.

The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

The term "thioether" includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, oalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include moieties with an alkyl, l, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group, and alkthioalkynyls" refers to moieties wherein an alkyl, l or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

As used herein, "amine" or "amino" refers to -NH2. "Alkylamino" includes groups of compounds wherein the nitrogen of -NH2 is bound to at least one alkyl group. es of alkylamino groups include amino, methylamino, ethylamino, phenethylamino, etc.

"Dialkylamino" includes groups wherein the nitrogen of -NH2 is bound to two alkyl groups.

Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. "Arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. "Aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy substituted with amino. "Alkylarylamino, 77 ccalkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. "Alkaminoalkyl" refers to an alkyl, l, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. "Acylamino" includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not d to, alkylcarbonylamino, arylcarbonylamino, oyl and ureido groups.

The term "amide" or "aminocarboxy" includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a rbonyl group. The term includes "alkaminocarboxy" groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes "arylaminocarboxy" groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy", "alkenylaminocarboxy", "alkynylaminocarboxy" and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, tively, are bound to a nitrogen atom which is in turn bound to the carbon of a yl group. Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide groups may be further substituted.

Compounds of the present disclosure that contain nitrogens can be converted to N- oxides by treatment with an ing agent (6. g., roperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other nds of the present sure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N—oxide derivative (which can be designated as N—>O or N+-O'). rmore, in other instances, the nitrogens in the compounds of the present disclosure can be converted to N—hydroxy or N—alkoxy compounds.

For example, N—hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its oxy (116., N—OH) and N-alkoxy (116., N-OR, wherein R is tuted or unsubstituted C1-C 6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3membered carbocycle or 3 membered heterocycle) derivatives.

In the present speciﬁcation, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. In addition, a l polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form e, or anhydride or e thereof is included in the scope of the present disclosure.

"Isomerism" means compounds that have identical lar formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one r are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture ning equal amounts of individual enantiomeric forms of te chirality is termed a "racemic mixture." A carbon atom bonded to four nonidentical substituents is termed a "chiral center." "Chiral isomer" means a compound with at least one chiral . Compounds with more than one chiral center may exist either as an dual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be terized by the absolute configuration (R or S) of that chiral center. te configuration refers to the arrangement in space of the substituents attached to the chiral . The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem.

Inter. Edit. 1966, 5, 385, errata 511, Cahn et al.,Angew. Chem. 1966, 78, 413, Cahn and Ingold, J. Chem. Soc. 1951 (London), 612, Cahn et al., Experientia 1956, 12, 81, Cahn, J.

Chem. Educ. 1964, 41, 116).

"Geometric isomer" means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are entiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

It is to be understood that the compounds of the present disclosure may be ed as different chiral isomers or geometric isomers. It should also be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of ty.

Furthermore, the structures and other compounds sed in this sure include all atropic isomers thereof, it being tood that not all atropic isomers may have the same level of ty. "Atropic isomers" are a type of stereoisomer in which the atoms of two s are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic s typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

"Tautomer" is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent ated double bonds.

Tautomers exist as a mixture of a tautomeric set in on. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed.

In keto-enol tautomerism a simultaneous shift of electrons and a en atom occurs.

Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam—lactim, amide- imidic acid erism in heterocyclic rings (eg, in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine. Examples of lactam-lactim tautomerism are as shown below.

Cb—OH,N // / N’N \ \ (MO N N HO 0 HO Nf \ I HN\ I HN\ HN HN N’ It is to be tood that the nds of the present disclosure may be ed as different tautomers. It should also be tood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not e any tautomer form. It will be understood that n tautomers may have a higher level of activity than others.

The term al polymorphs", "polymorphs" or "crystal forms" means l structures in which a compound (or a salt or solvate thereof) can crystallize in different l packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of llization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under ent conditions.

The compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions include de, e, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, triﬂuoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., triﬂuoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt.

Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The tuted benzene compounds also include those salts containing quaternary nitrogen atoms.

Additionally, the compounds of the present sure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as es with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, "Solvate" means solvent addition forms that contain either stoichiometric or nonstoichiometric amounts of solvent. Some compounds have a tendency to trap a ﬁxed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is l, the solvate formed is an alcoholate. Hydrates are formed by the ation of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H20.

As used herein, the term "analog" refers to a chemical nd that is structurally similar to another but s slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

As defined herein, the term "derivative" refers to compounds that have a common core ure, and are substituted with various groups as described herein. For example, all of the compounds ented by Formula (I) are amine-substituted aryl or heteroaryl compounds, and have Formula (I) as a common core.

The term "bioisostere" refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly r, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or gically based. Examples of ylic acid bioisosteres include, but are not limited to, acyl sulfonimides, oles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, es of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-l4.

The present disclosure provides s for the synthesis of the compounds of any of the Formulae described . The present disclosure also es ed methods for the synthesis of various disclosed compounds of the present disclosure according to the ing schemes as shown in the Examples.

In the descriptions and claims, articles such as cc 7) (C a an," and "the" may mean one or more than one unless indicated to the ry or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisﬁed if one, more than one, or all of the group s are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise t from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all, of the group members are t in, ed in, or otherwise relevant to a given product or process. As used herein, the expressions "one or more of A, B, or C," "one or more A, B, or C," "one or more of A, B, and C," "one or more A, B, and C", "selected from A, B, and C," ted from the group consisting of A, B, and C," and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and /or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless otherwise speciﬁed.

It is also noted that the term "comprising" is intended to be open and permits but does not require the ion of additional elements or steps. When the term "comprising" is used herein, the terms "consisting ially of" and "consisting of" are thus also encompassed and disclosed. Throughout the description, where compositions are described as having, including, or comprising speciﬁc components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are bed as having, including, or comprising speciﬁc process steps, the ses also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains le. Moreover, two or more steps or actions can be conducted aneously.

The synthetic processes of the sure can te a wide y of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired ﬁnal compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof Compounds of the present disclosure can be prepared in a variety of ways using cially available starting materials, nds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientiﬁc literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, isms, and Structure, 5th edition, John Wiley & Sons: New York, 2001, Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, R. , hensive Organic Transformations, VCH Publishers (1989), L. Fieser and M. Fieser, Fieser andFieser ’s Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia ofReagentsfor Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of c synthesis known to those in the art. The following descriptions of synthetic methods are designed to rate, but not to limit, general ures for the preparation of compounds of the present disclosure.

Compounds of the present disclosure can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this disclosure having any of the Formulae described herein may be prepared according to the procedures illustrated in s 1-9 below, from commercially available starting materials or starting materials which can be prepared using literature procedures. The variables (such as 11, R3, R7, R8, and R9, etc.) in Schemes 1-9 are as d in any Formula described herein, unless ise specified.

One of ordinary skill in the art will note that, during the on sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups.

One of ry skill in the art will recognize that certain groups may require tion from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., tive Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

Preferred protecting groups include, but are not limited to: [0287l For ahydroxyl : TBS, benzyl, THP, Ac [0288l For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allyl ester For amines: Cbz, BOC, DMB [029Ol For diols: Ac (X2) TBS (X2), or when taken together acetonides [0N\D l l For thiols: Ac [0N\DNl For benzimidazoles: SEM, benzyl, PMB, DMB [0N93l For aldehydes: di-alkyl acetals such as dimethoxy acetal or diethyl acetyl. [0294l In the reaction schemes described herein, multiple stereoisomers may be ed.

When no particular stereoisomer is indicated, it is understood to mean all le stereoisomers that could be produced from the reaction. A person of ordinary skill in the art will recognize that the reactions can be optimized to give one isomer entially, or new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as ative thin layer tography, preparative HPLC, preparative chiral HPLC, or preparative SFC may be used to separate the isomers.

The following abbreviations are used hout the speciﬁcation and are deﬁned below: [0296l ACN itrile [0297l Ac acetyl [02 l AcOH acetic acid [ 000 DJUJN OOKDKD OKDOO1 l AlCl3 um chloride [ l BINAP (2,2’-bis(diphenylphosphino)- l ,l ’-binaphthyl) [ l t-BuOK potassium t-butoxide [ 00 W0) 00N3 l tBuONa or t-BuONa sodium t-butoxide [ l br broad [ l BOC tert—butoxy carbonyl [ Cbz benzyloxy carbonyl [ l CDClgCHCl3 chloroform [ l CH2C12 dichloromethane [ [ 0000000 93939393939393 OOOOOO \DOO\]O\mJ> l l CH3CN acetonitrile l CsCO3 cesium carbonate [ 1 0l CH3NO3 nitromethane [ 00000 9393030303 11 l d doublet [ dd doublet of doublets [ l dq doublet of quartets [ l DCE 1,2 dichloroethane [ ﬁ—‘ﬁ—‘ﬁ—‘ﬁ—l (£th l l DCM dichloromethane [031 O\l A heat chemical shift DIEA N,N—diisopropylethylamine (Hunig's base) DMB 2,4 dimethoxy benzyl DMF N,N—Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 deuterated yl sulfoxide EA or EtOAc Ethyl acetate ES electrospray Et3N triethylamine equiv lents g grams h hours H20 water HCl hydrogen chloride or hydrochloric acid HPLC High performance liquid chromatography Hz Hertz IPA isopropyl alcohol i-PrOH isopropyl alcohol J NMR coupling nt K2CO3 potassium carbonate HI potassium iodide KCN ium cyanide LCMS or LC-MS Liquid chromatography mass spectrum M molar m multiplet milligram megahertz milliliter millimeter millimole molecular ion plus one mass unit mass/charge ratio m-CPBA meta-chloroperbenzoic acid WO 81177 [0351 l MeCN Acetonitrile [ l MeOH methanol [ 000 93939.) mmm hUJN l Mel Methyl iodide [ l min minutes [ l micron [ l Mesyl chloride [ l microwave irradiation [ l normal [ l sodium sulfate [ OOOOOOO 9393939393039.) QQMMMMW M1 l ammonia [ l \aBH(AcO)3 sodium triacetoxyborohydride [ l \ aI sodium iodide [ 00 W0) 00N3 l \a2804 sodium sulfate [ O D.) O\ J;l \H4Cl ammonium chloride [ l \H4HCO3 ammonium onate [ 00 W0) O\O\ QM l nm nanometer [ O D.) O\ \] l \IMP N—methylpyrrolidinone [ l \IMR Nuclear Magnetic Resonance [ l Pd(OAc)2 palladium (II) acetate [ l Pd/C Palladium on carbon [ 0000 93930303 \]\]O\O\ OKDOO1 l Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) [ OO Wu.) \]\1 N3 l PMB para methoxybenzyl [ l ppm parts per million [ l POCl3 phosphoryl chloride [ l prep-HPLC preparative High mance Liquid tography [ l PTSA para-toluenesulfonic acid [ l p-TsOH para-toluenesulfonic acid [ l RT retention time [ [ 0000000 9393939393939.) OO\]\]\]\]\]\] OKDOOﬂQm-b l 11 room temperature l S singlet [ O U.) 00 l l t triplet [ OO WU) 0000 DJNl t-BuXPhos 2-Di-terz‘-butylphosphino-2’, 4’, isopropylbiphenyl [ l TEA Triethylamine [038J;l TFA triﬂuoroacetic acid TfO triﬂate THP tetrahydropyran TsOH tosic acid UV ultraviolet Schemel CI / I (R7 (W )n 8 '38 I \ I? H Moi Rea/N IN\ 0' C1 R9 U (j R? ,R9 R7) M / n DMSO, DIEA /N / N PTSA i- PrOH A1 B1 A D1 Scheme 1 shows the synthesis of N2-phenylpyrimidine-2,4-diamine compounds D1 following a l route. 2,4-Dichloropyrimidine is combined in an organic solvent (6g, DMSO) with a dialkylamine A1 and a base (6. g. DIEA). The resulting 2-chloro- pyrimidine- 4-amine B1 is heated with a substituted aniline C1 and an acid (6g, PTSA) in an c solvent (6. g. and heated to afford the NZ-phenylpyn'midine-ZA-diamine D1. , i-PrOH) Scheme 2 Cl 7 I H2N /51 O N Q— \ N C, I Y or:0/ R7) DMSO, DIEA /N n PTSA, i-PrOH A2 32 A Scheme 2 shows the synthesis of phenylpyrimidine amine compounds D2 following a general route. 2,4-Dichloropyrimidine is combined in an organic solvent (6g, DMSO) with an alcohol A2 and a base (6. g. DIEA). The resulting 2-chloropyrimidine B2 is heated with a substituted e C2 and an acid (6g, PTSA) in an organic solvent (e.g., i- PrOH) and heated to afford the phenylpyrimidine amine D2.

Scheme 3 HZNQR 1. mCPBA R9/N8 "Yb/C PTSA,i-P::H SET);NJGMU.R8R9NH NMP Yj:GR?" Scheme 3 shows the synthesis ofN4-phenylpyrimidine-2,4-diamine compounds D3 following a l route. 2-Chloro(methylthio)pyrimidine A3 is heated in an organic solvent (eg, ) with a substituted aniline B3 and an acid (eg, PTSA). The ing substituted 2-(methylthio)-N-phenylpyrimidinamine C3 is treated with an oxidizing agent (eg, mCPBA), and then heated with an amine (e.g., NHRng) in an c solvent (6g, NMP) to afford the N4-phenylpyrimidine-2,4-diamine D3.

Scheme 4 $2 NGMH J\C| H2N H N OH 9/ POCI3 D4 9,N N N R (:1W? R U 10aw) omso DIEA PTSAi-PrOH / / n A4 E4 Scheme 4 shows the synthesis ofN4-phenylpyrimidine-2,4-diamine compounds E4 ing a general route. 2-Chloropyrimidinol is combined with a primary amine A4 and a base (e.g., DIEA) in an organic solvent (6g, DMSO) to afford 2-aminopyrimidinol B4, which is then treated with a chlorinating agent (6g, phosphoryl chloride). The resulting 4- pyrimidinamine C4 is heated with a substituted aniline D4 and an acid (6.g. , PTSA) in an organic solvent (6. g. to afford the N4-phenylpyrimidine-2,4-diamine E4. , i-PrOH) Scheme 5 (N1 OR7) HZN N /N 9’ Br R Br Pd2(dba)3BlNAP WUH(ER/ DMSO DIEA toluene, tBuONa A5 B5 D5 Scheme 5 shows the synthesis of N2-phenylpyridine-2,4-diamine compounds D5 following a general route. 2-Bromochloropyridine is combined with a primary amine A5 and a base (6g, DIEA) in an organic solvent (6g, DMSO). The resulting 2-bromo-pyridin- 4-amine B5 is coupled with a substituted aniline C5 in an c solvent (6. g. via a , toluene) Buchwald-Hartwig ion employing a catalyst (e.g., Pd2(dba)3), a ligand (e.g., BINAP), and a base (6. g. to afford the N2-phenylpyridine-2,4-diamine D5. , tBuONa) Scheme 6 Cl H / (TL ,N N R9 ‘ \—I(R7)" | H H , /N N R9 N F cs R9 \ \ I | H2N’ (R7) N / / n DMSO, DIEA CI Pd2(dba)3 BINAP e, tBuONa A6 BG D6 Scheme 6 shows the synthesis ofN4-phenylpyridine-2,4-diamine compounds D6 following a general route. 4-Chloroﬂuoropyridine is combined with a primary amine A6 and a base (eg, DIEA) in an organic solvent (eg, DMSO). The resulting 4-chloro-pyridin- 2-amine B6 is coupled with a substituted aniline C6 in an organic solvent (6. g. via a , toluene) Buchwald-Hartwig amination employing a catalyst (e.g., Pd2(dba)3), a ligand (e.g., BINAP), and a base (6. g. to afford the N4-phenylpyridine-2,4-diamine D6. , tBuONa) Scheme7 CI / \N 88 J3+(Rln F58 H R9—N N C I H2N ,N N N 8 CI \ C7 R9 \ \ RNR9 I I I (7 / / / RIn H DMSO, DIEA Pd2(dba)3 BINAP toluene, tBuONa A7 B7 D7 Scheme 7 shows the synthesis of N2-phenylpyridine-2,6-diamine compounds D7 following a general route. 2,6-Dichloropyridine is ed with an amine A7 and a base (6g, DIEA) in an organic solvent (e.g., DMSO). The resulting 6-chloro-pyridinamine B7 is coupled with a substituted aniline C7 in an organic t (eg, toluene) via a Buchwald- Hartwig amination employing a st (6g, Pd2(dba)3), a ligand (6g, BINAP), and a base (6. g. , tBuONa) to afford the N2-phenylpyridine-2,6-diamine D7.

Scheme 8 0R7)" 3 1J6 —B»8 We 1J6PTSA,AiPrOH Scheme 8 shows the synthesis ofN—phenylpyrimidinamine compounds C8 following a general route. 2-Chloro-pyrimidine A8 is heated with a substituted aniline B8 and an acid (e.g., PTSA) in an organic solvent (e.g., i-PrOH) to afford the N- phenylpyrimidinamine C8.

S_cheme9 we JJHwev666' HWJHwev Amination [ RRJJJHwew E9 F9 Scheme 9 shows the synthesis of 2-(alkylaminomethyl)-N—phenylpyrimidinamine compounds F9 following a l route. 4-Chloropyrimidinecarbonitrile A9 is heated with a tuted aniline B9 and an acid (e.g., PTSA) in an organic solvent (e.g., i-PrOH).

The resulting 4-(phenylamino)pyrimidinecarbonitrile C9 is d with a reducing agent (6. g. , Ni) to give the 2-(aminomethyl)-N-phenylpyrimidinamine D9. Reductive amination with a yl compound E9 affords the 2-(alkylamino)methyl)-N— phenylpyrimidinamine F9.

A person of ordinary skill in the art will recognize that in the above schemes the order of many of the steps are interchangeable.

Compounds of the present disclosure inhibit the e methyltransferase activity of G9a, also known as KMTlC (lysine methyltransferase 1C) or EHMT2 (euchromatic histone methyltransferase 2), or a mutant thereof and, accordingly, in one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, es, and disorders in which EHMT2 plays a role. The t disclosure provides methods for treating conditions and diseases the course of which can be inﬂuenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. Modulation of the methylation status of histones can in turn inﬂuence the level of expression of target genes ted by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such ent, a eutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomer thereof.

Unless otherwise stated, any ption of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

In still another aspect, this disclosure relates to a method of modulating the activity of EHMT2, which catalyzes the dimethylation of lysine 9 on histone H3 (H3K9) in a subject in need f. For example, the method comprises the step of administering to a subject having a cancer expressing a mutant EHMT2 a therapeutically effective amount of a compound described herein, wherein the compound(s) inhibits histone methyltransferase activity of EHMT2, thereby treating the cancer.

For example, the EHMT2-mediated cancer is selected from the group consisting of ia, prostate carcinoma, hepatocellular carcinoma, and lung cancer.

For e, the compounds disclosed herein can be used for treating cancer. For example, the cancer is a logical cancer.

For example, the cancer is selected from the group consisting of brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian , pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer. Preferably, a subject in need thereof is one who had, is having or is predisposed to developing brain and CNS cancer, kidney , ovarian cancer, pancreatic cancer, leukemia, ma, myeloma, and/or sarcoma. ary brain and central CNS cancer includes medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, astoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma.

Exemplary ovarian cancer es ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serous adenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor. Exemplary sarcoma includes chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise speciﬁed (NOS) sarcoma. Alternatively, cancers to be treated by the compounds of the present invention are non NHL cancers.

For example, the cancer is selected from the group consisting of acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), oblastoma, endroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serous arcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, osarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, intestinal stromal tumor, osteosarcoma, myosarcoma, and not ise ed (NOS) sarcoma. Preferably, the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), medulloblastoma, n clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, d plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epithelioid sarcoma, renal ary carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma.

For example, the EHMT2-mediated er is a hematological disorder.

The compound(s) of the present sure inhibit the histone methyltransferase activity of EHMT2 or a mutant thereof and, accordingly, the present sure also provides methods for treating conditions and diseases the course of which can be ced by modulating the methylation status of es or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. In one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders. Modulation of the methylation status of histones can in turn inﬂuence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the t disclosure.

As used herein, a "subject" is interchangeable with a "subject in need thereof", both of which refer to a subject having a disorder in which EHMT2-mediated protein methylation plays a part, or a subject having an increased risk of developing such disorder relative to the population at large. A "subject" es a mammal. The mammal can be e. g. a human or appropriate man mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having cancer or a precancerous condition. A subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition.

Alternatively, a t in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (lie. a subject who is predisposed to developing such disorder relative to the population at large). A t in need thereof can have a precancerous condition. A t in need thereof can have refractory or resistant cancer (i.e., cancer that doesn't respond or hasn’t yet responded to ent). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has cancer recurrence following remission on most recent therapy. In some embodiments, the t in need thereof received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In a preferred embodiment, the subject has cancer or a cancerous condition. For example, the cancer is leukemia, te carcinoma, hepatocellular oma, and lung cancer.

As used herein, "candidate compound" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, that has been or will be tested in one or more in vitro or in viva biological assays, in order to determine if that compound is likely to elicit a desired biological or medical response in a cell, , system, animal or human that is being sought by a researcher or clinician. A candidate nd is a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof. The biological or medical response can be the treatment of cancer. The ical or l response can be treatment or prevention of a cell proliferative disorder. The ical response or effect can also include a change in cell proliferation or growth that occurs in vitro or in an animal model, as well as other biological changes that are able in vitro. In vitro or in viva biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic ty shift , reporter gene assays, in vitro cell viability assays, and the assays described herein.

For example, an in vitro biological assay that can be used includes the steps of (1) mixing a histone substrate (e. g., an isolated histone sample or an isolated histone peptide representative of human histone H3 residues 1-15) with recombinant EHMT2 enzymes, (2) adding a compound of the disclosure to this mixture, (3) adding non-radioactive and 3H- labeled S-Adenosyl methionine (SAM) to start the reaction, (4) adding excessive amount of non-radioactive SAM to stop the reaction, (4) g off the free corporated 3H- SAM, and (5) detecting the ty of 3H-labeled histone substrate by any methods known in the art (e. g. a PerkinElmer TopCount plate reader).

For example, an in vitro study that can be used includes the steps of (1) treating cancer cells (e. g., breast cancer cells) with a compound of this disclosure, (2) ting the cells for a set period of time, (3) ﬁxing the cells, (4) treating the cells with primary antibodies that bind to dimethylated histone substrates, (5) treating the cells with a secondary antibody (e. g. an antibody conjugated to an infrared dye), (6) ing the quantity of bound antibody by any methods known in the art (e.g., by a Licor Odyssey Infrared Scanner).

As used herein, "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a ceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a e, condition or disorder, or to eliminate the disease, condition or er. The term "treat" can also include treatment of a cell in vitro or an animal model.

A compound of the present disclosure, or a pharmaceutically acceptable salt, rph or solvate thereof, can or may also be used to prevent a relevant disease, ion or disorder, or used to identify le candidates for such purposes. As used herein, nting, 7) ccprevent," or "protecting against" describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

One skilled in the art may refer to general reference texts for detailed descriptions of known ques sed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005), Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd n), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000), Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y., Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y., Fingl et al. , The Pharmacological Basis of Therapeutics (1975), Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

As used herein, "combination therapy" or "co-therapy" includes the stration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a c treatment regimen intended to e the ial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, cokinetic or codynamic co-action resulting from the combination of therapeutic .

The present disclosure also provides pharmaceutical compositions comprising a compound of any of the Formulae described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

A "pharmaceutical composition" is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol r or a vial. The quantity of active ingredient (e. g. a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an ive amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the l or ermal administration of a compound of this disclosure include powders, , ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a ceutically able r, and with any preservatives, buffers, or propellants that are required.

As used , the phrase "pharmaceutically acceptable" refers to those nds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable ent" means an ent that is useful in preparing a pharmaceutical composition that is generally safe, xic and neither ically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the speciﬁcation and claims includes both one and more than one such excipient.

A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include eral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, ﬁxed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or ates, and agents for the adjustment of ty such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or c.

A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.

For example, for treatment of cancers, a nd of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

The term "therapeutically effective amount", as used , refers to an amount of a pharmaceutical agent to treat, rate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or tory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subj ect’s body weight, size, and , the nature and extent of the condition, and the therapeutic or combination of therapeutics selected for stration. Therapeutically ive amounts for a given situation can be determined by e experimentation that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another , the disease or condition to be d is a cell proliferative er.

For any compound, the therapeutically ive amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the riate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LDSO/EDSO. ceutical compositions that exhibit large therapeutic s are preferred.

The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be stered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The pharmaceutical compositions containing active compounds of the present sure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, fying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be ated in a conventional manner using one or more ceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of , the appropriate formulation is dependent upon the route of administration chosen.

Pharmaceutical compositions suitable for inj e use e sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile inj ectable solutions or dispersion. For intravenous stration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be ﬂuid to the extent that easy syringeability exists. It must be stable under the conditions of cture and storage and must be preserved against the inating action of microorganisms such as bacteria and fungi. The r can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, ol, propylene , and liquid hylene glycol, and the like), and suitable mixtures thereof.

The proper y can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for e, parabens, chlorobutanol, , ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include ic , for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the inj ectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile inj ectable solutions can be prepared by orating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic sion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile inj ectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional d ingredient from a previously sterile-filtered solution thereof Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in n capsules or compressed into s. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a ﬂuid carrier for use as a mouthwash, wherein the compound in the ﬂuid carrier is applied orally and d and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a r nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin, an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch, a lubricant such as magnesium stearate or WO 81177 Sterotes, a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin, or a ﬂavoring agent such as mint, methyl salicylate, or orange ﬂavoring.

For stration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For ucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled e ation, including implants and microencapsulated ry systems.

Biodegradable, biocompatible polymers can be used, such as ethylene vinyl e, polyanhydrides, polyglycolic acid, collagen, thoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The als can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.

Liposomal suspensions ding liposomes ed to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary s for the t to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

The specification for the dosage unit forms of the disclosure are dictated by and ly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary ing on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or WO 81177 practitioner administering the therapy, among other factors affecting the selected dosage.

Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably g complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day, about 0.1 mg/day to about 25 g/day, about 0.1 mg/day to about 10 g/day, about 0.1 mg to about 3 g/day, or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient’s weight in kg, body surface area in m2, and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other ied observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. se in the diameter of a tumor indicates regression. sion is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term "dosage effective manner" refers to amount of an active compound to produce the d biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The compounds of the present disclosure are capable of further forming salts. All of these forms are also contemplated within the scope of the claimed disclosure.

As used herein, "pharmaceutically acceptable salts" refer to tives of the compounds of the present disclosure wherein the parent compound is ed by making acid or base salts f Examples of pharmaceutically acceptable salts include, but are not limited to, l or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not d to, those derived from inorganic and organic acids ed from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane onic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, lyarsanilic, hexylresorcinic, hydrabamic, romic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, lic, stearic, subacetic, succinic, sulfamic, sulfanilic, ic, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, ic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octenecarboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or nates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N—methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1,1:2, or 1:3.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or l forms (polymorphs) as deﬁned herein, of the same salt.

The nds of the present disclosure can also be prepared as esters, for example, pharmaceutically acceptable esters. For e, a carboxylic acid function group in a compound can be converted to its ponding ester, e.g., a methyl, ethyl or other ester.

Also, an alcohol group in a compound can be converted to its corresponding ester, 6. g. , acetate, propionate or other ester.

The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intrapeIitoneally, aneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally.

One skilled in the art will recognize the advantages of certain routes of administration.

The dosage regimen utilizing the nds is selected in accordance with a variety of factors including type, s, age, weight, sex and medical condition of the t, the severity of the condition to be d, the route of administration, the renal and hepatic function of the t, and the particular compound or salt thereof ed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice ofPharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described , and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically able carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

All percentages and ratios used herein, unless otherwise indicated, are by weight.

Other es and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present sure. The examples do not limit the d disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

In the synthetic schemes bed herein, compounds may be drawn with one particular configuration for simplicity. Such ular configurations are not to be construed as ng the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of s, tautomers, regioisomers or stereoisomers, however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, somer or stereoisomer. nds designed, selected and/or optimized by s described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional , including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up is using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for ming high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and US. Patent No. 5,763,263. hroughput assays can use one or more different assay ques including, but not limited to, those described below.

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was ically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it tute any admission as to the contents or date of the same. The invention having now been bed by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for es of illustration and not limitation of the claims that follow.

Example 1: Synthesis of Compound 1 Synthesis of Nz-(4-methoxy(3—(pyrrolidinyl)pr0p0xy)phenyl)—N4- methylpyrimidine—2,4-diamine: N \ /NH2 HCI (:1 N/ ch03 DMF CTJH\ 0""mePTSA, i-PrOH JEN/T"UZWD Step 1: Synthesis of 2--chloro-N-methylpyrimidin--amine: Into a 50-mL round-bottom ﬂask, was placed 2,4-dichloropyrimidine (1.1 g, 7.38 mmol, 1.00 equiv.), methanamine hydrochloride (498 mg, 7.38 mmol, 1.00 equiv.), potassium carbonate (3.07 g, 22.21 mmol, 3.00 equiv), N,N—dimethylformamide (10 mL).

The resulting on was stirred for 18 h at 20 0C. The resulting solution was diluted with 60 mL of H20. The resulting solution was extracted with 3x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 0.67 g (63%) of 2-chloro-N- methylpyrimidinamine as a white solid.

Step 2: Synthesis of methoxy(3-(pyrrolidin-l-yl)propoxy)phenyl)-N4- pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methylpyrimidinamine (200 mg, 1.39 mmol, 1.00 equiv.), 4-methoxy[3-(pyrrolidin-l-yl)propoxy]aniline (350 mg, 1.40 mmol, 1.00 equiv.), 4-methylbenzene-l-sulfonic acid (476 mg, 2.76 mmol, 2.00 equiv.), isopropanol (10 mL). The resulting solution was stirred for 3 h at 85 0C. The resulting mixture was concentrated under . The residue was applied onto a silica gel column WO 81177 with ACN/HZO (1/5). This resulted in 66.3 mg (13%) of 2-N-[4-meth0xy[3-(pyrrolidin yl)pr0p0xy]phenyl]N-methylpyrimidine-2,4-diamine as a pink solid.

Example 2: Synthesis of Compound 2 Synthesis ofN4-((1-(2,2-diﬂuoroethyl)piperidinyl)methyl)-N2-(4-methoxy (3-(pyrrolidinyl)propoxy)phenyl)pyrimidine-2,4—diamine: / N II I < F NH FT53-0 F N \ J\ TFA, DCM H N F N N c[ —, N CIYN\ "VG/Y H CIYN\ Boom NIJ DIEA, CH3CN, rt, 2h NIJ TSOH, i-PrOH, 90°C, 2h Step 1: Synthesis of 2-chlor0-N-(piperidinylmethyl)pyrimidinamine: Into a 50-mL 3-necked round-bottom ﬂask, was placed tert—butyl 4-[[(2- chloropyrimidinyl)amino]methyl]piperidinecarb0xylate (1.1 g, 3.37 mmol, 1.00 equiv.), triﬂuoroacetic acid (3 mL), dichloromethane (10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash tography with HZO/MeCN/NH4HC03. This ed in 1.5 g (crude) of 2-chloro-N-(piperidinylmethyl)pyrimidinamine as an off-white solid.

Step 2: Synthesis of 2-chlor0-N-((1-(2,2-diﬂuoroethyl)piperidin yl)methyl)pyrimidinamine: Into a 100-mL 3-necked round-bottom ﬂask, was placed 2-ch10r0-N-(piperidin ylmethyl)pyrimidinamine (1.5 g, 6.62 mmol, 1.00 equiv.), 2,2-diﬂu0r0ethyl triﬂuoromethanesulfonate (1.56 g, 7.29 mmol, 1.10 equiv), DIEA (1.7 g, 2.00 equiv), MeCN (20 mL). The resulting solution was stirred for 2 h at room temperature. The ing mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography.

This resulted in 1.1 g (57%) of 2-chlor0-N-[[1-(2,2-diﬂuor0ethyl)piperidin yl]methy1]py1imidinamine as a yellow solid.

Step 3: Synthesis 0fN4-((1-(2,2-diﬂu0r0ethyl)piperidiny1)methyl)-N2-(4- y(3-(pyrr01idinyl)pr0poxy)phenyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-ch10r0-N—[[1-(2,2- diﬂuoroethyl)piperidinyl]methyl]pyrimidinamine (291 mg, 1.00 mmol, 1.00 ), 4- methoxy[3-(pyrr01idinyl)pr0p0xy]aniline (250 g, 998.66 mmol, 1.00 equiv.), TsOH~H20 (380 mg, 2.00 mmol, 2.00 equiv.), isopropanol (5 mL). The resulting solution was stirred for 5 h at 90°C in an oil bath. The resulting e was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC. This resulted in 144.1 mg (29%) of -N-[[1-(2,2-diﬂuoroethyl)piperidinyl]methyl]N-[4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]pyrimidine-2,4-diamine as a white solid.

Example 3: Synthesis of Compound 3 Synthesis Nz-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4-((tetrahydr0- 2H-pyran-4—yl)methyl)pyrimidine-2,4-diamine: N\/\/Cl O‘K/VOHCI \O/Q/NOZ N02 C Pd/C,MeOH K2003 KI DMF NWOUNHZ o o 100 00 20h | | QWO .NH2 N Cl H 0 Cl Cl N HQ \f \ 2 \f \ | N / K2003,DMF N / PTSA,i-PrOH Step 1: Synthesis of 1-(3-(2-methoxynitrophenoxy)propyl)pyrrolidine: Into a 250-mL bottom ﬂask, was placed 2-methoxynitrophenol (10 g, 59.12 mmol, 1.00 equiv.), hloropropyl)pyrrolidine hydrochloride (10.8 g, 58.66 mmol, 1.00 equiv.), CszC03 (58 g, 178.01 mmol, 3.00 equiv.), NaI (8.9 g, 1.00 equiv.), N,N— dimethylformamide (100 mL). The resulting solution was stirred for 2 h at 110 0C. The resulting solution was diluted with 300 mL of H20. The ing solution was extracted with 3x400 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5x400 mL of brine. The ing mixture was concentrated under vacuum. This resulted in 14 g (84%) of 1-[3-(2-methoxynitrophenoxy)propyl] pyrrolidine as ayellow solid.

Step 2: Synthesis of 4-methoxy(3-(pyrrolidinyl)propoxy)aniline: Into a 250-mL round-bottom ﬂask, was placed 1-[3-(2-methoxy nitrophenoxy)propyl]pyrrolidine (14 g, 49.94 mmol, 1.00 equiv.), methanol (100 mL), ium carbon (2 g). The mixture underwent three hydrogen/air exchange cycles. The resulting solution was stirred for 15 h at 20 0C. The solids were ﬁltered out. The resulting WO 81177 mixture was concentrated under vacuum. This ed in 12.1 g (97%) of 4-methoxy[3- (pyrrolidinyl)propoxy]aniline as brown oil.

Step 3: Synthesis of 2-chloro-N-((tetrahydro-2H-pyranyl)methyl)pyrimidin amine: Into a 25-mL round-bottom ﬂask, was placed 2,4-dichloropy1imidine (500 mg, 3.36 mmol, 1.00 equiv.), oxanylmethanamine (389 mg, 3.38 mmol, 1.00 equiv.), potassium carbonate (932 mg, 6.74 mmol, 2.00 equiv.), N,N-dimethylformamide (3 mL). The resulting solution was stirred for 1 h at 20 0C. The solids were ﬁltered out. The residue was applied onto a silica gel column with ACN/HzO (1/5). This resulted in 0.44 g (58%) of 2-chloro-N- (oxanylmethyl)pyn'midinamine as a white solid.

Step 4: sis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- ((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-(oxan ylmethyl)py1imidinamine (150 mg, 0.66 mmol, 1.00 equiv.), 1-methanesulfonyl methylbenzene (181 mg, 1.06 mmol, 1.10 equiv.), 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (566 mg, 2.26 mmol, 5.00 equiv.), isopropanol (5 mL). The resulting on was stirred for 12 h at 85 0C in an oil bath. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers ed and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was puriﬁed by Flash- Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel, mobile phase, CH3CN/HzO(0.05%NH3.H20)=17% increasing to HZO(0.05%NH3.H20)=30% within 10 min, Detector, UV 254 nm. This resulted in 116 mg (40%) of -methoxy[3-(pyrrolidinyl)propoxy]phenyl]N-(oxan ylmethyl)py1imidine-2,4-diamine as a white solid.

Example 4: Synthesis of Compound 4 Synthesis of Nz-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4-((1-(2,2,2- triﬂuoroethyl)piperidinyl)methyl)pyrimidine-2,4-diamine: F /\ GWOUNYN\ N\/©NH F H H FVK/OTf GWO H 'J — DNYN\ N N / DMF N /'J (I) (I) Into a 8-mL Vial, was placed 2-N-[4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]- 4-N-(piperidinylmethyl)pyIimidine-2,4-diamine (250 mg, 0.57 mmol, 1.00 equiv.), 2,2,2- triﬂuoroethyl triﬂuoromethanesulfonate (197 mg, 0.85 mmol, 1.50 equiv.), N,N— dimethylformamide (3 mL). The resulting solution was stirred for overnight at room temperature. After concentration, the residue was d by ﬂash chromatography with HzO/MeCN/NH4HC03. This resulted in 77.6 mg (26%) of 2-N-[4-methoxy[3-(pyrrolidin- 1-yl)propoxy] phenyl] N- [ [1 -(2,2,2-triﬂuoroethyl)piperidin-yl]methyl] dine-2,4- diamine as a white solid.

Example 5: Synthesis of Compound 5 Synthesis of Nz-(4-meth0xy(3-(pyrrolidinyl)pr0poxy)phenyl)—N4- (tetrahydr0-2H-pyran-4—yl)pyrimidine-2,4-diamine: U" H CI N N 0""er elm/M CI 0 \Nlrj \Q) o N / K2C03,DMF,rt,1h p-TosOH, i-PrOH, 85 0c. 24h Ox: 0 H N H I j NIJ/ o Step 1: Synthesis of 2-chloro-N-(tetrahydro-2H-pyranyl)pyrimidinamine: Into a 50-mL round-bottom ﬂask, was placed 2,4-dichloropyrimidine (500 mg, 3.36 mmol, 1.00 equiv.), oxanamine (341.2 mg, 3.37 mmol, 1.00 equiv.), potassium ate (932.4 mg, 6.75 mmol, 2.00 equiv.), N,N—dimethylformamide (3 mL). The resulting on was stirred for 1 h at 20 0C. The solids were d out. The e was applied onto a silica gel column with dichloromethane/methanol (4:1). This resulted in 250 mg (35%) of 2-chloro- N—(oxanyl)pyrimidinamine as a white solid.

Step 2: sis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- (tetrahydro-2H-pyranyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-(oxanyl)pyrimidin amine (150 mg, 0.70 mmol, 1.00 equiv.), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (192 mg, 0.77 mmol, 1.10 equiv.), 4-methylbenzenesulfonic acid (603 mg, 3.50 mmol, .00 equiv.), i-prOH (5 mL). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The resulting solution was extracted with 3X30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum.

The crude product was puriﬁed by Prep-HPLC with the following conditions : Column: X Bridge RP, 19*150 mm, 5 um, Mobile Phase r/10mmol NH4HCO3 Mobile Phase B: ACN, Flow rate: 30 mL/min, nt: 16%B to 45%B in 10 min, 254nm.This resulted in 51.8 mg (17%) of 2-N-[4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]N-(oxan yl)pyrimidine-2,4-diamine as a white solid.

Example 6: Synthesis of Compound 6 Synthesis 0fN4-(tert-butyl)-N2-(4-meth0xy(3-(pyrrolidin yl)propoxy)phenyl)pyrimidine-2,4—diamine: CI /N CI N\ H HZN CIYNI N7< > Step 2: Synthesis ofN4-(tert-butyl)-N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)pyrimidine-2,4-diamine: Into a 25-mL round-bottom ﬂask, was placed N—tert—butylchloropyrimidin amine (200 mg, 1.08 mmol, 1.00 equiv.), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (325 mg, 1.30 mmol, 1.21 equiv.), TsOH (185.7 mg, 1.08 mol, 1 equiv.), isopropanol (2 mL).

The resulting solution was d for 3 h at 85 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC with the following ions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5um, 19*150mm, mobile phase, Waters (0.05%HCl) and ACN (5.0% ACN up to 15.0% in 6 min), Detector, UV 220nm. This resulted in 82.6 mg (18%) of rt-butylN—[4-methoxy[3-(pyrrolidin- 1-yl)propoxy]phenyl]pyrimidine-2,4-diamine hydrochloride as a brown solid.

Example 7: Synthesis of Compound 7 Synthesis of tert-butyl 4-(((4-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)pyrimidinyl)amino)methyl)piperidinecarboxylate: "(j 0"V H O NH? o\/ H /SYN\ N 0WD MCPBA,DCM IJ @ :3 N N I Y \ OWN \SJxN/ —> —>o I TsOH, IPA, 80 00, 5h N / O/ N / O/ Boo-ND—x HN BOC‘N H NH2 O\/H H HCI (6N), MeOH NO — H YN\ N OWN13— NMP, 150 °C | NYE/NﬂowN / O/ N / O/ Step 1: Synthesis ofN—(4-methoxy(3-(pyrr01idiny1)pr0p0xy)phenyl) (methylthio)pyrimidinamine: Into a 50-mL ed round-bottom ﬂask, was placed 4-meth0xy[3-(pyrrolidin- 1-y1)pr0p0xy]ani1ine (1 g, 3.99 mmol, 1.00 equiv), 4-ch1oro(methy1sulfanyl)pyrimidine (640 mg, 3.98 mmol, 1.00 equiv), TsOH~H20 (1.52 g, 2.00 , isopropanol (10 mL).

The resulting solution was stirred for 3 h at 70 0C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with HzO/MeCN. This resulted in 950 mg (64%) of eth0xy[3-(pyrr01idin yl)propoxy]phenyl](methylsulfanyl)pyrimidinamine as a black solid.

Step 2: Synthesis ofN—(4-methoxy(3-(pyrr01idiny1)pr0p0xy)phenyl) lsulfonyl)pyrimidinamine: Into a 50-mL 3-necked round-bottom ﬂask, was placed N-[4-meth0xy[3- (pyrrolidiny1)pr0p0xy]phenyl](methylsulfany1)pyrimidinamine (800 mg, 2.14 mmol, 1.00 equiv), mCPBA (736 mg, 4.27 mmol, 2.00 equiv), dichloromethane (10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with ZO. This resulted in 500 mg (58%) of 2-methanesulfonyl-N—[4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]pyrimidinamine as a dark red solid.

Step 3: Synthesis of tert-butyl 4-(((4-((4-methoxy(3-(pyrrolidin y1)pr0poxy)phenyl)amin0)pyrimidiny1)amino)methyl)piperidinecarb0xy1ate: Into a 10-mL sealed tube, was placed 2-methanesulf0ny1-N—[4-meth0xy[3- (pyrrolidinyl)pr0poxy]phenyl]pyrimidinamine (200 mg, 0.49 mmol, 1.00 equiv), tert- butyl 4-(amin0methy1)piperidinecarb0xylate (115.7 mg, 0.54 mmol, 1.10 equiv), NMP (2 mL). The resulting solution was stirred for overnight at 150°C in an oil bath. The residue was puriﬁed by ﬂash chromatography with HZO/MeCN. This resulted in 130 mg (49%) of tertbutyl 4-([[4-([4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]amino)pyrimidin yl]amino]methyl)piperidinecarboxylate as yellow oil.

Step 4: sis of tert-butyl 4-(((4-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)pyrimidinyl)amino)methyl)piperidinecarboxylate: Into a 10-mL sealed tube, was placed tert-butyl -([4-methoxy[3-(pyrrolidin- 1-yl)propoxy] phenyl] amino)pyrimidinyl] amino] methyl)piperidine-1 -carboxylate (13 0 mg, 0.24 mmol, 1.00 equiv.), hydrogen chloride (6N, 0.5 mL), methanol (0.5 mL). The resulting solution was d for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The e was puriﬁed by Prep-HPLC with the following conditions (2#- AnalyseHPLC-SHIMADZU (HPLC-10)): Column, t CSH Prep C18 OBD Column, 5um, 19*150mm, mobile phase, Waters (0.05%HCl) and ACN (3.0% ACN up to 15.0% in 6 min), Detector, UV 220nm. This resulted in 9.9 mg (9%) of 4-N-[4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]N-(piperidinylmethyl)pyrimidine-2,4-diamine hloride as an off-white solid.

Example 8: Synthesis of Compound 8 Synthesis of 1-(4-(((2-((4-chloro(3-(pyrrolidin yl)propoxy)phenyl)amino)pyrimidin-4—yl)amino)methyl)piperidinyl)ethan0ne: OZNOOH 052003 02N 0WD H2N Fe, NH4CI 0WD Nal, DMF Cl Cl Cl )Lby" O N\ CI )L L]: OVH H N NYN OWNO i—PrOH, PTSA LN Um Step 1: Synthesis of 1-(3-(2-chloronitrophenoxy)propyl)pyrrolidine: Into a 50-mL round-bottom ﬂask, was placed 2-chloronitrophenol (1 g, 5.76 mmol, 1.00 equiv.), N,N—dimethylformamide (10 mL), Cs2CO3 (5.6 g, 17.13 mmol, 3.00 equiv.), NaI (867 mg, 5.78 mmol, 1.00 equiv.), 1-(3-chloropropyl) pyrrolidine (1.1 g, 7.45 mmol, 1.00 equiv.). The resulting solution was stirred for 2 h at 110 0C in an oil bath. The reaction was ed by the on of water/ice. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The ing mixture was washed with 2x10 mL of Brine, drying with Na2S04.The resulting mixture was trated under vacuum. This resulted in 1.3 g (79%) of 1-[3-(2-chloronitrophenoxy)propyl] pyrrolidine as a yellow solid.

Step 2: Synthesis of 4-chloro(3-(pyrrolidinyl)propoxy)aniline: Into a 100-mL round-bottom ﬂask, was placed 2-chloro nitrophenoxy)propyl] pyrrolidine (900 mg, 3.16 mmol, 1.00 equiv.), methanol (20 mL), Fe (530.5 mg, 9.47 mmol, 3.00 equiv.), NH4Cl (502 mg, 9.38 mmol, 3.00 equiv.), water(1 mL).

The ing solution was stirred for 12 h at 100 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The e was applied onto a silica gel column with CH3CN/HzO (1:19). The collected fractions were combined and concentrated under vacuum. This resulted in 420 mg (52%) of 4-chloro[3-(pyrrolidin yl)propoxy]aniline as yellow oil.

Step 3: Synthesis of 1-(4-(((2-((4-chloro(3-(pyrrolidin yl)propoxy)phenyl)amino)pyrimidinyl)amino)methyl)piperidinyl)ethanone: Into a 10-mL sealed tube, was placed 4-chloro[3-(pyrrolidinyl)propoxy]aniline (400 mg, 1.57 mmol,1.00 equiv.), PTSA (541.7 mg, 3.15 mmol, 2.00 equiv.), 1-(4-[(2- chloropyrimidinyl)amino]methylpiperidinyl)ethanone (422 mg, 1.57 mmol, 1.00 equiv), isopropanol (5 mL). The resulting on was stirred for 10 h at 85°C in an oil bath.

The ing mixture was concentrated under vacuum. The crude t (150 mg) was puriﬁed by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, C18 silica gel, mobile phase, CH3CN/HzO(0.05%NH3.H20)=15% increasing to CH3CN/HZO(0.05%NH3.H20)=85% within 7 min, Detector, UV 254 nm. 78.3 mg product was obtained. This resulted in 78.3 mg (10%) of 1-[4-([[2-([4-chloro[3-(pyrrolidin yl)propoxy]phenyl]amino)pyrimidinyl]amino]methyl)piperidinyl]ethanone as a white solid.

Example 9: Synthesis of Compound 9 Synthesis of 2-((4-methoxy-3—(3-(pyrrolidinyl)propoxy)phenyl)amino)—N- methylpyrimidine—S-carboxamide: N/YkOH N/jim /NH2 CIA DCM DMF CIA TEA, DCM | H Step 1: Synthesis of 2-chloropyrimidinecarbonyl chloride: Into a 100-mL round-bottom ﬂask, was placed 2-chloropyrimidinecarboxylic acid (1 g, 6.31 mmol, 1.00 , dichloromethane (20 mL), N,N-dimethylformamide (0.2 mL).

This was followed by the addition of oxalic dichloride (1.2 g, 9.45 mmol, 1.50 equiv.) dropwise with ng at 0 0C. The resulting solution was stirred for 2 h at 20 0C. The resulting mixture was concentrated under vacuum. This resulted in 1.11 g (99%) of 2- pyrimidinecarbonyl chloride as a yellow solid.

Step 2: sis of 2-chloro-N-methylpyrimidinecarboxamide: Into a 100-mL round-bottom ﬂask, was placed methanamine hydrochloride (509 mg, 7.54 mmol, 1.20 equiv), romethane (20 mL), TEA (1.92 g, 18.97 mmol, 3.00 equiv.) This was followed by the addition of 2-chloropyrimidinecarbonyl chloride (1.11 g, 6.27 mmol, 1.00 equiv.) dropwise with stirring at 0 0C. The resulting solution was stirred for 2 h at 0C. The e was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :3). This resulted in 760 mg (71%) of 2-chloro-N-methylpyrimidinecarboxamide as a light yellow solid.

Step 3: Synthesis of 2-((4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)amino)-N- methylpyrimidine—5-carboxamide: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methylpyrimidine carboxamide (750 mg, 4.37 mmol, 1.00 equiv), 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (1.09 g, 4.35 mmol, 1.00 equiv), TsOH (2.24 g, 13.18 mmol, 3.00 equiv), isopropanol (10 mL). The resulting solution was stirred for 3 h at 85 0C in an oil bath.

The crude product was puriﬁed by Prep-HPLC with the following conditions (2#- AnalyseHPLC-SHIMADZU(HPLC-10)): Column, e Prep C18 OBD Column, 19X150mm 5um, mobile phase, Waters(0.05%NH3H20) and ACN (10.0% ACN up to 35.0% in 9 min), Detector, UV 220254nm. This resulted in 24.4 mg (1%) of 2-([4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]amino)-N-methylpyrimidinecarboxamide as an off-white solid.

Example 10: Synthesis of Compound 10 Synthesis of Nz-(4-methoxy(3—(pyrrolidinyl)pr0poxy)phenyl)-N4-(piperidin- 4-ylmethyl)pyridine-2,4-diamine: NH2 N \ ’\/\ D O NHZ N \ 3°C'N:>_’ Q G | ————————————> Br N ________, / H Br C] TEA, DMSO, N Pd(dba)3, BINAP, microwave Boc t-BuONa,toulene "I; 13L| . | NMO / HCI/dloxane / N N NMO"1)DN N H H ' H H N NH Step 1: Synthesis of tert-butyl 4-(((2-bromopyridinyl)amino)methyl)piperidine carboxylate: Into a 20-mL sealed tube, was placed 2-bromochloropyridine (1 g, 5.20 mmol, 1.00 equiv.), tert-butyl 4-(aminomethyl)cyclohexanecarboxylate (1.4 g, 6.56 mmol, 1.20 equiv.), TEA (1.1 g, 10.87 mmol, 2.00 equiv.), DMSO (10 mL). The ﬁnal reaction e was irradiated with microwave radiation for 1 h at 120 0C. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 510 mg (27%) of tert-butyl -bromopyridin yl)amino]methyl]cyclohexanecarboxylate as a light yellow solid.

Step 2: Synthesis of tert-butyl 4-(((2-((4-methoxy(3-(pyrrolidin poxy)phenyl)amino)pyridinyl)amino)methyl)piperidinecarboxylate: Into a 50-mL 3-necked bottom ﬂask, was placed tert—butyl 4-[[(2- bromopyridinyl)amino]methyl]piperidinecarboxylate (510 mg, 1.38 mmol, 1.00 ), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (346 mg, 1.38 mmol, 1.00 equiv.), a)3CHCl3 (127 mg, 0.14 mmol, 0.10 equiv.), BINAP (172 mg, 0.28 mmol, 0.20 equiv.), t-BuONa (265 mg, 2.76 mmol, 2.00 equiv.), toluene (10 mL). The resulting solution was stirred for 3 h at 85 0C in an oil bath. The ing solution was extracted with 3x50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with HZO/MeCN. This resulted in 410 mg (55%) of tert-butyl 4-([[2-([4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]amino)pyridin- 4-yl]amino]methyl)piperidinecarboxylate as a light yellow solid.

Step 3: Synthesis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- (piperidinylmethyl)pyridine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed tert-butyl 4-([[2-([4-methoxy[3- (pyrrolidinyl)propoxy]phenyl] pyridinyl] amino] methyl)piperidine-1 -carboxylate (390 mg, 0.72 mmol, 1.00 equiv), dioxane (4 mL), hydrogen chloride (2 mL). The resulting on was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 9 with potassium carbonate (1 mol/L). The crude product was d by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column: X Bridge RP, 19*150 mm, 5 um, Mobile Phase A:Water/10mmol NH4HCO3 Mobile Phase B: ACN, Flow rate: 30 mL/min, Gradient: 10%B to 40%B in 10 min, 254nm.This resulted in 28.6 mg (9%) of 2-N-[4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]N-(piperidinylmethyl)pyridine-2,4-diamine as a brown solid.

Example 11: Synthesis of Compound 11 Synthesis of N4-(4-methoxy(3—(pyrrolidinyl)pr0poxy)phenyl)-N2-(piperidin- 4-ylmethyl)pyridine—2,4-diamine: ,0: C nil/\NHZ N \ @MO NH2 Nl \ / —’ N Br F Br Et3N,DMSO,120°c, 0AH Pd2(dba)3,B|NAP, MW 1h Boc/ t-BuONa, e Step 1: Synthesis of tert-butyl 4-(((4-bromopyridinyl)amino)methyl)piperidine ylate: Into a 25-mL sealed tube, was placed tert-butyl 4-(aminomethyl)piperidine carboxylate (500 mg, 2.33 mmol, 1.00 equiv), 4-bromoﬂuoropyridine (727 mg, 4.13 mmol, 1.00 equiv), DMSO (8 mL), triethylamine (687 mg, 6.79 mmol, 2.0 equiv). The ﬁnal reaction mixture was ated with microwave radiation for 1 h at 120 0C. The reaction mixture was cooled to 20 degree C. The resulting solution was d with 30 mL of H20.

The resulting on was extracted with 3x30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium e. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with CN (1-0). This resulted in 400 mg (47%) of 2-chloro-N-[4-methoxy [3-(pyrrolidinyl)propoxy]phenyl]pyridinamine as a solid.

Step 2: Synthesis of tert-butyl 4-(((4-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)pyridinyl)amino)methyl)piperidinecarboxylate: Into a 50-mL round-bottom ﬂask, was placed oxy[3-(pyrrolidin yl)propoxy]aniline (270 mg, 1.08 mmol, 1.00 ), tert-butyl 4-[[(4-bromopyridin yl)amino]methyl]piperidinecarboxylate (400 mg, 1.08 mmol, 1.00 equiv.), BINAP (135 mg, 0.22 mmol, 0.20 equiv.), t-BuONa (201 mg, 2.09 mmol, 2.00 equiv.), Pd2(dba)3CHC13 (112 mg, 0.11 mmol, 0.10 equiv.), e. The resulting solution was stirred for 2.5 h at 85 0C in an oil bath. The reaction mixture was cooled to 20 degree C. The resulting solution was d with 20 mL of H20. The resulting solution was ted with 3X15 mL of dichloromethane and the organic layers ed and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with HzO/MeCN (3/1). This resulted in 320 mg (55%) of tert-butyl 4-([[4-([4-methoxy[3- (pyrrolidinyl)propoxy] phenyl] amino)pyridinyl] amino] )piperidine-1 -carboxylate as a solid.

Step 3: sis of N4-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N2- (piperidinylmethyl)pyridine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed tert-butyl 4-([[4-([4-methoxy[3- (pyrrolidinyl)propoxy] phenyl] amino)pyridinyl] amino] methyl)piperidine-1 -carboxylate (300 mg, 0.56 mmol, 1.00 equiv.), dioxane (15 mL), hydrogen chloride/dioxane (15 mL). The resulting solution was stirred for 16 h at 20 0C. The resulting mixture was trated under vacuum. The pH value of the solution was adjusted to 8-9 with potassium carbonate. The residue was applied onto a silica gel column with H20/MeCN (1-0). The crude product (200 mg) was puriﬁed by Prep-HPLC with the following conditions (2#-AnalyseHPLC- SHIMADZU(HPLC-10)): Column, XBridge Shield RP18 OBD Column,, 5um,19*150mm, mobile phase, Waters(0.05%NH3H20) and ACN (3.0% ACN up to 70.0% in 6 min), Detector, UV 254/220nm. 23.5 . This resulted in 23.5 mg (10%) of 4-N-[4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]N-(piperidinylmethyl)pyridine-2,4-diamine as a light yellow solid.

Example 12: Synthesis of Compound 12 Synthesis of S-meth0xy(3-(pyrrolidinyl)propoxy)-N-(2-(((tetrahydro-ZH- pyranyl)amin0)methyl)pyridin—4-yl)pyridin-Z-amine: Br / Ph Ph Ph Ph ,—fN:I 0 CI \n’ \n/ NHZ N_ o N A.H[2M 0_ / i. / o _ \ ,N I — \ Pd(OAC)2,CSZCOS I / \ t-BuXPhos,052003 NC N Xantphos,dioxane I NC N HN \ szdbaacHCla \ [N NC N CN —>NC§Raney—Ni 0423"]Q0:NaBH(ACO)3 HNQ: HN NQH Step 1: Synthesis of 4-((diphenylmethylene)amino)picolinonitrile: Into a 100-mL round-bottom ﬂask, was placed 4-chloropyridinecarbonitrile (1 g, 7.22 mmol, 1.00 equiv), diphenylmethanimine (1.9 g, 10.48 mmol, 1.50 equiv), CszCO3 (7 g, 21.48 mmol, 3.00 equiv), Xantphos (0.832 g, 0.20 equiv), )2 (346 mg, 1.54 mmol, 0.10 equiv), dioxane (30 mL). The resulting solution was d for 2 h at 80 0C in an oil bath. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting e was washed with 1x100 mL of brine. The mixture was dried over ous sodium sulfate. The solids were ﬁltered out. The resulting mixture was concentrated under . The crude product (1.9 g) was puriﬁed by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, C18 silica gel, mobile phase, MeCNzWater=0z5 increasing to ater=3zl within 120 min, Detector, UV 254 nm.

This ed in 1.3 g (33% yield) of 4-(diphenylamino)pyridinecarbonitrile as ayellow solid.

Step 2: Synthesis of 4-aminopicolinonitrile: Into a 50-mL round-bottom ﬂask, was placed 4-[(diphenylmethylidene)amino] pyridinecarbonitrile (1.23 g, 2.17 mmol, 1.00 equiv, 50%), hydrogen chloride(2M) (8 mL, 2.00 equiv), methanol (24 mL). The resulting solution was stirred for 120 min at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 2x10 mL of dichloromethane and the water phase combined. The pH value of the water phase was adjusted to 8 with sodium bicarbonate (sat. solution). The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The ing e was washed with 1x20 mL of brine, dried over NaZSO4, the solids were ﬁltered out. The residue was evaporated and the result solid was dried in an oven under reduced pressure. This resulted in 0.28 g (81%) of opyridinecarbonitrile as a yellow solid.

Step 3: Synthesis of 4-((5-methoxy(3-(pyrrolidinyl)propoxy)pyridin yl)amino)picolinonitrile: Into a 30-mL sealed tube, was placed 2-bromomethoxy[3-(pyrrolidin poxy]pyridine (314 mg, 1.00 mmol, 1.00 equiv.), 4-aminopyridinecarbonitrile (240 mg, 2.01 mmol, 2.00 equiv.), Pd2(dba)3-chloroform (0.1 g, 0.10 equiv.), t-BuXPhos (0.085 g, 0.20 equiv.), CszCO3 (970 mg, 2.97 mmol, 3.00 equiv.), dioxane (10 mL). The resulting solution was stirred for 16 h at 110 0C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The c layer was washed with 1x50 mL of brine, dried over ous sodium sulfate. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude t (3 mL) was puriﬁed by Flash- Prep-HPLC with the following conditions (CombiFlash-l): Column, C18 silica gel, mobile phase, MeCN:Water=1z5 increasing to ater=10:1 within 120 min, Detector, UV 254 nm. 70 mg product was obtained. This resulted in 70 mg (20%) of methoxy[3- (pyrrolidinyl)propoxy]pyridinyl]amino)pyridinecarbonitrile as an off-white solid.

Step 4: Synthesis of N—(2-(aminomethyl)pyridinyl)methoxy(3-(pyrrolidin- 1-yl)propoxy)pyridinamine: Into a 25-mL round-bottom ﬂask, was placed 4-([5-methoxy[3-(pyrrolidin yl)propoxy]pyridinyl]amino)pyridinecarbonitrile (70 mg, 0.20 mmol, 1.00 equiv.), Ni (0.2 g), methanol (5 mL). The mixture ent three hydrogen/air exchange cycles. The resulting solution was stirred for 120 min at room temperature. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 65 mg (92%) of N—[2-(aminomethyl)pyridinyl]methoxy[3-(pyrrolidin-1 - yl)propoxy]pyridinamine as an off-white solid Step 5: Synthesis of 5-methoxy(3-(pyrrolidinyl)propoxy)-N-(2-(((tetrahydro- 2H-pyranyl)amino)methyl)pyridinyl)pyridinamine: Into a 25-mL round-bottom ﬂask, was placed N-[2-(aminomethyl)pyridinyl] y[3-(pyrrolidinyl)propoxy]pyridinamine (66 mg, 0.18 mmol, 1.00 equiv.), 1- (sodioboranyl)ethanone acetyl acetate dihydrate (84 mg, 0.39 mmol, 3.50 equiv.), oxan one (18 mg, 0.18 mmol, 1.00 equiv.), dichloromethane (3 mL). The resulting solution was stirred for 120 min at room temperature. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. The crude product (1 mL) was puriﬁed by Prep-HPLC with the following conditions: Column, XBride Prep C18 OBD 19X150 mm 5umC-0013, mobile phase, Phase A:Waters(HCl) Phase B: ACN =1:1, Detector, 254/220nm. 30.1 mg product was obtained. This resulted in 30.1 mg (34%) of 5-methoxy-N-(2-[[(oxan yl)amino]methyl]pyridinyl)[3-(pyrrolidinyl)propoxy]pyridinamine hydrochloride as a white solid.

Example 13: Synthesis of nd 13 Synthesis of 1-(4-(((4-((4-meth0xy(3-(pyrrolidin yl)propoxy)phenyl)amino)pyridin-Z-yl)(methyl)amino)methyl)piperidinyl)ethan Br 0 O O N N N F H Mel I —’ Br N Br N —’ \ DMSO, DIEA \ I NaH, DMF I HCI / N N’\/‘o: 3 ‘NH Nk Cl H l 2 N\/\/0 N N Pd2(dba)3, BINAP \OU U Step 1: Synthesis of 1-(4-(((4-bromopyridinyl)amino)methyl)piperidin anone: Into a 50-mL round-bottom ﬂask, was placed aminomethyl)piperidin yl]ethanone hydrochloride (500 mg, 2.59 mmol, 1.00 equiv.), 4-bromoﬂuoropyridine (500 mg, 2.84 mmol, 1.10 equiv.), DIEA (0.546 g, 2.00 equiv.), DMso (10 mL). The resulting solution was stirred for 180 min at 120 0C in an oil bath. The on was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3X30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of BRINE. The mixture was dried over anhydrous sodium sulfate. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. The crude product (3 mL) was puriﬁed by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel, mobile phase, MeCN:Water=1 : 10 increasing to MeCN:Water=10:1 within 60 min, or, UV 254 nm. 0.34 g product was obtained. This resulted in 0.34 g (40%) of 1-(4- [[(4-bromopyridinyl)amino]methyl]piperidinyl)ethanone as off-white oil.

Step 2: Synthesis of 1-(4-(((4-bromopyridinyl)(methyl)amino)methyl)piperidin yl)ethanone: Into a 25-mL round-bottom ﬂask, was placed 1-(4-[[(4-bromopyridin yl)amino]methyl]piperidinyl)ethanone (340 mg, 1.09 mmol, 1.00 equiv.), N,N— dimethylformamide (3 mL). The e was cooled to 0 0C, then sodium hydride (28 mg, 1.20 mol, 1.10 equiv.) was added in one portion and d at 0 0C for 30 min, iodomethane (250 mg, 1.76 mmol, 1.50 equiv.) was added drop wise. The resulting solution was stirred for 120 min at 0 0C in a water/ice bath. The on was then quenched by the addition of 25 mL of water. The resulting solution was ted with of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product (3 mL) was puriﬁed by Flash- Prep-HPLC with the following ions (IntelFlash-l): , C18 silica gel, mobile phase, MeCN:Water=1:10 sing to MeCN:Water=10:1 within 120 min, Detector, UV 254 nm. 0.31 g product was obtained. This resulted in 0.31 g (87%) of 1-(4-[[(4- bromopyridinyl)(methyl)amino]methyl] piperidin-l-yl)ethanone as a white solid.

Step 3: Synthesis of 1-(4-(((4-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)pyridinyl)(methyl)amino)methyl)piperidinyl)ethanone: Into a 100-mL round-bottom ﬂask, was placed 1-(4-[[(4-bromopyridin yl)(methyl)amino]methyl]piperidinyl)ethanone (290 mg, 0.89 mmol, 1.00 equiv.), 4- methoxy[3-(pyrrolidinyl)propoxy]aniline (440 mg, 1.76 mmol, 2.00 equiv.), Pd2(dba)3 chloroform (0.092 g, 0.10 equiv.), BINAP (116 mg, 0.19 mmol, 0.20 equiv.), tBuONa (256 mg, 2.67 mmol, 3.00 equiv), toluene (15 mL). The resulting solution was stirred for 16 h at 100 0C in an oil bath. The reaction was then quenched by the addition of 100 of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the c layers combined. The resulting mixture was washed with 1x100 mL of BRINE. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was trated under vacuum. The crude product (1.5 mL) was ed by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD Column 19*150mm 5umC-0013, mobile phase, Phase A:Waters(0.05%NH3H20) Phase BzACN Gradient, Detector, 254/220. 60.5 mg product was obtained. This resulted in 60.5 mg (14%) of 1-[4-([[4-([4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]amino)pyridinyl](methyl)amino]methyl)piperidin yl]ethanone as a white solid.

Example 14: Synthesis of Compound 14 Synthesis of 1-(4-(((2-((4-meth0xy(3-(pyrrolidin yl)pr0poxy)phenyl)amino)pyrimidin-4—yl)0xy)methyl)piperidinyl)ethan-l-one: HO ,Boc CIYN C] LC"3°C OVO TFA DCM NJ ‘YJ j/OJCJHLC] OVOJL Cry 0 NH2 GOV" NJO NO m OﬁY"UZW Step 1: Synthesis of tert-butyl 4-(((2-chloropyrimidinyl)oxy)methyl)piperidine carboxylate: Into a 100-mL bottom ﬂask, was placed 2,4-dichloropyrimidine (1 g, 6.71 mmol, 1.00 equiv), tert-butyl 4-(hydroxymethyl)piperidinecarboxylate (1.45 g, 6.74 mmol, 1.00 , tetrahydrofuran (20 mL), t-BuOK (1.51 g, 13.46 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 20 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.5 g (68%) of tert-butyl 4-[[(2-chloropyrimidin yl)oxy]methyl]piperidinecarboxylate as an off-white solid.

Step 2: sis of 2-chloro(piperidinylmethoxy)pyrimidine: Into a 100-mL round-bottom ﬂask, was placed tert-butyl 4-[[(2-chloropyrimidin yl)oxy]methyl]piperidinecarboxylate (1.5 g, 4.58 mmol, 1.00 equiv), dichloromethane (15 mL), triﬂuoroacetic acid (5 mL). The resulting solution was stirred for 12 h at 20 0C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash- Prep-HPLC with the following conditions (IntelFlash-l): , silica gel, mobile phase, , Detector, UV 254 nm. This resulted in 1.8 mg (crude) of 2-chloro(piperidin ylmethoxy)pyrimidine as yellow crude oil.

Step 3: Synthesis of 1-(4-(((2-chloropyrimidinyl)oxy)methyl)piperidin yl)ethanone: Into a 100-mL ed round-bottom ﬂask, was placed ro(piperidin ylmethoxy)pyrimidine (1.5 g, 6.59 mmol, 1.00 equiv), romethane (10 mL), TEA (2 g, 19.76 mmol, 3.00 equiv). This was followed by the addition of acetyl chloride (780 mg, 9.94 mmol, 1.50 equiv.) dropwise with stirring at 0 0C. The resulting solution was stirred for 2 h at 0C. The resulting mixture was concentrated under vacuum. This resulted in 1 g (56%) of 1-(4-[[(2-chloropyrimidinyl)oxy]methyl]piperidinyl)ethanone as yellow oil.

Step 4: Synthesis of ((2-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)pyrimidinyl)oxy)methyl)piperidinyl)ethanone: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (278.8 mg, 1.11 mmol, 1.00 equiv), 1-(4-[[(2-chloropyrimidin yl)oxy]methyl]piperidinyl)ethanone (300 mg, 1.11 mmol, 1.00 equiv), TosOH (568.8 mg, 3.35 mmol, 3.00 equiv), isopropanol (5 mL). The resulting solution was stirred for 2 h at 85 0C in an oil bath. The crude product was puriﬁed by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, silica gel, mobile phase, , Detector, UV 254 nm. This resulted in 71.6 mg (13%) of 1-[4-([[2-([4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]amino)pyrimidinyl]oxy]methyl)piperidinyl]ethanone as a pink solid.

Example 15: Synthesis of nd 15 Synthesis of 1-(2-methoxy-5—((4-((piperidinylmethyl)amino)pyrimidin yl)amin0)phenoxy)—3-(pyrrolidinyl)pr0panol: Br 0 N OH HO No2 (13>—/ R/OUNo2 V 7 \ K2CO3, DMF O CHCI3, EtOH, reflux OxkjvoD/NozO l | 0 °" OH Pd/C, H2 (9) WOUNH2 TsOH, IPA <7 0 "WOUNwﬁ/NN /H g | I Step 1: Synthesis of 2-((2-methoxynitrophenoxy)methyl)oxirane: Into a 100-mL 3-necked round-bottom ﬂask, was placed a solution of 2-methoxy nitrophenol (2 g, 11.82 mmol, 1.00 ) in N,N—dimethylformamide (20 mL), 2- (bromomethyl)oxirane (2.43 g, 17.74 mmol, 1.50 equiv), potassium ate (3.27 g, 23.66 mmol, 2.00 equiv). The resulting solution was stirred for overnight at room temperature. The ing solution was diluted with 50 mL of EA, washed with 3X50 mL of brine, concentrated under . The e was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.71 g (64%) of 2-(2-methoxynitrophenoxymethyl)oxirane as an off-white solid.

Step 2: Synthesis of 1-(2-methoxynitrophenoxy)(pyrrolidinyl)propanol: Into a 50-mL 3-necked round-bottom ﬂask, was placed a on of 2-(2-methoxy nitrophenoxymethyl)oxirane (1.4 g, 6.22 mmol, 1.00 equiv.) in ethanol (8 mL), pyrrolidine (1.1 g, 15.47 mmol, 2.50 equiv), chloroform (8 mL). The ing solution was stirred for 2 h at 40 0C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol 10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.7 g (92%) of 1-(2-methoxynitrophenoxy)(pyrrolidinyl)propanol as yellow oil.

Step 3: Synthesis of 1-(5-aminomethoxyphenoxy)(pyrrolidinyl)propanol: Into a 100-mL round-bottom ﬂask, was placed 1-(2-methoxynitrophenoxy) (pyrrolidinyl)propanol (1.7 g, 5.74 mmol, 1.00 equiv.), Palladium carbon(10%) (200 mg) and Methanol (20 mL). The mixture underwent three hydrogen/air exchange cycles. The resulting solution was stirred for 4 h at room temperature. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 1.6 g (105%) of 1-(5- 2-methoxyphenoxy)(pyrrolidinyl)propanol as dark red oil.

Step 4: Synthesis of 1-(2-methoxy((4-((piperidinylmethyl)amino)pyrimidin yl)amino)phenoxy)(pyrrolidinyl)propanol: Into a 50 mL 3-necked round-bottom ﬂask, was placed 1-(5-amino methoxyphenoxy)(pyrrolidinyl)propanol (310 mg, 1.16 mmol, 1.00 equiv.), isopropanol (10 mL), tert-butyl 4-[[(2-chloropyrimidinyl)amino]methyl]piperidine carboxylate (381 mg, 1.17 mmol, 1.00 equiv.), TsOH (1H20) (1.107 g, 5.83 mmol, 5.00 equiv.) The resulting solution was stirred for 4 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 20 mL of H20. Sodium carbonate was ed to adjust the pH to 9. The ing solution was extracted with 3x20 mL of chloroform/ isopropanol (1/1) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under . The residue was puriﬁed by Flash tography with MeCN/HzO(40%). The ted fractions were combined and concentrated under vacuum. This resulted in 77.9 mg (15%) of ethoxy- -([4-((piperidinylmethyl)amino]pyrimidinyl)amino)phenoxy](pyrrolidin panol as a white solid.

Example 16: Synthesis of Compound 16 Synthesis of N2-(4-methoxy-3—(3—morpholin0pr0poxy)phenyl)-N4-(piperidin-4— ylmethyl)pyrimidine-2,4-diamine: /© (\NMCI 0d /O]: 1 Fe,NH4C| HCI {\NMO N02 —> HO o EtOH, H20 052003, Nal, DMF 0 H N / m C|\ﬁ\NjN¢© NH 0’ ‘N —0 (\NMO N/ \——/ —\—\ O PTSA, i-PrOH Step 1: Synthesis of 4-(3-(2-methoxynitrophenoxy)propyl)morpholine: Into a 50-mL round-bottom ﬂask, was placed 2-methoxynitrophenol (1.1 g, 6.50 mmol, 1.00 equiv), 4-(3-chloropropyl)morpholine hydrochloride (1.3 g, 6.50 mmol, 1.00 equiv), CszC03 (6.39 g, 19.61 mmol, 3.00 equiv), NaI (980 mg, 1.00 equiv), N,N— dimethylformamide (10 mL). The resulting solution was stirred for 16 h at 110 0C. The resulting solution was d with 50 mL of H20. The resulting on was extracted with 100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5x100 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 1.17 g (61%) of 4-[3-(2-methoxynitrophenoxy)propyl]morpholine as a yellow solid Step 2: Synthesis of oxy(3-morpholinopropoxy)aniline: [055 8] Into a 50-mL round-bottom ﬂask, was placed 4-[3-(2-methoxy nitrophenoxy)propyl]morpholine (450 mg, 1.52 mmol, 1.00 equiv), NH4Cl (242 mg, 4.52 mmol, 3.00 equiv), ethanol (12 mL), water(3 mL), Fe (256 mg, 4.57 mmol, 3.00 . The resulting on was stirred for 12 h at 85 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by C18 Flash: ACN/HZO(1/4).This resulted in 200 mg (49%) of 4-methoxy[3-(morpholin yl)propoxy]aniline as a yellow oil.

Step 3: Synthesis of N2-(4-methoxy(3-morpholinopropoxy)phenyl)-N4-(piperidin- 4-ylmethyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[3-(morpholin yl)propoxy]aniline (200 mg, 0.75 mmol, 1.00 equiv), tert-butyl chloropyrimidin yl)amino]methylpiperidinecarboxylate (184 mg, 0.56 mmol, 1.00 equiv), PTSA (485 mg, 2.82 mmol, 5.00 equiv), isopropanol (8 mL). The resulting solution was stirred for 2 h at 85 0C in an oil bath. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was d by Prep-HPLC with the following conditions : Column: X Bridge RP, 19*150 mm, 5 um, Mobile Phase AzWater/10mmol NH4HCO3 Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15%B to 43%B in 10 min; 254nm.This resulted in 31.1 mg (9%) of 2-N-[4- methoxy[3-(morpholinyl)propoxy]phenyl]N-(piperidinylmethyl)pyrimidine-2,4- e as a white solid.

Example 17: Synthesis of Compound 17 Synthesis 0fN2-(3-(2-((cyclopentylmethyl)amin0)ethyl)methoxyphenyl)-N4- (piperidinylmethyl)pyrimidine-2,4-diamine: 0 NC Cl NC / ("k/CK KCN, DMSO —>/o /0 Ice/NW" —> o N02 AlClg, CH3N03 85 °C, 3h 50 °C, 3h NO 2 2 NH2 H N N’Boc CkﬁN N¢© H H N,Boc H H N N N N Raney Ni,NH3/MeOH NC v \ N Pd(OAc)2,Xantphos, N / O H2N\/I:/NYN N.j/ K2C03, toulene, 110 °C, 36h | (I) /) , Boc H H N"U CT N VOW —. —.

NaBH(OAC)3,DCE N / VD [JN / Cl) (I) Step 1: Synthesis of 2-(chloromethyl)methoxynitrobenzene: Into a 250-mL ed round-bottom ﬂask, was placed 1-methoxynitrobenzene (12 g, 78.36 mmol, 1.00 equiv.), CH3NO3 (100 mL), AlCl3 (25.9 g, 2.50 equiv.). This was followed by the addition of 2-methoxyacetyl chloride (9.32 g, 85.88 mmol, 1.10 equiv.) se with ng at 0 0C. The resulting solution was stirred for 5 h at 20 0C. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 2X120 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The e was applied onto a silica gel column with dichloromethane/petroleum ether (1/4). The collected fractions were combined and concentrated under vacuum. This resulted in 6.9 g (44%) of 2-(chloromethyl)methoxy nitrobenzene as an off-white solid.

Step 2: Synthesis of ethoxynitrophenyl)acetonitrile: Into a 250-mL round-bottom ﬂask, was placed 2-(chloromethyl)methoxy nitrobenzene (6.9 g, 34.23 mmol, 1.00 equiv.), DMSO (100 mL), KCN (13.4 g, 205.77 mmol, 6.00 equiv.) The resulting solution was d for 2 h at 50 0C. The resulting solution was diluted with 200 mL of H20. The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4x300 mL of brine. The resulting e was trated under . The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1/ 1). This resulted in 4.58 g (70%) of 2-(2-methoxynitrophenyl)acetonitrile as an off-white solid.

Step 3: Synthesis of 2-(5-aminomethoxyphenyl)acetonitrile: Into a 250-mL round-bottom ﬂask, was placed 2-(2-methoxy nitrophenyl)acetonitrile (4.58 g, 23.83 mmol, 1.00 equiv.), Fe (4 g, 3.00 equiv.), NH4Cl (3.79 g, 70.85 mmol, 3.00 equiv.), ethanol (100 mL), water (20 mL). The resulting solution was stirred for 2 h at 85 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 3.6 g (93%) of 2-(5-aminomethoxyphenyl)acetonitrile as a brown solid.

Step 4: Synthesis of tert-butyl 4-(((2-((3-(cyanomethyl) methoxyphenyl)amino)pyrimidinyl)amino)methyl)piperidinecarboxylate: Into a 250-mL round-bottom ﬂask purged and ined with an inert atmosphere of nitrogen, was placed 2-(5-aminomethoxyphenyl)acetonitrile (1.8 g, 11.10 mmol, 1.00 equiv.), tert-butyl 4-[[(2-chloropyrimidinyl)amino]methyl]piperidinecarboxylate (3.62 g, 11.08 mmol, 1.00 equiv.), Pd(OAc)2 (249 mg, 1.11 mmol, 0.10 ), Xantphos (642 mg, 1.11 mmol, 0.20 equiv.), potassium carbonate (4.6 g, 33.28 mmol, 3.00 equiv), Toluene (100 mL). The resulting solution was stirred for 16 h at 115 0C. The solids were ﬁltered out.

The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with O (3/2). This resulted in 2.52 g (50%) of tert-butyl 4-[[(2-[[3- (cyanomethyl)methoxyphenyl] amino] pyrimidinyl)amino] ] piperidine carboxylate as ayellow solid.

Step 5: Synthesis of utyl 4-(((2-((3-(2-aminoethyl) methoxyphenyl)amino)pyrimidinyl)amino)methyl)piperidinecarboxylate: Into a 250-mL round-bottom ﬂask, was placed utyl 4-[[(2-[[3-(cyanomethyl) yphenyl]amino]pyrimidinyl)amino]methyl]piperidinecarboxylate (2.52 g, 5.57 mmol, 1.00 equiv.), NH3/MeOH (20 mL), ethyl acetate (10 mL), Raney Ni (1 g). The mixture underwent three hydrogen/air exchange cycles. The resulting solution was stirred for 18 h at 20 0C. The solids were ﬁltered out. The resulting e was concentrated under vacuum. This resulted in 2.4 g (94%) of tert-butyl 4-[[(2-[[3-(2-aminoethyl) methoxyphenyl]amino]pyrimidinyl)amino]methyl] piperidinecarboxylate as brown oil.

Step 6: Synthesis of tert-butyl 4-(((2-((3-(2-((cyclopentylmethyl)amino)ethyl) methoxyphenyl)amino)pyrimidinyl)amino)methyl)piperidinecarboxylate: Into a 50-mL round-bottom ﬂask, was placed tert-butyl 4-[[(2-[[3-(2-aminoethyl) methoxyphenyl]amino]pyrimidinyl)amino]methyl]piperidinecarboxylate (400 mg, 0.88 mmol, 1.00 equiv.), cyclopentanecarbaldehyde (69 mg, 0.70 mmol, 0.80 equiv.), dichloromethane (20 mL)and was stirred for 0.5h at 20 0C. This was followed by the addition of acetyl ethaneperoxoate sodioboranyl acetate (1.1 g, 5.19 mmol, 6.00 equiv.), in ns at 0 0C. The resulting solution was stirred for 1 h at 20 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with O (2/3). This resulted in 130 mg (28%) of utyl 4-[([2-[(3-[2- [(cyclopentylmethyl)amino]ethyl]methoxyphenyl)amino]pyrimidin yl]amino)methyl]piperidinecarboxylate as yellow oil.

Step 7: Synthesis of N2-(3-(2-((cyclopentylmethyl)amino)ethyl)methoxyphenyl)- N4-(piperidinylmethyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed utyl -[(3-[2- [(cyclopentylmethyl)amino]ethyl]methoxyphenyl)amino]pyrimidin yl]amino)methyl]piperidinecarboxylate (130 mg, 0.24 mmol, 1.00 equiv.), dichloromethane (10 mL), triﬂuoroacetic acid (1.5 mL). The resulting solution was stirred for 1 h at 20 0C. The resulting mixture was concentrated under vacuum. The ing solution was diluted with 10 mL of H20. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/HZO (1/6). This resulted in 48.2 mg (46%) of 2-N-(3-[2- [(cyclopentylmethyl)amino]ethyl]methoxyphenyl)N-(piperidinylmethyl)pyrimidine- 2,4-diamine as a white solid.

Example 18: Synthesis of Compound 18 Synthesis of ((2-((4-methoxy((l-methylpyrrolidin-S- yl)meth0xy)phenyl)amin0)pyrimidin-4—yl)amino)methyl)piperidinyl)ethanone: / O\ MsCI O2N O a Pd/C, MeOH —N —> —> Et3N, DCM 'Nl/OMS OZN OACN, Step 1: Synthesis of (1-methylpyrrolidinyl)methyl methanesulfonate: Into a 100-mL round-bottom ﬂask, was placed (1-methylpyrrolidinyl)methanol (500 mg, 4.34 mmol, 1.00 equiv), TEA (1.3 g, 12.85 mmol, 3.00 equiv), dichloromethane (20 mL). MsCl (743 mg, 1.50 equiv.) was added drop wise at 0 0C. The resulting solution was stirred for 2 h at 25 0C. The resulting solution was ed with 20 mL of water, extracted with 3x100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 700 mg (83%) of (1- methylpyrrolidinyl)methyl methanesulfonate as yellow oil.

Step 2: Synthesis of 3-((2-methoxynitrophenoxy)methyl)methylpyrrolidine: Into a 50-mL round-bottom ﬂask, was placed (1-methylpyrrolidinyl)methyl methanesulfonate (150 mg, 0.78 mmol, 1.00 equiv), CszC03 (760 mg, 2.33 mmol, 3.00 equiv), N,N-dimethylformamide (10 mL), 2-methoxynitrophenol (132 mg, 0.78 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 80 0C in an oil bath. The solids were d out. The residue was washed with 10 mL of water, extracted with 3x20 mL of ethyl acetate, the organic phase was combined and washed with 3x50 mL of brine, dried over Na2S04, the solid was ﬁltered out, the residue was ated, The crude product was d by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, silica gel, mobile phase, O=6/1, Detector, UV 254 nm. This resulted in 180 mg (87%) of 3-(2-methoxynitrophenoxymethyl)methylpyrrolidine as yellow oil.

Step 3: sis of oxy((1-methylpyrrolidinyl)methoxy)aniline: Into a 100-mL round-bottom ﬂask, was placed 3-(2-methoxy nitrophenoxymethyl)methylpyrrolidine (250 mg, 0.94 mmol, 1.00 equiv), Palladium carbon, methanol (30 mL), The mixture underwent three en/air exchange cycles. The resulting solution was stirred for 4 h at 25 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (90%) of oxy[(1- methylpyrrolidinyl)methoxy]aniline as a white solid.

Step 4: Synthesis of 1-(4-(((2-((4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)amino)pyrimidinyl)amino)methyl)piperidinyl)ethanone: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[(1-methylpyrrolidin yl)methoxy]aniline (150 mg, 0.63 mmol, 1.00 equiv), isopropanol (20 mL), p-TsOH (327 mg, 3.00 equiv), 1-(4-[(2-chloropyrimidinyl)amino]methylpiperidinyl)ethanone (170 mg, 0.63 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 85 0C in an oil bath. The resulting mixture was concentrated under . The crude product was puriﬁed by Prep-HPLC with the following conditions (Column: X Select C18, 19*150 mm, 5 um): Column; mobile phase, Mobile Phase A:Water/0.05% NH4HC03, Mobile Phase B: ACN, or. This resulted in 156.6 mg (53%) of 1-[4-([[2-([4-methoxy[(1-methylpyrrolidin- 2-yl)methoxy]phenyl]amino)pyrimidinyl]amino]methyl)piperidinyl]ethanone as a white solid.

Example 19: Synthesis of Compound 19 Synthesis of 1-(4-(((2-((4-meth0xy(3-(pyrrolidinyl)prop0xy)phenyl)amino)— 6-methylpyrimidinyl)amino)methyl)piperidinyl)ethan0ne: CI H2N\/©OHCI NJK C'YN N N’\/‘oﬁnNH2 N \ HVOJK Ct A / l CI N K2C03,DMF \ PTSA,i-PrOH Ahoy ::/\/D Step 1: sis of 1 -(-4(((2-chloro-methylpyrimidin- yl)amino)methyl)piperidinyl)ethanone: Into a 25-mL round-bottom ﬂask, was placed 1-[4-(aminomethyl)piperidin yl]ethanone (300 mg, 1.92 mmol, 1.00 equiv.), N,N—dimethylformamide (5 mL), ium carbonate (651 mg, 4.71 mmol, 3.00 equiv.), 2,4-dichloromethylpyrimidine (251 mg, 1.54 mmol, 1.00 ). The resulting solution was stirred for 7 h at 60 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H20/MeCN (1-0). This resulted in 0.21 g (48%) of 1-(4-[[(2-chloromethylpyrimidinyl)amino]methyl] piperidinyl)ethanone as a white solid.

Step 2: Synthesis of 1-(4-(((2-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)methylpyrimidinyl)amino)methyl)piperidinyl)ethan Into a 25-mL round-bottom ﬂask, was placed 1-(4-[[(2-chloromethylpyrimidin yl)amino]methyl]piperidinyl)ethanone (200 mg, 0.71 mmol, 1.00 equiv.), oxy [3-(pyrrolidinyl)propoxy]aniline (195 mg, 0.78 mmol, 1.10 equiv.), TsOH (269 mg, 1.42 mmol, 2.00 , isopropanol (5 mL). The resulting solution was stirred for 7 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H20/MeCN (1-0). This resulted in 61.2 mg (17%) of 1-[4-([[2- ([4-methoxy-3 - [3 -(pyrrolidinyl)propoxy]phenyl]amino)methylpyrimidin yl]amino]methyl)piperidinyl]ethanone as a pink solid.

Example 20: Synthesis of Compound 47 Compound 47: Synthesis of 1-(4-(((2-((4-meth0xy(3-(pyrrolidin yl)pr0poxy)phenyl)amino)pyrimidinyl)amino)methyl)piperidinyl)ethan-l-one Boc-N/\:>—\ ,Boc CWN O NH H Q 2 fl W ‘0 C] N C] K2003.DMF,r.t NIJ TsOH,[PA,85°C warjanwO —::: awojgijO O NH \O N / Step 1: Synthesis of tert-butyl 4-[[(2-chloropyrimidinyl)amino]methyl]piperidine- 1-carboxylate: Into a 250-mL 3-necked round-bottom ﬂask, was placed a solution of 2,4- ropyrimidine (5.0 g, 33.56 mol, 1 equiv) in N,N—dimethylformamide (50 mL), tyl 4-(aminomethyl)piperidinecarboxylate (7.18 g, 33.50 mol, 1 equiv), potassium carbonate (9.26 g, 2.00 equiv). The ing solution was stirred for 2 h at RT. The resulting solution was diluted with 50 mL of EA, washed with 3X50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10-1 :2). The collected fractions were combined and concentrated under . This resulted in 8.1 g (74%) of the title nd as colorless oil.

Analytical Data: (ES, m/z): RT = 1.449 min, LCMS 28: m/Z = 327 [M+1]. H-NMR: (400 MHz, Methanol-d4) 5 8.83 — 8.68 (m, 1H), 7.26 (d, J: 5.8 Hz, 1H), 5.01 — 4.56 (m, 2H), 4.06 — 3.80 (m, 2H), 3.49 (s, 2H), 2.58 — 2.37 (m, 3H), 2.20 (s, 9H), 1.95 — 1.69 (m, 2H).

Step 2: Synthesis of 2-N-[4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]N— (piperidinylmethyl)pyrimidine-2,4-diamine: Into a 50-mL 3-necked round-bottom ﬂask, was placed 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (764 mg, 3.05 mol, 1 equiv), tert-butyl 4-[[(2-chloropyrimidin yl)amino]methyl]piperidinecarboxylate (1 g, 3.06 mmol, 1 equiv), TsOH (2.9 g, 15.26 mmol, 5.00 equiv), IPA (10 mL). The resulting solution was stirred for 4 h at 85 0C in an oil bath. The resulting mixture was trated under vacuum. The residue was puriﬁed by ﬂash chromatography with ACN/1120(1/10). This resulted in 800 mg (59%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.900 min, LCMS 07: m/Z = 441 [M+1].

Step 3: Synthesis of 1-[4-([[2-([4-methoxy[3-(pyrrolidin yl)propoxy]phenyl] amino)pyrimidinyl] amino] methyl)piperidin-1 -yl] ethanone: Into a 10-mL sealed tube, was placed 2-N-[4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]N-(piperidinylmethyl)pyrimidine-2,4-diamine (250 mg, 0.57 mmol, 1 equiv), acetyl acetate (63.6 mg, 0.62 mmol, 1.10 equiv), TEA (114.5 mg, 2.00 equiv), ACN (3 mL). The resulting solution was stirred for 4 h at RT. The resulting mixture was trated under vacuum. The residue was puriﬁed by ﬂash chromatography with ACN/HZO (1/10). This resulted in 61.2 mg (22%) of 1-(4-(((2-((4-methoxy(3-(pyrrolidin- 1-yl)propoxy)phenyl)amino)pyrimidinyl)amino)methyl)piperidinyl)ethanone as a white solid.

Example 21: Synthesis of nd 205 Compound 205: Synthesis of methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine HN / CI N I C,"/\/\O NH2 TFA,i-PrOH OMO NJ\\N Step 1: Synthesis ofN2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4,6- ylpyrimidine-2,4-diamine: Into a 250-mL round-bottom ﬂask, was placed 2-chloro-N,6-dimethylpyrimidin amine (1.5 g, 9.52 mol, 1 , 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (864 mg, 3.45 mol, 1 equiv), triﬂuoroacetic acid (684 mg, 6.05 mol, 1 equiv), isopropanol (50 mL). The resulting solution was d overnight at 85 0C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC G. This resulted in 1.295 g (32%) ofN2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine as a solid.

WO 81177 Example 22: Synthesis of Compound 207 Compound 207: Synthesis of N4-methyl-N2-(3—(3—(pyrrolidin yl)propoxy)phenyl)pyrimidine-2,4-diamine O @MCI O Pd/C,MeOH N/\/\O0 @MO N02 NH2 HO NO2 Nal,052003 xN/I N/ a N r; )jI GMO NJ\\N -PrOH H Step 1: Synthesis of 1-[3-(3-nitrophenoxy)propyl]pyrrolidine: Into a 50-mL bottom ﬂask, was placed 3-nitrophenol (600 mg, 4.31 mmol, 1 equiv), 1-(3-ch1oropropy1)pyrrolidine hydrochloride (790 mg, 4.29 mol, 1 equiv), Cs2CO3 (4.22 g, 12.95 mmol, 3.00 equiv), NaI (647 mg, 4.31 mmol, 1 equiv), N,N— dimethylformamide (10 mL). The resulting solution was stirred for 4 h at 110 0C. The resulting solution was diluted with 30 mL of H20. The resulting solution was extracted with 3x60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4x60 mL of brine. The resulting mixture was concentrated under vacuum. This ed in 1 g (93%) of the title nd as brown oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.975 min, LCMS 53: m/Z = 251 [M+1].

Step 2: Synthesis of 3-[3-(pyrrolidiny1)propoxy]aniline: Into a 100-mL bottom ﬂask, was placed 1-[3-(3- nitrophenoxy)propy1]pyrrolidine (1 g, 4.00 mol, 1 equiv), methanol (20 mL), Pd/C (0.5 g).

The resulting solution was stirred for 1 h at 20 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 0.7 g (80%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.586 min, LCMS 07: m/Z = 221 [M+1].

Step 3; Synthesis ofN4-methy1-N2-(3-(3-(pyrrolidin yl)propoxy)phenyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 3-[3-(pyrrolidinyl)propoxy]aniline (400 mg, 1.82 mol, 1 equiv), 2-ch1oro-N-methy1pyrimidinamine (259 mg, 1.80 mmol, 1 , 4-methylbenzenesulfonic acid (464 mg, 2.69 mmol, 1.50 , isopropanol (10 mL). The resulting solution was stirred for 2 h at 85 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (1/5). This resulted in 104.7 mg (18%) ethyl-N2-(3-(3-(pyrrolidin yl)propoxy)phenyl)pyrimidine-2,4-diamine as a white solid.

Example 23: Synthesis of Compound 209 Compound 209: Synthesis of Nz-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyridine-2,4—diamine Br OD NHZCH3/THF / N CNVO NHZ /\/\O/:©\Hb N Pd2(dba)3CHCI3 BINAP, t-BuONa, Tol Step 1: Synthesis of 2-bromo-N-methylpyridinarnine: Into a 60-mL sealed tube, was placed 2-bromoﬂuoropyridine (500 mg, 2.84 mol, 1 equiv), NH2CH3-THF (20 mL). The resulting solution was stirred for 16 h at 80 0C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 480 mg (90%) of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/Z): RT = 0.758 min, LCMS 27: m/Z = 187 [M+l].

Step 2: Synthesis of methoxy(3-(pyrrolidinyl)propoxy)phenyl)—N4- methylpyridine-2,4-diarnine: Into a 16-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-N-methylpyridinamine (400 mg, 2.14 mmol, 1 , 4-methoxy [3-(pyrrolidinyl)propoxy]aniline (640 mg, 2.56 mmol, 1.20 equiv), t-BuONa (616 mg, 6.41 mmol, 3.00 , BINAP (133 mg, 0.21 mmol, 0.10 equiv), a)3CHCl3 (220 mg, 0.10 equiv), toluene (8 mL). The resulting solution was stirred for 3 h at 100 0C in an oil bath.

The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC with the following conditions (CombiFlash-l): Column, C18 silica gel, mobile phase, ol/H2O increasing to methanol/H20=9/1 within min, Detector, UV 254 nm product was ed.

The crude product was puriﬁed by Prep-HPLC H. This resulted in 57.5 mg (7%) of N2-(4- methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4-methylpyridine-2,4-diamine as a solid.

Example 24: Synthesis of Compound 256 Compound 256: Synthesis of Nz-(4-meth0xy(3-(pyrrolidin yl)propoxy)phenyl)-N4-(oxetanylmethyl)pyrimidine-2,4-diamine f" " Q CIﬂC1—’"2 l NAG] I {NH 0 K2CO3DMF oI:ANH O— Step 1: Synthesis of 2-chloro-N-(oxetanylmethyl)pyrimidinamine: Into a 20-mL vial, was placed N,N—dimethylformamide (3 mL), 2,4- dichloropyrimidine (595 mg, 3.99 mmol, 1 equiv), oxetanylmethanamine (350 mg, 4.02 mmol, 1.01 equiv), potassium carbonate (555 mg, 4.02 mmol, 1.01 equiv). The ing solution was stirred for 2 h at 20 0C. The residue was applied onto a silica gel column with ACN/HzO (1 :9). The collected fractions were combined and concentrated under .

This resulted in 570 mg (71%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = n, LCMS33: m/z = 200 [M+1].

Step 2: Synthesis of methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine: Into a 20-mL round-bottom ﬂask, was placed 2-chloro-N-(oxetan ylmethyl)pyrimidinamine (200 mg, 1 mol, 1 equiv), 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (251 mg, 1 mmol, 1 equiv), triﬂuoroacetic acid (195 mg, 1.73 mmol, 2.00 equiv), propanol (2 mL). The resulting solution was stirred for 2 h at 85 0C in an oil bath.

The resulting mixture was trated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC C. This resulted in 20.1 mg (4%) of N2-(4-methoxy(3-(pyrrolidin- ropoxy)phenyl)-N4-(oxetanylmethyl)pyrimidine-2,4-diamine as ayellow solid.

Example 25: Synthesis of Compound 257 Compound 257: Synthesis of N-(4-methoxy-3—(3-(pyrrolidin yl)propoxy)phenyl)—1-methyl-1H-pyrazolo[3,4-b]pyridinamine / NWOQNHZ CI N N\ N O CH3] / ‘ /‘N | /ON]©\U \ Pd2(dba)3CHC|3,Xantphos N/V\O Step 1: Synthesis of 6-chloromethyl-1H-pyrazolo[3,4-b]pyridine: Into a 100-mL round-bottom ﬂask, was placed N,N—dimethylformamide (10 mL), sodium hydride (235 mg, 9.79 mmol, 1.50 equiv).This was followed by addition of 6-chloro- 1H-pyrazolo[3,4-b]pyridine (1 g, 6.51 mol, 1 equiv) at 0 0C. The resulting solution was stirred for 30 min at 0 0C. To this above, iodomethane (1.02g, 7.19 mmol, 1.10 equiv) was added. The reaction was allowed to react for 2h at 0 0C. The on was then quenched by the addition of 5 mL of water. The residue was applied onto a C18 column with Water/ACN (7:3). This resulted in 500 mg (46%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.729min, LCMS 27: m/Z = 168 [M+l].

Step 2: Synthesis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- (oxetanylmethyl)pyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of en, was placed dioxane (10 mL), 6-chloromethyl-1H-pyrazolo[3,4-b]pyridine (200 mg, 1.19 mmol, 1 equiv), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (300 mg, 1.20 mol, 1 equiv), Pd2(dba)3CHCl3 (186 mg, 0.18 mmol, 0.15 equiv), os (210 mg, 0.36 mmol, 0.30 equiv), Cs2CO3 (780 mg, 2.39 mmol, 2.01 equiv). The resulting on was stirred for 14 h at 80 °C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by PLC D. This resulted in 97.0 mg (19%) ofN-(4- methoxy(3-(pyrrolidinyl)propoxy)phenyl)methyl-1H-pyrazolo[3,4-b]pyridin amine as a solid.

Example 26: Synthesis of Compound 258 Compound 258: Synthesis of N-(4-methoxy-3—(3-(pyrrolidin poxy)phenyl)—1-methyl-1H-imidaz0[4,5-c]pyridin-6—amine H H CljinCI MeNH2 N CI Fe,NH4C| CI / / /N / I I \ N \ N \ N OZN OzN H2N ﬁg} CI/[NE/r\in Z "0 £9 cszcgépﬁzwbah @MO m N/ Step 1: Synthesis of 2-chloro-N-methylnitropyridinamine: [055 8] Into a 30-mL sealed tube, was placed 2,4-dichloronitropyridine (2 g, 10.36 mol, 1 equiv), DIEA (2.69 g, 20.81 mmol, 2.00 equiv), tetrahydrofuran (20 mL), NH2CH3-HCl (1.06 g, 2.00 equiv). The resulting solution was stirred for 12 h at 25 °C. The crude product was puriﬁed by Flash-Prep-HPLC A. This ed in 1.2 g (62%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): 188 [M+1], R: 1.12 min.

Step 2: Synthesis of 6-chloroN-methylpyridine-3,4-diamine: Into a 100-mL bottom ﬂask, was placed 2-chloro-N-methylnitropyridin amine (2 g, 10.66 mmol, 1 equiv), Fe (2.99 g, 5.00 equiv), NH4Cl (5.7 g, 106.56 mmol, 10.00 equiv), methanol (20 mL), water (20 mL). The resulting solution was stirred for 12 h at 80 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 600 mg (36%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): 158 [M+1], R: 0.982 min.

Step 3: Synthesis of 6-chloromethyl-1H-imidazo[4,5-c]pyridine: Into a 100-mL round-bottom ﬂask, was placed 6-chloroN-methylpyridine-3,4- diamine (500 mg, 3.17 mol, 1 , trimethoxymethane (20 mL). The resulting solution was stirred for 4 h at 100 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC A. This resulted in 200 mg (38%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): 168 [M+1], R: 0.841 min.

Step 4: sis of N-[4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]methyl- 1H-imidazo[4,5-c]pyridinamine: Into a 30-mL sealed tube, was placed 6-chloromethyl-1H-imidazo[4,5-c]pyridine (300 mg, 1.79 mol, 1 equiv), Cs2CO3 (1.76 g, 5.40 mmol, 3.00 equiv), a)3-CHCl3 (100 mg), X-phos (100 mg), 1,4-dioxane (15 mL), 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (540 mg, 2.16 mmol, 1.20 equiv). The resulting solution was stirred for 4 h at 100 0C in an oil bath. The solids were ﬁltered out. The crude product was d by Prep-HPLC E. This resulted in 54.2 mg (7%) of N—(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)methyl-1H-imidazo[4,5-c]pyridinamine as a yellow solid.

Example 27: Synthesis of Compound 259 Compound 259: Synthesis of N2-(4-methoxy((2-methylazaspiro[4.5]decan- 8-yl)oxy)phenyl)-N4-((tetrahydr0-2H—pyranyl)methyl)pyrimidine-2,4—diamine (EiO)2POCH2COOEt | CH3N02 Raney- Ni NaH,DMF 1 M TBAFmTHF H2EiOH \_l o o o o oo\_/ \_/ \_/ ICbZ Cbz ,CbZ NH N’ N LiAIH4,THF CbZ-CI OH NaBH4 —. —. _, _.

NaZC03,H20,THF MeOH O] O, \ / 0 OH benzyl 1,4-dioxa-1O-azadispir0[4.2.48.25]ieiradecane-1O-carboxylaie N N02 N02 MsCI C52C03,DMF Q TFA Q HCHO,STAB —. —. —. —. 0M3 Cbz NH2 NNJ‘CI Pol/CH2 PTSAi-PrOH \ N\ Step 1: sis of ethyl 2-[1,4-dioxaspiro[4.5]decanylidene]acetate: Into a 250-mL bottom ﬂask, was placed ethyl 2-(diethoxyphosphoryl)acetate (14.4 g, 64.23 mol, 1 equiv), tetrahydrofuran (150 mL), sodium hydride (5.12 g, 213.33 mmol, 3.33 equiv), oxaspiro[4.5]decanone (10 g, 64.03 mol, 1 equiv). The resulting solution was stirred overnight at 0 0C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under .

The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5).

This resulted in 12 g (83%) of as ayellow liquid.

Analytical Data: 1H NMR (300 MHz, Chloroform—d) 5 5.67 (p, J = 1.1 Hz, 1H), 4.15 (q, J: 7.1 Hz, 2H), 3.98 (s, 4H), 3.00 (ddd, J: 7.8, 5.1, 1.2 Hz, 2H), 2.44 — 2.32 (m, 2H), 1.84 — 1.70 (m, 4H), 1.28 (t, J: 7.1 Hz, 3H).

Step 2: Synthesis of ethyl 2-[8-(nitromethyl)—1,4-dioxaspiro[4.5]decanyl]acetate: Into a 500-mL round-bottom ﬂask, was placed ethyl 2-[1,4-dioxaspiro[4.5]decan ylidene] acetate (12 g, 53.03 mmol, 1 equiv), tetrahydrofuran (150 mL), nitromethane (13 g, 212.98 mmol, 4.02 equiv), TBAF ydrofuran (80 mL). The resulting solution was stirred overnight at 70 0C. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined. The ing mixture was washed with 3x30 mL of H20.

The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 11 g (72%) of the title compound as ayellow liquid.

Analytical Data: 1H NMR (300 MHz, form—d) 5 4.73 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.95 (s, 4H), 2.57 (s, 2H), 1.85 — 1.63 (m, 6H), 1.35 — 1.18 (m, 3H).

Step 3: Synthesis of 1,4-dioxaazadispiro[4.2.48.25]tetradecanone: Into a 500-mL round-bottom ﬂask, was placed ethyl 2-[8-(nitromethyl)-1,4- piro[4.5]decanyl]acetate (5 g, 17.40 mol, 1 equiv), methanol (200 mL), Raney-Ni (1 g), TEA (5 g, 49.41 mmol, 2.84 equiv), en (500 mL). The resulting solution was stirred overnight at RT. The solids were ﬁltered out. The resulting e was concentrated under vacuum. This resulted in 4 g (100%) of the title compound as a white solid. ical Data: 1H NMR (300 MHz, Chloroform—d) 5 6.35 (s, 1H), 3.96 (s, 4H), 3.21 (s, 2H), 2.23 (s, 2H), 1.79 — 1.60 (m, 8H).

Step 4: Synthesis of 1,4-dioxaazadispiro[4.2.48.25]tetradecane: Into a 1-L round-bottom ﬂask, was placed 1,4-dioxa—10- azadispiro[4.2.48.25]tetradecanone (5.28 g, 24.99 mol, 1 equiv), tetrahydrofuran (500 mL), LAH (2.85 g, 75.10 mmol, 3.00 equiv) at 0 0C. After 1 h, the resulting solution was stirred overnight at 50 0C. The reaction was then quenched by the addition of 2.85 g of water, 2.85 g of 15% NaOH, 8.55 g of water The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 3.6 g (73%) of the title compound as a colorless Analytical Data: 1H NMR (300 MHz, Chloroform—d) 5 5.14 (s, 1H), 3.96 (s, 4H), 3.06 (t, J: 7.2 Hz, 2H), 2.81 (s, 2H), 1.65 (d, J: 6.2 Hz, 10H).

Step 5: sis of benzyl 1,4-dioxaazadispiro[4.2.48.25]tetradecane carboxylate: Into a 250-mL round-bottom ﬂask, was placed 1,4-dioxa—10- azadispiro[4.2.48.25]tetradecane (3.6 g, 18.25 mol, 1 equiv), sodium carbonate (7.3 g, 68.87 mmol, 3.77 equiv), water(20 mL), tetrahydrofuran (20 mL), benzyl chloroformate (3.7 g, 21.69 mmol, 1.19 equiv). The resulting on was stirred overnight at RT. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined.

The resulting mixture was washed with 3x50 mL of H20. The solid was dried in an oven under d pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2: 1). This resulted in 3.5 g (58%) of the title compound as a colorless liquid.

WO 81177 1H NMR (300 MHz, Chloroform—d) 5 7.47 — 7.30 (m, 5H), 3.96 (s, 4H), 3.49 (t, J: 7.2 Hz, 2H), 3.28 (s, 2H), 1.86 — 1.51 (m, 10H).

Step 6: Synthesis of benzyl 8-oxoazaspiro[4.5]decanecarboxylate: Into a 250-mL round-bottom ﬂask, was placed benzyl oxa—10- azadispiro[4.2.4/‘[8].2"[5]]tetradecanecarboxylate (2.5 g, 7.54 mol, 1 equiv), methanol (50 mL). This was ed by the addition of HCl (10 mL). 2N The resulting solution was stirred overnight at RT. The resulting on was extracted with 3x30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x30 mL of H20. The solid was dried in an oven under reduced pressure. This resulted in 2.0 g (83%) of the title compound as a colorless liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.877min, LCMS 45, m/Z =288 [M+1].

Step 7: Synthesis of benzyl 8-hydroxyazaspiro[4.5]decanecarboxylate: Into a 100-mL round-bottom ﬂask, was placed benzyl 8-oxoazaspiro[4.5]decane—2- carboxylate (1.77 g, 6.16 mmol, 1 equiv), methanol (30 mL), NaBH4 (350 mg, 9.25 mmol, 1.50 equiv). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 10 mL of water. The ing solution was extracted with 3x20 mL of dichloromethane and the organic layers combined. The resulting e was washed with 3x20 mL of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.6 g (81%) of the title compound as a colorless liquid.

LC-MS: (ES, m/Z): RT=0.876 min, LCMS 45, m/Z =290 [M+1].

Step 8: Synthesis of benzyl 8-(methanesulfonyloxy)azaspiro[4.5]decane carboxylate: Into a 250-mL round-bottom ﬂask, was placed benzyl 8-hydroxy ro[4.5]decanecarboxylate (1.87 g, 6.46 mmol, 1 equiv), dichloromethane (50 mL), TEA (1.96 g, 19.37 mmol, 3.00 equiv), MsCl (885 mg). The resulting solution was stirred for 1 h at 0 0C. The reaction was then quenched by the on of 20 mL of water. The resulting on was extracted with 3x30 mL of dichloromethane and the organic layers combined.

The resulting mixture was washed with 3x30 mL of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.0 g (76%) of the title compound as a colorless .

Analytical Data: LC-MS: (ES, m/z): RT=1.301 min, LCMS 53, m/Z =368 [M+1].

Step 9: Synthesis of benzyl 8-(2-methoxynitrophenoxy)azaspiro[4.5]decane carboxylate: Into a 100-mL round-bottom ﬂask, was placed benzyl 8-(methanesulfonyloxy) azaspiro[4.5]decanecarboxylate (2.5 g, 6.80 mol, 1 , 2-methoxynitrophenol (1.27 g, 7.51 mmol, 1.10 equiv), Cs2C03 (4.5 g, 13.81 mmol, 2.03 , N,N— dimethylformamide (25 mL). The ing solution was stirred for 5 h at 80 0C. The reaction was then quenched by the addition of 50 mL of water. The ing on was extracted with 3x50 mL of ether and the organic layers combined. The resulting e was washed with 3x50 mL of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl e/petroleum ether (2:1). This resulted in 970 mg (31%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT=1.486 min, LCMS 53, m/Z =441 [M+1].

Step 10: Synthesis of 8-(2-methoxynitrophenoxy)azaspiro[4.5]decane: Into a 100-mL round-bottom ﬂask, was placed benzyl 8-(2-methoxynitrophenoxy)- 2-azaspiro[4.5]decanecarboxylate (900 mg, 2.04 mmol, 1 equiv), triﬂuoroacetic acid (5 mL). The resulting solution was stirred for 2 h at 60 0C. The resulting mixture was concentrated under vacuum. This resulted in 900 mg (129%) of the title compound as a yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.968 min, LCMS 34, m/Z =307 [M+1].

Step 11: Synthesis of 8-(2-methoxynitrophenoxy)methyl azaspiro[4.5]decane: Into a 100-mL round-bottom ﬂask, was placed 8-(2-methoxynitrophenoxy) azaspiro[4.5]decane (800 mg, 2.61 mol, 1 equiv), ol (20 mL), NaBH3CN (832 mg, 13.24 mmol, 5.07 equiv), HCHO (780 mg). The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined.

The resulting e was washed with 3x50 mL of H20. The e was dried over anhydrous sodium sulfate. The crude product was puriﬁed by Flash-Prep-HPLC A MeOH.

This resulted in 300 mg (32%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.777 min, LCMS 45, m/Z =321 [M+1].

Step 12: Synthesis of 4-methoxy([2-methylazaspiro[4.5]decan yl]oxy)aniline: Into a 100-mL round-bottom ﬂask, was placed 8-(2-methoxynitrophenoxy) methylazaspiro[4.5]decane (300 mg, 0.94 mmol, 1 equiv), methanol (20 mL), Pd/Cl (50 mg), hydrogen (100 mL). The resulting solution was stirred for 2 h at RT. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. This resulted in 220 mg (73%) of the title compound as a light red liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.773 min, LCMS 28, m/Z =291 [M+l].

Step 13: Synthesis of N2-(4-methoxy((2-methylazaspiro[4.5]decan yl)oxy)phenyl)-N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine: Into a 10-mL round-bottom ﬂask, was placed 4-methoxy([2-methyl azaspiro[4.5]decanyl]oxy)aniline (120 mg, 0.41 mmol, 1 equiv), 2-chloro-N-(oxan ylmethyl)pyrimidinamine (94 mg, 0.41 mmol, 1 equiv), triﬂuoroacetic acid (50 mg, 0.44 mmol, 1.07 equiv), isopropanol (5 mL). The resulting solution was stirred for 2 h at 85 0C.

The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC C-HCl. This resulted in 14.0 mg (6%) of N2-(4-methoxy((2-methyl ro[4.5]decanyl)oxy)phenyl)-N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4- diamine as a white solid.

Example 28: Synthesis of Compound 260 Compound 260: Synthesis of N2-(4-methoxy-3—((2-methylazaspiro[3.5]n0nan- xy)phenyl)-N4-((tetrahydr0-2H-pyranyl)methyl)pyrimidine-2,4—diamine \o—<;>—No2 No2 Boo-N:><:>—OH—>MsC[,TEA ><:>*OMS HO C52C03,DMF —o O—<:><:N-Boc No2 No2 TFA NaBH3CN Pd/C,H2 —> Q Q —> \o 04<:><:NH HCHO,CH30H —o :N_ \ fl\N Q / N N NH N’kC] H / 0 Cf N, —o o~<:><:N— TFA,i-PrOH Step 1: Synthesis of tert-butyl 7-(methanesulfonyloxy)—2-azaspiro[3.5]nonane carboxylate: Into a 100-mL round-bottom ﬂask, was placed tert—butyl 7-hydroxy azaspiro[3.5]nonanecarboxylate (300 mg, 1.24 mol, 1 equiv), dichloromethane (10 mL), ylamine (377 mg, 3.73 mmol, 3.00 equiv), methanesulfonyl chloride (286 mg, 2.50 mmol, 2.01 equiv). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of dichloromethane and the c layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum.

This resulted in 350 mg (88%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.279min, LCMS 31: m/z= 320.45[M+1].

Step 2: Synthesis of utyl 7-(2-methoxynitrophenoxy)azaspiro[3.5]nonane- 2-carboxylate: Into a 50-mL round-bottom ﬂask, was placed tert-butyl 7-(methanesulfonyloxy) azaspiro[3.5]nonanecarboxylate (450 mg, 1.41 mol, 1 equiv), Cs2CO3 (1.38 g, 4.24 mmol, 3.01 equiv), N,N-dimethylformamide (5 mL), 2-methoxynitrophenol (358 mg, 2.12 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 80 0C. The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC A Grad. This resulted in 220 mg (40%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 2.215min, LCMS 45: m/z= [M+1]. 1H NMR (300 MHz, Chloroform-d) 5 7.90 (dd, J: 9.0, 2.6 Hz, 1H), 7.74 (d, J: 2.7 Hz, 1H), 6.92 (d, J: 9.0 Hz, 1H), 4.40 — 4.28 (m, 1H), 3.95 (s, 3H), 3.64 (d, J: 7.1 Hz, 4H), 2.05 — 1.92 (m, 4H), 1.77 — 1.58 (m, 4H), 1.45 (s, 9H).

Step 3: Synthesis of 7-(2-methoxynitrophenoxy)azaspiro[3.5]nonane: Into a 50-mL round-bottom ﬂask, was placed tert-butyl 7-(2-methoxy nitrophenoxy)azaspiro[3.5]nonanecarboxylate (220 mg, 0.56 mol, 1 equiv), triﬂuoroacetic acid (5 mL), dichloromethane (10 mL). The resulting solution was stirred for min at RT. The resulting mixture was trated under vacuum. This resulted in 150 mg (92%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.864 min, LCMS 45: m/z= 293.10 [M+1]. 1H NMR (300 MHz, Chloroform-d) 5 10.24 (s, 1H), 7.91 (dd, J: 9.0, 1.9 Hz, 1H), 7.75 — 7.71 (m, 1H), 6.93 (d, J: 9.0 Hz, 1H), 4.40 — 4.28 (m, 1H), 3.94 (s, 3H), 3.90 — 3.80 (m, 4H), 2.22 — 2.10 (m, 2H), 1.99 — 1.82 (m, 2H), 1.81 — 1.49 (m, 4H).

Step 4: Synthesis of 7-(2-methoxynitrophenoxy)methylazaspiro[3.5]nonane: Into a 50-mL round-bottom ﬂask, was placed 7-(2-methoxynitrophenoxy) ro[3.5]nonane (150 mg, 0.51 mmol, 1 equiv), HCHO (23 mg), ol (5 mL), NaBH3CN (162 mg, 2.58 mmol, 5.02 . The resulting on was stirred for 1 h at RT.

The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (64%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.817min, LCMS 45: m/z= 307.15 [M+l]. 1H NMR (300 MHz, Chloroform-d) 5 8.00 — 7.88 (m, 1H), 7.76 (d, J: 2.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.40 — 4.31 (m, 1H), 3.96 (s, 3H), 3.44 (d, J: 5.7 Hz, 4H), 2.62 (s, 3H), 2.20 — 2.04 (m, 2H), 2.02 — 1.88 (m, 2H), 1.80 — 1.61 (m, 4H).

Step 5: sis of oxy([2-methylazaspiro[3.5]nonanyl]oxy)aniline: Into a 50-mL round-bottom ﬂask purged and maintained with H2, was placed 7-(2- ynitrophenoxy)methylazaspiro[3.5]nonane (100 mg, 0.33 mmol, 1 equiv), Pd/C(20 mg), methanol (10 mL). The ing solution was stirred for 1 h at RT. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 80 mg (89%) of the title compound as a light yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.734min, LCMS 15: m/z= 277.10 [M+l]. 1H NMR (300 MHz, Chloroform-d) 5 6.72 (d, J: 8.4 Hz, 1H), 6.38 — 6.22 (m, 2H), 4.19 — 4.08 (m, 1H), 3.77 (s, 3H), 3.31 (d, J: 11.4 Hz, 4H), 2.53 (s, 3H), 2.16 — 2.01 (m, 2H), 1.96 — 1.81 (m, 2H), 1.73 — 1.52 (m, 4H).

Step 6: Synthesis of N2-(4-methoxy((2-methylazaspiro[3.5]nonan yl)oxy)phenyl)-N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy([2-methyl azaspiro[3.5]nonanyl]oxy)aniline (75 mg, 0.27 mmol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (62 mg, 0.54 mmol, 2.00 equiv), 2-chloro-N-(oxanylmethyl)pyrimidin- 4-amine (62 mg, 0.27 mol, 1 equiv). The ing solution was stirred for 2 h at 80 0C. The crude product was puriﬁed by PLC F. This resulted in 86.1 mg (63%) of N2-(4- methoxy((2-methylazaspiro[3.5]nonanyl)oxy)phenyl)-N4-((tetrahydro-2H-pyran yl)methyl)pyrimidine-2,4-diamine as a solid.

Example 29: Synthesis of Compound 261 Compound 261: Synthesis of 6-meth0xy-N2-(4-methoxy—3-(3—(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine Cl M)? CINMO/20NHD «allay/0 lej\ / O/ TsOH((1),eq)i-,PrOH 50°C, 3d O1 /NH2 "r1 Nd OMO NAN\ o Pd2(dba)3CHC[3,Xantphos H | Step 1: Synthesis of 4-chloromethoxy-N-[4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]pyrimidinamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (800 mg, 3.20 mol, 1 equiv), 2,4-dichloromethoxypyrimidine (573 mg, 3.20 mmol, 1 equiv), TsOH (608 mg, 3.20 mol, 1 equiv), isopropanol (10 mL). The resulting solution was stirred for 3d at 50 0C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with HZO/ACN/NH4HC03. This resulted in 120 mg (10%) as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.113 min, LCMS 28: m/z =393 [M+1].

Step 2: Synthesis of 6-methoxy-N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed romethoxy-N—[4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]pyrimidinamine (350 mg, 0.89 mol, 1 equiv), amine 2M in ydrofuran (0.9 mg, 2.00 equiv), Pd2(dba)3CHCl3 (93 mg, 0.10 equiv), BINAP (111 mg, 0.18 mmol, 0.20 equiv), t-BuONa (256 mg, 2.66 mmol, 3.00 equiv), Toluene (10 mL). The resulting solution was stirred for overnight at 80 0C in an oil bath under N2 (g) atmosphere.

The resulting mixture was concentrated under vacuum. The solids were ﬁltered out. The e was d by ﬂash chromatography with ACN/HzO(1/10). This ed in 40.3 mg (12%) of 6-methoxy-N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as an off-white solid.

Example 30: Synthesis of nds 262a and 262b Compound 262a and 262b: Synthesis of N4-methyl-N2-((1R,3S)—3-(3-(pyrrolidin- 1-yl)propoxy)cyclohexyl)pyrimidine-2,4-diamine and N4-methyl-N2-((1S,3R)(3- (pyrrolidinyl)propoxy)cyclohexyl)pyrimidine-2,4—diamine PTSA IPA 110 °C HZN 0WD—.Rh/AIZO3HOAC HZN OWNO é» O 60atm 100°C U KEN/ C’M0., "A1\ H ﬁAN N/ Step 1: Synthesis of 3-[3-(pyrrolidinyl)propoxy]cyclohexan-l-amine: Into a 30-mL pressure tank reactor (60 atm), was placed pyrrolidin-l- yl)propoxy]aniline (500 mg, 2.27 mol, 1 equiv), acetic acid (15 mL), Rh/A1203 (0.3 g), hydrogen (1 g). The resulting on was stirred for 5 h at 100 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 1.9 g (crude) of as an oil. ical Data: LC-MS: (ES, m/z): MS = 227 [M+1].

Step 2: Synthesis of N4-methyl-N2-((1R,3S)(3-(pyrrolidin yl)propoxy)cyclohexyl)pyrimidine-2,4-diamine and N4-methyl-N2-((l S,3R)(3-(pyrrolidin- 1-yl)propoxy)cyclohexyl)pyrimidine-2,4-diamine: Into a 30-mL pressure tank reactor, was placed 2-chloro-N-methylpyrimidinamine (550 mg, 3.83 mmol, 1.20 equiv), 3-[3-(pyrrolidinyl)propoxy]cyclohexanamine (720 mg, 3.18 mol, 1 equiv), PTSA (1 g, 5.81 mmol, 2.00 equiv), IPA (10 mL). The resulting on was stirred for 12 h at 110 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A MeOH. The crude t 120mg was puriﬁed by Chiral-Prep-HPLC This resulted in 42.6 mg (3%) of omer I (randomly assigned) as yellow oil and 32.0 mg (2%) enantiomer 2 (randomly assigned) as an oil.

Example 31: Synthesis of Compound 263 Compound 263: Synthesis of Nz-(4-meth0xy(3-(pyrrolidin yl)pr0poxy)phenyl)-N4-methquuinazoline-2,4-diamine o HN/ c1 0 C,NMO CL / NH N/ l NHZCHSITHF, I )\\ Cl/[LNI _ N/\/\ D ko N N C] N TFA,IPA H Step 3: Synthesis of 2-chloro-N-methylquinazolinamine: Into a 50-mL round-bottom ﬂask, was placed 2,4-dichloroquinazoline (1 g, 5.02 mol, 1 equiv), tetrahydrofuran (10 mL), TEA (772 mg, 7.63 mmol, 1.50 equiv), THF (7.5 mL, 3.00 equiv). The resulting solution was stirred for 1 h at 0 0C in a ice bath. The resulting mixture was concentrated under . The residue was applied onto a silica gel column with CH3CN/HZO (1:7). This resulted in 900 mg (93%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.33min, LCMS33: m/z = 194 [M+l]. 1H NMR (400 MHz, Methanol-d4) 5 8.08 — 8.00 (m, 1H), 7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.54- 7.49 (m, 1H), 3.13 (s, 3H).

Step 4: Synthesis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- methylquinazoline-2,4-diamine: Into a 25-mL round-bottom ﬂask, was placed 2-chloro-N-methylquinazolinamine (300 mg, 1.55 mol, 1 equiv), triﬂuoroacetic acid (354.4 mg, 3.14 mmol, 2.00 equiv), 4- methoxy[3-(pyrrolidinyl)propoxy]aniline (388.6 mg, 1.55 mol, 1 equiv), propanol (5 mL). The resulting solution was stirred for 2 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude t (300 mg) was d by Prep- HPLC D. This resulted in 64.7 mg (10%) of N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylquinazoline-2,4-diamine as an off-white solid.

Example 32: Synthesis of Compound 264 Compound 264: Synthesis of (methylamin0)pyrimidin-2—yl)amino)—2-(2- (pyrrolidinyl)ethyl)-3,4-dihydroisoquinolin-1(2H)-0ne FWD")2: H2 N/\’N CINE", N/\/N NO NH2 —>_ N’\/N N \N N/ 2 MeOH TFA, I-PI’OH H H O o Step 1: Synthesis of 7-amino[2-(pyrrolidinyl)ethyl]-1,2,3,4- tetrahydroisoquinolin-1 -one: Into a 100-mL round-bottom ﬂask, was placed 7-nitro[2-(pyrrolidinyl)ethyl]- 1,2-dihydroisoquinolinone (100 mg, 0.35 mol, 1 equiv), methanol (20 mL), Pd(OH2), hydrogen. The resulting solution was stirred for 16 h at 25 0C. The solids were d out.

The resulting e was concentrated under vacuum. This resulted in 60 mg (66%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.302min, LCMS 31, m/z =260 [M+l].

Step 2: Synthesis of 7-((4-(methylamino)pyrimidinyl)amino)(2-(pyrrolidin yl)ethyl)-3 ,4-dihydroisoquinolin-1(2H)-one: Into a 25-mL round-bottom ﬂask, was placed o[2-(pyrrolidinyl)ethyl]- 1,2,3,4-tetrahydroisoquinolinone (60 mg, 0.23 mol, 1 equiv), 2-chloro-N- methylpyrimidinamine (34 mg, 0.24 mol, 1 , isopropanol (6 mL), triﬂuoroacetic acid (52 mg, 0.46 mmol, 2.00 equiv). The resulting solution was stirred for 4 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 45.3 mg (41%) of the title compound as a solid.

Example 33: Synthesis of Compound 265 Compound 265: Synthesis of ethoxy(3-(pyrrolidin yl)pr0p0xy)phenyl)—1H-indolamine MO:C‘NO/o NH CN / 2 "I; ii) 3rd-Brettphos N Br CF/\/\0 K2003,DMSO Step 1: Synthesis of ethoxy(3-(pyrrolidinyl)propoxy)phenyl)-1H-indol- 4-amine: Into a 50-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed o-1H-indole (200 mg, 1.02 mmol, 1 equiv), 3rd-BrettPhos (46 mg, 0.05 mmol, 0.05 equiv), potassium methaneperoxoate (283 mg, 2.03 mmol, 2.00 equiv), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (256.4 mg, 1.02 mol, 1 equiv), DMSO (5 mL). The resulting solution was d for 6 h at 85 0C in an oil bath. The resulting solution was diluted with 10 mL of H20. The pH value of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with 3x10 mL of dichloromethane and the c layers combined. HCl (aq) was employed to adjust the pH to 4. The ing mixture was washed with 3x10 mL of H20. The resulting mixture was concentrated under vacuum.

The crude product (200 mg) was puriﬁed by Prep-HPLC C TFA. This resulted in 91.9 mg (19%) of N—(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-1H-indolamine as a white solid.

Example 34: Synthesis of Compound 266 Compound 266: Synthesis of N-(4-methoxy-3—(3-(pyrrolidin yl)propoxy)phenyl)-1H-pyrrolo[3,2—c]pyridinamine / o o / / /I \ Brettphos,C52CO3,dioxane @MO N \N Step 1: Synthesis ofN-[4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]-1H- pyrrolo[3,2-c]pyridinamine: Into a 20-mL vial, was placed dioxane (2 mL), 4-chloro-1H-pyrrolo[3,2-c]pyridine (200 mg, 1.31 mol, 1 equiv), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (329 mg, 1.31 mol, 1 equiv), Brettphos (230 mg), CszC03 (781 mg, 2.40 mmol, 1.83 equiv). The vial was purged and maintained with N2.The resulting solution was stirred for 12 h at 100°C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Chiral-Prep-HPLC D TFA. This ed in 74.1 mg (12%) of N—(4-methoxy(3- (pyrrolidinyl)propoxy)phenyl)-1H-pyrrolo[3,2-c]pyridinamine as a an solid.

Example 35: Synthesis of nd 267 Compound 267: Synthesis of N4-methyl-N2-(6-((2-(pyrrolidin oxy)methyl)pyridinyl)pyridine-2,4-diamine N’\’OH O \ O \ | JR | I C! N/ BrLGINO Br / N/ kN N Br H NaH, DMF GINO szdba3,XPhos N/\/0 50 "01 N NH2 szdba3 Step 1: sis of 2-bromo[[2-(pyrrolidinyl)ethoxy]methyl]pyridine: Into a 250-mL round-bottom ﬂask, was placed 2-bromo(bromomethyl)pyridine (2 g, 7.97 mol, 1 equiv), sodium hydride (956 mg, 39.83 mmol, 5.00 equiv), N,N— dimethylformamide (80 mL), rolidinyl)ethanol (1.1 g, 9.55 mmol, 1.20 equiv).

The resulting solution was stirred for 1 h at 0 0C in a water/ice bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the c layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 910 mg (40%) of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT= 0.85 min, LCMS 34: m/z = 285 [M+1].

Step 2: Synthesis of N—(6-[[2-(pyrrolidinyl)ethoxy]methyl]pyridinyl)acetamide: Into a 250-mL round-bottom ﬂask, was placed 2-bromo[[2-(pyrrolidin yl)ethoxy]methyl]pyridine (910 mg, 3.19 mol, 1 equiv), X-phos (100 mg), Cs2C03 (3.134 g, 9.62 mmol, 3.00 equiv), dioxane (10 mL), Pd2(dba)3.CHC13 (100 mg), acetamide (567 mg, 9.60 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 80 0C in an oil bath. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 460 mg (55%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT= 0.72 min, LCMS 28: m/z = 264 [M+1].

Step 3: Synthesis of 6-[[2-(pyrrolidinyl)ethoxy]methyl]pyridinamine: Into a 100-mL bottom ﬂask, was placed [2-(pyrrolidin yl)ethoxy]methyl]pyridinyl)acetamide (460 mg, 1.75 mol, 1 equiv), sodiumol (350 mg, 8.75 mmol, 5.00 equiv), methanol (20 mL), water(20 mL). The ing solution was stirred for 12 h at 70 0C. The crude product was puriﬁed by Prep-HPLC A 1:1. This resulted in 230 mg (59%) of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT= 0.62 min, LCMS 53: m/z = 222 [M+1].

Step 4; sis ofN4-methyl-N2-(6-((2-(pyrrolidinyl)ethoxy)methyl)pyridin yl)pyridine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-bromo-N-methylpyridinamine (180 mg, 0.96 mol, 1 equiv), 6-[[2-(pyrrolidinyl)ethoxy]methyl]pyridinamine (255.3 mg, 1.15 mmol, 1.20 equiv), Cs2C03 (939 mg, 2.88 mmol, 3.00 equiv), szdba3-CHC13 (10 mg), X-phos (10 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 10 h at 100 0C.

The crude product was d by Flash-Prep-HPLC A 1:1.This resulted in 39.3 mg (11%) of N4-methyl-N2-(6-((2-(pyrrolidinyl)ethoxy)methyl)pyridinyl)pyridine-2,4-diamine as a light yellow solid.

Example 36: Synthesis of Compound 268 Compound 268: Synthesis of Nz-methyl-N4-(6-((2-(pyrrolidin yl)eth0xy)methyl)pyridin-Z-yl)pyridine-2,4-diamine /[\l \ / N \ \ Br N’ I | l H / \ / ONO /\/O N M H/ G N NH? Pdgdba3 Step 1; Synthesis ofN2-methyl-N4-(6-((2-(pyrrolidinyl)ethoxy)methyl)pyridin yl)pyridine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 6-[[2-(pyrrolidin yl)ethoxy]methyl]pyridinamine (220 mg, 0.99 mol, 1 equiv), 4-bromo-N-methylpyridin- 2-amine (224 mg, 1.20 mmol, 1.20 equiv), Cs2CO3 (978 mg, 3.00 mmol, 3.00 , szdba3-CHC13 (50 mg), Xantphos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 0C. The crude product was puriﬁed by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, silica gel, mobile phase, ACN/H20=1/1, Detector, Uv 254 nm. This resulted in 56.5 mg (17%) ofN2-methyl-N4-(6-((2-(pyrrolidin yl)ethoxy)methyl)pyridinyl)pyridine-2,4-diamine as a solid.

Example 37: sis of Compound 272 Compound 272: nd Synthesis of S-ﬂuoro-Nz-(4-methoxy(3— (pyrrolidinyl)pr0poxy)phenyl)-N4-methylpyridine-2,4—diamine 0‘ F HN/ /O / Cl V I) F N o NH2 | / _NH2 F \ I / N THF I OMO N Cl \N \N PTSAJ-PrOH Step 1: Synthesis of 2-chloroﬂuoro-N-methylpyridinamine: Into a 20-mL vial, was placed tetrahydrofuran (8 mL), 2,4-dichloroﬂuoropyridine (300 mg, 1.81 mol, 1 equiv), a solution of methanamine (113 mg, 3.64 mmol, 2.01 equiv) in ydrofuran (1.82 mL). The resulting solution was stirred for 18 h at 80 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether . This resulted in 200 mg (69%) of as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.469 min, LCMS 32: m/Z = 161 [M+1].

Step 2: sis of 5-ﬂuoro-N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)- N4-methylpyridine-2,4-diamine: Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed e (10 mL), 2-chloroﬂuoro-N-methylpyridinamine (190 mg, 1.18 mol, 1 equiv), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (327 mg, 1.31 mmol, 1.10 equiv), Pd2(dba)3-CHCl3 (184 mg, 0.18 mmol, 0.15 equiv), BINAP (222 mg, 0.36 mmol, 0.30 equiv), t-BuONa (342 mg, 3.56 mmol, 3.01 equiv). The resulting solution was d for 13 h at 100 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with Water (0.05% HCl)/ACN (5:1). This resulted in 89.1 mg (18%) of 5- ﬂuoro-NZ-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)—N4-methylpyridine-2,4-diamine as a light yellow solid.

Example 38: Synthesis of Compound 276 Compound 276: Synthesis of N2-(3-(2-ﬂu0r0—3—(pyrrolidinyl)pr0poxy)phenyl)- N4-methylpyrimidine-2,4-diamine N 0r1NC —> £1 CIr Ctr/YO —> or; 2 NH2 THE-78 °c C, /Y\N —. O"F00ONAJj Step 1: Synthesis of 1-[2-ﬂuoro(3-nitrophenoxy)propyl]pyrrolidine: Into a 50-mL 3-necked bottom ﬂask, was placed 1-(3-nitrophenoxy)—3- lidinyl)propanol (500 mg, 1.88 mmol, 1 equiv), dichloromethane (15 mL). This was followed by the on of a solution of DAST (363 mg, 2.25 mmol, 1.20 equiv) in dichloromethane (3 mL) dropwise with stirring at -78 0C in 1 min. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 5M/M mL of water. The resulting on was extracted with 3X10 mL of romethane and the s layers combined and concentrated under vacuum. This resulted in 400 mg (71%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.950 min, LCMS 31, m/Z =269.0 [M+1].

Step 2: Synthesis of 3-[2-ﬂuoro(pyrrolidinyl)propoxy]aniline: Into a 100-mL round-bottom ﬂask, was placed 1-[2-ﬂuoro(3- nitrophenoxy)propyl]pyrrolidine (400 mg, 1.49 mmol, 1 equiv), methanol (5 mL), hydrogen (100 mL), Pd/C (100 mg). The resulting solution was stirred for 2 h at RT. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 370 mg (104%) of the title compound as a yellow liquid.

LC-MS: (ES, m/Z): RT=1.040 min, LCMS 34, m/Z =239.0 [M+1]. 1H NMR: (300 MHz, Chloroform—cD 5 7.08 (t, J: 8.0 Hz, 1H), 6.43 — 6.25 (m, 3H), 4.83 (d, J: 4.4 Hz, 1H), 4.75 — 4.63 (m, 1H), 4.28 — 4.07 (m, 2H), 3.69 (s, 2H), 3.18 — 2.69 (m, 5H), 2.01 — 1.77 (m, Step 3: Synthesis of N2-(3-(2-ﬂuoro(pyrrolidinyl)propoxy)phenyl)—N4- methylpyrimidine-2,4-diamine: Into a 8-mL bottom ﬂask, was placed 2-chloro-N-methylpyrimidinamine (120 mg, 0.84 mol, 1 , 3-[2-ﬂuoro(pyrrolidinyl)propoxy]aniline (80 mg, 0.34 mmol, 0.40 equiv), triﬂuoroacetic acid (0.2 mL), isopropanol (3 mL). The resulting solution was stirred ght at 85 0C. The crude t was puriﬁed by Prep-HPLC C TFA. This ed in 37.4 mg (11%) of N2-(3-(2-ﬂuoro(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as a white solid.

Example 39: Synthesis of Compound 277 Compound 277: Synthesis of N2-(3-(2,2-diﬂuoro-3—(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine TEA,DCM 052003,DMF MsC[,TEA HOYOH—> Ho/YOTs —» Q —> F F 2 F F "0660 DCM Q N L] Neat Q Pd/C,H2,MeOH Mso/§(\o NO2 N02 F F Cid/YoF F C’N/KOONJTNN / TFA, IPA | Step 1: Synthesis of 2,2-diﬂuoro[[(4-methylbenzene)sulfonyl]oxy]propanol: Into a 100-mL round-bottom ﬂask, was placed 2,2-diﬂuoropropane-1,3-diol (600 mg, .35 mol, 1 equiv), TEA (1.4 g, 13.84 mmol, 3.00 equiv), romethane (50 mL), 4- methylbenzene-l-sulfonyl de (1.02 g, 5.35 mmol, 1 equiv). The resulting solution was stirred for 12 h at 25 0C. The resulting solution was extracted with 3X100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x100 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 500 mg (35%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): R: 1.19 min, 267 [M+1].

Step 2: Synthesis of 2,2-diﬂuoro(3-nitrophenoxy)propanol: Into a 100-mL round-bottom ﬂask, was placed 2,2-diﬂuoro[[(4- benzene)sulfonyl]oxy]propanol (550 mg, 2.07 mol, 1 equiv), Cs2CO3 (2 g, 6.14 mmol, 3.00 equiv), N,N-dimethylformamide (50 mL), 3-nitrophenol (431 mg, 3.10 mmol, 1.50 equiv). The resulting solution was stirred for 12 h at 100 0C in an oil bath. The resulting solution was extracted with 3x100 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium e and trated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 60 mg (12%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): R: 1.086 min, 234 [M+1]. 1H-NMR: (Chloroform—d, ppm): 5 7.91-7.92 (m, 1H), 7.80 (t, J: 2.4 Hz, 1H), 7.50 (t, J: 8.2 Hz, 1H), 7.31-7.33 (m, 1H), 4.38 (t, J: 11.6 Hz, 2H), 4.03 (t, J: 12.5 Hz, 2H).

Step 3: Synthesis of 2,2-diﬂuoro(3-nitrophenoxy)propyl esulfonate: Into a 100-mL round-bottom ﬂask, was placed 2,2-diﬂuoro(3- nitrophenoxy)propanol (50 mg, 0.21 mol, 1 equiv), MsCl (37 mg, 1.50 equiv), TEA (65 mg, 0.64 mmol, 3.00 equiv), dichloromethane (50 mL). The resulting solution was d for 2 h at 25 0C. The resulting solution was extracted with 3x100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This ed in 60 mg (90%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): R: 1.266 min, 312 [M+1]. 1H-NMR: (DMSO-dG, ppm): 5 7.96 — 7.85 (m, 2H), 7.71 — 7.49 (m, 2H), 4.82 — 4.57 (m, 4H), 3.33 (s, 3H).

Step 4: Synthesis of 1-[2,2-diﬂuoro(3-nitrophenoxy)propyl]pyrrolidine: Into a 20-mL sealed tube, was placed 2,2-diﬂuoro(3-nitrophenoxy)propyl methanesulfonate (60 mg, 0.19 mol, 1 equiv), pyrrolidine (10 mL). The resulting solution was stirred for 12 h at 80 0C in an oil bath. The resulting mixture was concentrated under . The ing solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate. This ed in 50 mg (91%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 287 [M+1], R: 0.962 min.

Step 5: Synthesis of -diﬂuoro(pyrrolidinyl)propoxy]aniline: Into a 100-mL round-bottom ﬂask, was placed 1-[2,2-diﬂuoro(3- nitrophenoxy)propyl]pyrrolidine (50 mg, 0.17 mol, 1 equiv), Raney-Ni, hydrogen, methanol (10 mL). The resulting solution was stirred for 4 h at 25 0C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 40 mg (89%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 257 [M+1], R: 0.734 min.

Step 6: Synthesis of N2-(3-(2,2-diﬂuoro(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 3-[2,2-diﬂuoro(pyrrolidin yl)propoxy]aniline (40 mg, 0.16 mmol, 1 equiv), triﬂuoroacetic acid (35 mg, 0.31 mmol, 2.00 equiv), isopropanol (10 mL), 2-chloro-N-methylpyrimidinamine (27 mg, 0.19 mmol, 1.20 equiv). The resulting solution was stirred for 4 h at 80 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC F TFA. This resulted in 39.2 mg (53%) ofN2-(3-(2,2-diﬂuoro(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as a white solid.

Example 40: Synthesis of Compound 279 Compound 279: Synthesis 0fN4-methyl-N2-(3-(1-(2-(pyrrolidin yl)ethoxy)ethyl)phenyl) pyrimidine-2,4-diamine MscL TEA, DCM CNN/OH HO M50 N/\/O NO NO N02 2 2 NaH, DMF lN’N\ N/ Pd/C, H2 o | N/\/ H —> NH2 N/\/0 N*N MeOH PrOH Cl H Step 1: Synthesis of 1-(3-nitrophenyl)ethyl methanesulfonate: Into a 50-mL 3-necked round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed itrophenyl)ethanol (1 g, 5.98 mmol, 1 equiv), romethane (15 mL, 1.50 equiv), TEA (1.8 g, 17.79 mmol, 3.00 . This was followed by the addition of MsCl (1.1 g) se with stirring at 0 0C. The resulting solution was stirred for 3 h at 0 0C in a water/ice bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the c layers combined. The resulting mixture was washed with 2x100 mL of water and 2x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum.

This resulted in 1.4 g (95%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, W2): RT=0.801 min. 1H NMR (300 MHz, DMSO-d6) 8.36 — 8.15 (m, 2H), 8.02 — 7.87 (m, 1H), 7.79 — 7.65 (m, 1H), 5.97 (q, J: 6.5 Hz, 1H), 3.20 (s, 3H), 1.67 (d, J: 6.5 Hz, 3H).

Step 2: Synthesis of 1-[2-[1-(3-nitrophenyl)ethoxy]ethyl]pyrrolidine: Into a 100-mL 3-necked round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (1.14 g, 28.50 mmol, 7.00 equiv, 60%), N,N—dimethylformamide (5 mL). This was followed by the addition of a solution of 2- lidinyl)ethanol (2.82 g, 24.48 mmol, 6.00 equiv) in N,N—dimethylformamide (8 mL) dropwise with stirring at -20 °C. The resulting solution was stirred for 0.5 h at -20 0C in an ice/salt bath. To this was added a solution of 1-(3-nitrophenyl)ethyl methanesulfonate (1 g, 4.08 mol, 1 equiv) in N,N—dimethylformamide (7 mL) dropwise with stirring at -20 0C. The resulting solution was stirred for 1 h at -20 0C in an ice/salt bath. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The ing mixture was washed with 3x50 mL of water and 2x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A Grad. This resulted in 400 mg (37%) of the title nd as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.740min, LCMS 40, m/Z =265 [M+l]. 1H NMR (300 MHz, DMSO-dG) 5 8.23 — 8.07 (m, 2H), 7.85 — 7.74 (m, 1H), 7.76 — 7.60 (m, 1H), 4.64 (q, J: 6.4 Hz, 1H), 3.55 — 3.39 (m, 1H), 3.41 — 3.25 (m, 1H), 2.68 — 2.30 (m, 6H), 1.73 — 1.54 (m, 4H), 1.37 (d, J: 6.5 Hz, 3H).

Step 3: Synthesis of 3-[1-[2-(pyrrolidinyl)ethoxy]ethyl]aniline: Into a 100-mL round-bottom ﬂask, was placed 1-[2-[1-(3- nitrophenyl)ethoxy]ethyl]pyrrolidine (430 mg, 1.63 mol, 1 equiv), methanol (30 mL), Pd/Cl, hydrogen. The resulting solution was stirred for 4 h at 25 °C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 370 mg (97%) of the title nd as yellow oil.

Analytical Data: LC-MS: (ES, m/Z): RT=0.742min, LCMS 45, m/Z =235 [M+l].

Step 4; Synthesis ofN4-methyl-N2-(3-(1-(2-(pyrrolidinyl)ethoxy)ethyl)phenyl) pyrimidine-2,4-diamine: Into a 100-mL bottom ﬂask, was placed 3-[1-[2-(pyrrolidin oxy]ethyl]aniline (350 mg, 1.49 mol, 1 , 2-chloro-N-methylpyrimidinamine (214 mg, 1.49 mol, 1 equiv), isopropanol (20 mL), triﬂuoroacetic acid (341 mg, 3.02 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 90 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by PLC C TFA. This resulted in 171.5 mg (25%) ofN4-methyl-N2-(3-(1-(2-(pyrrolidin yl)ethoxy)ethyl)phenyl) dine-2,4-diamine as a semisolid.

Example 41: Synthesis of Compound 280 Compound 280: Synthesis of Nz-(3-(3-(diethylamin0)prop0xy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine NMOnob CIMO"do nNJ\\N ACN, Nal, K2003 N N H 2 Step 1: Synthesis of N2-(3-(3-(diethylamino)propoxy)methoxyphenyl)-N4- methylpyrimidine-2,4-diamine: Into a 16-mL sealed tube, was placed 2-N-[3-(3-chloropropoxy)methoxyphenyl] N—methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), NaI (100 mg, 1 equiv), potassium carbonate (180 mg, 1.30 mmol, 2.00 equiv), ACN (8 mL), diethylamine (100 mg, 1.37 mmol, 2.00 equiv). The resulting solution was d for 3 h at 85 0C in an oil bath. The solids were ﬁltered out. The resulting e was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC D HCl. This resulted in 73.7 mg (30%) of N2-(3-(3- (diethylamino)propoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine as a light yellow solid.

Example 42: Synthesis of Compound 283 Compound 283: sis of methoxy(3-(3-methoxypyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine \o \ H H / D N/ HN /N "J3" I /NYN OWN CIMO Na|,K2CO3,CH3CN KN @o/ Step 1: Synthesis of N2-(4-methoxy(3-(3-methoxypyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 8-mL round-bottom ﬂask, was placed 2-N—[3-(3-chloropropoxy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mol, 1 equiv), 3- methoxypyrrolidine (303 mg, 3.00 mmol, 3.22 , NaI (150 mg), potassium carbonate (414 mg, 3.00 mmol, 3.22 equiv), CH3CN (5 mL). The resulting solution was stirred overnight at 70 0C. The crude product was puriﬁed by Prep-HPLC C NH3. This resulted in 59.7 mg (17%) ofN2-(4-methoxy(3-(3-methoxypyrrolidinyl)propoxy)phenyl)-N4- pyrimidine-2,4-diamine as a white solid.

Example 43: Synthesis of Compound 285 Compound 285: Synthesis of Nz-(4-methoxy(3-(3-(triﬂuoromethyl)pyrrolidin- 1-yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine /H\EN/IN HNij 0 \rNOZf/C' 032003,N31,CH3CN /N\:N/\rNUZYVN Step 1: Synthesis of N2-(4-methoxy(3-(3-(triﬂuoromethyl)pyrrolidin yl)pr0poxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chlor0pr0p0xy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mol, 1 equiv), CszCO3 (911 mg, 2.80 mmol, 3.00 equiv), NaI (13.98 mg, 0.10 equiv), 3-(triﬂu0romethyl)pyrrolidine (388.5 mg, 2.79 mmol, 3.00 equiv), CH3CN (6 mL). The resulting solution was stirred for 16 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC C TFA. This resulted in 88 mg (18%) of t N2- (4-methoxy(3-(3-(triﬂuoromethyl)pyrrolidinyl)pr0p0xy)phenyl)-N4-methylpyrimidine- 2,4-diarnine as a white solid.

Example 44: Synthesis of Compound 286 Compound 286: Synthesis of 1-(3-(2-methoxy((4-(methylamino)pyrimidin no)phenoxy)propyl)pyrrolidin-3—ol ZW H6 C52C03,NalDMF HEY":ﬂvvj Step 1: sis of 1-(3-(2-methoxy((4-(methylamino)pyrimidin yl)amino)phenoxy)propyl)pyrrolidinol: Into a 20-mL vial, was placed N,N—dimethylf0rmamide (5 mL), 2-N-[3-(3- chloropropoxy)—4-meth0xyphenyl]N-methylpyrimidine-2,4-diamine (250 mg, 0.77 mmol, 1 equiv), pyrrolidinol (135 mg, 1.55 mmol, 2.00 equiv), Cs2C03 (506 mg, 1.55 mmol, 2.01 equiv), NaI (117 mg). The resulting solution was stirred for 2 h at 80 0C. The solids were ﬁltered out. The crude product was d by PLC C NH3. This resulted in 64.7mg (22%) of 2-methoxy((4-(methylamino)pyrimidin yl)amino)phen0xy)propyl)pyrrolidinol as a white solid.

Example 45: Synthesis of Compound 287 Compound 287: Synthesis of 1-(3-(2-methoxy((4-(methylamino)pyrimidin-2— yl)amino)phenoxy)propyl)pyrrolidinecarbonitrile H N H 0\/\/C' CN H H / LN/ \Ir a Na],K2CO3 /N ’NYN\CEO/OWN[j 0/ + N TBA[,ACN H, KIN Step 1: Synthesis of 1-(3-(2-methoxy((4-(methy1amino)pyrimidin y1)amino)phenoxy)propyl)pyrrolidinecarbonitri1e: Into a 20-mL vial, was placed ACN (3 mL), 2-N-[3-(3-chloropropoxy) methoxyphenyl]N-methy1pyrimidine-2,4-diamine (300 mg, 0.93 mol, 1 equiv), pyrrolidinecarbonitri1e (98 mg, 1.02 mmol, 1.10 equiv), NaI (140 mg), potassium carbonate (257 mg, 1.86 mmol, 2.00 equiv), TBAI (34 mg, 0.09 mmol, 0.10 equiv). The resulting solution was stirred for 14 h at 80 0C. The residue was applied onto a silica gel column with H20/ACN (4:1). The collected ons were combined and concentrated under vacuum. The crude product (100 mg) was puriﬁed by Prep-HPLC D HCl. This resulted in 43 mg (11%) of 1-(3-(2-methoxy((4-(methy1amino)pyrimidin yl)amino)phenoxy)propyl)pyrrolidinecarbonitri1e as a white solid.

Example 46: sis of Compound 288 Compound 288: Synthesis of methoxy(2-(1-methylpyrrolidin yl)ethoxy)phenyl)-N4-methylpyrimidine-2,4-diamine C] N w Ab 02NU0 H N2 \Q:o OZNOOH m Rany-Ni,H2(g) 0 0/ H N H 0 [\ll PTSA,i-PrOH / \Eer Um \ 0/ Step 1: Synthesis of 2-[2-(2-methoxynitrophenoxy)ethyl]methy1pyrrolidine: Into a 50-mL round-bottom ﬂask, was placed methylformamide (10 mL), 2- methoxy-S-nitrophenol (500 mg, 2.96 mol, 1 , Cs2C03 (1.93 g, 5.92 mmol, 2.00 , NaI (444 mg, 2.96 mol, 1 equiv), 2-(2-chloroethy1)methylpyrrolidine (870 mg, .89 mmol, 1.99 equiv). The resulting solution was stirred for 2 h at 80 0C. The resulting solution was diluted with 10 mL of H20. The resulting solution was extracted with 3X10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x10 mL of water and 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were collected by ﬁltration. The resulting e was concentrated under vacuum. This resulted in 540 mg (65%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.836 min, LCMS 27: m/Z = 281 [M+l].

Step 2: Synthesis of 4-methoxy[2-(1-methylpyrrolidinyl)ethoxy]aniline: Into a 100-mL round-bottom ﬂask, was placed methanol (30 mL), 2-[2-(2-methoxy nitrophenoxy)ethyl]methylpyrrolidine (520 mg, 1.86 mol, 1 equiv), Rany-Ni (100 mg).The ﬂask was purged and maintained with H2.The resulting on was stirred for 3 h at 20 0C. The solids were ﬁltered out. The resulting e was concentrated under .

This ed in 460 mg (99%) of the title compound as a light red oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.398 min, LCMS 32: m/Z = 251 [M+l].

Step 3: Synthesis of N2-(4-methoxy(2-(1-methylpyrrolidinyl)ethoxy)phenyl)- N4-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed isopropanol (10 mL), 2-chloro-N- methylpyrimidinamine (252 mg, 1.76 mol, 1 equiv), 4-methoxy[2-(1- methylpyrrolidinyl)ethoxy]aniline (440 mg, 1.76 mol, 1 equiv), PTSA (303 mg, 1.76 mol, 1 equiv). The resulting solution was stirred for 2 h at 85 0C. The crude product (600 mg) was puriﬁed by Prep-HPLC D HCl. 310 mg product was obtained. This resulted in 310 mg (45%) of N2-(4-methoxy(2-(1-methylpyrrolidinyl)ethoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as light yellow oil. e 47: Synthesis of Compound 289 [073 8] Compound 289: Synthesis of Nz-(4-meth0xy((l-methylpyrrolidin-Z- yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine OZN<10OH r 30p 003> HOp \ TEA DCM \ 02003DMF Y H N H / KY @WU Pd/C MEN/N Hz/N::\©:WU N\ CH30H TFAIPA 0/ Step 1: Synthesis of (1-methylpyrrolidinyl)methyl methanesulfonate: Into a 50-mL round-bottom ﬂask, was placed (1-methylpyrrolidinyl)methanol (1 g, 8.68 mol, 1 equiv), TEA (2.66 g, 26.29 mmol, 3.00 equiv), dichloromethane (10 mL), methanesulfonyl chloride (1.29 g, 11.26 mmol, 1.30 equiv). The resulting solution was stirred for 1 h at 20 0C. This ed in 2 g (119%) of the title compound as yellow oil.

Step 2: Synthesis of 2-(2-methoxynitrophenoxymethyl)methylpyrrolidine Into a 50-mL sealed tube, was placed (1-methylpyrrolidinyl)methyl methanesulfonate (1 g, 5.17 mol, 1 equiv), Cs2C03 (3.75 g, 11.51 mmol, 2.00 equiv), 2- methoxynitrophenol (876 mg, 5.18 mol, 1 equiv), N,N—dimethylformamide (10 mL). The resulting solution was stirred for 16 h at 90 0C in an oil bath. The residue was applied onto a silica gel column with H20:CH3CN (1 :5). This resulted in 500 mg (36%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.73min, LCMS40: m/z = 267.25 [M+1].

Step 3: Synthesis of 4-methoxy[(1-methylpyrrolidinyl)methoxy]aniline: Into a 50-mL round-bottom ﬂask, was placed 2-(2-methoxynitrophenoxymethyl)- 1-methylpyrrolidine (500 mg, 1.88 mmol, 1 , ol (20 mL), Pd/C (1 g, 1 equiv), hydrogen. The resulting solution was stirred for 1 h at 20 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This ed in 350 mg (79%) of the title nd as ayellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.39min, LCMS07: m/z = 237.25 [M+1].

Step 4: Synthesis of methoxy((1-methylpyrrolidinyl)methoxy)phenyl)- N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[(1-methylpyrrolidin yl)methoxy]aniline (350 mg, 1.48 mmol, 1 equiv), triﬂuoroacetic acid (338 mg, 2.99 mmol, 2.00 equiv), 2-chloro-N-methylpyrimidinamine (212 mg, 1.48 mol, 1 equiv), propan 01 (10 mL). The resulting solution was stirred for 6 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep- HPLC C NH3. This resulted in 64.7 mg (13%) of 4-methoxy[(1-methylpyrrolidin hoxy]aniline as an off-white solid.

Example 48: Synthesis of Compound 290 Compound 290: Synthesis of N2-(4-methoxy(3-(2-methylpyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine H H N \ N N N OWCI HN / / )L / \Ir N/\/\O N N \ N H Step 1: sis of methoxy(3-(2-methylpyrrolidinyl)propoxy)phenyl)- N4-methylpyrimidine-2,4-diamine: Into a 25-mL bottom ﬂask, was placed N,N—dimethylformamide (5 mL), 2-N- [3-(3-chloropropoxy)methoxyphenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mol, 1 equiv), 2-methylpyrrolidine (53 mg, 0.62 mol, 1 equiv), CszCO3 (405 mg, 1.24 mmol, 2.01 equiv), NaI (93 mg, 0.62 mol, 1 equiv). The resulting solution was stirred for 4 h at 80 0C. The solids were ﬁltered out. The crude product (200 mg) was d by Prep- HPLC D HCl. 39.7 mg light yellow solid N2-(4-methoxy(3-(2-methylpyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine was obtained.

Example 49: Synthesis of Compound 291 Compound 291: Synthesis of N-ethyl((4-(methylamino)pyrimidin yl)amin0)picolinamide N \ N \ \ I ANHZ HO / V" I H2 N' / —> H N02 / N02 \/ CDI,DMF Pd/C ""2 O O o \NH HN/ N \ Cl N \/HYa J\\N§| Pd(OAc)2,Xantphos,DBU,dioxane,100oC H N Step 1: Synthesis of N—ethylnitropyridinecarboxamide: Into a 50-mL round-bottom ﬂask, was placed 4-nitropyridinecarboxylic acid (400 mg, 2.38 mol, 1 equiv), CDI (582 mg, 3.59 mmol, 1.50 equiv), methylformamide (10 mL), ethanamine (1.2 mL). The resulting solution was stirred for 6 h at 25 0C. The resulting mixture was concentrated under . The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3X50 mL of ethyl acetate and the organic layers combined. This resulted in 464mg (99%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.871 min, LCMS 34: m/z = 195 [M+1].

Step 2: Synthesis of 4-amino-N-ethylpyridinecarboxamide: Into a 50-mL round-bottom ﬂask, was placed N—ethylnitropyridinecarboxamide (464 mg, 2.38 mol, 1 equiv), Pd/C (156.3 mg), hydrogen. The resulting solution was stirred for 4 h at 25 0C. The solids were collected by ion. This resulted in 370 mg (94%) of the title compound as a yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.684 min, LCMS 34: m/z = 166 [M+l].

Step 3: Synthesis of N—ethyl((4-(methylamino)pyrimidin yl)amino)picolinamide: Into a 50-mL round-bottom ﬂask, was placed 4-amino-N-ethylpyridine amide (200 mg, 1.21 mol, 1 equiv), 2-chloro-N-methylpyrimidinamine (174 mg, 1.21 mol, 1 , Xantphos (140.3 mg, 0.24 mmol, 0.20 equiv), DBU (368.5 mg, 2.42 mmol, 2.00 equiv), e (10 mL), Pd(OAc)2 (27.1 mg, 0.12 mmol, 0.10 equiv). The resulting solution was stirred for 24 h at 100 0C in an oil bath. The resulting solution was extracted with 3X10 mL of water and the c layers combined. The crude product was puriﬁed by (ACN/HzO=1/20). This resulted in 30.2 mg (8%) of N—ethyl((4- (methylamino)pyrimidinyl)amino)picolinamide as a white solid.

Example 50: Synthesis of Compound 293 Compound 293: Synthesis of N2-(4-methoxy(3-(3-methylpyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine HN ~oNH /o 1/NI \ M A /N5 N o N N CIMO N N Nal,ACN 85 00 ‘0 H Step 1: Synthesis of methoxy(3-(3-methylpyrrolidinyl)propoxy)phenyl)- N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mol, 1 equiv), 3- methylpyrrolidine hydrochloride (112.7 mg, 0.93 mmol, 1 equiv), Cs2CO3 (939 mg, 2.88 mmol, 3.00 equiv), NaI (279.5 mg, 2.00 equiv), CH3CN (10 mL). The mixture solution was stirred for 20 h at 85 0C. The resulting solution was diluted with 20 mL of water and extracted with 3x30 mL of ethyl acetate and the organic layers combined. The crude product was puriﬁed by Prep-HPLC C NH4HCO3. The resulting solution was stirred for 24 h at 85 0C in an oil bath. This resulted in 39.3mg (11%) of N2-(4-methoxy(3-(3-methylpyrrolidin yl)propoxy)phenyl)-N4-methylpyn'midine-2,4-diamine as a white solid.

Example 51: Synthesis of Compound 298 Compound 298: Synthesis of Nz-(3-(3-(3-azabicyclo[3.1.0]hexanyl)propoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine H H H H ’7 N N N o /N /N\rN O\/\/C' HN / \E/T \Q: WNW LIN @ \ N o/ 0/ CsZCO3,NaI,DMF,80 °c Step 1: Synthesis of N2-(3-(3-(3-azabicyclo[3.1.0]hexanyl)pr0poxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chlor0pr0p0xy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mol, 1 equiv), 3- azabicyclo[3.1.0]hexane hydrochloride (166.3 mg, 1.39 mmol, 1.50 equiv), Cs2C03 (609 mg, 1.87 mmol, 2.00 equiv), NaI (279 mg, 1.86 mmol, 2.00 equiv), N,N—dimethylf0rmamide (5 mL). The resulting solution was stirred for 12 h at 80 0C in an oil bath. The solids were ﬁltered out. The crude product was puriﬁed by Prep-HPLC D NH3. This resulted in 33.5 mg (10%) of N2-(3-(3-(3 cyclo[3. 1 .0]hexanyl)pr0p0xy)meth0xyphenyl)—N4- methylpyrimidine-2,4-diamine as a white solid.

Example 52: Synthesis of nd 299 Compound 299: sis of (R)(2-methoxy((4-(methylamino)pyrimidin yl)amino)phenoxy)(pyrrolidinyl)propanol Br /0 O O O NH / / >4 1; Q H. f0 N02 N I)NO— HO NO2 "0 2 K3003,DMF EtOH/CHCI3 O MeOH o | / I) "ﬁrN OI) I Ctr/\po NH2 N/\./\O N \N OH IPA, TFA 5H H Step 1: Synthesis of 2-(2-methoxynitr0phen0xymethyl)oxirane: Into a 250-mL round-bottom ﬂask, was placed 2-methoxynitr0phenol (3.5 g, 20.69 mol, 1 equiv), momethyl)oxirane (2.84 g, 20.73 mmol, 1 equiv), potassium carbonate (5.7 g, 41.24 mmol, 2.00 equiv), N,N-dimethylformamide (80 mL). The resulting solution was stirred for 16 h at 25 0C. The resulting solution was allowed to react, with stirring, for an onal 3 h while the temperature was maintained at 50 0C in an oil bath. The resulting mixture was washed with 1X100 mL of H20. The resulting on was extracted with 3x300 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 3x200 mL of water and 2x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4.2 g (crude) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): 2 min. 1H NMR (300 MHz, DMSO-d6) 5 7.93 (dd, J: 9.0, 2.7 Hz, 1H), 7.78 (d, J: 2.7 Hz, 1H), 7.20 (d, J: 9.0 Hz, 1H), 4.49 (dd, J: 11.4, 2.4 Hz, 1H), 3.99 — 3.86 (m, 4H), 3.43 — 3.28 (m, 1H), 2.91 — 2.81 (m, 1H), 2.78 — 2.68 (m, 1H).

Step 2: Synthesis of 1-(2-methoxynitrophenoxy)(pyrrolidinyl)propanol: Into a 50-mL round-bottom ﬂask, was placed 2-(2-methoxy nitrophenoxymethyl)oxirane (500 mg, 2.22 mol, 1 equiv), ethanol (10 mL), chloroform (10 mL), idine (394 mg, 5.54 mmol, 2.50 equiv). The resulting solution was d for 3 h at 60 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A DCM/MeOH. This resulted in 600 mg (91%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.927min, LCMS 31, m/z =297[M+1]. 1H NMR (400 MHz, DMSO-d6) 5 7.90 (dd, J: 9.0, 2.7 Hz, 1H), 7.79 (d, J: 2.7 Hz, 1H), 7.18 (d, J: 9.0 Hz, 1H), 4.99 (s, 1H), 4.19 — 4.05 (m, 1H), 4.04 — 3.87 (m, 5H), 2.71 — 2.41 (m, 6H),1.76 — 1.61 (m, 4H).

Step 3: Synthesis of 1-(5-aminomethoxyphenoxy)(pyrrolidinyl)propanol: Into a 100-mL round-bottom ﬂask, was placed 1-(2-methoxynitrophenoxy) (pyrrolidinyl)propanol (700 mg, 2.36 mol, 1 equiv), methanol (40 mL), Pd/Cl, hydrogen. The resulting solution was d for 16 h at 25 0C. The solids were ﬁltered out.

The resulting mixture was concentrated under vacuum. This resulted in 600 mg (95%) of the title compound as yellow oil.

LC-MS: (ES, m/Z): RT=0.671min, LCMS 31, m/Z =267 [M+1].

Step 4: Synthesis of (R)(2-methoxy((4-(methylamino)pyrimidin yl)amino)phenoxy)(pyrrolidinyl)propanol: Into a 50-mL round-bottom ﬂask, was placed minomethoxyphenoxy) (pyrrolidinyl)propanol (600 mg, 1 equiv), 2-chloro-N-methylpyrimidinamine (324 mg, 2.26 mol, 1 , isopropanol (10 mL), triﬂuoroacetic acid (514 mg, 4.55 mmol, 2.00 equiv). The resulting on was stirred for 3 h at 90°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Chiral-Prep-HPLC ID.

This resulted in 42 mg (5%) of 1-(5-aminomethoxyphenoxy)(pyrrolidinyl)propan 01 (600 mg, 1 equiv), 2-chloro-N-methylpyrimidinamine as a light yellow solid.

Example 53: Synthesis of Compound 300 Compound 300: Synthesis of (2-methoxy((4-(methylamino)pyrimidin no)phenoxy)(pyrrolidinyl)propanol /Oj:j CIE?!" CINﬁAo NH2 OH IPA TFA ON"mONES Step 1: Synthesis of (S)(2-methoxy((4-(methylamino)pyrimidin no)phenoxy)(pyrrolidinyl)propanol: Into a 50-mL round-bottom ﬂask, was placed 1-(5-aminomethoxyphenoxy) (pyrrolidinyl)propanol (600 mg, 2.25 mol, 1 equiv), 2-chloro-N-methylpyrimidin amine (324 mg, 2.26 mol, 1 equiv), isopropanol (10 mL), triﬂuoroacetic acid (514 mg, 4.55 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 90 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was d by Chiral- Prep-HPLC 1B4. This resulted in 41.1 mg (5%) of (2-methoxy((4- (methylamino)pyrimidinyl)amino)phenoxy)—3-(pyrrolidinyl)propanol as a light yellow solid.

Example 54: Synthesis of Compound 301 Compound 301: Synthesis of N2-(3-ﬂuoro-4—methoxy(3—(pyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4—diamine | F F NMOH O /0 Pd/C,MeOH F NO C’NMO t—BuOK,THF,O°C H2 | F NH | F \NH Ni\ | O cm 1/ OMO NH2 C]N/\/\o " N TFA,i-PrOH,85°C Step 1: Synthesis of 1-[3-(3-ﬂuoromethoxynitrophenoxy)propyl]pyrrolidine: Into a 250-mL round-bottom ﬂask, was placed ﬂuoromethoxy nitrobenzene (1 g, 5.29 mol, 1 , 3-(pyrrolidinyl)propanol (683 mg, 5.29 mol, 1 equiv), t-BuOK (10.6 mL, 2.00 equiv), tetrahydrofuran (15 mL). The resulting solution was stirred for 1 h at 0 0C in a water/ice bath. The resulting mixture was concentrated under vacuum. The crude product (5 mL) was puriﬁed by ACN/HzO(1/1).This resulted in 550mg (35%) ofas ayellow solid. ical Data: LC-MS: (ES, m/z): RT = 0.986min, LCMS 53: m/z = 299 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.75 (s, 1H), 7.73 (s, 1H), 4.28 — 4.25 (m, 2H), 4.03 — 3.99 (m, 6H), 2.78 — 2.66 (m, 2H), 2.65 — 2.62 (m, 2H), 2.03 — 1.99 (s, 3H), 1.88 — 1.85 (m, Step 2: Synthesis of 3-ﬂuoromethoxy[3-(pyrrolidinyl)propoxy]aniline: Into a 250-mL round-bottom ﬂask, was placed 3-ﬂuoromethoxy nitrophenoxy)propyl]pyrrolidine (450 mg, 1.51 mmol, 1 equiv), methanol (10 mL), Pd/C (150 mg), hydrogen. The resulting solution was stirred for 2 h at 25 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 350 mg (86%) of the title compound as yellow oil. ical Data: LC-MS: (ES, m/z): RT = 0.803min, LCMS 34: m/z = 269 [M+1].

Step 3: Synthesis of N2-(3-ﬂuoromethoxy(3-(pyrrolidinyl)propoxy)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 3-ﬂuoromethoxy[3-(pyrrolidin- 1-yl)propoxy]aniline (300 mg, 1.12 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin amine (176 mg, 1.12 mmol, 1 equiv), triﬂuoroacetic acid (255.2 mg, 2.26 mmol, 2.00 equiv), isopropanol (15 mL). The resulting solution was stirred for 24 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude t was puriﬁed by Prep- HPLC C NH3. This resulted in 9.7 mg (2%) of N2-(3-ﬂuoromethoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a yellow solid.

Example 55: sis of Compound 302 Compound 302: Synthesis of Nz-(Z-ﬂu0r0meth0xy(3-(pyrrolidin yl)pr0poxy)phenyl)-N4,6-dimethylpyrimidine-Z,4-diamine o F O F /O F / / IMCI U OAc D: RaneyNi,MeOH,50°C —'Cl/\/\O —’ CIMO ‘ ' HO 2 \NH \NH | | N/ | CIA/\OOrr*'WCIMO \ NH2 rtgrt_9""NalCH3CN N/\/\O "*N Step 1: Synthesis 1-(3-chloropropoxy)ﬂuoromethoxybenzene: Into a 50-mL round-bottom ﬂask, was placed 4-ﬂuoromethoxyphenol (1 g, 7.04 mol, 1 equiv), 1-chloroiodopropane (2.87 g, 14.04 mmol, 2.00 equiv), potassium carbonate (2.92 g, 21.13 mmol, 3.00 equiv), ACN (15 mL). The resulting solution was stirred for 14 h at 85 0C. The solids were ﬁltered out. The ing mixture was concentrated under . This resulted in 1.5 g (98%) of as yellow oil.

Step 2: Synthesis of 1-(3-chloropropoxy)ﬂuoromethoxynitrobenzene: Into a 100-mL round-bottom ﬂask, was placed hloropropoxy)ﬂuoro ybenzene (1.53 g, 7.00 mmol, 1 equiv), acetyl acetate (25 mL). This was followed by the addition of HN03 (2.56 g, 4.00 equiv) dropwise with stirring at 0 0C. The resulting solution was stirred for 16 h at 20 0C. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 2x80 mL of ethyl acetate and the organic layers combined. The resulting e was washed with 2x100 mL of sodium bicarbonate and 2x100 mL of brine. The resulting mixture was washed and the ﬁltrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 1.62 g (88%) of the title compound as ayellow solid.

Analytical Data: 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.06 (s, 1H), 4.20 (t, J: 5.9 Hz, 2H), 3.79 (r, J: 6.4 Hz, 2H), 2.26 (q, J: 6.1 Hz, 2H), 2.03 (s, 3H).

Step 3: Synthesis of hloropropoxy)ﬂuoromethoxyaniline: Into a 100-mL round-bottom ﬂask, was placed 1-(3-chloropropoxy)ﬂuoro methoxynitrobenzene (200 mg, 0.76 mol, 1 equiv), RaneyNi (0.1 g), methanol (20 mL).

The resulting on was stirred for 16 h at 50 0C. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. This resulted in 170 mg (96%) of the title compound as a brown oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.032 min, LCMS34: m/z = 234 [M+1].

Step 4: Synthesis of 2-N-[5-(3-chloropropoxy)ﬂuoromethoxyphenyl]N,6- dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 5-(3-chloropropoxy)ﬂuoro methoxyaniline (150 mg, 0.64 mol, 1 equiv), 2-chloro-N,6-dimethylpyrimidinamine (101 mg, 0.64 mol, 1 equiv), triﬂuoroacetic acid (125 mg, 1.11 mmol, 2.00 equiv), isopropanol (10 mL). The resulting on was stirred for 16 h at 85 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (1/1). This resulted in 180 mg (79%) of the title compound as brown oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.153 min, LCMS34: m/z = 255 [M+1].

Step 5: sis N2-(2-ﬂuoromethoxy(3-(pyrrolidinyl)propoxy)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL bottom ﬂask, was placed 2-N-[5-(3-chloropropoxy)ﬂuoro yphenyl]N,6-dimethylpyrimidine-2,4-diamine (162 mg, 0.46 mmol, 1 equiv), pyrrolidine (64 mg, 0.90 mmol, 2.00 equiv), NaI (69 mg, 0.46 mmol, 1 equiv), Cs2CO3 (298 mg, 0.91 mmol, 2.00 equiv), CH3CN (10 mL). The resulting on was stirred for 16 h at 85 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/HZO (1/1). This resulted in 46 mg (26%) of N2-(2-ﬂuoro methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a solid.

Example 56: Synthesis of Compound 303 Compound 303: Synthesis of Nz-(S-methoxy(3-(pyrrolidin yl)propoxy)pyridin-2—yl)-N4,6-dimethylpyrimidine-2,4—diamine N/ HN/ C|)\\N I | O O I m)N: I CINMO / / NH2 DMSO,3rd-Brettphos @MO m \N Step 1: Synthesis ofN2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed 5-methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (200 mg, 0.80 mol, 1 equiv), 2-chloro-N,6-dimethylpyrimidinamine (125.1 mg, 0.79 mol, 1 equiv), CszCO3 (779.3 mg, 2.39 mmol, 3.00 equiv), 3rd-BrettPhos (72.2 mg, 0.08 mmol, 0.20 equiv), Pd2(dba)3-CHCl3 (41.2 mg, 0.04 mmol, 0.10 equiv), DMSO (5 mL). The ing solution was stirred for 2 h at 100 0C in an oil bath. The solids were ﬁltered out. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 133.8 mg (35%) of N2-(5- methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 57: sis of Compound 305 Compound 305: Synthesis of Nz-(S-meth0xy(3-(pyrrolidin yl)pr0poxy)pyridinyl)-N4-methylpyridine-2,4-diamine \NH \NH O /| \N \ Br N O OMO / NH2Pd2(dba)3CHC|3,Xphos,DMSO Step 1: Synthesis ofN2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N4- methylpyridine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 5-methoxy[3-(pyrrolidin yl)propoxy]pyridinamine (135 mg, 0.54 mol, 1 equiv), 2-bromo-N-methylpyridin amine (100 mg, 0.53 mol, 1 equiv), Xphos (51.2 mg, 0.20 equiv), Cs2CO3 (350.5 mg, 1.08 mmol, 2.00 equiv), DMSO (5 mL), Pd2(dba)3-CHCl3 (55.6 mg, 0.10 . The resulting solution was d for 24 h at 100 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was puriﬁed by Flash-Prep-HPLC A Grad. This resulted in 18.6 mg (7%) of N2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N4- pyridine-2,4-diamine as a yellow solid.

Example 58: Synthesis of Compound 306 Compound 306: Synthesis of N4-(5-methoxy(3-(pyrrolidin yl)propoxy)pyridinyl)-N2,6-dimethylpyrimidine-2,4-diamine \ NH | NH | O O \ NCN N \N NAN I QM '/ kk NMO / NH2 N/\/\o N 3rd Brettphos,C52CO3,DMSO H Step 1: Synthesis ofN4-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)- N2,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed 5-methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (200 mg, 0.80 mol, 1 equiv), 3rd Brettphos (130 mg, 0.14 mmol, 0.10 equiv), Cs2CO3 (650 mg, 1.99 mmol, 2.00 , 4-chloro-N,6-dimethylpyrimidinamine (140 mg, 0.89 mol, 1 equiv), WO 81177 DMSO (10 mL). The resulting solution was stirred for 3 h at 100 0C in an oil bath. The solids were ﬁltered out. The crude product was applied onto a silica gel column with TFA/HZOIACN (10: 1),Detector, UV 254 nm. This resulted in 88.6 mg (22%) of N4-(5- methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N2,6-dimethylpyrimidine-2,4-diamine as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.83 min, LCMS 53: m/Z = 373.0 [M+l]. 1H NMR (400 MHz, Methanol-d4) 5 8.04 (s, 1H), 7.37 (s, 1H), 6.46 (s, 1H), 4.33 (s, 2H), 3.96 (d, J: 1.3 Hz, 3H), 3.91 — 3.73 (m, 2H), 3.48 (t, J: 7.3 Hz, 2H), 3.24 — 3.12 (m, 2H), 3.09 (d, J: 1.8 Hz, 3H), 2.38 — 2.35 (m, 5H), 2.29 — 2.17 (m, 2H), 2.10 — 2.09 (m, 2H).

Example 59: sis of Compound 307 Compound 307: Synthesis of Nz-(S-meth0xy—4—(3-(pyrrolidin yl)propoxy)pyridin-2—yl)—N4,6-dimethylpyridine-2,4—diamine I ‘NH | I f1 C’NMO / C] N IQ fl NH2 @MO / H \N 3rd-Brettphos,DMSO,CSZCO3 Step 1: Synthesis ofN2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)- N4,6-dimethylpyridine-2,4-diamine: Into a 100-mL round-bottom ﬂask purged and ined with an inert atmosphere of nitrogen, was placed oxy[3-(pyrrolidinyl)propoxy]pyridinamine (200 mg, 0.80 mol, 1 equiv), Cs2C03 (75 mg, 0.23 mmol, 3 equiv), 3rd-Brettphos (140 mg, 0.20 equiv), 2-chloro-N,6-dimethylpyridinamine (130 mg, 0.83 mmol, 1 equiv), DMSO (15 mL). The resulting solution was stirred for 3 h at 100 0C in an oil bath. The solids were ﬁltered out. The crude product (200 mg) was applied onto a silica gel column with TFA/HZO:ACN (8: 1). This resulted in 64.6 mg (21%) of N2-(5-methoxy(3-(pyrrolidin yl)propoxy)pyridinyl)-N4,6-dimethylpyridine-2,4-diamine as a white solid.

Example 60: Synthesis of Compound 308 Compound 308: Synthesis of meth0xy—4—(3-(pyrrolidin yl)propoxy)pyridin-2—yl)—N2,6-dimethylpyridine-2,4—diamine N I N I \ I |N @MO / CI / \ 3rd Brttphos, oszcospmso @MO [1] Step 1: Synthesis of N4-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridineyl)- N2,6-dimethylpyridine-2,4-diamine: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of en, was placed 5-methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (200 mg, 0.80 mol, 1 equiv), 3rd Brettphos (140 mg, 0.15 mmol, 0.20 equiv), Cs2C03 (750 mg, 2.30 mmol, 3.00 equiv), 4-chloro-N,6-dimethylpyridinamine (130 mg, 0.83 mmol, 1 equiv), DMSO (15 mL). The ing solution was stirred for 3 h at 100 0C in an oil bath. The solids were ﬁltered out. The crude product (300 mg) was applied onto a silica gel column with TFA/HZO:ACN (10: ector, UV 254 nm. This resulted in 121.9 mg (30%) of N4-(5- methoxy(3-(pyrrolidinyl)propoxy)pyridineyl)-N2,6-dimethylpyridine-2,4-diamine as a white solid.

Example 61: Synthesis of Compound 309 Compound 309: Synthesis of S-ﬂuoro-Nz-(S-meth0xy(3-(pyrrolidin yl)propoxy)pyridin-2—yl)—N4,6-dimethylpyridine-2,4—diamine NH2 BOC~ F F NH F / / F | H202,TFA m KN03,H2804 m Fe/HOAC KI (800)20 F \ —> / \ — — —> Br N Br Br N I‘.‘ \N I .. Br \ O O Br N ‘N’B°° N" \ B Om (L F CH3I.NaH G‘VO NH2 on ffTFA’DCM _, F —. —> Mmfl/ \ / / \ N N O H N O I 3rd Brettphos,052003 Br \N OMO Step 1: Synthesis 6-bromoﬂuoromethylpyridine 1-0Xide: Into a 50-mL bottom ﬂask, was placed 6-bromoﬂuoromethylpyridine (1 g, 5.26 mol, 1 equiv), H202 (4 mL), triﬂuoroacetic acid (10 mL). The resulting solution was stirred for 20 h at 70 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with romethane/methanol (100/0). This resulted in 1.09 g (101%) of the title nd as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.714 min, LCMS40: m/z = 206 [M+1]. 1H NMR (400 MHZ, Chloroform—d) 57.61 (d, J: 9.1 Hz, 1H), 7.13 (d, J: 9.2 Hz, 1H), 2.61 (s, Step 2: Synthesis of 6-bromoﬂuoromethylnitropyridine 1-oxide: Into a 50-mL round-bottom ﬂask, was placed 6-bromoﬂuoromethylpyridine 1- oxide (1 g, 4.85 mol, 1 equiv), sulfuric acid (10 mL), potassium nitrate (1.97 g, 4.00 .

The resulting solution was stirred for 6 h at 120 0C. The reaction mixture was cooled with a water/ice bath. The resulting solution was extracted with 2x50 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 2x50 mL of sodium bicarbonate. The resulting mixture was washed with 100 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 650 mg (53%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.068 min, LCMS33: m/z = 251 [M+1].

Step 3: Synthesis of 6-bromoﬂuoromethylpyridinamine: Into a 50-mL round-bottom ﬂask, was placed 6-bromoﬂuoromethyl nitropyridine 1-oxide (600 mg, 2.39 mmol, 1 equiv), acetic acid (10 mL), Fe (672 mg, 5.00 equiv). The ing solution was stirred for 1 h at 100 0C. The reaction was then ed by the addition of water/ice. The ing solution was extracted with 100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The e was applied onto a silica gel column with ACN/HZO (1/10). This resulted in 260 mg (53%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.774 min, : m/z = 205 [M+1]. 1H NMR (400 MHz, 6) 5 6.67 (d, J: 5.9 Hz, 1H), 6.46 (s, 2H), 2.24 (s, 3H).

Step 4: Synthesis of utyl N—(6-bromoﬂuoromethylpyridinyl)carbamate: Into a 50-mL round-bottom ﬂask, was placed a solution of 6-bromoﬂuoro methylpyridinamine (250 mg, 1.22 mol, 1 equiv) in dichloromethane (10 mL), 4- dimethylaminopyridine (299 g, 2.45 mol, 2.00 equiv), (Boc)20 (536 mg, 2.46 mmol, 2.00 equiv), TEA (0.34 mL). The resulting solution was stirred for 16 h at 20 0C. The reaction was then quenched by the addition of 10 mL of 10% NaOH. The resulting solution was extracted with 20 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1/1). This resulted in 0.3 g (81%) of as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.458 min, LCMS53: m/z = 305 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.19 (s, 1H), 2.52 (s, 1H), 2.42 (s, 3H), 1.56 (d, J: 2.2 Hz, Step 5: sis of tert-butyl N—(6-bromoﬂuoromethylpyridinyl)-N— methylcarbamate: Into a 50-mL bottom ﬂask, was placed a solution of tert-butyl N—(6-bromo ﬂuoromethylpyridinyl)carbamate (278 mg, 0.91 mmol, 1 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of sodium hydride (110 mg, 3.00 , in portions at 0 0C in 1 hr. To this was added CH31 (388 mg, 2.73 mmol, 3.00 equiv) dropwise with stirring at 0 0C. The resulting solution was stirred for 18 h at 20 0C. The reaction was then quenched by the addition of 30 mL of water. The ing solution was extracted with 2x50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with romethane/petroleum ether (1/1).

This resulted in 150 mg (52%) of as a yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.449 min, LCMS53: m/z = 319 [M+1].

Step 6: Synthesis of tert-butyl N-[3-ﬂuoro([5-methoxy[3-(pyrrolidin yl)propoxy]pyridinyl]amino)methylpyridinyl]-N-methylcarbamate: [083 8] Into a 50-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed oxy[3-(pyrrolidinyl)propoxy]pyridinamine (112 mg, 0.45 mol, 1 equiv), tert-butyl N—(6-bromoﬂuoromethylpyridinyl)—N— methylcarbamate (140 mg, 0.44 mol, 1 equiv), 3rd Brettphos (40 mg, 0.10 equiv), CszC03 (287 mg, 0.88 mmol, 2.00 equiv), DMSO (4 mL). The resulting solution was stirred for 4 h at 100 0C. The resulting solution was diluted with 15 mL of H20. The resulting solution was extracted with 2x50 mL of ethyl acetate and the c layers combined. The resulting mixture was washed with 3x50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/HZO (1/5). This resulted in 80 mg (37%) of as colorless crude oil. ical Data: LC-MS: (ES, m/z): RT = 1.015 min, LCMS53: m/z = 490 [M+1].

Step 7: Synthesis of 5-ﬂuoro-N2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridin- 2-yl)-N4,6-dimethylpyridine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed tert-butyl N-[3-ﬂuoro([5-methoxy [3 -(pyrrolidinyl)propoxy]pyridinyl]amino)methylpyridinyl]-N-methylcarbamate (80 mg, 0.16 mol, 1 equiv), dichloromethane (6 mL), triﬂuoroacetic acid (1.5 mL). The ing solution was stirred for 16 h at 20 0C. The resulting mixture was concentrated under vacuum. The e was applied onto a silica gel column with ACN/HZO (1/5). This ed in 33.1 mg (40%) of 5-ﬂuoro-N2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)- N4,6-dimethylpyridine-2,4-diamine as a brown solid.

Example 62: Synthesis of Compound 311 Compound 311: Synthesis of N2-(4-methoxy(2-methoxyethoxy)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine | | | O o O D / \/\C[ Pd/C,MeOH HO NO 052003,Na| D / \/\O NO2 Step-2 NH N/I o (JAN 0Jr:/ I Step 1: Synthesis of 1-methoxy(2-methoxyethoxy)—4-nitrobenzene: Into a 100-mL round-bottom ﬂask, was placed 2-methoxynitrophenol (1 g, 5.91 mol, 1 , CszCO3 (3.8 g, 11.66 mmol, 2.00 equiv), NaI (1.8 g, 12.00 mmol, 2.00 equiv), N,N—dimethylformamide (40 mL), romethoxyethane (850 mg, 8.99 mmol, 1.5 equiv). The resulting solution was stirred for 2 h at 100 0C in an oil bath. The reaction was then quenched by the addition of 50 mL ofNaHS03. The resulting solution was extracted with 3x50 mL of ethyl e and the c layers were washed with 3x20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. This resulted in 1.18 g (86%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.21 min, LCMS 33: m/Z = 228.0 [M+l]. 1H NMR (300 MHz, DMSO-dG) 5 7.91 (q, J: 9.0 Hz, 1H), 7.76 (d, J: 2.7 Hz, 1H), 7.19 (d, J: 9.0 Hz, 1H), 4.27 — 4.17 (m, 2H), 3.92 (s, 3H), 3.76 — 3.65 (m, 2H), 3.34 — 3.32 (s, 3H).

Step 2: Synthesis of 4-methoxy(2-methoxyethoxy)aniline: Into a 100-mL round-bottom ﬂask, was placed 1-methoxy(2-methoxyethoxy) nitrobenzene (580 mg, 2.55 mol, 1 equiv), Pd/C (200 mg), methanol (25 mL). The resulting on was stirred for 1 h at 25 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 430 mg (85%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.72 min, LCMS 33: m/Z = 198.0 [M+l].

Step 3: sis of N2-(4-methoxy(2-methoxyethoxy)phenyl)—N4,6- dimethylpyrimidine-2,4-diamine: Into a 100-mL bottom ﬂask, was placed 4-methoxy(2- methoxyethoxy)aniline (430 mg, 2.18 mol, 1 equiv), TsOH (825 mg, 4.79 mmol, 2.00 equiv), 2-chloro-N,6-dimethylpyrimidinamine (340 mg, 2.16 mol, 1 equiv), isopropanol (23 mL). The resulting solution was stirred for 3 h at 90 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was applied onto a silica gel column with NH4HC03:ACN (1:1), Detector, UV 254 nm. 75 mg product was obtained. This resulted in 75 mg (11%) of N2-(4-methoxy(2-methoxyethoxy)phenyl)-N4,6- ylpyrimidine-2,4-diamine as a solid.

Example 63: sis of Compound 312 Compound 312: Synthesis of N2-(4-methoxy(3-methoxypr0p0xy)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine oD o /O\/\/CI D Pd/C,MeOH,H2(g) O HO N02 052003,Na|,DMF \o/\/\o NO \o/\/\o NH2 \NH \NH ll | / 0 CI N | \ /\/\ )\\ o o N N Step 1: Synthesis of 1-methoxy(3-methoxypropoxy)nitrobenzene: Into a 100-mL round-bottom ﬂask, was placed 2-methoxynitrophenol (1 g, 5.91 mol, 1 equiv), romethoxypropane (645 mg, 5.94 mol, 1 equiv), CszCO3 (3.8 g, 11.66 mmol, 2.00 equiv), NaI (1.3 g, 1.50 equiv), N,N—dimethylformamide (20 mL). The resulting solution was stirred for 2 h at 100 0C in an oil bath. The resulting solution was diluted with 50 mL of EA. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.4 g (98%) of as ayellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.317 min, LCMS 33: m/Z = 242 [M+1].

Step 2: Synthesis of 4-methoxy(3-methoxypropoxy)aniline: Into a 50-mL round-bottom ﬂask, was placed 1-methoxy(3-methoxypropoxy)—4- nitrobenzene (500 mg, 2.07 mol, 1 , Pd/C (10%) (100 mg), methanol (10 mL). The resulting on was stirred for 1 h at RT under H2 (g) atmosphere. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 410 mg (94%) of the title nd as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.792 min, LCMS 33: m/Z = 212 [M+1]. [085 8] Step 3: Synthesis of N2-(4-methoxy(3-methoxypropoxy)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy(3- ypropoxy)aniline (350 mg, 1.66 mol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin amine (262 mg, 1.66 mol, 1 equiv), CF3COOH (378 mg, 3.32 mmol, 2.00 equiv), isopropanol (5 mL). The resulting solution was stirred for overnight at 80 0C in an oil bath.

The resulting mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with H20/NH4HCO3/ACN (41%). This resulted in 315.0 mg (57%) of N2- hoxy(3-methoxypropoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid. e 64: Synthesis of Compound 313 Compound 313: Synthesis of Nz-(4-cyclopropyl-3—(3—(pyrrolidin yl)pr0poxy)phenyl)-N4,6-dimethylpyrimidine-Z,4-diamine [>—B/ @MCI an \OH HC' Pdd CI KCO —> NMO N02 w N/\/\O N02 HO N02 Nal,CH3CN,CSZCO3 H20,1,4-dloxane.80°c \NH \NH ijN/ N/I Fe,NH4CI,EtOH,H20 @MOh CI N NH2 —> —, NJ\\N Step 1: Synthesis of 1-[3-(2-bromonitrophenoxy)propyl]pyrrolidine: Into a 100-mL round-bottom ﬂask, was placed 2-bromonitrophenol (2 g, 9.17 mol, 1 equiv), 1-(3-chloropropyl)pyrrolidine hydrochloride (1.69 g, 9.18 mol, 1 equiv), NaI (1.65 g, 1.20 equiv), Cs2C03 (5.96 g, 18.29 mmol, 2.00 equiv), CH3CN (30 mL). The resulting solution was stirred for 5 h at 80 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was trated under vacuum. The residue was puriﬁed by ﬂash chromatography with O(28%). This resulted in 2.4 g (79%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.964 min, LCMS33: m/Z = 329 [M+1].

Step 2: Synthesis of 1-[3-(2-cyclopropylnitrophenoxy)propyl]pyrrolidine: Into a 250-mL 3-necked round-bottom ﬂask, was placed 1-[3-(2-bromo nitrophenoxy)propyl]pyrrolidine (1.9 g, 5.77 mol, 1 equiv), cyclopropylboronic acid (745 mg, 8.67 mmol, 1.50 equiv), Pd(dppf)C12 (845 mg, 1.15 mmol, 0.20 equiv), potassium carbonate (1.59 g, 11.50 mmol, 2.00 equiv), water(2 mL), 1,4-dioxane (20 mL). The resulting on was stirred for 16 h at 80 0C in an oil bath under N2 (g) atmosphere. The resulting e was concentrated under vacuum. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with HZO/ACN (32%). This resulted in 440 mg (26%) of as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.956 min, LCMS39 : m/Z = 291 [M+1].

Step 3: sis of 4-cyclopropyl[3-(pyrrolidinyl)propoxy]aniline: Into a 100-mL round-bottom ﬂask, was placed 1-[3-(2-cyclopropyl nitrophenoxy)propyl]pyrrolidine (400 mg, 1.38 mmol, 1 equiv), Fe (385 mg, 6.88 mmol, 5.00 equiv), NH4Cl (368 mg, 6.88 mmol, 5.00 equiv), water (6 mL), ethanol (12 mL). The resulting solution was stirred for 3 h at 80 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 1.1 g of the title compound as w crude solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.794 min, LCMS33 : m/Z = 261 [M+1].

Step 4: Synthesis of N2-(4-cyclopropyl(3-(pyrrolidinyl)propoxy)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Into a 5-mL bottom ﬂask, was placed opropyl[3-(pyrrolidin yl)propoxy]aniline (300 mg, 1.15 mol, 1 equiv), 2-chloro-N,6-dimethylpyrimidinamine (181.2 mg, 1.15 mol, 1 equiv), CF3COOH (263.1 mg, 2.31 mmol, 2.00 equiv), isopropanol (5 mL). The ing solution was d for overnight at 80 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash-Prep- HPLC C NH3. This resulted in 40.6 mg of N2-(4-cyclopropyl(3-(pyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 65: Synthesis of Compound 314 Compound 314: Synthesis of Nz-(4-cyclopropyl-3—(3—(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine \NH \NH 2:)N / N/ GMO CI N NH2 N/\/\O NJ\\N TFAJ-PI'OH C] H Step 1: Synthesis ofNZ-(4-cyclopropyl(3-(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-cyclopropyl[3-(pyrrolidin yl)propoxy]aniline (300 mg, 1.15 mol, 1 equiv), 2-chloro-N-methylpyrimidinamine (166 mg, 1.16 mmol, 1 equiv), CF3COOH (263 mg, 2.31 mmol, 2.00 , isopropanol (5 mL).

The resulting solution was stirred for overnight at 80 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was d by Prep-HPLC C TFA. This resulted in 21.9 mg of N2-(4-cyclopropyl(3-(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as a white solid.

Example 66: Synthesis of Compound 315 Compound 315: Synthesis of N4-methyl-N2-(3-(3-(pyrrolidinyl)propoxy) (triﬂuoromethoxy)phenyl)pyrimidine-2,4-diamine F30\ F3C O \O ('31:?) o OZN HO @MCI 0 CI,NaN02 HC' 0 JK F D — H20,H2804 NaI,DMF,cho3,90°c @Mo Br szwba)3,XantPhos5520033000 Br Br ‘3F3 \NH ('ng The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate. This resulted in 1 g (50%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT =1.715min, LCMS 53: m/z = 257 [M+1]. 1H NMR (400 MHZ, DMSO-dG) 5 13.29 (s, 1H), 7.96 (s, 1H), 7.77 — 7.51 (m, 1H), 7.44 (d, J: 8.5 Hz, 1H).

Step 2: Synthesis of 5-bromo(triﬂuoromethoxy)phenoxy]propyl]pyrrolidine: Into a 100-mL round-bottom ﬂask, was placed 5-bromo(triﬂuoromethoxy)phenol (1000 mg, 3.89 mol, 1 equiv), 1-(3-chloropropy1)pyrrolidine hydrochloride (720 mg, 3.91 mol, 1 equiv), Cs2C03 (2550 mg, 7.83 mmol, 2.00 equiv), NaI (589 mg, 1 equiv), N,N— dimethylformamide (10 mL). The ing solution was stirred for 2 h at 90 0C in an oil bath.

The resulting on was extracted with 3x50 mL of ethyl acetate and the organic layers ed. The resulting mixture was washed with 3x30 mL of brine. The mixture was dried over anhydrous sodium e and concentrated under . This resulted in 1.4 g (98%) of the title compound as red oil. ical Data: LC-MS: (ES, m/z): RT =1.346min, LCMS 53: m/z =368 [M+1].

Step 3: Synthesis of N—[3-[3-(pyrrolidinyl)propoxy](triﬂuoromethoxy)phenyl] acetamide: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[3-[5-bromo(triﬂuoromethoxy)phenoxy] propyl]pyrrolidine (700 mg, 1.90 mol, 1 equiv), acetamide (228.9 mg, 3.88 mmol, 2.00 equiv), CszC03 (1.24 g, 3.81 mmol, 2.00 equiv), XantPhos (220.5 mg, 0.38 mmol, 0.20 equiv), Pd2(dba)3-CHCl3 (197.4 mg, 0.10 equiv), dioxane (20 mL). The resulting on was stirred for 12 h at 80 0C in an oil bath. The solids were collected by ﬁltration. The crude product was puriﬁed by ACN/HZO=2/5. This resulted in 450 mg (68%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.940min, LCMS 33: m/z =347[M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.63 (d, J: 2.4 Hz, 1H), 7.21 (d, J: 8.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.14 (t, J: 5.9 Hz, 2H), 3.63 (q, J: 7.0 Hz, 1H), 2.97 — 2.83 (m, 5H), 2.19 — 2.09 (m,4H), 1.94 — 1.83 (m, 4H), 1.21 (t, J: 7.1 Hz, 1H).

Step 4: Synthesis of 3-[3-(pyrrolidinyl)propoxy](triﬂuoromethoxy)aniline: Into a 50-mL round-bottom ﬂask, was placed N—[3-[3-(pyrrolidinyl)propoxy] oromethoxy)phenyl]acetamide (450 mg, 1.30 mmol, 1 equiv), ethanol (6 mL), water(2 mL), sodium ide (208 mg, 5.20 mmol, 4.00 equiv). The resulting solution was stirred for 12 h at 80 0C in an oil bath. The resulting mixture was concentrated under . The crude product was puriﬁed by ACN/HzO = 1/20. This resulted in 350 mg (89%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.930min, LCMS 31: m/z =305 [M+1].

Step 5: Synthesis of N4-methyl-N2-(3-(3-(pyrrolidinyl)propoxy) (triﬂuoromethoxy)phenyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 3-[3-(pyrrolidinyl)propoxy] (triﬂuoromethoxy)aniline (350 mg, 1.15 mmol, 1 equiv), ro-N-methylpyrimidin amine (164.7 mg, 1.15 mmol, 1 , triﬂuoroacetic acid (262.5 mg, 2.32 mmol, 2.00 equiv), isopropanol (6 mL). The resulting solution was stirred for 4 h at 80 0C in an oil bath.

The resulting mixture was concentrated under vacuum. The crude product (450 mg) was puriﬁed by PLC C NH3. This resulted in 104 mg (17%) of hyl-N2-(3-(3- (pyrrolidinyl)propoxy)(triﬂuoromethoxy)phenyl)pyrimidine-2,4-diamine as a white solid.

Example 67: Synthesis of Compounds 329 and 317 Compound 329 and 317: Synthesis of Diastereomer 1: Nz-(3-((1r,3r) (dimethylamino)cyclobutoxy)—4-methoxyphenyl)-N4,6-dimethylpyrimidine—Z,4-diamine and Diastereomer 2: Nz-(3-((1s,3s)(dimethylamino)cyclobutoxy)—4-methoxyphenyl)- N4,6-dimethylpyrimidine-2,4-diamine WM NO2 DEADPPh3THF ""nﬁrm"U,:11NO2 NaBH3CNMeOH N: O: :JN:‘NA ‘NH H mi + \NH "m£sz | Pd/C MeOH JimENHZD CI N’ [L o / N, TFA,|PA Ex0 k I o N N Step 1: Synthesis oftert-butyl N-[3-(2-methoxy nitrophenoxy)cyclobutyl]carbamate: Into a 100-mL 3-necked round-bottom ﬂask purged and maintained with an inert atmosphere of en, was placed tert-butyl N-(3-hydroxycyclobutyl)carbamate (500 mg, 2.67 mol, 1 equiv), 2-methoxynitr0phenol (452 mg, 2.67 mol, 1 equiv), PPh3 (1.541 g, .88 mmol, 2.20 equiv), ydrofuran (20 mL). This was followed by the addition of a solution of DEAD (1.188 g, 5.88 mmol, 2.20 equiv) in tetrahydrofuran (5 mL) se with stirring at 0 0C. The resulting on was stirred for 10 min at 0 0C. The resulting solution was stirred for 16 h at 25 0C. The resulting mixture was concentrated under vacuum. The crude t was puriﬁed by Flash-Prep-HPLC A EA/PE. This resulted in 900 mg (100%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.707min, LCMS 40, m/Z =239 [M+1]. 1H NMR (300 MHZ, DMSO-dG) 5 8.98 (s, 1H), 8.00 — 7.69 (m, 1H), 7.62 — 7.47 (m, 1H), 7.28 — 7.13 (m, 1H),5.01— 4.46 (m, 1H), 3.91 (d, J: 3.0 Hz, 3H), 2.89 — 2.68 (m, 1H), 2.45 — 2.28 (m, 2H), 2.10 — 1.93 (m, 2H), 1.39 (d, J: 3.3 Hz, 9H).

Step 2: Synthesis of 3-(2-meth0xynitr0phen0xy)cyclobutanamine: Into a 50-mL round-bottom ﬂask, was placed tert-butyl N-[3-(2-meth0xy nitrophenoxy)cyclobutyl]carbamate (900 mg, 2.66 mol, 1 , dichloromethane (10 mL), triﬂuoroacetic acid (5 mL). The resulting solution was stirred for 30 min at 25 0C. This resulted in 1.2 g (crude) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.557min, LCMS 30, m/Z =239[M+1]. 1H NMR (300 MHz, DMSO-dG) 5 8.17 (s, 2H), 8.00 — 7.86 (m, 1H), 7.64 — 7.42 (m, 2H), 5.20 — 4.62 (m, 1H), 3.93 (s, 3H), 3.89 — 3.34 (m, 1H), 2.97 — 2.57 (m, 2H), 2.38 — 2.15 (m, 2H).

Step 3: Synthesis of 3-(2-methoxynitrophenoxy)-N,N-dimethylcyclobutan amine: Into a 50-mL round-bottom ﬂask, was placed 3-(2-methoxy nitrophenoxy)cyclobutanamine, triﬂuoroacetic acid (942 mg, 2.67 mol, 1 equiv), ol (20 mL), formaldehyde (241 mg, 8.03 mmol, 3.00 , NaBH3CN (843 mg, 13.42 mmol, 5.00 . The resulting solution was stirred for 6 h at 25 0C. The resulting mixture was concentrated under vacuum. The crude product was d by Flash-Prep- HPLC A MeOH/HZO. This ed in 330 mg (46%) of the title compound as yellow oil. ical Data: LC-MS: (ES, m/z): RT=0.901min, LCMS 15, m/Z =267 [M+1]. 1H NMR (300 MHZ, DMSO-dG) 5 7.92 (dd, J: 9.0, 2.7 Hz, 1H), 7.63 — 7.42 (m, 1H), 7.20 (dd, J = 9.1, 2.5 Hz, 1H), 4.94 — 4.51 (m, 1H), 3.92 (s, 3H), 2.92 — 2.56 (m, 2H), 2.46 — 2.12 (m, 2H), 2.07 (d, J: 6.8 Hz, 6H), 1.94 — 1.77 (m, 1H).

Step 4: Synthesis of 3-[3-(dimethylamino)cyclobutoxy]methoxyaniline: Into a 50-mL round-bottom ﬂask, was placed 3-(2-methoxynitrophenoxy)-N,N- dimethylcyclobutan-l-amine (330 mg, 1.24 mmol, 1 equiv), methanol (20 mL), Pd/C, hydrogen. The resulting on was stirred for 1 h at 25 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 285 mg (97%) of the title compound as yellow oil. ical Data: LC-MS: (ES, m/z): RT=0.261min, LCMS 31, m/Z =237 [M+1]. 1H NMR (300 MHZ, DMSO-dG) 5 6.64 (dd, J: 8.3, 1.8 Hz, 1H), 6.25 — 6.00 (m, 2H), 4.72 — 4.51 (m, 2H), 4.36 — 4.14 (m, 1H), 3.61 (d, J: 2.7 Hz, 3H), 2.85 — 2.54 (m, 2H), 2.38 — 1.98 (m, 8H), 1.87 — 1.72 (m, 1H).

Step 5: Synthesis of Diastereomer 1: N2-(3-((1r,3r)—3-(dimethylamino)cyclobutoxy)- 4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine and Diastereomer 2: N2-(3- ((1s,3s)(dimethylamino)cyclobutoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine: Into a 50-mL round-bottom ﬂask, was placed 3-[3-(dimethylamino)cyclobutoxy] methoxyaniline (250 mg, 1.06 mol, 1 equiv), 2-chloro-N,6-dimethylpyrimidinamine (167 mg, 1.06 mol, 1 equiv), IPA (10 mL), triﬂuoroacetic acid (242 mg, 2.14 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 90 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Chiral-Prep-HPLC IF.

The crude product was puriﬁed by Prep-HPLC C HCl. This resulted in 49.6 mg (12%) ofN2- (3-((1r,3r)(dimethylamino)cyclobutoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine diastereomer 1 (randomly assigned) as an off-white solid. And 69.4 mg (17%) of N2- s,3s)(dimethylamino)cyclobutoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine diastereomer 2 (randomly assigned) as an off-white solid.

Example 68: Synthesis of Compound 318 Compound 318: sis of Nz-(3-((1s,3s)—3-((dimethylamino)methyl) cyclobutoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-Z,4—diamine \NH NH O I I RhDo LAH \ N/ J\\ I InD)\\ o N N o M N H Step 1: Synthesis of ((1s,3s)((dimethylamino)methyl)cyclobutoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 3-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenoxy)-N,N—dimethylcyclobutanecarboxamide (200 mg, 0.52 mol, 1 equiv), LAH (78.96 mg, 2.08 mmol, 4.00 equiv), oxolane (10 mL).

The resulting solution was stirred for 2 h at 0 0C in a water/ice bath. The reaction was then quenched by the addition of 200 mg of water/ice. The pH value of the solution was adjusted to 8 with sodium hydroxide (aq) (10 %). The ing solution was diluted with 2 mL of H20. The resulting solution was extracted with 20 mL of ethyl acetate and the organic layers combined and dried over ous sodium sulfate. The solids were d out. The crude product was puriﬁed by Prep-HPLC A. This resulted in 61.8 mg (32%) of N2-(3-((1s,3s) ((dimethylamino)methyl)cyclobutoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine as a white solid.

Example 69: Synthesis of nd 319 Compound 319: Synthesis of 6-ethylﬂu0ro-Nz-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine CI \NH /\M9Br F N/ /NH2 F CliNl N/ E13N |2 THF C|)\\N I K2C031DMF C|)\\N GAO \ I)" ' NH | on 1’ I @MO M \N X-phos, C32CO3, Pd2(dba)3 Step 1: sis of 2,4-dichloroethylﬂuoropyrimidine: Into a 100-mL 3-necked round-bottom ﬂask, was placed 2,4-dichloro ﬂuoropyrimidine (1 g, 5.99 mol, 1 , GDE (3 mL), 12 (1.5 g, 1 , tetrahydrofuran (8 mL), TEA (605 mg, 5.98 mol, 1 equiv), ethyl)magnesium (1.2 g, 9.00 mmol, 1.50 equiv). The resulting on was stirred for 1 h at 0 0C in a water/ice bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of NaHSO3. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 600 mg (51%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 195 [M+l], RT: 1.38 min.

Step 2: Synthesis of 2-chloroethylﬂuoro-N-methylpyrimidinamine: Into a 50-mL round-bottom ﬂask, was placed chloroethylﬂuoropyrimidine (300 mg, 1.54 mol, 1 equiv), CH3NH2-HCl (206 mg, 2.00 equiv), Cs2C03 (1 g, 3.07 mmol, 2.00 equiv), N,N—dimethylformamide (10 mL). The resulting solution was stirred for 12 h at 80 0C. The crude product was d by Flash-Prep-HPLC A 1:1. This resulted in 150 mg (51%) of the title compound as a light yellow solid. ical Data: LC-MS: (ES, m/z): 190 [M+l], R: 0.79 min.

Step 3: Synthesis of 6-ethylﬂuoro-N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloroethylﬂuoro-N— methylpyrimidinamine (100 mg, 0.53 mol, 1 equiv), 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (198 mg, 0.79 mmol, 1.50 equiv), Cs2C03 (508 mg, 1.56 mmol, 3.00 equiv), Pd2(dba)3.CHC13 (50 mg), X-phos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 0C. The crude product was puriﬁed by Flash-Prep-HPLC with the following conditions (1ntelFlash-1): Column, silica gel, mobile phase, 0=1/1, Detector, UV 254 nm product was obtained. This ed in 44.1 mg (21%) of 6-ethylﬂuoro-N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as a light yellow solid. e 70: Synthesis of Compound 320 Compound 320: Synthesis of opr0pyl-N2-(4-meth0xy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine CI CI NJ§N [>—MgBr NJ§N /NH2 HCI CIMCII Cul, THF 01W| K2C03, DMF ji' VOID (L "H WW TFA,i—PrOH @M0 | "*N Step 1: Synthesis of 2,4-dichlorocyclopropylpyrimidine: Into a 50-mL 3-necked round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed 2,4,6-trichloropyrimidine (1 g, 5.45 mol, 1 equiv), tetrahydrofuran (20 mL), CuI (110 mg, 0.58 mmol, 0.10 equiv). This was followed by the addition of bromo(cyclopropyl)magnesium (5.5 mL, 1 equiv) dropwise with stirring at 0 0C.

The resulting solution was stirred for 2 h at 0 0C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25 0C. The reaction was then quenched by the addition ofNH4Cl. The resulting mixture was concentrated under vacuum.

The resulting solution was extracted with 3X100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x100 mL of water and 2x100 mL of Brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude t was puriﬁed by Flash-Prep-HPLC A EA/PE.

This ed in 300 mg (29%) of the title compound as ayellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=1.355min, LCMS 53, m/Z =189 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 7.77 (s, 1H), 2.27 — 2.13 (m, 1H), 1.29 — 1.03 (m, 4H).

Step 2: Synthesis of 2-chlorocyclopropyl-N-methylpyrimidinamine: Into a 8-mL sealed tube, was placed 2,4-dichlorocyclopropylpyrimidine (200 mg, 1.06 mol, 1 , N,N—dimethylformamide (4 mL), ium carbonate (365 mg, 2.64 mmol, 2.50 equiv), methanamine hloride (72 mg, 1.07 mol, 1 equiv). The resulting solution was stirred for 2 h at 0 0C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an onal 2 h at 25 0C. The solids were ﬁltered out. The crude product (4 mL) was puriﬁed by Flash-Prep-HPLC A Grad. This resulted in 80 mg (41%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.682min, LCMS 30, m/Z =184[M+l]. 1H NMR (300 MHZ, DMSO-d6) 5 7.61 (s, 1H), 6.33 (s, 1H), 2.76 (d, J: 4.8 Hz, 3H), 1.91 — 1.85 (m, 1H), 0.95 — 0.85 (m, 4H).

Step 3: Synthesis of 6-cyclopropyl-N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 8-mL sealed tube, was placed 2-chlorocyclopropyl-N-methylpyrimidin amine (80 mg, 0.44 mol, 1 equiv), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (109 mg, 0.44 mol, 1 equiv), isopropanol (5 mL), roacetic acid (100 mg, 0.88 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 90 0C in an oil bath. The resulting solution was ted with of ethyl acetate and the organic layers combined. The crude product (5mL) was puriﬁed by Prep-HPLC C HCl. This resulted in 91.9 mg (49%) of 6-cyclopropyl- N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine as a solid. e 71: Synthesis of Compound 321 Compound 321: sis of N-(5-methoxy—4-(3-(pyrrolidin yl)propoxy)pyridin-2—yl)imidaz0[1,2-a]pyridinamine NH 0 Q 0 O "(le / HCI<2moI/L) A/ —>N —. N \ Pd2(dba)3CHC]3 N BlNAP,t-BuoNa O O HZN/R/ ' \ G" O Br l N N/\/\O / N/K/ Pd2(dba)3CHCl3 CI H Xantphos,CsZCO3 Step 1: Synthesis of N-(diphenylmethylidene)imidazo[1,2-a]pyridinamine: Into a 100-mL 3-necked round-bottom ﬂask, was placed toluene (20 mL), 3- iodoimidazo[1,2-a]pyridine (2 g, 8.20 mmol, 1 equiv), diphenylmethanimine (1.5 g, 8.28 mmol, 1.01 equiv), Pd2(dba)3CHCl3 (1.3 g), BINAP (1.5 g, 2.41 mmol, 0.29 equiv), t-BuONa (2.4 g, 24.97 mmol, 3.05 equiv). The resulting solution was stirred for 5 h at 80 0C. The resulting solution was diluted with 10 mL of H20. The 3-necked round-bottom ﬂask was purged and maintained with N2. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers ed and dried over anhydrous sodium sulfate and concentrated under vacuum. This ed in 1.5 g (62%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.769 min, LCMS 32: m/Z = 297 [M+l].

Step 2: Synthesis of o[l,2-a]pyridinamine: Into a 250-mL round-bottom ﬂask, was placed HCl(2M) (30 mL), N- (diphenylmethylidene)imidazo[1,2-a]pyridinamine (1.5 g, 5.04 mol, 1 equiv). The resulting solution was stirred for 12 h at 20 0C. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined. The pH value of the solution was adjusted to 10 with sodium hydroxide. The resulting mixture was washed with 3x20 mL of chloromethane2. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 370 mg (55%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.290 min, LCMS 40: m/Z = 133 [M+l].

Step 3: Synthesis ofN-[imidazo[1,2-a]pyridinyl]methoxy[3-(pyrrolidin poxy]pyridinamine: Into a 40-mL vial, was placed dioxane (20 mL), imidazo[1,2-a]pyridinamine (180 mg, 1.35 mol, 1 equiv), 2-bromomethoxy[3-(pyrrolidinyl)propoxy]pyridine (469 mg, 1.49 mmol, 1.10 , Pd2(dba)3-CHCl3 (1035 mg), os (247 mg, 0.43 mmol, 0.32 equiv), Cs2CO3 (880 mg, 2.70 mmol, 2.00 equiv). The vial was purged and maintained with N2.The resulting solution was stirred for 12 h at 80 0C. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was d by Prep-HPLC C TFA.

This resulted in 262.2 mg (40%) of N-[imidazo[1,2-a]pyridinyl]methoxy[3- (pyrrolidinyl)propoxy]pyridinamine as a light brown solid.

Example 72: Synthesis of Compound 322 Compound 322: Synthesis of meth0xy(3-(pyrrolidin yl)propoxy)pyridin-2—yl)-N5-methylpyridazine-3,5-diamine CI I NH /| 2W <;N’V‘0' CI \N’N N’N TFAi-PrOH OMO H Step 1: Synthesis of 6-chloro-N-methylpyridazinamine: Into a 20-mL sealed tube, was placed 3,5-dichloropyridazine (1 g, 6.71 mol, 1 equiv), CH3NH2-H20 (2 mL), dioxane (2 mL). The resulting solution was stirred for 2 h at 50 0C in an oil bath. The ing solution was diluted with 2 mL of methanol. The residue was applied onto a silica gel column with CH3CNzH20 . This resulted in 620 mg (64%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.62min, LCMSO7: m/z = 144.00 [M+1].

Step 2: Synthesis of N3-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N5- methylpyridazine-3,5-diamine: Into a 50-mL round-bottom ﬂask, was placed 6-chloro-N-methylpyridazinamine (300 mg, 2.09 mol, 1 equiv), triﬂuoroacetic acid (604 mg, 5.34 mmol, 3.00 equiv), 5- methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (526.6 mg, 2.10 mol, 1 equiv), isopropanol (5 mL). The resulting solution was stirred for 2 h at 85 0C in an oil bath. The resulting e was concentrated under vacuum. The crude t (300 mg) was puriﬁed by Prep-HPLC G. This resulted in 83.1 mg (8%) of N3-(5-methoxy(3-(pyrrolidin yl)propoxy)pyn'dinyl)-N5-methylpyridazine-3,5-diamine as a white solid.

Example 73: Synthesis of Compound 323 Compound 323: Synthesis of methoxy—4—(3-(pyrrolidin yl)pr0poxy)pyridin-2—yl)-N3-methylpyridazine-3,5-diamine 0' Cl \NH \ I'll dioxane \ Ill] '11] 0' \ H2N H2N 0 . N o / \ 3rd-brettphos C’NMO n Step 1: sis 6-chloropyridazinamine: Into a 25-mL round-bottom ﬂask, was placed 3,5-dichloropyridazine (1 g, 6.71 mol, 1 equiv), ammonia (8 mL), dioxane (2 mL). The ing solution was stirred overnight at 100 0C. The solids were collected by ﬁltration. This resulted in 570 mg (62%) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.434 min, LCMS 53, m/Z = 130 [M+1].

Step 2: Synthesis of 3-N-methylpyridazine-3,5-diamine: Into a 50-mL round-bottom ﬂask, was placed 6-chloropyridazinamine (570 mg, 4.40 mol, 1 equiv), e (20 mL), CH3NH2-H2O (4 mL). The resulting solution was stirred overnight at 140 0C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A. This ed in 320 mg (59%) of the title compound as ayellow solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.187 min, LCMS 45, m/Z = 125 [M+l].

Step 3: Synthesis of NS-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N3- methylpyridazine-3,5-diamine: Into a 100-mL round-bottom ﬂask, was placed 3-N-methylpyridazine-3,5-diamine (250 mg, 2.01 mol, 1 equiv), 2-bromomethoxy[3-(pyrrolidinyl)propoxy]pyridine (628 mg, 1.99 mmol, 0.99 equiv), 3rd-Brettphos (181.2 mg), Cs2CO3 (1.3 g, 3.99 mmol, 1.98 equiv), DMSO (25 mL). The resulting solution was stirred for 1 h at 80 0C. The crude t was puriﬁed by Prep-HPLC C HCl. This resulted in 31.2 mg (4%) of NS-(5-methoxy(3- (pyrrolidinyl)propoxy)pyridinyl)-N3-methylpyridazine-3,5-diamine as a light yellow solid. e 74: Synthesis of Compound 324 Compound 324: Synthesis of N4-(5-methoxy(3-(pyrrolidin yl)propoxy)pyridinyl)-N6-methylpyrimidine—4,6-diamine CI 00 (I) ‘:\ / N HZHCI GJVO NH2 / J'N / \ J NJN N/\/\O N \N CI N Pd(dba)3CHC13xantphos H Step 1: Synthesis of 6-chloro-N-methylpyrimidinamine: Into a 100-mL bottom ﬂask, was placed N,N—dimethylformamide (10 mL), 4,6- dichloropyrimidine (1 g, 6.71 mol, 1 equiv), Cs2CO3 (4.4 g, 13.50 mmol, 2.01 equiv), methanamine hydrochloride (905 mg, 13.40 mmol, 2.00 equiv). The resulting solution was d for 14 h at 80 0C. The resulting solution was diluted with 10 mL of H20. The resulting solution was extracted with 4x10 mL of ethyl acetate and the c layers combined. The resulting mixture was washed with 1x10 mL of H20. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 750 mg (78%) of as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.476min, LCMS 32: m/Z = 144 [M+l].

Step 2: Synthesis of N4-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-N6- pyrimidine-4,6-diamine: Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed dioxane (10 mL), 6-chloro-N-methylpyrimidinamine (114 mg, 0.79 mol, 1 equiv), 5-methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (200 mg, 0.80 mol, 1 equiv), Pd2(dba)3-CHCl3 (123 mg, 0.12 mmol, 0.15 equiv), xantphos (138 mg, 0.24 mmol, 0.30 equiv), Cs2CO3 (520 mg, 1.60 mmol, 2.01 equiv). The resulting solution was stirred for 14 h at 80 0C. The ing mixture was concentrated under . The resulting solution was diluted with 5 mL of H20. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC D TFA. This resulted in 40.6 mg (11%) ofN4- (5 -methoxy(3-(pyrrolidin-1 -yl)propoxy)pyridinyl)-N6-methylpyrimidine-4,6-diamine as a white solid.

Example 75: Synthesis of Compound 325 Compound 325: Synthesis of N4-(5-meth0xy(3-(pyrrolidin yl)propoxy)pyridinyl)-N6,2-dimethylpyrimidine-4,6-diamine rJ\NaBHsCNMeOH I}. M OI‘/N J\ mm/ Pd2(dba)3CHCI3xantphos OMO \NJ\ Step 1: Synthesis of 6-chloro-N,2-dimethylpyrimidinamine: Into a 40-mL vial, was placed N,N—dimethylformamide (10 mL), 4,6-dichloro methylpyrimidine (500 mg, 3.07 mol, 1 equiv), methanamine hydrochloride (411 mg, 6.09 mmol, 1.98 equiv), Cs2C03 (1.9 g, 5.83 mmol, 1.90 equiv). The resulting solution was stirred for 12 h at 80 0C. The resulting solution was diluted with 10 mL of H20. The resulting on was extracted with 3x20 mL of dichloromethane and the c layers combined.

The resulting mixture was washed with 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 450 mg (93%) of the title compound as a yellow solid. ical Data: LC-MS: (ES, m/z): RT = 0.763 min, LCMS 07: m/Z = 157 [M+1].

Step 2: Synthesis of methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)- N6,2-dimethylpyrimidine-4,6-diamine: Into a 20-mL vial, was placed dioxane (10 mL), 6-chloro-N,2-dimethylpyrimidin amine (114 mg, 0.72 mol, 1 equiv), oxy[3-(pyrrolidinyl)propoxy]pyridin amine (200 mg, 0.80 mmol, 1.10 , Pd2(dba)3-CHCl3 (112 mg), Xantphos (133 mg, 0.23 mmol, 0.32 equiv), Cs2C03 (472 mg, 1.45 mmol, 2.00 equiv).The vial was purged and maintained with N2. The resulting solution was stirred for 12 h at 80 0C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC D TFA. This resulted in 48.8 mg (14%) of N4-(5-methoxy(3-(pyrrolidin yl)propoxy)pyridinyl)-N6,2-dimethylpyrimidine-4,6-diamine as a white solid.

Example 76: Synthesis of Compound 409 Compound 409: sis of Nz-(3-((1-is0propylpyrrolidinyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine jﬂIHCEZ/VCNH A JEN/Y"ZOEoNvC"1/ NaBHgCNMeOH Compound 409 was synthesized as illustrated above.

Example 77: Synthesis of Compound 326 Compound 326: Synthesis of N-(5-methoxy(3-(pyrrolidin yl)pr0poxy)pyridin-2—yl)—2-methyl-7H-pyrrolo[2,3-d]pyrimidinamine / NH ('3 o m. — w" CNVO NH2 / N—< H 3rd-Bretphos Step 1: Synthesis of N—(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl) methyl-7H-pyrrolo[2,3-d]pyrimidinamine: Into a 40-mL vial purged and maintained with an inert here of nitrogen, was placed e (10 mL), 5-methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (200 mg, 0.80 mol, 1 equiv), 4-chloromethyl-7H-pyrrolo[2,3-d]pyrimidine (133 mg, 0.79 mmol, 1 equiv), Pd2(dba)3-CHCl3 (124 mg, 0.12 mmol, 0.15 equiv), xantphos (138 mg, 0.24 mmol, 0.30 equiv), Cs2C03 (519 mg, 1.59 mmol, 2.00 equiv). The resulting on was stirred for 14 h at 80 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC D TFA. This resulted in 47.2 mg (12%) of N—(5-methoxy(3-(pyrrolidinyl)propoxy)pyridinyl)—2-methyl-7H- pyrrolo[2,3-d]pyrimidinamine as a white solid.

Example 78: Synthesis of Compound 328 Compound 328: Synthesis of Nz-(4-meth0xy(3-(pyrrolidin yl)pr0poxy)phenyl)-N4-methyl-6,7-dihydro-SH—cyclopenta[d]pyrimidine-2,4-diamine O / / HN CI / VODNH; O N/ /NH2 HCl G" | —> N/ | —> DJN: I CIAN\ (SI/KN \ K2C03,DMF TFA,[ PrOH._ O1/\/\0 m N Step 1: Synthesis of 2-chloro-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidinamine: Into a 50-mL round-bottom ﬂask, was placed 2,4-dichloro-5H,6H,7H- cyclopenta[d]pyrimidine (850 mg, 4.50 mol, 1 equiv), potassium carbonate (1.87 g, 13.53 mmol, 3.01 , N,N-dimethylformamide (5 mL), methanamine hydrochloride (303 mg, 4.49 mol, 1 equiv). The resulting solution was stirred for 1 h at 0 0C. The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC A Grad. This ed in 500 mg (61%) of the title nd as an off white solid. ical Data: LC-MS: (ES, m/z): RT = 0.856 min, LCMS 45: m/Z = 184.0 [M+1].1H NMR (300 MHz, DMSO-d6) 5 8.19 (s, 1H), 2.86 (s, 3H), 2.82 — 2.70 (m, 2H), 2.63 (t, J: 7.5 Hz, 2H), 2.12 — 1.95 (m, 2H).

Step 2: Synthesis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)—N4- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methyl-5H,6H,7H- cyclopenta[d]pyrimidinamine (200 mg, 1.09 mmol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (249 mg, 2.18 mmol, 2.01 equiv), 4-methoxy[3-(pyrrolidin poxy]aniline (273 mg, 1.09 mol, 1 equiv). The resulting solution was stirred for 2 h at 80 0C. The crude product was puriﬁed by Prep-HPLC A. This resulted in 93.2 mg (20%) of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine as an off white solid. e 79: Synthesis of Compound 331 Compound 331: Synthesis of Nz-(3-((1r,3r) ((dimethylamin0)methyl)cyclobutoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine O O 01) N/ Pd/C H2 MsC],TEA HO N02 l —> / N —> —> o I | HO MsO 0 l \NH , o | O 0 \ 0 Raney-Ni Cl N N/ —. —. I I]! D N02 0 NH2 \NM0I o NJ\\N LAH \N/IHIQ‘OD N / —. I O NJ\\N Step 1: Synthesis of 3-hydroxy-N,N-dimethylcyclobutane—1-carboxamide: Into a 250-mL round-bottom ﬂask, was placed zyloxy)-N,N— dimethylcyclobutane-l-carboxamide (3 g, 12.86 mol, 1 equiv), ol (100 mL), Pd/C, hydrogen . The resulting solution was stirred for 3 h at 50 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 1.8 g (98%) of the title compound as ayellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.56min, LCMSO7: m/z =144 [M+l].

Step 2: sis of 3-(dimethylcarbamoyl)cyclobutyl methanesulfonate: Into a 50-mL round-bottom ﬂask, was placed 3-hydroxy-N,N-dimethylcyclobutane carboxamide (900 mg, 6.29 mol, 1 equiv), romethane (10 mL), MsCl (2.1 g, 3.00 , TEA (1.9 g, 18.78 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 20 0C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3X10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x10 mL of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.5 g (108%) of the title nd as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.85min, : m/z =222 [M+l].

Step 3: Synthesis of 3-(2-methoxynitrophenoxy)-N,N-dimethylcyclobutane carboxamide: Into a 50-mL bottom ﬂask, was placed 3-(dimethylcarbamoyl)cyclobutyl methanesulfonate (1.3 g, 5.88 mol, 1 equiv), CS2C03 (5.75 g, 17.59 mmol, 3.00 equiv), 2- ynitrophenol (994 mg, 5.88 mol, 1 equiv), N,N—dimethylformamide (10 mL). The resulting solution was stirred for 10 h at 80 0C in an oil bath. The resulting solution was diluted with 10 mL of H20. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x10 mL of H20. The resulting mixture was washed with 2x10 mL of sodium chloride(aq). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane/methanol (10: 1). This resulted in 1.2 g (69%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.82min, LCMS32: m/z =295 [M+l].

Step 4: Synthesis of 3-(5-aminomethoxyphenoxy)-N,N—dimethylcyclobutane carboxamide: Into a 250-mL round-bottom ﬂask, was placed ethoxynitrophenoxy)-N,N- dimethylcyclobutanecarboxamide (600 mg, 2.04 mol, 1 equiv), methanol (150 mL), Raney-Ni, hydrogen. The resulting solution was stirred for 1 h at 20 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 480 mg (89%) of the title nd as blue green oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.79min, LCMS33: m/z =265 [M+l]. 1H NMR (400 MHZ, Methanol-d4) 5 6.76 (dd, J: 8.3, 3.8 Hz, 1H), 6.43 — 6.21 (m, 2H), 4.78 — 4.54 (m, 1H), 3.75 (d, J: 8.4 Hz, 3H), 3.55 — 3.47 (m, 1H), 3.06 — 2.92 (m, 6H), 2.77 — 2.64 (m, 2H), 2.50-2.31 (m, 2H).

Step 5: Synthesis of 3-(2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenoxy)-N,N-dimethylcyclobutanecarboxamide: Into a 50-mL bottom ﬂask, was placed 3-(5-aminomethoxyphenoxy)-N,N- dimethylcyclobutanecarboxamide (467 mg, 1.77 mol, 1 equiv), 2-chloro-N,6- ylpyrimidinamine (277 mg, 1.76 mol, 1 equiv), IPA (10 mL), triﬂuoroacetic acid (514.7 mg, 4.55 mmol, 3.00 equiv). The resulting solution was d for 2 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 967 mg (>100% crude) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = n, LCMS07: m/z =386 [M+l].

Step 6: Synthesis of N2-(3-((1r,3r)((dimethylamino)methyl)cyclobutoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 3-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenoxy)-N,N—dimethylcyclobutanecarboxamide (200 mg, 0.52 mol, 1 equiv), oxolane (0 mg), LAH (78.96 mg, 2.08 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at 0 0C in a water/ice bath. The reaction was then quenched by the addition of 200 mg of water/ice. The pH value of the solution was adjusted to 8 with sodium hydroxide(aq) (10 mol/L). The resulting solution was extracted with 20 mL of ethyl acetate and the c layers combined and dried in an oven under reduced pressure.

The solids were ﬁltered out. The crude product (400 mg) was puriﬁed by Prep-HPLC C HCl.

The crude product (300 mg) was puriﬁed by -Prep-HPLC 1C. This resulted in 66.4 mg (34%) ofN2-(3-((1r,3r)((dimethylamino)methyl)cyclobutoxy)—4-methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine as a white solid.

Example 80: Synthesis of Compound 332 Compound 332: Synthesis of meth0xy(3-(pyrrolidin yl)propoxy)pyridin-3—yl)-N4,6-dimethylpyrimidine-2,4—diamine N Cl /\/‘ \ Cl D UN Cl N o\ I MeOHMeONa LI )LNH2 / —> —> —> Br OH / DMD / DMD 052003,DMF Br Br 3rd-Brettphos 0 mo\ NaOH,MeOH £56K /E::|N:j/(NJ‘CI A" / DMD / DMD TFAi-PrOH J\NLIZQQ Step 1: Synthesis of 5-bromochloro[3-(pyrrolidinyl)propoxy]pyridine: Into a 100-mL round-bottom ﬂask, was placed 5-bromochloropyridinol (1.1 g, .28 mol, 1 equiv), Cs2C03 (5.3 g, 16.27 mmol, 3.08 , methylformamide (10 mL), 1-(3-chloropropyl)pyrrolidine hloride (1 g, 5.43 mmol, 1.03 equiv). The resulting solution was stirred for 2 h at 80 0C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3X50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.05 g (62%) of as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.827min, LCMS 45: m/z= 319.00 [M+1]. 1H-NMR: (300 MHz, Chloroform-d) 5 8.05 (d, J: 2.0 Hz, 1H), 7.41 (d, J: 2.0 Hz, 1H), 4.15 (t, J: 6.3 Hz, 2H), 2.73 — 2.46 (m, 6H), 2.17 — 1.93 (m, 2H), 1.92 — 1.73 (m, 4H).

Step 2: Synthesis of 5-bromomethoxy[3-(pyrrolidinyl)propoxy]pyridine: Into a 50-mL round-bottom ﬂask, was placed 5-bromochloro[3-(pyrrolidin yl)propoxy]pyridine (1 g, 3.13 mmol, 1 equiv), methanol (10 mL), methoxysodium (849 mg, .72 mmol, 5.02 equiv). The resulting solution was stirred for 48 h at 70 0C. The reaction was then quenched by the on of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 100 mL of sodium chloride. The mixture was dried over ous sodium sulfate and trated under vacuum. This resulted in 910 mg (92%) of as a light yellow liquid.

Analytical data: LC-MS: (ES, m/z): RT = 13min, LCMS 31: m/z= 315.35 [M+1]. 1H- NMR: (300 MHz, Chloroform—d) 5 7.77 (d, J: 2.0 Hz, 1H), 7.23 (d, J: 2.1 Hz, 1H), 4.12 (t, J: 6.5 Hz, 2H), 3.98 (s, 3H), 2.62 — 2.51 (m, 6H), 2.15 — 2.02 (m, 2H), 1.85 — 1.78 (m, 4H).

Step3: Synthesis of N-[6-methoxy[3-(pyrrolidinyl)propoxy]pyridin yl]acetamide: Into a 50-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromomethoxy[3-(pyrrolidinyl)propoxy]pyridine (870 mg, 2.76 mol, 1 equiv), Cs2C03 (2.7 g, 8.29 mmol, 3.00 equiv), 3rd-Brettphos (251 mg), dioxane (5 mL), ide (245 mg, 4.15 mmol, 1.50 equiv). The resulting solution was d for 16 h at 65 0C. The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC A Grad. This resulted in 200 mg (25%) of as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.541min, LCMS45: m/z= 294.10 [M+1]. lH-NMR-PH-EPISOK4: (300 MHz, ium Oxide) 5 7.57 (d, J: 2.1Hz, 1H), 7.33 (d, J: 2.1 Hz, 1H), 4.09 — 3.97 (m, 1H), 3.85 (s, 3H), 3.08 — 2.87 (m, 2H), 2.23 — 1.80 (m, 9H).

Step 4: Synthesis of 6-methoxy[3-(pyrrolidinyl)propoxy]pyridin amine: Into a 100-mL round-bottom ﬂask, was placed N-[6-methoxy[3-(pyrrolidin- 1-yl)propoxy]pyridinyl]acetamide (180 mg, 0.61 mol, 1 equiv), potassium hydroxide (172 mg, 3.07 mmol, 5.00 equiv), water (5 mL), methanol (5 mL). The ing solution was stirred for 16 h at 60 0C. The resulting solution was extracted with 4X50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 110 mg (71%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.414min, LCMS53: m/z= 252.20 [M+1]. 1H-NMR: (300 MHz, Methanol-d4) 5 7.19 (d, J: 2.4 Hz, 1H), 6.81 (d, J: 2.3 Hz, 1H), 4.15 — 3.92 (m, 2H), 3.86 (s, 3H), 2.78 — 2.51 (m, 4H), 2.04 (m, 2H), 1.95 — 1.70 (m, Step 5: Synthesis of N2-(6-methoxy(3-(pyrrolidinyl)propoxy)pyridin yl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 25-mL bottom ﬂask, was placed 6-methoxy[3-(pyrrolidin yl)propoxy]pyridinamine (100 mg, 0.40 mol, 1 equiv), panol (5 mL), triﬂuoroacetic acid (91 mg, 0.80 mmol, 2.01 equiv), 2-chloro-N,6-dimethylpyrimidin amine (63 mg, 0.40 mol, 1 equiv). The resulting solution was stirred for 2 h at 80 0C. The crude product was puriﬁed by PLC C HCl. This resulted in 71 mg (44%) of N2-(6- methoxy(3-(pyrrolidinyl)propoxy)pyridin-3 -yl)-N4,6-dimethylpyrimidine-2,4-diamine as an off-white solid.

Example 81: Synthesis of Compound 334 nd 334: Synthesis of Nz-(3-((1-ethylazetidinyl)meth0xy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4—diamine / I HN I) 2 "/I *\ ' V0 NJ\\N NaBH3CN,MeOH,HOAc MNOAO H N HN H Step 1: Synthesis of ((1-ethylazetidinyl)methoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 2-N-[3-(azetidinylmethoxy)— 4-methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.91 mol, 1 equiv), acetaldehyde (32.1 mg, 0.73 mmol, 0.80 equiv), methanol (15 mL), NaBH3CN (344.68 mg, .49 mmol, 6.00 equiv), HOAC (0.002 mL). The resulting solution was stirred for 20 min at 0C. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25 0C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC D TFA. This resulted in 32.4 mg (8%) of N2-(3-((1-ethylazetidinyl)methoxy)- 4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 82: Synthesis of Compound 335 nd 335: Synthesis of N-(S—methoxy—4—(3-(pyrrolidin yl)propoxy)pyridineyl)-1H-pyrrolo[2,3—b]pyridin-4—amine /NH NH | / A / / \ X-phos, Cszcog, a)3 Cl Step 1: Synthesis of N—(5-methoxy(3-(pyrrolidinyl)propoxy)pyridin yl)-1H-pyrrolo[2,3-b]pyridinamine: Into a 50-mL round-bottom ﬂask, was placed oxy[3-(pyrrolidin yl)propoxy]pyridinamine (128 mg, 0.51 mol, 1 equiv), 4-bromo-1H-pyrrolo[2,3- b]pyridine (100 mg, 0.51 mol, 1 equiv), Cs2CO3 (496 mg, 1.52 mmol, 3.00 equiv), Pd2(dba)3-CHCl3 (50 mg), X-phos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 0C. The crude product was puriﬁed by Flash-Prep A 1:1. This resulted in .8 mg (15%) of ethoxy(3-(pyrrolidinyl)propoxy)pyridinyl)-1H-pyrrolo[2,3- b]pyridinamine as a white solid.

Example 83: Synthesis of Compound 336 Compound 336: sis of N-(5-methoxy—4—(3-(pyrrolidin yl)pr0poxy)pyridin-Z-yl)methyl-1H-pyrrolo[2,3-b]pyridin-4—amine é h , @Mo /NH2 /N\ X phos, C32C03, Pd2(dba)3_ Cit/mo H Step 1: Synthesis of N—(5-methoxy(3-(pyrrolidinyl)propoxy)pyridin yl)methyl-1H-pyrrolo[2,3-b]pyridinamine: Into a 50-mL round-bottom ﬂask, was placed 4-chloromethyl-1H- pyrrolo[2,3-b]pyridine (150 mg, 0.90 mol, 1 equiv), 5-methoxy[3-(pyrrolidin yl)propoxy]pyridinamine (228 mg, 0.91 mol, 1 equiv), Cs2CO3 (884 mg, 2.71 mmol, 3.00 equiv), Pd2(dba)3-CHCl3 (50 mg), X-phos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 0C. The crude t was puriﬁed by Prep-HPLC A 1:1. This resulted in 35.9 mg (9.5%) of ethoxy(3-(pyrrolidinyl)propoxy)pyridin- 2-yl)methyl-1H-pyrrolo[2,3-b]pyridinamine as a light yellow solid.

Example 84: Synthesis of Compound 388 Compound 388: Synthesis of (3-(dimethylamino)pr0pyl)—1H- indazolyl)-N4-methylpyrimidine-2,4-diamine \ CI [If/D N, \ ‘N Rany—Ni,MeOH No2—, H No2 C32003,KI,DMF /N’\// "LDNH/ PTSA,i—PrOH \ MDb/ N/\// 2 \ N N N / /N/\// H Step 1: Synthesis of dimethyl[3-(6-nitro-2H-indazolyl)propyl] amine: WO 81177 Into a 40-mL vial, was placed N,N—dimethylformamide (20 mL), 6-nitro-1H- le (1 g, 6.13 mol, 1 equiv), (3-chloropropyl)dimethylamine hydrochloride (963 mg, 6.09 mmol, 0.99 equiv), Cs2C03 (4 g, 12.28 mmol, 2.00 equiv), K1 (1 g). The resulting solution was stirred for 12 h at 60 0C. The resulting solution was diluted with 20 mL of H20.

The ing solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x20 mL of water and 3x20 mL of brine.

The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1). This resulted in 200 mg (13%) of the title compound as yellow 011.

Analytical Data: LC-MS: (ES, m/z): RT =0.861 min, LCMS 07: m/Z = 249 [M+1].

Step 2: Synthesis of dimethylamino)propyl]-2H-indazolamine: ] Into a 100-mL round-bottom ﬂask, was placed methanol (30 mL), Raney-Ni (40 mg), dimethyl[3-(6-nitro-2H-indazolyl)propyl] amine (200 mg, 0.81 mol, 1 equiv), hydrogen. The ing solution was stirred for 2 h at 20 0C. The solids were ﬁltered out. The ﬂask was purged and maintained with H2.The resulting mixture was concentrated under . This ed in 190 mg (108%) of the title compound as yellow 011. ical Data: LC-MS: (ES, m/z): RT =0.322 min, LCMS 33: m/Z = 219 [M+1].

Step 3; Synthesis ofNZ-(l-(3-(dimethylamino)propyl)-1H-indazolyl)-N4- methylpyrimidine-2,4-diamine: Into a 20-mL vial, was placed isopropanol (2 mL), 2-[3- (dimethylamino)propyl]-2H-indazolamine (150 mg, 0.69 mmol, 1 equiv), 2-chloro-N- methylpyrimidinamine (109 mg, 0.76 mmol, 1.10 equiv), PTSA (118 mg, 0.69 mmol, 1 equiv). The resulting solution was stirred for 12 h at 80 0C. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was puriﬁed by Prep-HPLC G. This resulted in 35.1 mg (14%) ofNZ-(l-(3-(dimethylamino)propyl)-1H-indazolyl)-N4- methylpyrimidine-2,4-diamine as a yellow solid.

Example 85: Synthesis of Compound 404 Compound 404: Synthesis of N2-(2-(2-(dimethylamino)ethyl)-2H-indazol- 6-yl)-N4-methylpyrimidine-2,4-diamine | \ N/,:©\ HC[ Raney-Ni /N—\_Ni1 \ {—N/:©\N N02 ﬂ No2 052003,DMF,NaI N NH N_ 2 HN’ HN/ CIERI \N / XCQ N/ x ' TFA,I-PrOH_ N N N Step 1: Synthesis of dimethyl[2-(6-nitro-2H-indazolyl)ethyl]amine: Into a 100-mL round-bottom ﬂask, was placed 6-nitro-1H-indazole (1 g, 6.13 mmol, 1 equiv), N,N—dimethylformamide (10 mL), Cs2C03 (8 g, 24.48 mmol, 3.99 equiv), iodosodium (920 mg, 6.14 mmol, 1 equiv). Reaction 30 min at RT. And then added (2- chloroethyl)dimethylamine hydrochloride (1.75 g, 12.15 mmol, 1.98 equiv). The resulting solution was stirred for 16 h at 60 0C. The on was then quenched by the addition of water. The resulting solution was extracted with 3x100 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 3x mL of sodium chloride. The mixture was dried over ous sodium sulfate and trated under vacuum. This resulted in 480 mg (33%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.629min, LCMS45: m/z= 235.10 [M+1].

Step 2: Synthesis of dimethylamino)ethyl]-2H-indazolamine: Into a 100-mL round-bottom ﬂask purged and maintained with H2, was placed dimethyl[2-(6-nitro-2H-indazolyl)ethyl]amine (480 mg, 2.05 mol, 1 equiv), Ni (50 mg), methanol (10 mL). The resulting solution was stirred for 2 h at RT. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 380 mg (91%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.373min, LCMS31: m/z= 205.48 [M+1].

Step 3; Synthesis ofN2-(2-(2-(dimethylamino)ethyl)-2H-indazolyl)-N4- methylpyrimidine-2,4-diamine: Into a 50-mL bottom ﬂask, was placed 2-[2-(dimethylamino)ethyl]-2H- indazolamine (370 mg, 1.81 mol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (414 mg, 3.63 mmol, 2.00 equiv), 2-chloro-N-methylpyrimidinamine (259 mg, 1.80 mol, 1 equiv). The resulting on was stirred for 2 h at 80 0C. The crude product was puriﬁed by Prep-HPLC F HCl. This resulted in 73 mg (12%) of N2-(2-(2-(dimethylamino)ethyl)-2H- indazolyl)-N4-methylpyrimidine-2,4-diamine as a light yellow solid.

WO 81177 Example 86: Synthesis of Compound 407 nd 407: Synthesis of Nz-(4-methoxy(((1-methylpyrrolidin-3— yl)oxy)methyl)phenyl)-N4-methylpyrimidine-2,4-diamine C \ O N2 EN‘ HO o Fe,NH4C| OZN o —. —.

\ NaH,DMF o H2N 0E T CC i | H H 9 \N /" "Y" E \ | TFA,i-PrOH LI \ N o/ Step 1: Synthesis of 3-[(2-methoxynitropheny1)methoxy] methylpyrrolidine: Into a 250-mL bottom ﬂask, was placed 1-methylpyrrolidinol (900 mg, 8.90 mmol, 1.10 equiv), N,N—dimethylformamide (30 mL). This was followed by the addition of sodium hydride (1.96 g, 81.67 mmol, 6.00 equiv) in several batches at 0 0C. 60%.The resulting solution was stirred for 30 min at 0 0C in a water/ice bath. To this was added 2-(bromomethy1)methoxynitrobenzene (2 g, 8.13 mol, 1 equiv). The resulting on was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 20 0C in an oil bath. The reaction was then quenched by the addition of 60 mL of water. The resulting solution was extracted with 3X100 mL of ethyl acetate and the organic layers ed and dried in an oven under reduced pressure. This resulted in 740 mg (34%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.923 min, LCMS34: m/z = 267.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.36 — 8.14 (m, 2H), 7.17 — 7.07 (m, 1H), 4.63 — 4.47 (m, 2H), 3.99 (d, J: 1.2 Hz, 3H), 2.85 — 2.70 (m, 2H), 2.58 — 2.36 (m, 5H), 2.31 — 2.12 (m, 2H), 2.09 — 1.90 (m, 1H).

Step 2: Synthesis of 4-methoxy[[(1-methylpyrrolidin yl)oxy]methy1]aniline: Into a 50-mL round-bottom ﬂask, was placed methoxy henyl)methoxy]methylpyrrolidine (700 mg, 2.63 mol, 1 equiv), Fe (735.0 mg, 13.12 mmol, 5.00 equiv), NH4C1 (714 mg, 13.35 mmol, 5.00 equiv), water(3 mL), ethanol (10 mL). The resulting solution was stirred for 2 h at 80 0C in an oil bath. The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC A. This resulted in 1.5 g (crude) of the title compound as a crude solid.

] Analytical Data: LC-MS: (ES, m/z): RT = 0.687 min, LCMS53: m/z = 237.2 [M+l].

Step 3: Synthesis of N2-(4-methoxy(((1-methylpyrrolidin )methyl)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[[(1- pyrrolidinyl)oxy]methyl]aniline (200 mg, 0.85 mol, 1 equiv), ro-N- methylpyrimidinamine (121.2 mg, 0.84 mol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (193.2 mg, 1.71 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C HCl. This resulted in 49.0 mg (15%) of N2-(4-methoxy(((1-methylpyrrolidin yl)oxy)methyl)phenyl)-N4-methylpyrimidine-2,4-diamine as an oil.

Example 87: Synthesis of Compound 408 Compound 408: Synthesis of Nz-(3-((1-ethylpyrrolidin-S-yl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine H H N N N o CH CHO3 H N H / o\/CNW / / Tr \/CNH / v \ N / CH3OH NaBH3CN \ N / Step 1: Synthesis of N2-(3-((1-ethylpyrrolidinyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin ylmethoxy)phenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.61 mmol, 1 equiv), methanol (10 mL), NaBH3CN (114.9 mg, 1.83 mmol, 3.00 equiv), acetaldehyde (26.7 mg, 0.61 mol, 1 . The resulting solution was stirred for 2 h at 20 °C. The reaction was then quenched by the addition of ice. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC C TFA. This ed in 29 mg (12%) of N2-(3-((1-ethylpyrrolidinyl)methoxy)methoxyphenyl)-N4- methylpyrimidine-2,4-diamine as a white solid.

Example 88: Synthesis of Compound 410 nd 410: Synthesis of Nz-(4-methoxy((1-(2- methoxyethyl)pyrrolidin-S-yl)meth0xy)phenyl)-N4-methylpyrimidine-2,4-diamine H H 5: WH H H w "WOW°"WmOKN DMF,K2CO3 \ N o/ 0 Step 1: Synthesis of N2-(4-methoxy((1-(2-methoxyethyl)pyrrolidin yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 30-mL sealed tube, was placed 2-N-[4-methoxy(pyrrolidin ylmethoxy)phenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.61 mmol, 1 equiv), N,N— dimethylformamide (10 mL), ium carbonate (252 mg, 1.82 mmol, 3.00 equiv), 1- bromomethoxyethane (101 mg, 0.73 mmol, 1.20 . The resulting solution was d for 12 h at 50 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 60.9 mg (20%) of N2-(4-methoxy((1-(2-methoxyethyl)pyrrolidin yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 89: Synthesis of Compound 411 Compound 411: Synthesis of N2-(3-((1-cyclopropylpyrrolidin-S- yl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine /%%WmoooﬂﬂNaBH3CNMeOH ] Step 1: Synthesis of N2-(3-((1-cyclopropylpyrrolidinyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 25-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin ylmethoxy)phenyl]N-methylpyrimidine-2,4-diamine (250 mg, 0.76 mmol, 1 equiv), methanol (10 mL), (1-ethoxycyclopropoxy)trimethylsilane (200 mg, 1.15 mmol, 1.50 equiv), NaBH3CN (144 mg, 2.29 mmol, 3.00 equiv), AcOH (0.2 mL). The resulting solution was d for 16 h at 65 0C in an oil bath. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 95.3 mg (26%) of ((1-cyclopropylpyrrolidin yl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 90: Synthesis of Compound 412 ] Compound 412: Synthesis of Nz-(4-methoxy((1-methylpiperidin yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine v0 OZNUOH 0 N oV0N M$C|,TEA,DCM 0/ 2 U \ N\ —, HO \ CSZCO3,DMF O/ )\\ | H H Pd/C,MeOH OZNUO N\ CI N /N\EN/\IrN\©[O N\ '. N O/ TsOH,| PrOH \ 0/ Step 1: sis of (1-methylpiperidinyl)methyl methanesulfonate: Into a 100-mL round-bottom ﬂask, was placed (1-methylpiperidin yl)methanol (1 g, 7.74 mol, 1 equiv), dichloromethane (20 mL), TEA (2.349 g, 23.21 mmol, 3.00 equiv), MsCl (1.326 g, 11.63 mmol, 1.50 . The resulting solution was stirred for 2 h at 20 0C. The resulting mixture was concentrated under vacuum. This resulted in 1.6 g (100%) of the title compound as ayellow solid.

Step 2: Synthesis of 3-(2-methoxynitrophenoxymethyl) methylpiperidine: Into a 50-mL round-bottom ﬂask, was placed 2-methoxynitrophenol (1.09 g, 6.44 mol, 1 equiv), (1-methylpiperidinyl)methyl methanesulfonate (1.6 g, 7.72 mmol, 1.20 equiv), CszCO3 (4.21 g, 12.92 mmol, 2.00 equiv), N,N—dimethylformamide (10 mL).

The resulting solution was stirred for 24 h at 90 0C in an oil bath. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The crude product was puriﬁed by Flash-Prep-HPLC A Grad. This resulted in 900 mg (50%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.901 min, LCMS07: m/z = 281.15 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.96 — 7.92 (m, 1H), 7.80 (d, J: 2.7 Hz, 1H), 7.13 (d, J: 9.0 Hz, 1H), 4.08 — 3.88 (m, 5H), 3.11 — 3.07 (m, 1H), 2.89 — 2.85 (m, 1H), 2.33 (s, 3H), 2.26 — 1.49 (m, 6H), 1.29 — 1.14 (m, 1H).

Step 3: sis of 4-methoxy[(1-methylpiperidinyl)methoxy]aniline: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of H2, was placed 3-(2-methoxynitrophenoxymethyl)methylpiperidine (900 mg, 3.21 mmol, 1 equiv), methanol (20 mL), Pd/C (300 mg). The ing on was d for 2 h at 20 0C. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. This resulted in 800 mg (100%) of as dark red oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.149 min, LCMS48: m/z = 281.2 [M+1].

WO 81177 Step 4: Synthesis of N2-(4-methoxy((1-methylpiperidin yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-methoxy[(1- methylpiperidinyl)methoxy]aniline (300 mg, 1.20 mol, 1 equiv), 2-chloro-N- methylpyrimidinamine (170.9 mg, 1.19 mol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (272.5 mg, 2.41 mmol, 2.00 equiv). The resulting solution was d for 12 h at 85 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C HCl. This resulted in 93.5 mg (20%) of N2-(4-methoxy((1-methylpiperidinyl)methoxy)phenyl)- N4-methylpyrimidine-2,4-diamine as an off-white solid.

Example 91: Synthesis of Compound 413 Compound 413: Synthesis of Nz-(4-methoxy((1-methylpiperidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine Q U/H N o N\ TFAi-PrOH N/ 2 53 + 27:1 0 Step 1: Synthesis of N2-(4-methoxy((1 -methylpiperidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL bottom ﬂask, was placed 4-methoxy[(1- methylpiperidinyl)methoxy]aniline (300 mg, 1.20 mol, 1 equiv), 2-chloro-N,6- dimethylpyrimidinamine (187.6 mg, 1.19 mmol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (272.5 mg, 2.41 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC G NH4HCO3.

This resulted in 43.1 mg (10%) of methoxy((1-methylpiperidin hoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as an off-white solid.

Example 92: Synthesis of Compound 414 Compound 414: Synthesis of 1-(3-(2-meth0xy((4- (methylamin0)pyrimidin-Z-yl)amin0)phenoxy)propyl)azetidinol 615 "W"HCIK2003 NalACN LN/V:Oj©\1215 Step 1: Synthesis of 2-methoxy((4-(methylamino)pyrimidin yl)amino)phenoxy)propyl)azetidinol: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), NaI (93 mg), ium carbonate (514 mg, 3.72 mmol, 6.00 equiv), ACN (10 mL), azetidinol hydrochloride (203 mg, 1.85 mmol, 2.99 equiv). The resulting solution was stirred for 16 h at 80 0C. The solids were ﬁltered out. The crude product was puriﬁed by Prep-HPLC C HCl.

This resulted in 59.3 mg (24%) of 1-(3-(2-methoxy((4-(methylamino)pyrimidin yl)amino)phenoxy)propyl)azetidinol as a light yellow solid.

Example 93: Synthesis of Compounds 415 and 416 Compound 415 and 416: Synthesis of (S)-N2-(4-meth0xy((1- methylpyrrolidin-S-yl)methoxy)phenyl)-N4-methylpyrimidine-2,4—diamine and (R)-N2- (4-meth0xy((l-methylpyrrolidin-3—yl)methoxy)phenyl)-N4-methylpyrimidine-2,4- diamine OZN OH \/CN MsCI \/CN 1:10, OZN o\/CN\ Uo Ni,H2 HZN Ox/CN\ HO —.M50 — —.

\ \ M C52C03,DMF / I I Step 1: Synthesis of hylpyrrolidinyl)methyl methanesulfonate: Into a 100-mL round-bottom ﬂask, was placed (1-methylpyrrolidin yl)methanol (1.5 g, 13.02 mol, 1 equiv), TEA (4.0 g, 39.53 mmol, 3.00 equiv), dichloromethane (15 mL), methanesulfonyl chloride (2.23 mg, 0.02 mmol, 1.5 equiv). The resulting solution was stirred for 3 h at 25 0C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 15 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 1.78 g (crude) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.34 min, LCMS 33: m/Z = 194.0 [M+1].

Step 2: sis of 3-(2-methoxynitrophenoxymethyl) methylpyrrolidine: ] Into a 100-mL round-bottom ﬂask, was placed (1-methylpyrrolidin yl)methyl methanesulfonate (1.78 g, 9.21 mol, 1 equiv), Cs2CO3 (9 g, 27.62 mmol, 3.00 equiv), oxynitrophenol (2.3 g, 13.60 mmol, 1.5 equiv), methylformamide (40 mL). The resulting solution was stirred for 2 h at 80 0C in an oil bath. The resulting solution was extracted with 3x40 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x30 mL of sodium chloride. The e was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1.46 g (58%) of the title compound as a white solid.

] Analytical Data: LC-MS: (ES, m/z): RT = 0.89 min, LCMS 07: m/Z = 267.0 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.93 (q, J: 2.7 Hz, 1H), 7.80 (d, J: 2.7 Hz, 1H), 7.12 (d, J: 9.0 Hz, 1H), 4.11 — 3.99 (m, 2H), 3.97 (s, 3H), 2.94 — 2.64 (m, 4H), 2.56 (q, J: 9.4 Hz, 1H), 2.43 (s, 3H), 2.23 — 2.02 (m, 1H), 1.72 — 1.69 (m, 1H).

Step 3: Synthesis of 4-methoxy[(1-methylpyrrolidinyl)methoxy]aniline: Into a 100-mL round-bottom ﬂask, was placed 3-(2-methoxy nitrophenoxymethyl)methylpyrrolidine (1.46 g, 5.48 mol, 1 equiv), Raney-Ni (300 mg), methanol (25 mL). The resulting solution was stirred for 1 h at 25 0C. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. This resulted in 630 mg (42%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.60 min, LCMS 07: m/Z = 237.0 [M+1].

Step 4: Synthesis of (S)-N2-(4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine (E1) and (R)-N2-(4-methoxy((1- methylpyrrolidinyl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine (E2): Into a 100-mL round-bottom ﬂask, was placed 4-methoxy[(1- methylpyrrolidinyl)methoxy]aniline (300 mg, 1.27 mol, 1 equiv), triﬂuoroacetic acid (290 mg, 2.57 mmol, 2.00 equiv, 98%), 2-chloro-N-methylpyrimidinamine (182 mg, 1.27 mol, 1 equiv), isopropanol (15 mL). The resulting solution was stirred for 3 h at 90 0C in an oil bath. The resulting e was concentrated under vacuum. The crude product was applied onto a silica gel column with NH4HC03:ACN (1:1), or, UV 254 nm. This resulted in 23 mg (5%) of (S)-N2-(4-methoxy((1-methylpyrrolidinyl)methoxy)phenyl)- N4-methylpyrimidine-2,4-diamine E1 (arbitrarily assigned, S) and 22.7 mg (5%) of (R)-N2- (4-methoxy((1-methylpyrrolidinyl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine E2 (arbitrarily assigned, R) as a white solid.

Example 94: Synthesis of Compounds 417 and 418 Compound 417 and 418: Synthesis of -(4-methoxy((1- methylpyrrolidinyl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine and (R)- Nz-(4-methoxy((1-methylpyrrolidinyl)methoxy)phenyl)-N4,6-dimethylpyrimidine- 2,4—diamine | | O O OVC \ )L"5, / Cl N N )NL \, / JNL \/ / H2N N o N N N o N N N H H + H H 0/ TFA,[—PrOH _ -N/I", Step 1: Synthesis of (S)-N2-(4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine (E1) and (R)—N2-(4-methoxy ((1-methylpyrrolidinyl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine (E2): Into a 100-mL round-bottom ﬂask, was placed 4-methoxy[(1- methylpyrrolidinyl)methoxy]aniline (300 mg, 1.27 mol, 1 , 2-chloro-N,6- dimethylpyrimidinamine (200 mg, 1.27 mol, 1 equiv), triﬂuoroacetic acid (290 mg, 2.57 mmol, 2.00 equiv, 98%), isopropanol (15 mL). The resulting solution was stirred for 3 h at 90 0C in an oil bath. The resulting e was concentrated under vacuum. The crude product (300 mg) was applied onto a silica gel column with NH4HCO3zACN (1 : 1),Detector, UV 254 nm. This resulted in 82.4 mg (18%) of (S)-N2-(4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine E1 (arbitrarily assigned, S) as a white solid. And 49.6 mg (11%) of (R)-N2-(4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine E1 (arbitrarily assigned, R) as a white solid.

Example 95: Synthesis of Compound 419 Compound 419: sis of Nz-(3-(((1-ethylpyrrolidinyl)oxy)methyl)- 4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine J3 " \ CIANI H H OZN N‘Boc / N N N o / / T CN‘BOC . o Raney N1 \ N / O O O | | TFA, iPrOH C H H H H CH3CHO N N N /" "$1330 NH / ,CNJ _. ii f \ N O 0/ CHSOH,NaBH3CN ] Step 1: Synthesis of tert-butyl mino methoxyphenoxymethyl)pyrrolidinecarboxylate: Into a 250-mL round-bottom ﬂask, was placed tert-butyl 3-(2-methoxy nitrophenoxymethyl)pyrrolidinecarboxylate (600 mg, 1.70 mol, 1 equiv), methanol (50 mL), Raney-Ni, hydrogen. The resulting solution was stirred for 1 h at 20 0C. The solids were ﬁltered out. The ing mixture was concentrated under vacuum. This resulted in 496 mg (90%) of as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.76min, LCMS33: m/z = 322 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 6.77 (d, J: 8.5 Hz, 1H), 6.47 (d, J: 2.6 Hz, 1H), 6.33 (dd, J: 8.5, 2.5 Hz, 1H), 4.02 — 3.85 (m, 2H), 3.76 (s, 3H), 3.63 — 3.48 (m, 2H), 3.26 (dd, J: 20.0, 11.5 Hz, 2H), 2.77 — 2.66 (m, 1H), 2.10 (d, J: 10.7 Hz, 1H), 1.85 (dd, J: 13.9, 6.7 Hz, 1H), 1.48 (s, 9H).

Step 2: Synthesis of tert-butyl ethoxy[[4-methyl (methylamino)pyrimidinyl] amino]phenoxymethyl)pyrrolidinecarboxylate: Into a 100-mL round-bottom ﬂask, was placed tert-butyl mino methoxyphenoxymethyl)pyrrolidinecarboxylate (496 mg, 1.54 mol, 1 equiv), 2-chloro- N,6-dimethylpyrimidinamine (242 mg, 1.54 mol, 1 equiv), triﬂuoroacetic acid (445 mg, 3.94 mmol, 3.00 equiv), panol (10 mL). The resulting solution was stirred for 2 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with CH3CN/HZO (1:5). This resulted in 560 mg (82%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.15min, : m/z = 444 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.29 (s, 1H), 7.13 — 6.99 (m, 2H), 5.99 (d, J: 1.2 Hz, 1H), 5.51 (s, 1H), 4.02 (q, J: 8.0, 6.8 Hz, 2H), 3.87 (s, 3H), 3.68 — 3.38 (m, 3H), 3.00 (s, 3H), 2.73 (s, 1H), 2.29 (s, 3H), 2.12 (s, 1H), 1.86 (s, 1H), 1.48 (s, 9H).

Step 3: Synthesis of -methoxy(pyrrolidinylmethoxy)phenyl] N,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed tert-butyl 3-(2-methoxy[[4- methyl(methylamino)pyrimidinyl] amino] phenoxymethyl)pyrrolidine-1 -carboxylate (560 mg, 1.26 mol, 1 equiv), triﬂuoroacetic acid (364 mg, 3.22 mmol, 3.00 equiv), dichloromethane (10 mL). The resulting solution was stirred for 3 h at 20 0C. The resulting mixture was concentrated under vacuum. TEA was employed to adjust the pH to 8. The resulting mixture was concentrated under vacuum. This resulted in 900 mg (>100%) of the title compound as a solid.

WO 81177 Analytical Data: LC-MS: (ES, m/z): RT = n, LCMSO7: m/z = 344 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.28 (d, J: 2.5 Hz, 1H), 7.19 (dd, J: 8.7, 2.5 Hz, 1H), 7.04 (d, J: 8.7 Hz, 1H), 5.99 (d, J: 1.1 Hz, 1H), 4.19 — 4.04 (m, 2H), 3.88 (s, 3H), 3.71 — 3.47 (m, 3H), 3.01 (s, 5H), 2.37 — 2.22 (m, 4H), 2.12-1.94 (m, 1H).

Step 4: Synthesis of N2-(3-(((1-ethylpyrrolidinyl)oxy)methyl) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin ylmethoxy)phenyl]N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.87 mol, 1 equiv), NaBH3CN (165.3 mg, 2.63 mmol, 3.00 equiv), acetaldehyde (38.5 mg, 0.87 mol, 1 equiv), ol (10 mL). The ing solution was stirred for 2 h at 20 °C. The reaction was then quenched by the addition of water/ice. The resulting mixture was concentrated under vacuum.

The crude product (300 mg) was puriﬁed by Prep-HPLC C HCl. This resulted in 77.6 mg (22%) osz-(3-(((1-ethylpyrrolidinyl)oxy)methyl)methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine as a white solid.

Example 96: Synthesis of Compound 420 Compound 420: sis of Nz-(4-methoxy((l-propylpyrrolidin-S- yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine H H H H /N N N OVCNH \A /N N N OVCN\/\ T3 1:1 0 \ N o/ NaBchN,MeOH,AcOH T3 (1\ N 0/ Step 1: Synthesis of N2-(4-methoxy((1-propylpyrrolidin yl)methoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: ] Into a 50-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin oxy)phenyl]N-methylpyrimidine-2,4-diamine (300 mg, 0.91 mmol, 1 equiv), propanal (60 mg, 1.03 mmol, 1.10 equiv), methanol (15 mL), NaBH3CN (172 mg, 2.74 mmol, 3.00 equiv), AcOH (0.2 mL). The resulting solution was stirred for 2 h at 25 °C. The reaction was then ed by the addition of water. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 144.6 mg (33%) of N2-(4-methoxy((1-propylpyrrolidinyl)methoxy)phenyl)-N4- methylpyrimidine-2,4-diamine as an off-white solid.

Example 97: Synthesis of Compound 421 Compound 421: Synthesis of Nz-(4-methoxy(((1-methylpyrrolidin yl)oxy)methyl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine miiH NENE ERR TFA,-iPrOH NEW/Na Step 1: Synthesis of N2-(4-methoxy(((1 -methylpyrrolidin yl)oxy)methyl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-meth0xy[[(1- methylpyrrolidinyl)oxy]methyl]aniline (200 mg, 0.85 mol, 1 equiv), 2-chlor0-N,6- ylpyrimidinamine (133.0 mg, 0.84 mol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (193.2 mg, 1.71 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC G NH4HCO3.

This resulted in 54.2 mg (18%) of N2-(4-methoxy(((1-methylpyrrolidin )methyl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as an off-white solid. e 98: Synthesis of Compound 422 Compound 422: sis of N2-(3-((1-(cyclopropylmethyl)pyrrolidin yl)methoxy)—4-methoxyphenyl)-N4-methylpyrimidine-2,4-diamine JN ONHVC DJO \QNN:\©:/ NaBchNMeOH /N\:N/\|NrN:\©:/VOVTB Step 1: sis of N2-(3-((1 -(cyclopropylmethyl)pyrrolidinyl)methoxy)- 4-methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin ylmethoxy)phenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.61 mol, 1 equiv), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 1.50 equiv), methanol (10 mL). After 10 min, added NaBH3CN (191 mg, 3.04 mmol, 5.01 equiv). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The crude product was puriﬁed by PLC C HCl. This resulted in 66.4 mg (26%) of N2-(3-((1- (cyclopropylmethyl)pyrrolidin-3 -yl)meth0xy)meth0xyphenyl)-N4-methylpyrimidine-2,4- diamine as an off-white solid.

Example 99: Synthesis of Compound 423 Compound 423: Synthesis of Nz-(4-methoxy—3—(3-(3-methylazetidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine A "H N / LN" on "W I W k H I) N K2C03 Nal LNMO Step 1: Synthesis of N2-(4-methoxy(3-(3-methylazetidin yl)pr0poxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chlor0pr0p0xy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mol, 1 equiv), potassium methaneperoxoate (257.1 mg, 1.85 mmol, 3.00 equiv), acetonitrile (10 mL), 3- methylazetidine hydrochloride (132.9 mg, 1.24 mmol, 2.00 equiv), iodosodium (93.2 mg, 0.62 mol, 1 equiv). The ing solution was stirred for 12 h at 85 0C. The solids were ﬁltered out. The ing mixture was trated under vacuum. The crude product (200 mg) was d by Prep-HPLC C TFA. This resulted in 75.3 mg (26%) of N2-(4-methoxy- 3-(3-(3-methylazetidinyl)pr0poxy)phenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 100: Synthesis of Compound 424 Compound 424: Synthesis of Nz-(3-(3- ((cyclopropylmethyl)(methyl)amino) propoxy)—4—methoxyphenyl)-N4- pyrimidine-2,4-diamine \NH 0 | N / MODNkN0 N2] m"/ v/\N/\/\ D X3] I O N I N CI K2C03,Na| Step 1: Synthesis of N2-(3-(3-((cyclopropylmethyl)(methyl)amin0)pr0p0xy)— 4-methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chlor0pr0p0xy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mol, 1 equiv), potassium ate (257 mg, 1.86 mmol, 3.00 equiv), NaI (93 mg, 1 , CH3CN (10 mL), (cyclopropylmethyl)(methyl)amine (150 mg, 1.76 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Flash- Prep-HPLC A. This resulted in 41.8 mg (14%) of N2-(3-(3- opropylmethyl)(methyl)amino)propoxy)methoxyphenyl)-N4-methylpy1imidine-2,4- diamine as an off-white solid.

Example 101: Synthesis of Compound 425 Compound 425: sis of N2-(4-methoxy(3-(3-methoxyazetidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine \NH \NH | | 011 I NH I \OL CIMO \N OI) I I m m \N , Nal, ACN [011 11] Step 1: Synthesis of N2-(4-methoxy(3-(3-methoxyazetidin yl)propoxy)phenyl)-N4-methylpy1imidine-2,4-diamine: ] Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mol, 1 equiv), 3- yazetidine hydrochloride (228 mg, 1.84 mmol, 3.00 equiv), NaI (93 mg, 1 equiv), potassium carbonate (513 mg, 3.71 mmol, 6.00 equiv), ACN (10 mL). The resulting solution was stirred for 12 h at 80 0C. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1.

This resulted in 74.9 mg (25%) of N2-(4-methoxy(3-(3-methoxyazetidin y1)propoxy)pheny1)-N4-methy1pyn'midine-2,4-diamine as a white solid.

Example 102: sis of Compound 426 Compound 426: Synthesis of Nz-(3-((5-cyclopropylisoxazol—3-yl)meth0xy)— 4-methoxyphenyl)-N4-methylpyrimidine-2,4—diamine WWLAH,THF WOH MsC[,TEA Won/IS OaN OrN O’N | ‘NH \ OD x \ / HO NJ‘N N H )\\ / o N N 052003, DMF I H Step 1: Synthesis of (5-cyclopropy1-1,2-oxazoly1)methanol: Into a 100-mL ed round-bottom ﬂask, was placed tetrahydrofuran (20 mL), LAH (1.99 g, 52.44 mmol, 4.00 equiv). This was followed by the addition of a solution of 5-cyclopropyl-1,2-oxazolecarboxylic acid (2 g, 13.06 mol, 1 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at 0 0C. The resulting solution was stirred for 3 h at 0 0C. The reaction was then quenched by the addition of 2 mL of water. The resulting solution was diluted with 100 mL of EA. The e was dried over anhydrous sodium sulfate. The solids were d out. The resulting mixture was concentrated under vacuum. This ed in 1.8 g (99%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.572 min, LCMS 32: m/Z = 140 [M+1].

Step 2: Synthesis of (5-cyclopropyl-1,2-oxazolyl)methyl methanesulfonate: Into a 100-mL round-bottom ﬂask, was placed dichloromethane (50 mL), (5- cyclopropyl-1,2-oxazolyl)methanol (1.8 g, 12.94 mol, 1 equiv), TEA (3.96 g, 39.13 mmol, 3.03 equiv). This was followed by the addition of MsCl (1.9 g, 16.67 mmol, 1.29 equiv) dropwise with stirring at 0 0C. The resulting solution was stirred for 14 h at 20 0C. The resulting mixture was washed with 3x10 mL of H20. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.2 g (43%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.834 min, LCMS 07 Step 3: Synthesis of N2-(3-((5-cyclopropylisoxazolyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 40-mL vial, was placed methylformamide (5ml), (5-cyclopropyl- azolyl)methyl methanesulfonate (200 mg, 0.92 mmol, 1 equiv), 2-methoxy[[4- lamino)pyrimidinyl]amino]phenol (270 mg, 1.10 mmol, 1.19 equiv), Cs2CO3 (600 mg, 1.84 mmol, 2.00 equiv). The resulting on was stirred for 4 h at 80 0C. The solids were filtered out. The crude t (200 mg) was puriﬁed by Prep-HPLC C HCl. This resulted in 72.6 mg (20%) of N2-(3-((5-cyclopropylisoxazolyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine as an off-white solid.

Example 103: Synthesis of Compound 428 Compound 428: Synthesis of Nz-(4-methoxy(3-(pyrrolidin yl)pr0poxy)phenyl)-N4-methyl(2,2,2-triﬂu0r0ethyl)pyrimidine-2,4-diamine \ O I O i Br N\ A 4 F F NJ§N G MeONa/MeOH N N i HN NH \N Fgc o’\ I NaBH4,MeOH 0M0 I —> | —> F / /—> o POBr3,To|uene, Br)\/k3r BrMO -78°C-rt.THF HO CI 8 2fo J§ >—o F F F N N 0 AIBN (n-Bu) Sn/0m | F con.HC|,ref|ux,o/n m F I F , 3 F / / \ N\ N F —> N N F F DMAP,DCM to]uene,reflux Y OH / N_ O \ OH F F GJVOD‘NHZ /O C' N/ Poo]3 ml:—’ m': —’ OMODNXN/ /NH2 /H | Y Y H Cl CI Step 1: Synthesis of 2,4,6-tribromopyrimidine: Into a 1-L 3-necked round-bottom ﬂask, was placed 1,3-diazinane-2,4,6-trione (30 g, 234.22 mol, 1 equiv), N,N—dimethylaniline (42.54 g, 351.05 mmol, 1.50 equiv), POBr3 (263 g, 4.00 equiv), e (300 mL). The resulting solution was stirred for 3 h at 110 0C. The resulted e was cooled into RT, the yellow organic layer decanted off. The red gum was rinse once with EA. The combined organic layer was washed with 3x500 mL of Saturated sodium bicarbonate, 3x500 mL of brine and 2x500 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 54 g of the title compound as a yellow crude solid.

] Step 2: Synthesis of 4-bromo-2,6-dimethoxypyrimidine: Into a 2-L 3-necked round-bottom ﬂask, was placed 2,4,6-tribromopyrimidine (54 g, 170.47 mol, 1 equiv), methanol (500 mL), diethyl ether (500 mL), and MeONa/MeOH (30%) (76.7 g, 2.50 equiv) was added dropwise. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The resulting on was diluted with 1 L of EA. The resulting mixture was washed with 3x500 mL of brine. The resulting mixture was concentrated under vacuum. The residue was d onto a silica gel column with ethyl acetate/petroleum ether (1 : 100-1 : 10). The ted fractions were combined and concentrated under vacuum. This resulted in 23 g (62%) of the title nd as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.287 min, LCMS 28: m/Z = 219 [M+1].

Step 3: Synthesis of 1-(2,6-dimethoxypyrimidinyl)-2,2,2-triﬂuoroethane- 1,1-diol: Into a 1-L 3-necked round-bottom ﬂask purged and ined with an inert atmosphere of nitrogen, was placed 4-bromo-2,6-dimethoxypyrimidine (23 g, 105.01 mmol, 1 equiv), tetrahydrofuran (250 mL), Diethyl ether (250 mL). And n-BuLi(2.5M) (46.2 mg, 0.72 mmol, 1.10 equiv) was added dropwise at -78 0C. After d for 5 min at -78 0C, ethyl 2,2,2-triﬂuoroacetate (16.4 g, 115.43 mmol, 1.10 equiv) was added dropwise. After stirred for min at -78 0C, the ing solution was stirred for overnight at RT. The reaction was then quenched by the addition of 200 mL of saturated NH4Cl. Sodium carbonate was employed to adjust the pH to 8. The resulting solution was diluted with 1 L of EA. The resulting mixture was washed with 3x500 mL of brine. The resulting mixture was concentrated under vacuum.

The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 100- 1:10). The collected fractions were combined and concentrated under vacuum. This ed in 15 g (56%) of the title compound as an off-white solid.

] Analytical Data: LC-MS: (ES, m/z): RT = 0.739 min, LCMS 32: m/Z = 255 [M+1].

] Step 4: Synthesis of 1-(2,6-dimethoxypyrimidinyl)-2,2,2-triﬂuoroethan-1 - Into a 500-mL 3-necked round-bottom ﬂask, was placed 1-(2,6- dimethoxypyrimidinyl)-2,2,2-triﬂuoroethane-1,1-diol (15 g, 59.02 mol, 1 equiv), methanol (150 mL), and NaBH4 (8.98 g, 237.38 mmol, 4.00 equiv) was added portionwise at 0 0C. The ing solution was stirred for 1h at RT. The reaction was then quenched by the addition of 50 mL of saturated NH4Cl. The resulting solution was diluted with 500 mL of EA.

The resulting mixture was washed with 3x500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10). The collected fractions were ed and concentrated under vacuum. This resulted in 14 g of the title compound as an off-white solid. ical Data: LC-MS: (ES, m/z): RT = 0.806 min, LCMS 32: m/Z = 239 [M+1]. 1H NMR (300 MHz, DMSO-dG) 5 7.14 (d, J: 6.4 Hz, 1H), 6.72 (s, 1H), 5.01-4.95 (m, 1H), 3.92 (d, J: 5.4 Hz, 6H).

Step 5: sis of [1-(2,6-dimethoxypyrimidinyl)-2,2,2- triﬂuoroethoxy](phenoxy) methanethione: Into a 500-mL 3-necked round-bottom ﬂask, was placed 1-(2,6- dimethoxypyrimidinyl)-2,2,2-triﬂuoroethanol (14 g, 58.78 mol, 1 equiv), 4- dimethylaminopyridine (21.53 g, 176.23 mmol, 3.00 equiv), dichloromethane (200 mL). And phenyl chloromethanethioate (10.76 g, 62.33 mmol, 1.50 equiv) was added dropwise at 0 0C.

The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The ing on was diluted with 200 mL of EA. The resulting mixture was washed with 3x200 mL of brine. The mixture was dried over anhydrous sodium sulfate and trated under vacuum. This resulted in 37 g of the title compound as a yellow crude solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.806 min, LCMS 32: m/Z = 375 [M+l].

Step 6: Synthesis of 2,4-dimethoxy(2,2,2-triﬂuoroethyl)pyrimidine: Into a 1-L 3-necked round-bottom ﬂask, was placed [1-(2,6- dimethoxypyrimidinyl)-2,2,2-triﬂuoroethoxy](phenoxy)methanethione (37 g, 98.84 mmol, 1 equiv), AIBN (3.2 g, 19.49 mmol, 0.20 equiv), (n-Bu)3SnH (114.76 g, 4.00 equiv), Toluene (500 mL). The resulting solution was stirred for 2 h at 110 0C in an oil bath. The resulting solution was diluted with 1 L of EA. The resulting mixture was washed with 3x1 L of brine.

The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 100-1: 10). The collected fractions were combined and concentrated under vacuum. This resulted in 13 g (59%) of the title compound as yellow crude oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.271 min, LCMS 28: m/Z = 223 [M+l].

Step 7: Synthesis of 6-(2,2,2-triﬂuoroethyl)pyrimidine-2,4-diol: Into a 500-mL 3-necked round-bottom ﬂask, was placed methoxy (2,2,2-triﬂuoroethyl)pyrimidine (11 g, 49.51 mol, 1 equiv), Conc. HCl (150 mL). The resulting solution was stirred for 6 h at 105 0C in an oil bath. The ing mixture was trated under vacuum. This resulted in 7.7 g (80%) of the title compound as an off- white solid. ical Data: LC-MS: (ES, m/z): RT = 0.773 min, LCMS 15: m/Z = 195 [M+l].

Step 8: Synthesis of 2,4-dichloro(2,2,2-triﬂuoroethyl)pyrimidine: Into a 50-mL round-bottom ﬂask, was placed ,2- triﬂuoroethyl)pyrimidine-2,4-diol (2.2 g, 11.33 mol, 1 equiv), phosphoroyl trichloride (5 mL). The resulting solution was stirred for 3 h at 120°C in an oil bath. The resulted mixture was poured into ice/water. The resulting solution was extracted with 2x50 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 2x50 mL of brine.

The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This ed in 760 mg (29%) of the title compound as colorless oil.

Analytical Data: 1H NMR (300 MHz, Chloroform—d) 5 7.41 (s, 1H), 3.63 (q, J = 10.2 Hz, 2H).

Step 9: Synthesis of 2-chloro-N-methyl(2,2,2-triﬂuoroethyl)pyrimidin amine: Into a 50-mL round-bottom ﬂask, was placed 2,4-dichloro(2,2,2- triﬂuoroethyl)pyrimidine (720 mg, 3.12 mmol, 1 equiv), methanamine hydrochloride (318 mg, 4.71 mmol, 1.50 , potassium carbonate (1.29 g, 9.33 mmol, 3.00 equiv), N,N— dimethylformamide (10 mL). The resulting solution was stirred for 4 h at RT. The ing solution was diluted with 50 mL of EA. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum.

The residue was d onto a silica gel column with ethyl acetate/petroleum ether (1 : 100- 1:10). The ted fractions were combined and concentrated under vacuum. This resulted in 300 mg (43%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.799 min, LCMS 32: m/Z = 226 [M+1]. 1H NMR (400 MHz, DMSO-dG) 5 8.06 (d, J: 5.5 Hz, 1H), 6.52 (m, 1H), 3.76 — 3.52 (m, 2H), 2.94 — 2.70 (m, 3H).

] Step 10: Synthesis of N2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)- N4-methyl(2,2,2-triﬂuoroethyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methyl(2,2,2- triﬂuoroethyl)pyrimidinamine (260 mg, 1.15 mol, 1 equiv), 4-methoxy[3-(pyrrolidin- 1-yl)propoxy]aniline (288 mg, 1.15 mmol, 1 equiv), CF3COOH (393 mg, 3.45 mmol, 3.00 equiv), isopropanol (5 mL). The resulting solution was stirred for overnight at 80 0C in an oil bath. The resulting e was concentrated under vacuum. The residue was puriﬁed by ﬂash chromatography with N/NH4HCO3. This resulted in 72.6 mg (14%) ofN2-(4- methoxy(3-(pyrrolidinyl)propoxy)phenyl)-N4-methyl(2,2,2- triﬂuoroethyl)pyrimidine-2,4-diamine as an off-white solid.

Example 104: Synthesis of Compound 429 Compound 429: Synthesis of Nz-(4-methoxy(3-(2-methylazetidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine / / HN HCI HN "1) Nu "H CIA/\o "*N K2003,NaI,ACN bN/mo"11 Na"*N WO 81177 Step 1: Synthesis of N2-(4-methoxy(3-(2-methylazetidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: ] Into a 16-mL sealed tube, was placed 2-N-[3-(3-chloropropoxy)—4- methoxyphenyl]N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mol, 1 equiv), ACN (8 mL), NaI (93 mg, 1 equiv), potassium carbonate (214 mg, 1.55 mmol, 2.50 equiv), 2- methylazetidine hydrochloride (100 mg, 0.93 mmol, 1.50 equiv). The resulting solution was stirred for 3 h at 80 0C in an oil bath. The solids were ﬁltered out. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 36.7 mg (13%) of N2-(4-methoxy(3-(2- methylazetidinyl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 105: sis of Compound 430 Compound 430: Synthesis of Nz-(4-ethoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine 1 2:] \ N/ E NH I) 0' N I) M @MO TFA i-PFOH @MO NH2 "*N Step 1: Synthesis of N2-(4-ethoxy-3 -(3 -(pyrrolidinyl)propoxy)phenyl)-N4- methylpyrimidine-2,4-diamine: ] Into a 50-mL round-bottom ﬂask, was placed 4-ethoxy[3-(pyrrolidin yl)propoxy]aniline (250 mg, 0.95 mol, 1 equiv), 2-chloro-N-methylpyrimidinamine (135.4 mg, 0.94 mol, 1 equiv), ol (5 mL), triﬂuoroacetic acid (275.6 mg, 2.44 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 80v°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (250 mg) was puriﬁed by Prep-HPLC C HCl. This resulted in 87.6 mg (23%) of N2-(4-ethoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 106: Synthesis of Compound 432 ] Compound 432: Synthesis of Nz-(4-ethoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine W E HO:©\N02o N’V\C| HCI 0:3 Raney-Ni D (352603,Nal 9M0 N02 H2,CH30H @MO MHZ xiNT‘H \ \NH CI N | TFA,i-PrOH @MODHAN Step 1: Synthesis of 1-[3-(2-ethoxynitrophenoxy)propyl]pyrrolidine: Into a 50-mL round-bottom ﬂask, was placed 2-ethoxynitrophenol (1 g, .46 mol, 1 equiv), N,N—dimethylformamide (5 mL), Cs2C03 (5.3 g, 16.22 mmol, 3.00 equiv), iodosodium (819.7 mg, 5.47 mol, 1 equiv), hloropropyl)pyrrolidine hydrochloride (1 g, 5.43 mol, 1 equiv). The resulting solution was stirred for 2 h at 110 0C in an oil bath. The reaction was then quenched by the addition of ice. The resulting solution was extracted with 3X10 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 2X10 mL of sodium chloride (aq). The resulting mixture was washed with 2x10 mL of H20. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.48 g (92%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.96min, LCMS07: m/z = 295.05 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.36 (dd, J: 2.5, 0.9 Hz, 1H), 7.24 — 7.14 (m, 2H), 4.15 (q, J: 7.0 Hz, 2H), 4.05 (t, J: 6.1 Hz, 2H), 2.75 — 2.57 (m, 6H), 2.08- 1.98(m, 2H), 1.90 — 1.79 (m, 4H), 1.41 (t, J: 7.0 Hz, 3H).

] Step 2: Synthesis of 4-ethoxy[3-(pyrrolidinyl)propoxy]aniline: ] Into a 250-mL round-bottom ﬂask, was placed 1-[3-(2-ethoxy nitrophenoxy)propyl]pyrrolidine (800 mg, 2.72 mmol, 1 equiv), Raney-Ni, methanol (100 mL). The ing on was stirred for 2 h at 20 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 700 mg (97%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.77min, LCMS33: m/z = 265.19 [M+1]. 1H NMR: (400 MHz, Methanol-d4) 5 6.72 (d, J: 8.7 Hz, 1H), 6.40 (d, J: 2.9 Hz, 1H), 6.23 (dd, J: 8.7, 2.9 Hz, 1H), 4.12 — 3.85 (m, 4H), 2.70 — 2.56 (m, 6H), 2.05 — 1.73 (m, 6H), 1.40 (t, J: 7.0 Hz, 3H).

Step 3: Synthesis of N2-(4-ethoxy(3-(pyrrolidinyl)propoxy)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-ethoxy[3-(pyrrolidin yl)propoxy]aniline (250 mg, 0.95 mol, 1 , roacetic acid (275.6 mg, 2.44 mmol, 3.00 equiv), 2-chloro-N,6-dimethylpyrimidinamine (148.7 mg, 0.94 mol, 1 equiv), propanol (5 mL). The resulting solution was d for 2 h at 80 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (250 mg) was puriﬁed by Prep-HPLC C HCl. This resulted in 111 mg (28%) of N2-(4-ethoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 107: Synthesis of Compound 433 Compound 433: Synthesis of Nz-(3-((5-cyclopr0pyl-1,2,4—oxadiazol yl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine HO‘N [>_< />—\ 0‘" 0' CI HZN-OH HCI | CI DMF ,N CI \ —> Cl —> —> I :N NH Na2003,H20 2 TEA,DCM o O’N I \NH \NH N’ O / A I HO N N .

[ N H I) i / 0 u \N 052003, DMF ovN Step 1: Synthesis of chloro-N’-hydroxyethenimidamide Into a 100-mL round-bottom ﬂask, was placed water (20 g), 2- chloroacetonitrile (5 g, 66.23 mol, 1 equiv), hydroxylamine hydrochloride (4.6 g, 66.20 mmol, 1 equiv). This was followed by the addition of sodium carbonate (3.5 g, 33.02 mmol, 0.50 equiv), in portions. The resulting solution was d for 2 h at 20 0C. The ing solution was ted with 4x20 mL of ether and the organic layers combined and dried over anhydrous sodium e. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 3.9 g (54%) of the title compound as a white solid. Analytical Data: LC-MS: (ES, m/z): RT =0.259 min, LCMS 33: m/z = 109 [M+1].

Step 2: Synthesis of (Z)-(1-aminochloroethylidene)amino cyclopropanecarboxylate: Into a 250-mL round-bottom ﬂask, was placed dichloromethane (100 mL), cyclopropanecarbonyl chloride (5.5 g, 52.61 mmol, 1.50 equiv), (E)—2-chloro-N’- hydroxyethenimidamide (3.8 g, 35.01 mmol, 1 equiv).The resulting solution was d for min at 20 0C. This was followed by addition of TEA (3.9 g, 38.54 mmol, 1.10 equiv). The resulting solution was allowed to react, with stirring, for an additional 1 h at 20 0C. The resulting mixture was washed with 2x50 mL of water and 1x50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were d out. The resulting e was concentrated under vacuum. This resulted in 5.2 g (84%) of the title compound as light red Oil. Analytical Data: LC-MS: (ES, m/Z): RT =0.504 min, LCMS 32: m/Z = 177 [M+l].

Step 3: Synthesis of oromethyl)cyclopropyl-1,2,4-oxadiazole: Into a 20-mL sealed tube, was placed N,N—dimethylformamide (10 mL), (Z)- (1-aminochloroethylidene)amino cyclopropanecarboxylate (1.5 g, 8.49 mol, 1 equiv).

The resulting solution was stirred for 3 h at 135 0C. The resulting solution was diluted with mL of H20. The resulting solution was extracted with 3x10 mL of ethyl e and the organic layers combined. The resulting mixture was washed with 3x10 mL of water and 2x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 550 mg (41%) of the title nd as an oil. Analytical Data: LC-MS: (ES, m/z): RT =0.775 min, LCMS 32: W2 =159[M+1].

Step 4: Synthesis of N2-(3-((5-cyclopropyl-1,2,4-oxadiazolyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed N,N—dimethylformamide (5 mL), 3-(chloromethyl)cyclopropyl-1,2,4-oxadiazole (550 mg, 3.47 mmol, 4.27 equiv), 2- methoxy[[4-(methylamino)pyrimidinyl]amino]phenol (200 mg, 0.81 mol, 1 equiv), Cs2CO3 (530 mg, 1.63 mmol, 2.00 equiv), NaI (122 mg). The resulting solution was stirred for 8 h at 80 0C. The solids were ﬁltered out. The crude product (300 mg) was d by PLC C NH4HCO3. This resulted in 36.8 mg (12%) of ((5-cyclopropyl-1,2,4- oxadiazolyl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine as a light yellow solid.

Example 108: Synthesis of Compound 434 Compound 434: Synthesis of Nz-(3-((1-cyclopropyl-1H-1,2,3-triazol yl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine HN/ka—/I>—B(OH)2 L.IAIHA SOCI2 \ Dﬂq/VLO/ wN/W/NJH "NM\ CI N=N N‘N ‘ 'N ] Step 1: Synthesis of methyl 1-cyclopropyl-1H-1,2,3-triazole—4-carboxylate: Into a 250-mL round-bottom ﬂask, was placed methyl lH-l,2,3-triazole carboxylate (2 g, 15.74 mol, 1 equiv), )2 (8.6 g, 47.35 mmol, 3.00 equiv), pyridine (12.4 g, 156.76 mmol, 10.00 equiv), tetrahydrofuran (100 mL), cyclopropylboronic acid (2.7 g, 31.43 mmol, 2.00 equiv). The resulting solution was stirred for 72 h at 55 0C in an oil bath.

The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 150 mg (6%) of the title compound as a yellow solid. Analytical Data: LC-MS: (ES, m/z): 168 [M+1], R: 1.065 min. 1H-NMR: (DMSO-dG, ppm): 5 8.84 (s, 1H), 4.06-4.08 (m, 1H), 3.83 (s, 3H), 1.31 — 1.06 (m, 4H).

Step 2: Synthesis of (1-cyclopropyl-1H-1,2,3-triazolyl)methanol: Into a 100-mL round-bottom ﬂask, was placed methyl 1-cyclopropyl-1H- 1,2,3-triazolecarboxylate (120 mg, 0.72 mol, 1 equiv), LiAlH4 (144 mg, 3.79 mmol, .00 equiv), tetrahydrofuran (20 mL). The resulting solution was stirred for 1 h at 0 0C in a water/ice bath. The on was then quenched by the addition of water. The solids were ﬁltered out. The crude t was puriﬁed by Flash-Prep-HPLC A. This resulted in 30 mg (30%) of the title compound as a white solid. Analytical Data: LC-MS: (ES, m/z): 140 [M+1], R: 0.856 min.

Step 3: Synthesis of 4-(chloromethyl)cyclopropyl-1H-1,2,3-triazole: Into a 100-mL round-bottom ﬂask, was placed (1-cyclopropyl-1H-1,2,3- triazolyl)methanol (20 mg, 0.14 mmol, 1 , phosphoroyl trichloride (4 mL). The ing solution was d for 3 h at 100 0C in an oil bath. The resulting mixture was concentrated under compound as a white solid. Analytical Data: LC-MS: (ES, m/z): 158 [M+1], R: 1.267 min.

Step 4: Synthesis of N2-(3-((1-cyclopropyl-1H-1,2,3-triazolyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: ] Into a 50-mL round-bottom ﬂask, was placed 4-(chloromethyl)cyclopropyl- 1H-1,2,3-triazole (100 mg, 0.63 mol, 1 equiv), Cs2C03 (619 mg, 1.90 mmol, 3.00 equiv), N,N—dimethylformamide (10 mL), 2-methoxy[4-(methylamino)pyrimidin yl]aminophenol (156 mg, 0.63 mol, 1 equiv). The resulting on was stirred for 2 h at 50 0C in an oil bath. The solids were ﬁltered out. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 21.3 mg (7%) of N2-(3-((1-cyclopropyl-1H-1,2,3-triazol yl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 109: Synthesis of Compound 435 Compound 435: Synthesis of Nz-(4-methoxy((1-methylpiperidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine (5 HN o Boo Boo HOONE’NI IO\/ o HN— EA \N H Boo—N N— OH —> —> DCM 0M5 DMF, 052003 HIV—(N / TFA O HN_ HCHO —. H04 N_ —.

DCM 0 ml HN—<\ NaBH3CN / H N O/\ / ] Step 1: Synthesis of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine carboxylate: Into a 250-mL round-bottom ﬂask, was placed tert-butyl 4- (hydroxymethyl)piperidinecarboxylate (500 mg, 2.32 mol, 1 , methanesulfonyl chloride (530 mg, 4.63 mmol, 2.00 equiv), TEA (704 mg, 6.96 mmol, 3.00 equiv), dichloromethane (15 mL). The resulting solution was stirred for 1 h at 25 0C. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 550 mg (81%) of as light yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT= 1.26 min, LCMS 53: m/z = 294 [M+1]. lH-NMR: dG, ppm): 5 4.07 (d, J: 6.4 Hz, 2H), 3.96 (d, J: 13.0 Hz, 2H), 3.18 (s, 3H), 2.72 (s,2H), 1.92 — 1.78 (m, 1H), 1.72 — 1.57 (m, 2H), 1.40 (s, 9H), 1.18 — 0.99 (m, 4H).

] Step 2: Synthesis of tert-butyl 4-(2-methoxy[[4-methyl (methylamino)pyrimidinyl] amino]phenoxymethyl)piperidinecarboxylate: Into a 250-mL round-bottom ﬂask, was placed 2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenol, triﬂuoroacetic acid (730 mg, 1.95 mmol, 1 equiv), tert-butyl 4-[(methanesulfonyloxy)methyl]piperidinecarboxylate (720 mg, 2.45 mmol, 1.20 equiv), Cs2C03 (2 g, 6.14 mmol, 3.00 equiv), N,N—dimethylformamide (30 mL).

The resulting solution was stirred for 12 h at 80 0C. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting e was washed with x mL of sodium chloride. The crude product was puriﬁed by Prep-HPLC A 1:1. This resulted in 600 mg (67%) of the title compound as light yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT= 1.14 min, LCMS 15: m/z = 458 [M+1].1H-NMR: dG, ppm):5 8.78 — 8.71 (m, 1H), 7.81 (s, 1H), 7.19 — 7.09 (m, 1H), 6.93 (s, 1H), 6.80 (d, J: 8.7 Hz, 1H), 5.75 (s, 1H), 3.98 (d, J: 12.7 Hz, 2H), 3.79 (d, J: 6.4 Hz, 2H), 3.69 (s, 3H), 2.83 (d, J: 4.5 Hz, 3H), 2.74 (s, 2H), 2.10 (s, 3H), 1.97 — 1.87 (m, 1H), 1.76 (d, J: 13.3 Hz, 2H), 1.40 (s, 9H), .03 (m, 2H).

Step 3: Synthesis of 2-N-[4-methoxy(piperidinylmethoxy)phenyl] N,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed tert-butyl 4-(2-methoxy[[4- methyl(methylamino)pyrimidinyl] amino] ymethyl)piperidinecarboxylate (600 mg, 1.31 mmol, 1 , triﬂuoroacetic acid (10 mL), dichloromethane (20 mL). The resulting solution was stirred for 1 h at 25 0C. The crude product was puriﬁed by Flash-Prep- HPLC A 1:1. This resulted in 420 mg (90%) of the title compound as a solid.

] Analytical Data: LC-MS: (ES, m/z): RT= 1.14 min, LCMS 15: m/z = 358 [M+1].

Step 4: Synthesis of N2-(4-methoxy((1 -methylpiperidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(piperidin- 4-ylmethoxy)phenyl]N,6-dimethylpyrimidine-2,4-diamine (210 mg, 0.59 mol, 1 equiv), HCHO (364 mg, 10.00 equiv), NaBH3CN (280 mg, 4.46 mmol, 16.00 equiv), methanol (15 mL). The resulting solution was stirred for 4 h at 25 0C. The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC A. This resulted in 94.0 mg (39%) of N2-(4- methoxy((1-methylpiperidinyl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 110: sis of Compound 436 Compound 436: Synthesis of N2-(3-((1-(cyclopropylmethyl)piperidin yl)methoxy)meth0xyphenyl)—N4,6-dimethylpyrimidine-2,4-diamine HN/ HN/ | | o o N/ / N/ o N N o N N H NaBH30N A»! H Step 1: Synthesis of N2-(3-((1 -(cyclopropylmethyl)piperidinyl)methoxy)- 4-methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(piperidin- 4-ylmethoxy)phenyl]N,6-dimethylpyrimidine-2,4-diamine (270 mg, 0.76 mol, 1 equiv), ropanecarbaldehyde (847 mg, 12.08 mmol, 16 equiv), NaBH3CN (476 g, 7.57 mol, .00 equiv), ol (15 mL), HOAC (0.5 mL). The resulting solution was stirred for 2 h at 25°C. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 111.1 mg (3.3%) ofN2-(3-((1-(cyclopropylmethyl)piperidinyl)methoxy)methoxyphenyl)- N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 111: Synthesis of Compound 437 Compound 437: Synthesis of N2-(3-(azetidinylmethoxy)—4- methoxyphenyl)-N4,6-dimethylpyrimidine-2,4—diamine / HN/ HN/ | HN Von/[s CI) cl; HODNkN0 N/ N/ B0C’ | w. N’ | —> I) Ax l CSZCOwMF Boc’N/D/\O N N HNVODNAN ] Step 1: Synthesis of tert—butyl 3-(2-methoxy[[4-methyl (methylamino)pyrimidinyl] amino]phenoxymethyl)azetidinecarboxylate: ] Into a 100-mL round-bottom ﬂask, was placed 2-methoxy[[4-methyl lamino)pyrimidinyl]amino]phenol (2 g, 7.68 mol, 1 equiv), tert-butyl 3- [(methanesulfonyloxy)methyl]azetidine-l-carboxylate (2.4 g, 9.05 mmol, 1.20 equiv), Cs2CO3 (5.0 g, 15.35 mmol, 2.00 equiv), N,N—dimethylformamide (20 mL). The resulting solution was stirred for 12 h at 80 0C in an oil bath. The ing solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The crude product was puriﬁed by Flash-Prep-HPLC A. This ed in 0.5 g (15%) of the title compound as a light brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.130 min, LCMS53: m/z = 430.2 [M+1].

] Step 2: Synthesis of N2-(3-(azetidinylmethoxy)methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed tert-butyl 3-(2-methoxy[[4- (methylamino)pyrimidinyl]amino]phenoxymethyl)azetidinecarboxylate (500 mg, 1.16 mmol, 1 equiv), dichloromethane (10 mL), triﬂuoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 20 0C. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC A. This resulted in 39.4 mg (10%) 3-(azetidinylmethoxy)methoxyphenyl)—N4,6-dimethylpyrimidine-2,4- e as a light brown solid.

Example 112: Synthesis of Compounds 438 and 439 Compound 438 and 439: Synthesis of N2-(3-(((3S,4S)-1,4- dimethylpyrrolidinyl)methoxy)meth0xyphenyl)-N4-methylpyrimidine-2,4-diamine and N2-(3-(((3R,4R)-1,4-dimethylpyrrolidinyl)methoxy)meth0xyphenyl)-N4- methylpyrimidine-2,4-diamine I | M01o N \ BOC‘NxOH M CLTEAs BOC‘NrOMS H on m Boc—Nro NAN/ N/ 052003DMF H H O on "9 N \ o NAN/ N/ _ ‘N LAH/THF JL chural-hplc H H o N N/ N/ H H | * \ CD "1 ~ \0 NXN/ N/ H H Step 1: Synthesis of tert-butyl 3-[(methanesulfonyloxy)methyl] methylpyrrolidinecarboxylate: Into a 100-mL round-bottom ﬂask, was placed dichloromethane (10 mg, 0.12 mmol, 0.05 equiv), utyl 3-(hydroxymethyl)methylpyrrolidinecarboxylate (500 mg, 2.32 mol, 1 equiv), TEA (712 mg, 7.04 mmol, 3.03 equiv).This was followed by addition of MsCl (345 mg, 3.03 mmol, 1.30 equiv)at 0 0C. The resulting solution was stirred for 2 h at 20 0C. The resulting solution was diluted with 10 mL of DCM. The resulting e was washed with 2x10 mL of water and 1X10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 800 mg (N/A) of the title compound as off-white oil.

] Analytical Data: LC-MS: (ES, m/z): LCMS 32: m/Z = 294 [M+1].

Step 2: Synthesis of tert-butyl 3-(2-methoxy[[4-(methylamino)pyrimidin- 2-yl]amino]phenoxymethyl)methylpyrrolidinecarboxylate: Into a 100-mL round-bottom ﬂask, was placed N,N—dimethylformamide (20 L), tert-butyl 3-[(methanesulfonyloxy)methyl]methylpyrrolidinecarboxylate (800 mg, 2.73 mol, 1 equiv), 2-methoxy[[4-(methylamino)pyrimidinyl]amino]phenol (739 mg, 3.00 mmol, 1.10 equiv), Cs2C03 (1.78 g, 5.46 mmol, 2.00 equiv). The ing solution was d for 4 h at 80 0C. The resulting solution was diluted with 20 mL of H20. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers ed. The resulting mixture was washed with 3x10 mL of water and 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were ﬁltered out. The resulting e was concentrated under . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (7:3). This resulted in 900 mg (74%) of the title compound as a solid. ] ical Data: LC-MS: (ES, m/z): RT =0.848 min, LCMS 32: m/Z = 444 [M+1].

Step 3: Synthesis of 2-N-[3-[(1,4-dimethylpyrrolidinyl)methoxy] methoxyphenyl]N-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed tetrahydrofuran (20 mL), LAH (386 mg, 10.17 mmol, 5.01 equiv).This was followed by on of a solution of tert-butyl 3- (2-methoxy[[4-(methylamino)pyrimidinyl]amino]phenoxymethyl)methylpyrrolidine- 1-carboxylate (900 mg, 2.03 mol, 1 equiv) in tetrahydrofuran (2 mL) at 0 0C. The ing solution was stirred for 5 h at 80 0C. The reaction was then quenched by the addition of 0.4 mL of water and 0.4 mL as a solution ofNaOH in H20 (0.4ml). The resulting solution was diluted with 50 mL of EA. The mixture was dried over anhydrous sodium sulfate. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 440 mg (61%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT =0.589 min, LCMS 32: m/Z = 358 [M+1].

Step 4: Synthesis of N2-(3-(((3S,4S)-1,4-dimethylpyrrolidinyl)methoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine and N2-(3-(((3R,4R)-1,4- dimethylpyrrolidinyl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 2-N-[3-[(1,4- dimethylpyrrolidinyl)methoxy]methoxyphenyl]N-methylpyrimidine-2,4-diamine (450 mg, 1.26 mol, 1 equiv). This resulted in 48.8 mg (11%) ofNZ-(3-(((3S,4S)-1,4- dimethylpyrrolidinyl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine E1 (randomly assigned) as a light yellow solid. And 75.0 mg (17%) of N2-(3-(((3R,4R)-1,4- dimethylpyrrolidinyl)methoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine E2 (randomly ed) as a light yellow solid.

Example 113: Synthesis of Compound 440 Compound 440: Synthesis of Nz-(3-(2-(cyclopentyloxy)eth0xy)—4— methoxyphenyl)-N4-methylpyrimidine-2,4-diamine 55 \NH O/Om:QNHZ TFAIPrOH OCR/\O "AK Step 1: Synthesis of NZ-(3-(2-(cyclopentyloxy)ethoxy)methoxyphenyl)-N4- methylpyrimidine-2,4-diamine: Into a 20-mL vial, was placed isopropanol (2 mL), 3-[2- (cyclopentyloxy)ethoxy]methoxyaniline (150 mg, 0.60 mmol, 1 equiv), ro-N- methylpyrimidinamine (103 mg, 0.72 mmol, 1.20 equiv), triﬂuoroacetic acid (136 mg, 1.20 mmol, 2.02 equiv). The resulting solution was stirred for 2 h at 80 0C. The crude product was puriﬁed by PLC B TFA. This resulted in 124.7 mg (44%) of (2- (cyclopentyloxy)ethoxy)methoxyphenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 114: sis of Compound 441 Compound 441: Synthesis of N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)—6-(methoxymethyl)—N4-methylpyrimidine-2,4-diamine O 0 \NH [ii Cl MeONa, MeOH [it POCI3 HzN— N / N / Cl 0 CIJTN I Cl)\\N l 0 ﬂ 0 ﬂ \ O\ l \ CD I NH CM on C/\/\ N O N N TFA, IPA H Step 1: Synthesis of 6-(methoxymethyl)-1,2,3,4-tetrahydropyrimidine-2,4- dione: Into a 20-mL round-bottom ﬂask, was placed 6-(chloromethyl)-1,2,3,4- tetrahydropyrimidine-2,4-dione (2 g, 12.46 mol, 1 equiv), methanol, methoxysodium (10 mL). The resulting on was stirred for 3 h at 70 0C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of H20. The pH value of the solution was adjusted to 7 with HCl (2 mmol). The resulting on was extracted with 3x30 mL of ethyl acetate and the organic layers combined. This resulted in 350 mg (17%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.467 min, LCMS 07, m/Z =157 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 5.70 (d, J: 1.2 Hz, 1H), 4.23 (d, J: 1.0 Hz, 2H), 3.33 (s, 3H).

Step 2: Synthesis of 2,4-dichloro(methoxymethyl)pyrimidine: Into a 100-mL round-bottom ﬂask, was placed 6-(methoxymethyl)-1,2,3,4- tetrahydropyrimidine-2,4-dione (350 mg, 2.24 mol, 1 equiv), phosphoroyl trichloride (5 mL). The resulting solution was stirred for 5 h at 120 0C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the on of 30 mL of water. The pH value of the solution was adjusted to 7 with sodium bicarbonate-H20 (100 %).

The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x20 mL of H20. The mixture was dried over anhydrous sodium sulfate. This ed in 360 mg (75%) of the title compound as a light yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.914 min, LCMS07, m/Z =193 [M+1].

] Step 3: Synthesis of 2-chloro(methoxymethyl)-N-methylpyrimidin amine: Into a 50-mL round-bottom ﬂask, was placed chloro (methoxymethyl)pyrimidine (350 mg, 1.81 mol, 1 equiv), TEA (545 mg, 5.39 mmol, 2.97 equiv), tetrahydrofuran (10 mL), MeNHz-THF (2.7 mL). The resulting solution was stirred for 2 h at 0 0C. The resulting mixture was concentrated under . The crude product was puriﬁed by Flash-Prep-HPLC A. This resulted in 160 mg (42%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.650 min, LCMS 45, m/Z =188 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 6.44 (s, 1H), 4.41 (s, 2H), 3.51 (s, 3H), 3.06 — 2.97 (m, 3H).

Step 4: Synthesis of methoxy(3-(pyrrolidinyl)propoxy)phenyl) xymethyl)-N4-methylpyrimidine-2,4-diamine: Into a 25-mL round-bottom ﬂask, was placed 2-chloro(methoxymethyl)-N— methylpyrimidinamine (158 mg, 0.84 mol, 1 equiv), 4-methoxy[3-(pyrrolidin yl)propoxy]aniline (210 mg, 0.84 mol, 1 equiv), isopropanol (5 mL), triﬂuoroacetic acid (287 mg, 2.54 mmol, 3.02 equiv). The resulting solution was stirred for 2 h at 80 0C. The resulting e was concentrated under vacuum. The crude product was puriﬁed by Prep- HPLC C HCl. This resulted in 61.2 mg (16%) of N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)(methoxymethyl)-N4-methylpyrimidine-2,4-diamine as a light brown solid.

Example 115: Synthesis of Compound 442 Compound 442: sis of Nz-(4-meth0xy((1-methylazetidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine HN/ I HN I o HNVODNkNI I) II NaBchNMeOH NVO N \N / H ] Step 1: sis of N2-(4-methoxy((1-methylazetidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(azetidinylmethoxy)- 4-methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.91 mol, 1 equiv), methanol (10 mL), HCHO (90 mg, 3.00 mmol, 1 equiv), NaBH3CN (360 mg, 5.73 mmol, 6.00 equiv). The resulting solution was stirred for 2 h at 20 0C. The crude product was puriﬁed by Prep-HPLC C HCl. This resulted in 30.4 mg (9%) of N2-(4-methoxy((1- methylazetidinyl)methoxy)phenyl)—N4,6-dimethylpyrimidine-2,4-diamine as an off-white solid.

Example 116: Synthesis of Compound 445 Compound 445: Synthesis of Nz-(3-((1-(cyclopropylmethyl)azetidin hoxy)meth0xyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine HN/ HN/ | /o I O >—/ 0]:1"JN\/ | on i/ | N NaBH3CN,MeOH A/N/j/N) " N Step 1: Synthesis of ((1-(cyclopropylmethyl)azetidinyl)methoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(azetidinylmethoxy)- 4-methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.91 mol, 1 equiv), methanol (10 mL), cyclopropanecarbaldehyde (63.8 mg, 0.91 mmol, 1 equiv), NaBH3CN (361 mg, 5.74 mmol, 6.00 equiv). The resulting solution was stirred for 2 h at 20 0C. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 65.8 mg (15%) of N2-(3- ((1-(cyclopropylmethyl)azetidin-3 -yl)methoxy)methoxyphenyl)—N4,6-dimethylpyrimidine- 2,4-diamine as a white solid.

Example 117: Synthesis of Compound 446 Compound 446: Synthesis of ((1-cyclobutylpyrrolidin yl)methoxy)meth0xyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine / HN | HN | N/ if "/ )\\ I O NJ\\N HNQ/\o M N NaBH3CN,AcOH,MeOH O‘NQA H Step 1: sis of N2-(3-((1-cyclobutylpyrrolidinyl)methoxy)—4- methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: N2-(3-((1-cyclobutylpyrrolidinyl)methoxy)methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine was prepared as for N2-(3-(((1-ethylpyrrolidin yl)oxy)methyl)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine using cyclobutanone in place of acetaldehyde in the ﬁnal step.

Example 118: Synthesis of Compounds 447 and 448 Compound 447 and 448: Synthesis of methoxy—3—(3—(pyrrolidin yl)pr0poxy)phenyl)amino)methylpyrimidinol and 4-((4-meth0xy(3-(pyrrolidin- 1-yl)pr0poxy)phenyl)amino)methylpyrimidinol N/\/\:I>\NH2 (I; OH A OH C]N%\ Ct A I j N/ I j N’ N NJ\\N I + @MO NJ\)\ H H Step 1: Synthesis of 2-((4--methoxy---3(3-(pyrrolidin yl)propoxy)phenyl)amino)—6-methylpyrimidinol and 4-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)methylpyrimidinol: Into a 100-mL round-bottom ﬂask, was placed 2-chloromethylpyrimidin 01 (360 mg, 2.49 mol, 1 equiv), 4-methoxy[3-(pyrrolidinyl)propoxy]aniline (600 mg, 2.40 mol, 1 equiv), TsOH (900 mg, 5.23 mmol, 2.00 equiv, 96%), isopropanol (40 mL).

The resulting solution was stirred for 3 h at 85 0C in an oil bath. The resulting e was concentrated under vacuum. The crude t was applied onto a silica gel column with NH4HCO3:ACN (1 : 1),Detector, UV 254 nm. This resulted in 84.4 mg (9%) of 2-((4- methoxy(3-(pyrrolidinyl)propoxy)phenyl)amino)methylpyrimidinol, regioisomer 1 as a solid. And 30.6 mg (3%) of 4-((4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)amino)methylpyrimidinol, regioisomer 2 as a solid. e 119: Synthesis of Compound 449 Compound 449: Synthesis of Nz-(4-meth0xy((1-(0xetanyl)pyrrolidin- 3-yl)meth0xy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine l HN I HN O<>=O O OI) "’ I; *\ NaBH3CN,MeOH o&Q"o N N HNO/\o N N N Step 1: Synthesis of N2-(4-methoxy((1-(oxetanyl)pyrrolidin yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: N2-(4-methoxy((1-(oxetanyl)pyrrolidinyl)methoxy)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine was prepared as for N2-(3-(((1-ethylpyrrolidin yl)oxy)methyl)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine using oxetanone in place of acetaldehyde in the ﬁnal step.

Example 120: sis of Compound 450 ] Compound 450: Synthesis of N2-(4-methoxy(3-(pyrrolidin yl)pr0p0xy)phenyl)-N4-methyl(pyrrolidinyl)pyrimidine-2,4-diamine HN/ HN | | min ""0 51110 @Mo \N N O " Cl T N N D Step 1: Synthesis ofN2-(4-methoxy(3-(pyrrolidinyl)propoxy)phenyl)- N4-methyl(pyrrolidinyl)pyrimidine-2,4-diamine: Into a 10-mL Vial, was placed 6-chloroN-[4-methoxy[3-(pyrrolidin yl)propoxy]phenyl]N-methylpyrimidine-2,4-diamine (150 mg, 0.38 mmol, 1 equiv), pyrrolidine (2 mL). The resulting on was stirred for 3 h at 100 0C in an oil bath. The crude product (150 mg) was puriﬁed by Prep-HPLC C HCl. This resulted in 96.1 mg (54%) ofN2-(4-methoxy-3 yrrolidinyl)propoxy)phenyl)-N4-methyl(pyrrolidin yl)pyrimidine-2,4-diamine as a solid.

Example 121: Synthesis of Compound 451 Compound 451: sis of Nz-(4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)methyl-N4-((tetrahydro-2H—pyranyl)methyl)pyrimidine-2,4- diamine OD NH oC>—/HN /N Boo-NOAO HN \ N o \ / N —> N—< CI TsOH,i—PrOH,85 °c HN 0 HYO \DW 0 NaBH3CN,MeOH,HOAc HN_<\ :é Step 1: Synthesis of N2-(4-methoxy(pyrrolidinylmethoxy)phenyl)—6- -N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine: ] Into a 100-mL round-bottom ﬂask, was placed 2-chloromethyl-N-(oxan ylmethyl)pyrimidinamine (870 mg, 3.60 mol, 1 equiv), tert-butyl 3-(5-arnino methoxyphenoxymethyl)pyrrolidinecarboxylate (1.163 g, 3.61 mmol, 1 equiv), TsOH (1.242 g, 7.21 mmol, 2.00 equiv), isopropanol (20 mL). The resulting solution was stirred for 24 h at 85 0C in an oil bath. The crude product was puriﬁed by (CH3OH/H2021/10). This resulted in 1.1 g (71%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.885 min, LCMS28: m/z = 428 [M+1].

Step 2: Synthesis of N2-(4-methoxy((1-methylpyrrolidin yl)methoxy)phenyl)methyl-N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4- Into a 100-mL round-bottom ﬂask, was placed N2-(4-methoxy(pyrrolidin ylmethoxy)phenyl)—6-methyl-N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine (300 mg, 0.70 mol, 1 equiv). This was followed by the addition ofHCHO (70.3 mg, 2.34 mol, 1 equiv, 30% aq), methanol (20 mL)was stirred for 0.5h at 20 0C. Then NaBH3CN (265.6 mg, 4.23 mmol, 6.00 , HOAC (0.2 mL) was added and stirred for 2h at 25 0C.

The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC D TFA. This resulted in 71.2 mg (18%) ofN2-(4-methoxy((1- methylpyrrolidinyl)methoxy)phenyl)methyl-N4-((tetrahydro-2H-pyran y1)methyl)pyrimidine-2,4-diamine as a white solid.

Example 122: Synthesis of Compound 452 Compound 452: Synthesis of N2-(4-methoxy((tetrahydrofuran yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine \ NH I NH The crude product was puriﬁed by Prep-HPLC C HCl. This resulted in 95.4 mg (35%) of N2-(4-methoxy((tetrahydrofuran-Z-yl)methoxy)phenyl)-N4,6-dimethylpyrimidine-2,4- diamine as a light brown solid.

Example 123: Synthesis of Compound 453 Compound 453: Synthesis of Nz-(3-(2-cyclopropoxyethoxy) methoxyphenyl)-N4-methylpyrimidine-2,4-diamine ('3 NI N: (I) \NH Fe,NH4C] C] ('3 —> N \ «(k/\o CH3OH'H20 No2 OwOmNHZ «ov\oj:j\miij Step 1: Synthesis of 3-(2-cyclopropoxyethoxy)methoxyaniline Into a 50-mL round-bottom ﬂask, was placed 2-(2-cyclopropoxyethoxy) methoxynitrobenzene (300 mg, 1.18 mol, 1 equiv), NH4Cl (192 mg, 3.59 mmol, 3.00 equiv), iron (199 mg, 3.56 mmol, 3.00 equiv), methanol (5 mL), water (1 mL). The resulting solution was stirred for 12 h at 90 0C in an oil bath. The solids were ﬁltered out. The resulting e was concentrated under vacuum. The residue was applied onto a silica gel column with methanol/HzO (1 :4). This resulted in 200 mg (76%) of the title compound as a light brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.82min, LCMSO7: m/z = 224 [M+1].

Step 2: Synthesis of N2-(3-(2-cyclopropoxyethoxy)methoxyphenyl)-N4- methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 3-(2-cyclopropoxyethoxy) methoxyaniline (200 mg, 0.90 mol, 1 equiv), triﬂuoroacetic acid (306.7 mg, 2.71 mmol, 3.00 equiv), IPA (10 mL), 2-chloro-N-methylpyrimidinamine (129 mg, 0.90 mmol, 1 equiv). The resulting solution was stirred for 5 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC D TFA. This resulted in 65 mg (16%) ofN2-(3-(2-cyclopropoxyethoxy)methoxyphenyl)-N4- methylpyrimidine-2,4-diamine as a white solid.

Example 124: sis of Compound 456 nd 456: sis of Nz-(3-((1-cyclopentylpyrrolidin yl)methoxy)meth0xyphenyl)-N4,6-dimethylpyrimidine-2,4—diamine \00": N 0% 01> A"/I / \ NaBH3CN,MeOH,HOAc Step 1: Synthesis of N2-(3-((1-cyclopentylpyrrolidinyl)methoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: N2-(3-((1-cyclopentylpyrrolidinyl)methoxy)methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine was prepared as for (((1-ethylpyrrolidin yl)oxy)methyl)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine using cyclopentanone in place of acetaldehyde in the ﬁnal step.

Example 125: Synthesis of Compound 458 ] nd 458: Synthesis of 6-cyclopentyl-Nz-(4-methoxy(3- (pyrrolidinyl)pr0poxy)phenyl)-N4-methylpyrimidine-2,4—diamine / I HN I HN N/ O—BPIN D j: | Pd/C,H2,DCM J\\ I — N’\/\o —> N N 9M0 N N c] Pdldppﬁc'szazcosx H H dioxane,H20 on J: | @M0 u N Step 1: Synthesis of 6-(cyclopentenyl)N-[4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]N-methylpyrimidine-2,4-diamine: Into a 40-mL round-bottom ﬂask, was placed 6-chloroN-[4-methoxy[3- (pyrrolidinyl)propoxy]phenyl]N-methylpyrimidine-2,4-diamine (300 mg, 0.77 mmol, 1 equiv), Pd(dppf)C12 (127 mg, 0.17 mmol, 0.23 equiv), sodium carbonate (245 mg, 2.31 mmol, 3.02 equiv), dioxane (9 mL), 3 mL), LiCl (37 mg), [cyclopenten yl(iodo)boranyl]phosphanimine (173 mg, 0.69 mmol, 0.90 equiv). The resulting solution was stirred ght at 80 0C. The resulting mixture was concentrated under vacuum. The ing solution was diluted with 10 mL of H20. The resulting solution was ted with 3x20 mL of dichloromethane and the organic layers combined and dried in an oven under reduced pressure. The resulting mixture was washed with 3x50 mL of 1N HCl/HZO. The pH value of the solution was adjusted to 9 with sodium carbonate (100 %). The resulting solution was ted with 3x50 mL of dichloromethane and the organic layers combined dried in an oven under reduced pressure. The resulting e was concentrated under vacuum. This ed in 500 mg (crude) of as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.914 min, LCMS 07, m/Z =424 [M+1].

Step 2: Synthesis of 6-cyclopentyl-N2-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 6-(cyclopentenyl)N- [4-methoxy[3-(pyrrolidinyl)propoxy]phenyl]N-methylpyrimidine-2,4-diamine (500 mg, 1.18 mol, 1 equiv), Pd/C (100 mg), hydrogen (100 mL), dichloromethane (20 mL). The resulting solution was d overnight at RT. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC C HCl. This resulted in 50.9 mg (9%) of 6-cyclopentyl-NZ-(4-methoxy(3-(pyrrolidin yl)propoxy)phenyl)-N4-methylpyrimidine-2,4-diamine as a white solid.

Example 126: sis of Compound 459 Compound 459: sis of N2-(4-methoxy-3—(3-(pyrrolidin yl)propoxy)phenyl)-N4-methyl(tetrahydro-2H—pyranyl)pyrimidine-2,4-diamine HN | HN | / o NlPB-CO o GMODNkN/ N, 2,DCM | | Pd(dppf)C|2, N32003 @Mo N Cl dioxane,H20 H "*N CD "/I OIMO "*N Step 1: Synthesis of N2-(4-methoxy(3-(pyrrolidinyl)pr0poxy)phenyl)- N4-methyl(tetrahydr0-2H-pyranyl)pyrimidine-2,4-diamine: N2-(4-methoxy-3 -(3 -(pyrrolidinyl)pr0p0xy)phenyl)-N4-methyl (tetrahydr0-2H-pyranyl)pyrimidine-2,4-diamine was prepared as for 6-cyclopentyl-N2-(4- methoxy(3-(pyrrolidinyl)pr0poxy)phenyl)-N4-methylpyrimidine-2,4-diamine using 2- (3,6-dihydro-2H-pyranyl)—4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of 2- (cyclopent-l-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxab0rolane in step 1.

Example 127: Synthesis of Compound 460 Compound 460: Synthesis of N-(S—methoxy(3-(pyrrolidin yl)propoxy)pyridineyl)methyl-1H-pyrazolo[4,3-c]pyridineamine CI N 3rd-Brettphos Step 1: Synthesis -methoxy(3-(pyrrolidinyl)pr0p0xy)pyridine yl)methyl-1H-pyrazolo[4,3-c]pyridineamine: Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed DMSO (10 mL), 4-chlor0methyl-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.60 mol, 1 equiv), 5-methoxy[3-(pyrrolidinyl)pr0poxy]pyridinamine (180 mg, 0.72 mmol, 1.20 equiv), ettphos (81 mg, 0.09 mmol, 0.15 equiv), CszCO3 (390 mg, 1.20 mmol, 2.01 equiv). The resulting solution was stirred for 4 h at 80 0C. The resulting solution was diluted with 10 mL of H20. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The ing mixture was washed with 3x10 mL of water and 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was puriﬁed by Prep-HPLC D TFA. This resulted in 30.4 mg (10%) ofN- (5-methoxy(3-(pyrrolidinyl)propoxy)pyridineyl)methyl-1H-pyrazolo[4,3- c]pyridineamine as a white solid. e 128: Synthesis of nd 461 Compound 461: Synthesis of 2-(3-((2-meth0xy((4-methyl (methylamin0)pyrimidin-Z-yl)amino)phenoxy)methyl)pyrrolidinyl)ethan01 \NH \ I NH o O I) 1’ I WM I) I I — \ o N \N 052CO3,DMF O N N HN N H HOf H Step 1: Synthesis of 2-(3-((2-methoxy((4-methyl (methylamino)pyrimidinyl)amino)phenoxy)methyl)pyrrolidinyl)ethanol: Into a 100-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin- 3-ylmethoxy)phenyl]N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.58 mol, 1 equiv), 2-bromoethanol (70 mg, 0.56 mol, 1 equiv), CszCO3 (380 mg, 1.17 mmol, 2.00 , NaI (170 mg, 2.00 equiv), ACN (15 mL). The resulting solution was stirred for 4 h at 80 0C in an oil bath. The solids were ﬁltered out. The residue was applied onto a silica gel column with TFA:ACN (5: 1). This resulted in 44.2 mg (15%) of 2-(3-((2-methoxy((4-methyl (methylamino)pyrimidinyl)amino)phenoxy)methyl)pyrrolidinyl)ethanol as a solid.

Example 129: Synthesis of Compound 462 Compound 462: Synthesis of N2-(3-((1-cyclopropylpyrrolidin-S— yl)methoxy)methoxyphenyl)methyl-N4-((tetrahydr0-2H—pyran yl)methyl)pyrimidine-2,4—diamine NH \spxb OZN OZN OVE) / \ o A Pd/C,MeOH o N,MeOH,HOAc NMAvg} 9 QO/\CN"4 TsOH,l—PrOH85°C HN—<\:2 Step 1: Synthesis 1-cyclopropyl(2-methoxy nitrophenoxymethyl)pyrrolidine: Into a 100-mL round-bottom ﬂask, was placed 3-(2-methoxy nitrophenoxymethyl)pyrrolidine (340 mg, 1.35 mmol, 1 equiv), (1- ethoxycyclopropoxy)trimethylsilane (354 mg, 2.03 mmol, 1.50 equiv), methanol (20 mL), NaBH3CN (512 mg, 8.15 mmol, 6.00 equiv), HOAc (0.02 mL). The resulting solution was d for 30 min at 25 0C. The resulting solution was allowed to react, with stirring, for an additional 24 h while the temperature was maintained at 65 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by (HZO/ACN=1/1). This resulted in 300 mg (76%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.930min, LCMS 27: m/z = 293 [M+1].

Step 2: Synthesis of3-[(1-cyclopropylpyrrolidinyl)methoxy] yaniline: Into a 100-mL round-bottom ﬂask, was placed 1-cyclopropyl(2-methoxy henoxymethyl)pyrrolidine (280 mg, 0.96 mol, 1 equiv), Pd/C (100 mg, 0.30 equiv), methanol (15 mL), hydrogen. The resulting solution was d for 1 h at 25 0C. The solids were ﬁltered out and concentrated under vacuum. This resulted in 243 mg (97%) of the title compound as yellow oil. ical Data: LC-MS: (ES, m/z): RT =0.702min, LCMS 07: m/z = 263 [M+1].

Step 3: Synthesis of N2-(3-((1-cyclopropylpyrrolidinyl)methoxy) methoxyphenyl)methyl-N4-((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed cyclopropylpyrrolidin yl)methoxy]methoxyaniline (200 mg, 0.76 mol, 1 equiv), TsOH (257 mg, 1.49 mmol, 2.00 equiv), 2-chloromethyl-N-(oxanylmethyl)pyrimidinamine (180 mg, 0.74 mol, 1 equiv), isopropanol (15 mL). The resulting solution was stirred for 4 h at 85 0C in an oil bath. The crude product was puriﬁed by (HZO/ACN=1/1). This resulted in 107.4 mg (24%) of N2-(3-((1-cyclopropylpyrrolidinyl)methoxy)methoxyphenyl)methyl-N4- ((tetrahydro-2H-pyranyl)methyl)pyrimidine-2,4-diamine as a white solid.

Example 130: Synthesis of Compound 463 Compound 463: Synthesis of Nz-(3-(3- (cyclopropyl(methyl)amino)pr0poxy)—4—methoxyphenyl)-N4,6-dimethylpyrimidine—2,4- diamine HN/ I HN 01) N/ v" A on N/ \ | CIMO NJ\\N| N/\/\O "*N H K2003,ACN,Na| | ] Step 1: sis of N2-(3-(3-(cyclopropyl(methyl)amino)propoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 40-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.89 mmol, 1 , N- methylcyclopropanamine (76 mg, 1.07 mmol, 1.20 equiv), potassium carbonate (368 mg, 2.66 mmol, 2.99 equiv), CH3CN (20 mL), NaI (134 mg). The resulting solution was stirred overnight at 80 0C. The solids were ﬁltered out. The crude t was puriﬁed by Prep- HPLC c HCl. This resulted in 38.5 mg (11%) of N2-(3-(3- (cyclopropyl(methyl)amino)propoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine as a white solid.

Example 131: Synthesis of Compound 464 Compound 464: Synthesis of N2-(5-methoxy-4—(3-(pyrrolidin poxy)pyridinyl)methyl-N4-((tetrahydr0-2H-pyranyl)methyl)pyridine-2,4- diamine Pd2(dba)3CHC[3 g NH + m/ —> I m OMO NH2 Xantphos,052003 | onn' ' / \ \N OMO u N Step 1: Synthesis of N2-(5-methoxy(3-(pyrrolidinyl)propoxy)pyridin yl)methyl-N4-((tetrahydro-2H-pyranyl)methyl)pyridine-2,4-diamine: Into a 20-mL vial, was placed DMSO (10 mg, 0.13 mmol, 0.15 equiv), 2- chloromethyl-N-(oxanylmethyl)pyridinamine (200 mg, 0.83 mmol, 1 , 5- methoxy[3-(pyrrolidinyl)propoxy]pyridinamine (250 mg, 0.99 mmol, 1.20 equiv), Pd2(dba)3-CHCl3 (130 mg), Xantphos (150 mg, 0.26 mmol, 0.31 equiv), Cs2CO3 (54 mg, 0.17 mmol, 0.20 equiv). The vial was purged and maintained with N2. The resulting on was stirred for 12 h at 80°C. The resulting mixture was concentrated under vacuum. The e was d onto a silica gel column with H20/ACN (9:1). The crude t was puriﬁed by Prep-HPLC D HCl. This ed in 30.2 mg (7%) of N2-(5-methoxy(3-(pyrrolidin yl)propoxy)pyridinyl)methyl-N4-((tetrahydro-2H-pyranyl)methyl)pyridine-2,4- diamine as a white solid. e 132: Synthesis of Compound 465 Compound 465: Synthesis of 1-(3-(2-meth0xy((4-methyl (methylamin0)pyrimidin-Z-yl)amin0)phenoxy)propyl)azetidinol | LNH mN/ Ax | 01) N/ HQ O N | HCI CIA/\o HkN K2003,CH30N LNV Step 1: Synthesis of 1-(3-(2-methoxy((4-methyl (methylamino)pyrimidinyl)amino)phenoxy)propyl)azetidinol: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.59 mmol, 1 equiv), potassium methaneperoxoate (246.4 mg, 1.77 mmol, 3.00 equiv), azetidinol hydrochloride (129.8 mg, 1.18 mmol, 2.00 equiv), acetonitrile (10 mL). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC D TFA. This resulted in 72.5 mg (25%) of 1-(3-(2-methoxy((4-methyl(methylamino)pyrimidin yl)amino)phenoxy)propyl)azetidinol as a solid.

Example 133: Synthesis of Compound 466 Compound 466: Synthesis of Nz-(3-((1-cyclopropylpiperidinyl)oxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4—diamine / SI g HN / O HN/ H0011 V‘m AN I o H \N NaBH3CN QODNkNI Step 1: Synthesis of N2-(3-((1-cyclopropylpiperidinyl)0xy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed -meth0xy(piperidin yloxy)phenyl]N,6-dimethylpyrimidine-2,4-diamine (150 mg, 0.44 mmol, 1 equiv), NaBH3CN (86 mg, 1.37 mmol, 3.00 equiv), methanol (5 mL), (1-eth0xycyclopr0p0xy) trimethylsilane (118.9 mg, 0.68 mmol, 1.50 equiv), acetic acid (10 mg, 0.17 mmol, 0.38 equiv). The resulting solution was stirred for 6 h at 65 0C in an oil bath. The ing mixture was concentrated under vacuum. The crude product (150 mg) was puriﬁed by Prep-HPLC D TFA. This resulted in 55.7 mg (26%) of N2-(3-((1-cyclopropylpiperidinyl)0xy) methoxyphenyl)-N4,6-dimethylpyrimidine-ZA-diamine as a white solid. e 134: Synthesis of nds 481 and 482 Compound 481 and 482: Synthesis of (S)-N2-(3-((1-cyclopropylpyrrolidin- 3-yl)methoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine and (R)-N2-(3- ((1-cyclopropylpyrrolidinyl)methoxy)—4-methoxyphenyl)-N4,6-dimethylpyrimidine- 2,4—diamine / / I HN HN M6351 oJ l o O I o—ﬁ N / J\\ —. I 0 NJ\\ HNQ/\o Chiral—separation " N DCM,NaB(CN)H3 D‘NQA N —> HN/ HN/ | | O OD j N/ N I + "AN | "*N {>.N/\:;/\O \ "NOAO Step 1: Synthesis of (S)-N2-(3-((1-cyclopropylpyrrolidinyl)methoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine and (R)-N2-(3-((1- cyclopropylpyrrolidinyl)meth0xy)methoxyphenyl)-N4,6-dimethylpyrirnidine-2,4- diamine: Into a 100-mL round-bottom ﬂask, was placed 2-N-[4-methoxy(pyrrolidin- 3-ylmethoxy)phenyl]N,6-dimethylpyrimidine-2,4-diamine (400 mg, 1.16 mol, 1 equiv), (1-ethoxycyclopropoxy)trimethylsilane (300 mg, 1.72 mmol, 1.50 equiv), AcOH (0.4 mL), methanol (20 mL), NaBH3CN (330 mg, 5.25 mmol, 3.00 equiv). The ing solution was stirred for 24 h at 65 0C in an oil bath. The resulting mixture was concentrated under vacuum.

The residue was applied onto a silica gel column with TFA:ACN (5:1). This resulted in 31.9 mg (3%) of the racemic mixture as a white solid.

The product was Prep-Chiral-HPLC: Column: pak ID-2, , 5um,Mobile Phase A:Hex 0.1%DEA) HPLC, Mobile Phase B: IPA--HPLC, Flow rate: 20 , Gradient: 20 B to 20 B in 30 min, 220/254 nm. This resulted in 27.7 mg (2%) of (S)-N2-(3-((1-cyclopropylpyrrolidin-3 thoxy)methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine E1 (randomly ed S) and 25.5mg (2%) (R)-N2-(3-((1- cyclopropylpyrrolidinyl)methoxy)methoxyphenyl)-N4,6-dimethylpyrimidine-2,4- diamine E2 (randomly assigned R).

Example 135: Synthesis of Compound 498 Compound 498: Synthesis of N2-(3-(3-(5-azaspiro[2.4]heptan-5— yl)propoxy)methoxyphenyl)—N4,6-dimethylpyrimidine-Z,4—diamine \ I in NH 02mgo , ~/ >01 CIA/\O "*N W V H Step 1: Synthesis of N2-(3-(3-(5-azaspiro[2.4]heptanyl)propoxy) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 20-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.89 mmol, 1 equiv), potassium carbonate (300 mg, 2.17 mmol, 2.44 equiv), CH3CN (5 mL), NaI (135 mg), 5- azaspiro[2.4]heptane (372 mg, 3.83 mmol, 4.30 equiv). The resulting solution was stirred for 48 h at 80 0C. The crude product was puriﬁed by Prep-HPLC D TFA. This resulted in 75.7 mg (16%) of N2-(3-(3-(5-azaspiro[2.4]heptanyl)propoxy)methoxyphenyl)-N4,6- dimethylpyrimidine-2,4-diamine as a white solid.

Example 136: sis of Compound 504 Compound 504: Synthesis of N2-(4-methoxy-3—(3-(2-methylpyrrolidin yl)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine (I) Nil/Ni K2C03,NaI,ACN ODj]: | Step 1: sis of N2-(4-methoxy(3-(2-methylpyrrolidin yl)pr0poxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-N-[3-(3-chlor0pr0p0xy) methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.59 mmol, 1 equiv), 2- methylpyrrolidine (101 mg, 1.19 mmol, 2.00 equiv), NaI (89 mg, 1 equiv), potassium carbonate (246 mg, 1.78 mmol, 3.00 equiv), ACN (10 mL). The resulting solution was stirred for 12 h at 85 0C in an oil bath. The solids were ﬁltered out. The crude product was puriﬁed by Flash-Prep-HPLC A 1:1. This resulted in 78.7 mg (31%) of N2-(4-methoxy(3-(2- methylpyrrolidin-l-yl)pr0poxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 137: Synthesis of Compound 518 Compound 518: Synthesis of 4-cyclopentylmethoxy-N-methyl(3- (pyrrolidinyl)propoxy)quinazolinamine g 0' \N (HI D j: CM,H2 OMO NACI Pd(dppf)2,Na2003 C’NMO N c1 | | \ N O MeNHz-EtOH \" @MO N/ Cl @MO NAM/ Step 1: sis of 2-chlor0(cyclopentenyl)meth0xy[3- (pyrrolidinyl)pr0p0xy] quinazoline: Into a 20-mL vial purged and maintained with an inert here of nitrogen, was placed chlor0methoxy[3-(pyrrolidinyl)propoxy]quinazoline (500 mg, 1.40 mol, 1 equiv), f)2 (115 mg, 0.10 equiv), 2-(cyclopentenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (273 mg, 1.41 mol, 1 equiv), sodium methaneperoxoate (447.9 mg, WO 81177 4.19 mmol, 3.00 equiv), dioxane (8 mL), water (2 mL). The ing solution was stirred for 4 h at 60 0C in an oil bath. The resulting solution was diluted with 5 mL of H20. The resulting on was extracted with 3x10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3X10 mL of H20. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with methanol/HzO (10: 1). This resulted in 300 mg (55%) of as a solid.

] Analytical Data: LC-MS: (ES, m/z): RT = 1.03min, m/z = 388 [M+1].

Step 2: Synthesis of 2-chlorocyclopentylmethoxy[3-(pyrrolidin yl)propoxy]quinazoline: Into a 250-mL round-bottom ﬂask, was placed ro(cyclopenten yl)methoxy[3-(pyrrolidinyl)propoxy]quinazoline (300 mg, 0.77 mmol, 1 equiv), dichloromethane (100 mL), dioxoplatinum, hydrogen . The resulting solution was stirred for 12 h at 20 0C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with CH3CN/HzO (1 :5). This resulted in 200 mg (66%) of the title compound as a brown solid.

] Analytical Data: LC-MS: (ES, m/z): RT = 0.871min, m/z =390 [M+1].

Step 3: Synthesis of 4-cyclopentylmethoxy-N-methyl[3-(pyrrolidin yl)propoxy]quinazolinamine: Into a 10-mL sealed tube, was placed 2-chlorocyclopentylmethoxy[3- (pyrrolidinyl)propoxy]quinazoline (130 mg, 0.33 mol, 1 equiv), ethanol, methanamine (2 mL). The resulting solution was stirred for 3 h at 80°C in an oil bath. The resulting e was concentrated under vacuum. The crude product (130 mg) was puriﬁed by Flash-Prep- HPLC A Grad. This resulted in 31.2 mg (19%) of 4-cyclopentylmethoxy-N-methyl[3- lidinyl)propoxy]quinazolinamine as a yellow solid.

Example 138: Synthesis of Compound 523 Compound 523: Synthesis of 4-cyclohexylmethoxy-N-methyl(3- (pyrrolidinyl)pr0p0xy)quinazolinamine I CI HQ \ N BQ O HO \N Pt02,DCM,H2 /\/\O O OMO NAG]/ N c1 PdCI2 CHzc'z O Step—2 M g, GMO N/J\C| @MO NAM/ Step 1: Synthesis of 2-chloro(cycloheXenyl)methoxy[3- lidinyl)propoxy]quinazoline: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed 2,4-dichloromethoxy[3-(pyrrolidin yl)propoxy]quinazoline (300 mg, 0.84 mol, 1 equiv), (cycloheX-l-enyl)boronic acid (116 mg, 0.92 mmol, 1.1 equiv), Pd(dppf)C12 dichloromethane (69 mg, 0.10 equiv), sodium carbonate (179 mg, 1.69 mmol, 2.00 , dioxane (16 mL), water(4 mL). The resulting solution was stirred for 7 h at 60 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The crude product (350 mg) was puriﬁed by Flash HPLC MeOH. This resulted in 220 mg (64%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.08 min, LCMS 53: m/Z = 402.0 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.47 (s, 1H), 7.25 (s, 1H), 6.25 — 6.22 (m, 1H), 4.29 (t, J: 6.1 Hz, 2H), 3.98 (s, 3H), 2.82 — 2.74 (m, 2H), 2.67 — 2.60 (m, 4H), 2.56 — 2.49 (m, 2H), 2.39 — 2.20 (m, 2H), 2.17 — 2.10 (m, 2H), 1.97 — 1.78 (m, 8H).

Step 2: sis of 2-chlorocyclohexylmethoxy[3-(pyrrolidin poxy]quinazoline: ] Into a 100-mL round-bottom ﬂask, was placed 2-chloro(cycloheXen yl)methoxy[3-(pyrrolidinyl)propoxy]quinazoline (220 mg, 0.55 mmol, 1 equiv), PtOz (200 mg), methanol (15 mL). The resulting solution was stirred for 12 h at 25 0C under H2(g). The solids were ﬁltered out. The resulting mixture was concentrated under vacuum.

This resulted in 218 mg (87%) of as a yellow solid.

] Analytical Data: LC-MS: (ES, m/z): RT = 1.15 min, LCMS 53: m/Z = 404.0 [M+1].

Step 3: Synthesis of 4-cyclohexylmethoxy-N-methyl[3-(pyrrolidin yl)propoxy]quinazolinamine: Into a 50-mL round-bottom ﬂask, was placed 2-chlorocyclohexyl methoxy[3-(pyrrolidinyl)propoxy]quinazoline (200 mg, 0.50 mol, 1 equiv), Methylamine ethanol solution(32%) (15 mL, 1 equiv). The resulting solution was stirred for 1 h at 80 0C in an oil bath. The resulting mixture was concentrated under . The crude product (210mg) was puriﬁed by Flash HPLC A Grad. This resulted in 71.8 mg (35%) of 4- cyclohexylmethoxy-N-methyl[3-(pyrrolidinyl)propoxy]quinazolinamine as a yellow solid.

Example 139: Synthesis of Compound 538 nd 538: sis of N4-methyl-N2-(4-(3-(pyrrolidin yl)pr0p0xy)—1H-indazolyl)pyrimidine-2,4—diamine cN CN O\ F F HOWBD F OWN[3 DlBAL-H,DCM F 0WDNH2NH2-H20 O —. —. —.

L'HMD. s:THF w noOH Br Br N Br Br H :N: : .r a "a SEMC], NaH Nﬁ TFA50 °C / 3rdbrettphoses2co3 SEMI/ﬁn] N\/Nj\N—> "1%,"le N *1 Br X.

Step 1: Synthesis of 4-bromoﬂuoro[3-(pyrrolidin yl)propoxy]benzonitrile: Into a 100-mL round-bottom ﬂask, was placed 4-bromo-2,6- diﬂuorobenzonitrile (1 g, 4.59 mol, 1 equiv), LiHMDS (5.5 mL), tetrahydrofuran (30 mL), 3-(pyrrolidinyl)propanol (710 mg, 5.50 mmol, 1.20 equiv). The resulting on was stirred for 30 min at 25 0C. The resulting solution was d to react, with stirring, for an additional 2 h at 25 0C. The reaction was then quenched by the addition of water. The ing on was extracted with 2x100 mL of dichloromethane and the c layers combined and concentrated under vacuum. The crude product was puriﬁed by Flash-Prep- HPLC A. This resulted in 0.18 g of the title compound as yellow oil.

Analytical Data: 1H NMR (300 MHz, Chloroform—d) 5 7.13 — 6.95 (m, 2H), 4.22 (t, J: 6.3 Hz, 2H), 2.65 — 2.35 (m, 4H), 2.11 - 1.76 (m, 6H).

Step 2: Synthesis of 4-bromoﬂuoro[3-(pyrrolidin yl)propoxy]benzaldehyde: Into a 250-mL round-bottom ﬂask, was placed 4-bromoﬂuoro[3- (pyrrolidinyl)propoxy]benzonitrile (2.3 g, 7.03 mmol, 1 equiv), DIBAL-H (12 mL), romethane (50 mL). The resulting on was stirred for 1 h at 25 0C. The resulting solution was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 40 0C in an oil bath. The reaction was then ed by the addition of HCl.

The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Flash-Prep-HPLC and this resulted in 1 g (39%) of the title compound as ayellow solid.

Analytical Data: 1H NMR (300 MHz, DMSO-dG) 5 10.29 (d, J: 1.4 Hz, 1H), .14 (s, 1H), 7.32 (d, J: 10.0 Hz, 2H), 4.28 (t, J: 5.8 Hz, 2H), 3.65 — 6.48 (m, 2H), 3.02 — 2.98 (m, 2H), 2.26 — 1.82 (m, 6H).

Step 3: Synthesis of 6-bromo[3-(pyrrolidinyl)propoxy]-1H-indazole: Into a 50-mL round-bottom ﬂask, was placed 4-bromoﬂuoro[3- (pyrrolidinyl)propoxy]benzaldehyde (1 g, 3.03 mol, 1 equiv), NH2NH2H2O (3 mL), ethylene glycol (5 mL). The resulting solution was stirred for 2 h at 120 0C in an oil bath. The resulting solution was extracted with 2x100 mL of dichloromethane and the organic layers combined. The crude t was puriﬁed by Flash-Prep-HPLC and this resulted in 0.45 g (41%) of the title compound as a light yellow solid.

Analytical Data: 1H NMR (300 MHz, Chloroform-d) 5 10.35 (s, 1H), 8.08 (d, J: 1.0 Hz, 1H), 7.26 (t, J: 1.2 Hz, 1H), 6.63 (d, J: 1.2 Hz, 1H), 4.21 (t, J: 6.2 Hz, 2H), 2.79 (t, J: 7.5 Hz, 2H), 2.70 (s, 4H), 2.18 (p, J: 6.6 Hz, 2H), 1.89 (p, J: 3.3 Hz, 4H).

Step 4: Synthesis of 6-bromo[3-(pyrrolidinyl)propoxy][[2- (trimethylsilyl)ethoxy]methyl]-1H-indazole: ] Into a 250-mL round-bottom ﬂask, was placed 6-bromo[3-(pyrrolidin-l- yl)propoxy]-1H-indazole (400 mg, 1.23 mmol, 1 equiv), sodium hydride (300 mg, 1250 mmol, 10.13 equiv), tetrahydrofuran (40 mL), SEMCl (0.6 g). The resulting solution was stirred for 20 min at 0 0C in a water/ice bath. The resulting solution was allowed to react, with ng, for an additional 3 h at 25 0C. The reaction was then quenched by the addition of water. The resulting on was ted with 2x100 mL of dichloromethane and the c layers combined. The crude product was puriﬁed by Flash-Prep-HPLC and this resulted in 0.22 g (39%) of the title compound as yellow oil.

] Analytical Data: 1H NMR (300 MHz, Chloroform-d) 5 8.14 — 8.02(m, 1H), 7.49 - 7.35(m, 1H), 6.67 — 6.48 (m, 1H), 5.66 (d, J: 2.6 Hz, 2H), 4.25 — 4.15(m, 2H), 3.69 — 3.47 (m, 2H), 3.08 — 2.48 (m, 6H), 2.25 — 2.12 (m, 2H), 1.27 (d, J: 1.6 Hz, 1H), 1.03 — 0.84 (m, 2H), 0.10 — 0.01 (m, 12H).

Step 5: Synthesis of 4-N-methylN-[4-[3-(pyrrolidinyl)propoxy][[2- (trimethylsilyl)ethoxy]methyl]-1H-indazolyl]pyrimidine-2,4-diamine: ] Into a 10-mL bottom ﬂask, was placed 4-N-methylpyrimidine-2,4- diamine (200 mg, 1.61 mmol, 4.07 equiv), 6-bromo[3-(pyrrolidinyl)propoxy][[2- (trimethylsilyl)ethoxy]methyl]-1H-indazole (180 mg, 0.40 mol, 1 equiv), 3rd-brettphos (50 mg), Cs2C03 (300 mg, 0.92 mmol, 2.32 equiv), dioxane (5 mL). The resulting solution was d for 12 h at 110 0C in an oil bath. The resulting solution was extracted with 2x50 mL of dichloromethane and the organic layers ed. The resulting mixture was washed with 1x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.22 g of the title compound as an oil.

Step 6: sis of N4-methyl-N2-(4-(3-(pyrrolidinyl)propoxy)-1H- indazolyl)pyrimidine-2,4-diamine: Into a 25-mL round-bottom ﬂask, was placed 4-N-methylN—[4-[3- (pyrrolidinyl)propoxy][[2-(trimethylsilyl)ethoxy]methyl]-1H-indazolyl]pyrimidine- 2,4-diamine (40 mg, 0.08 mol, 1 equiv), triﬂuoroacetic acid (3 mL). The resulting solution was stirred for 30 min at 50 0C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was puriﬁed by Prep-HPLC B. This resulted in 10 mg (33%) of N4-methyl-N2-(4-(3-(pyrrolidinyl)propoxy)-1H-indazolyl)pyrimidine-2,4-diamine as yellow oil.

Example 140: Synthesis of nd 541 Compound 541: Synthesis of N4-methyl-N2-(piperidinyl)pyrimidine- 2,4—diamine ,CL \ )L/ TFA, IPA N N CI N H Step 1: Synthesis of N4-methyl-N2-(piperidinyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methylpyrimidin amine (150 mg, 1.04 mol, 1 equiv), tert-butyl 3-aminopiperidinecarboxylate (220 mg, 1.10 mmol, 1.05 equiv), triﬂuoroacetic acid (380 mg, 3.36 mmol, 3.00 equiv), IPA (5 mL).

The resulting solution was stirred for 16 h at 90 0C in an oil bath. The crude product was d by Prep-HPLC c NH4HCO3. This resulted in 132.4 mg (61%) ofN4-methyl-N2- (piperidinyl)pyrimidine-2,4-diamine as a white powder.

Example 141: Synthesis of Compound 542 Compound 542: Synthesis of N4-methyl-N2-(piperidinyl)pyrimidine- amine \NH NH Boc—N NH2 HN N \ N \ )L / )L / TFA, IPA N N CI N H Step 1: Synthesis of N4-methyl-N2-(piperidinyl)pyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methylpyrimidin amine (150 mg, 1.04 mmol, 1 equiv), roacetic acid (480 mg, 4.25 mmol, 4.00 equiv), IPA (5 mL), tert-butyl 4-aminopiperidinecarboxylate (250 mg, 1.25 mmol, 1.19 equiv).

The resulting on was stirred for 16 h at 90 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C NH4HCO3. This resulted in 42.2 mg (19%) ofN4-methyl-N2- (piperidinyl)pyrimidine-2,4-diamine as light yellow oil.

Example 142: Synthesis of Compound 543 nd 543: Synthesis of N2-butyl-N4-methylpyrimidine-2,4-diamine WNH N \ N \ A / A / TFA IPA N N CI N ‘ H Step 1: sis of NZ-butyl-N4-methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methylpyrimidin amine (150 mg, 1.04 mmol, 1 equiv), butan-l-amine (80 mg, 1.09 mmol, 1.05 , triﬂuoroacetic acid (380 mg, 3.36 mmol, 3.00 equiv), IPA (5 mL). The resulting solution was stirred for 16 h at 90 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C NH4HCO3. This resulted in 35.1 mg (19%) of NZ-butyl-N4-methylpyrimidine-2,4-diamine as white oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.15 min, LCMS 07: m/Z = 181.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.61 (d, J: 6.0 Hz, 1H), 5.77 (d, J: 6.0 Hz, 1H), 3.34 (t, J: 4.5 Hz, 1H), 3.32 (t, J: 1.5 Hz,1H), 2.87 (s, 3H),1.63 — 1.53 (m, 2H),1.48 — 1.36 (m, 2H), 0.98 (t, J: 7.2 Hz, 3H).

Example 143: Synthesis of Compound 546 Compound 546: Synthesis of N4-methyl-N2-(3-methylpiperidin-3— yl)pyrimidine-2,4-diamine \NH UNHz Nl \ HN / CIAN/NIJE TFA, IPA Step 1: Synthesis of N4-methyl-N2-(3-methylpiperidinyl)pyrimidine-2,4- diamine: Into a 50-mL round-bottom ﬂask, was placed 2-chloro-N-methylpyrimidin amine (200 mg, 1.39 mmol, 1 equiv), tert-butyl 3-aminomethylpiperidinecarb0xylate (357 mg, 1.67 mmol, 1.20 equiv), triﬂuoroacetic acid (791 mg, 7.00 mmol, 5.02 equiv), IPA (4 mL). The resulting solution was stirred for 16 h at 90 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C NH4HCO3. This resulted in 52.4 mg (17%) N4-methyl-N2-(3- methylpiperidinyl)pyrimidine-2,4-diamine as a light yellow solid.

Example 144: Synthesis of nd 547 ] Compound 547: Synthesis of N4-methyl-N2-(4-methylpiperidin-4— imidine-2,4-diamine \NH /O\NH2 Nl : )NLJj BOG HON N TFA IPA CI N ' Step 1: Synthesis of N4-methyl-N2-(4-methylpiperidinyl)pyrimidine-2,4- diamine: Into a 50-mL round-bottom ﬂask, was placed ro-N-methylpyrimidin amine (400 mg, 2.79 mmol, 1 equiv), triﬂuoroacetic acid (1109 mg, 9.81 mmol, 4.00 equiv), IPA (10 mL), tert—butyl 4-aminomethylpiperidinecarb0xylate (573 mg, 2.67 mmol, 1.10 equiv). The resulting solution was stirred for 16 h at 90 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C NH4HCO3. This resulted in 34 mg (6%) of N4-methyl-N2-(4- piperidinyl)pyrimidine-2,4-diamine as a white semisolid. e 145: Synthesis of Compound 548 Compound 548: Synthesis of Nz-((1R,3S)aminocyclopentyl)-N4- pyrimidine-2,4-diamine 800 'Q HN N \ \ N NH2 HzN'Q JL / l A N N \N / TFA IPA N CI ] Step 1: Synthesis of N2-((1R,3S)amin0cyclopentyl)-N4-methylpyrimidine- 2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed ro-N—methylpyrimidin amine (300 mg, 2.09 mmol, 1 equiv), triﬂuoroacetic acid (2.375 g, 21.01 mmol, 10.06 equiv), IPA (5 mL), tert-butyl N—[(1S,3R)amin0cyclopentyl]carbamate (459 mg, 2.29 mmol, 1.10 . The resulting solution was stirred for 16 h at 90 0C in an oil bath. The crude product was puriﬁed by Prep-HPLC C TFA. This resulted in 33.2 mg (5%) of N2-((1R,3S) aminocyclopentyl)-N4-methylpyrimidine-2,4-diamine as light yellow oil.

Example 146: Synthesis of Compound 549 Compound 549: Synthesis of N2-(1-butylmethylpiperidin-3—yl)—N4- methylpyrimidine-2,4-diamine \NH \NH N\ g, h HUNJLN/ 032003, DMF MUMAN/ Step 1: sis of N2-(1-butylmethylpiperidinyl)-N4- methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-N-methylN—(3- methylpiperidinyl)pyrimidine-2,4-diamine (150 mg, 0.68 mol, 1 equiv), CsCO3 (231 mg, 2.50 equiv), N,N—dimethylformamide (2 mL), 1-i0d0butane (187 mg, 1.02 mmol, 1.50 equiv). The resulting solution was stirred for 3 days at 20 0C. The crude product was puriﬁed by Prep-HPLC C TFA. This ed in 53.6 mg (20%) of N2-(1-butylmethylpiperidin yl)-N4-methylpyrimidine-2,4-diamine as a light yellow oil.

Example 147: Synthesis of Compound 550 Compound 550: Synthesis of Nz-(l-butylmethylpiperidin-4—yl)—N4- methylpyrimidine-2,4-diamine \NH \NH 6N4? MIN \ N \ KNQQAN/ H" H H 032003, DMF Step 1: Synthesis of N2-(1-butylmethylpiperidinyl)-N4- methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed 4-N-methylN—(4- methylpiperidinyl)pyrimidine-2,4-diamine (220 mg, 0.99 mol, 1 equiv), Cs2C03 (338.5 mg), N,N—dimethylformamide (3 mL), 1-iodobutane (275 mg, 1.49 mmol, 1.50 equiv). The resulting solution was stirred for 2 days at 20 0C. The residue was applied onto a silica gel column with CH3CN/HZO (40%). This resulted in 62.1 mg (23%) of N2-(1-butyl methylpiperidinyl)-N4-methylpyrimidine-2,4-diamine as light yellow oil.

Example 148: Synthesis of Compound 551 Compound 551: Synthesis of Nz-(3-(3- (cyclobutyl(methyl)amin0)propoxy)—4-methoxyphenyl)—N4,6-dimethylpyrimidine-2,4— diamine | HN E \ N/ oI) x NH N / 6\ k l l ' [M0 H N 01M0 m N K2003,CH30N ] Step 1: Synthesis of N2-(3-(3-(cyclobutyl(methyl)amino)propoxy)—4- methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 2-N-[3-(3-chloropropoxy) methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.59 mmol, 1 equiv), potassium carbonate (246 mg, 1.78 mmol, 3.00 equiv), NaI (89 mg, 1 , N- cyclobutanamine (144 mg, 1.69 mmol, 2.00 equiv), CH3CN (20 mL). The resulting on was stirred for 10 h at 85 0C in an oil bath. The solids were d out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was d by Prep- HPLC c HCl. This resulted in 82.3 mg (33%) ofNZ-(3-(3- butyl(methyl)amino)propoxy)methoxyphenyl)—N4,6-dimethylpyrimidine-2,4- diamine as a white solid.

Example 149: Synthesis of Compound 642 Compound 642: Synthesis of 2-N-(6-meth0xy[[(3R) methylpyrrolidin-S-yl]methoxy]pyridinyl)N,6-dimethylpyrimidine-2,4-diamine C] N\ | C] / N\ MsCl HO Br | M ON6 a BOG-NJ OH /\/\ OMS / TEADCM Boc—NQ chospMF Boc—N\/:£/\O Br MeOH (I) HN/ HN/ N j: I I | \ HZN N O N / TFA,DCM O N I \ —> N I N/ Boc—N/\::/\O / 3rdBrettphos I Br \;/\O:[;\NJ\\NH HNMOMNXN\ \/ \/= \/: H HCHO N\ N/ NaBchN MOMNXN Step 1: Synthesis of utyl (3R) [(methanesulfonyloxy)methyl] pyrrolidine-l -carboxylate: Into a 100-mL round-bottom ﬂask, was placed tert-butyl (3R) (hydroxymethyl)pyrrolidinecarboxylate (1 g, 4.97 mmol, 1.00 equiv), dichloromethane (10 mL), TEA (1.5 g, 14.82 mmol, 3.00 equiv), MsCl (850 mg, 7.46 mmol, 1.50 equiv). The resulting solution was d for 2 h at 25 0C. The resulting mixture was concentrated under vacuum. This resulted in 2 g (crude) of the title compound as yellow crude oil.

Step 2: Synthesis of utyl (3R)[[(5-bromochloropyridin yl)oxy]methyl]pyrrolidinecarboxylate: ] Into a 100-mL round-bottom ﬂask, was placed 5-bromochloropyridinol (1.04 g, 4.99 mmol, 1.00 equiv), tert-butyl (3R)[(methanesulfonyloxy)methyl]pyrrolidine- 1-carboxylate (1.4 g, 5.01 mmol, 1.00equiv), potassium carbonate (2.06 g, 14.90 mmol, 3.00 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 12 h at 80 0C in an oil bath. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The ing mixture was washed with 3x30 mL of brine. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :3). This resulted in 1.4 g (72%) of the title compound as a white solid.

WO 81177 Analytical Data: LCMS: (ES, m/z): RT = 1.469 min, LCMS15: m/z = 393 [M+1]. 1H NMR: (400 MHz, Methanol-d4) 5 8.07 (d, J: 2.0 Hz, 1H), 7.75 (d, J: 2.0 Hz, 1H), 4.19 — 4.09 (m, 2H), 3.69 — 2.69 (m, 8H), 2.24 — 1.76 (m, 2H), 1.48 (s, 9H).

Step 3: Synthesis of : tert-butyl (3R)—3-[[(5-bromomethoxypyridin yl)oxy]methyl]pyrrolidinecarboxylate Into a 25-mL round-bottom ﬂask, was placed tert-butyl (3R)[[(5-bromo chloropyridinyl)oxy]methyl]pyrrolidinecarboxylate (1.4 g, 3.57 mmol, 1.00 equiv), methanol (4 mL), NaOCHg/MeOH (2 mL, 1.00 equiv). The resulting solution was stirred for 12 h at 70 0C in an oil bath. The resulting e was concentrated under vacuum. The resulting solution was ted with 3x30 mL of ethyl acetate and the organic layers combined. This resulted in the title compound 1.4 g (crude) of as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.491 min, LCMS28: m/z = 387 [M+1].

Step 4: sis of tert-butyl (3R)[[(2-methoxy[[4-methyl (methylamino)pyrimidinyl] amino] pyridin-3 -yl)oxy]methyl]pyrrolidinecarboxylate: Into a 50-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl -[[(5-bromomethoxypyridin yl)oxy]methyl]pyrrolidinecarboxylate (500 mg, 1.29 mmol, 1.00 , 4-N,6- dimethylpyrimidine-2,4-diamine (196.6 mg, 1.42 mmol, 1.10 equiv), CszCO3 (1.26 g, 3.87 mmol, 3.00 equiv), 3rd-Brettphos (117.4 mg, 0.13 mmol, 0.10 equiv), DMSO (5 mL). The resulting solution was stirred for 12 h at 100 0C in an oil bath. The solids were d out.

The crude product was puriﬁed by Flash-Prep-HPLC with the following conditions Flash-l): Column, silica gel, mobile phase, H20:ACN = 40% , Detector, UV 254 nm.

This resulted in 340 mg (59%) of the title nd as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.077 min, LCMS53: m/z = 445 [M+1].

Step 5: Synthesis of 2-N-[6-methoxy[(3R)-pyrrolidinylmethoxy]pyridin- 4-N,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom ﬂask, was placed tert-butyl (3R)—3-[[(2-methoxy[[4-methyl(methylamino)pyrimidinyl] amino]pyridinyl)oxy] methyl] pyrrolidine-1 - carboxylate (340 mg, 0.76 mmol, 1.00 equiv), dichloromethane (5 mL), triﬂuoroacetic acid (1 mL). The resulting solution was stirred for 2 h at 25 0C. The resulting mixture was concentrated under vacuum. This resulted in 1 g (crude) of the title compound as yellow crude oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.814 min, LCMS33: m/z = 345 [M+1].

Step 6: Synthesis of 2-N-(6-methoxy[[(3R)—1-methylpyrrolidin yl]methoxy]pyridinyl)N,6-dimethylpyrimidine-2,4-diamine Into a 50-mL round-bottom ﬂask, was placed 2-N-[6-methoxy[(3R)- pyrrolidinylmethoxy]pyridinyl]N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.29 mmol, 1.00 equiv), methanol (5 mL), HCHO (29 mg, 0.97 mmol, 1.00 equiv), NaBH3CN (115 mg, 1.83 mmol, 6.00 equiv). The resulting solution was stirred for 2 h at 25 0C. The crude product was puriﬁed by Prep-HPLC with Method C NH4HCO3. This ed in 55.8 mg (54%) of the title compound as a white solid.

Example 150: Synthesis of Compound 644 Compound 644: sis of :2—N-[4-methoxy—3—([[2—(pyrrolidin-1— yl)ethyl]amino]methyl)phenyl]N,6-dimethylpyrimidine-Z,4-diamine O C, O (Boc)20,TEA, —, H —> GINN 0 "3% NaBHsCN @NN N02 No2 DMAP,DCM N02 | / \NH 0 j: | A Raney—NI,EA 3% Cl \N Il3c:©\ N/I GIN NH2 J\\ TFA,i-ProH @NN | NH TFA,DCM o —) N / H J\\ I F F Step 1: Synthesis of [(2-methoxynitrophenyl)methyl][2-(pyrrolidin yl)ethyl]amine: Into a 100-mL bottom ﬂask, was placed methanol (50 mL), 2-methoxy- -nitrobenzaldehyde (1 g, 5.52 mmol, 1.00 equiv), rolidinyl)ethanamine (630 mg, .52 mmol, 1.00 equiv), N (1 g, 15.91 mmol, 2.88 equiv). The resulting solution was d for 1 h at 20 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H20/ACN (10:1). This resulted in 240 mg (16%) of the title as yellow oil.

Analytical Data: LC-MS: (ES, m/Z): RT = in, LCMS 69: m/Z = 280 [M+1].

] Step 2: Synthesis of tert-butyl methoxynitrophenyl)methyl]-N-[2- (pyrrolidinyl)ethyl]carbamate: Into a 50-mL round-bottom ﬂask, was placed dichloromethane (10 mL), [(2- methoxynitrophenyl)methyl][2-(pyrrolidinyl)ethyl]amine (240 mg, 0.86 mmol, 1.00 equiv), Boc20 (281 mg, 1.29 mmol, 1.50 equiv), TEA (261 mg, 2.58 mmol, 3.00 equiv), 4- dimethylaminopyridine (10 mg, 0.08 mmol, 0.10 equiv). The resulting on was stirred for 12 h at 20 0C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H20/ACN (1:1). This resulted in 170 mg (52%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/Z): RT = 0.76 min, LCMS 45: m/Z = 380 [M+1].

Step 3: Synthesis of tert-butyl N-[(5-aminomethoxyphenyl)methyl]-N-[2- (pyrrolidinyl)ethyl]carbamate: Into a 100-mL round-bottom ﬂask, was placed ethyl acetate (10 mL), tert- butyl N—[(2-methoxynitrophenyl)methyl]-N-[2-(pyrrolidinyl)ethyl]carbamate (170 mg, 0.45 mmol, 1.00 equiv), Raney-Ni (20 mg). The ﬂask was purged and maintained with H2.The resulting solution was stirred for 1 h at 20°C. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 110 mg (70%) of the title nd as yellow oil.

Analytical Data: LC-MS: (ES, m/Z): RT = 0.86 min, LCMS 28: m/Z = 350 [M +1]. 1H NMR (300 MHz, Methanol-d4) 5 6.78 (d, J: 8.5 Hz, 1H), 6.74 — 6.60 (m, 2H), 4.41 (s, 2H), 3.76 (s, 3H), 2.57 (d, J: 13.2 Hz, 7H), 1.85 — 1.74 (m, 5H), 1.48 (d, J: 17.1 Hz, Step 4: Synthesis of tert-butyl N—[(2-methoxy[[4-methyl (methylamino)pyrimidinyl] amino] phenyl)methyl] -N- [2-(pyrrolidinyl)ethyl] carbamate: Into a 100-mL round-bottom ﬂask, was placed panol (10 mL), tert-butyl N—[(5-aminomethoxyphenyl)methyl]-N-[2-(pyrrolidinyl)ethyl]carbamate (110 mg, 0.31 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidinamine (49 mg, 0.31 mmol, 0.99 equiv), triﬂuoroacetic acid (61 mg, 0.54 mmol, 1.71 equiv). The resulting solution was stirred for 2 h at 20°C. The ing mixture was concentrated under vacuum. This resulted in 248 mg (167%) ofas yellow oil. ] ical Data: LC-MS: (ES, m/z): RT = 1.45 min, LCMS 33: m/Z = 471 [M+1].

Step 5: Synthesis of 2-N-[4-methoxy([[2-(pyrrolidin yl)ethyl]amino]methyl)phenyl]N,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed dichloromethane (2 mL), tert- butyl N-[(2-methoxy[[4-methyl(methylamino)pyrimidinyl]amino]phenyl)methyl]-N- [2-(pyrrolidinyl)ethyl]carbamate (248 mg, 0.53 mmol, 1.00 , triﬂuoroacetic acid (2 mL). The resulting solution was stirred for 1 h at 20 0C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was puriﬁed by Prep-HPLC with Method C TFA. This resulted in 70.6 mg (28%) of the title compound as a triﬂuoroacetic acid as an off-white solid.

Example 151: Synthesis of Compound 524 Compound 524: Synthesis of 6-meth0xy-N-methyl-4—(oxan-4—yl)—7-[3- (pyrrolidinyl)pr0p0xy] quinolin-Z-amine 04:10 :\F CH30H O G‘VOQ""2 DMAPDCC O O [wk/[KO O OH H SO FIE: 2 4 POCI3 MeNHz-HZO /o F \ /o /o \ \ Step 1: Synthesis of 2,2-dimethyl[(oxanyl)carbonyl]-1,3-dioxane-4,6- dione: Into a 250-mL round-bottom ﬂask, was placed oxanecarboxylic acid (6 g, 46.10 mmol, 1.00 , 4-dimethylaminopyridine (8.4 g, 68.76 mmol, 1.49 equiv), DCC (9.6 g, 46.53 mmol, 1.01 equiv), romethane (50 mL), 2,2-dimethyl-1,3-dioxane-4,6- dione (6.6 g, 45.79 mmol, 0.99 equiv). The ing solution was stirred for 1 overnight at 0 0C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This ed in 9.2 g (78%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.422 min, LCMS34, m/z=255 [M+1].

Step 2: Synthesis of methyl 3-(oxanyl)oxopropanoate: Into a 100-mL round-bottom ﬂask, was placed 2,2-dimethyl[(oxan yl)carbonyl]-1,3-dioxane-4,6-dione (5 g, 19.51 mmol, 1.00 equiv), ol (20 mL). The ing solution was stirred for 1 overnight at 60 0C. The resulting mixture was concentrated under . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (31/69). This resulted in 3.2 g (88%) of the title compound as an off- white liquid.

Analytical Data: LC-MS: (ES, m/Z): RT=0735 min, LCMS34, m/z=185 [M- 1]. 1H NMR: (300 MHz, Chloroform-d) 5 4.08 — 3.96 (m, 2H), 3.75 (s, 3H), 3.52 (s, 2H), 3.49 — 3.38 (m, 2H), 2.79 — 2.65 (m,1H), 1.87 — 1.62 (m, 4H).

Step 3: N-[4-methoxy[3-(pyrrolidinyl)propoxy]phenyl](oxanyl)- ropanamide: Into a 10-mL vial, was placed methyl 3-(oxanyl)oxopropanoate (500 mg, 2.69 mmol, 1.00 equiv), AlMe3 (0.4 mL, 3.00 equiv), toluene (2 mL), 4-methoxy[3- (pyrrolidinyl)propoxy]aniline (672 mg, 2.68 mmol, 1.00 equiv). The resulting solution was d for 48 h at 80 0C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 880 mg (81%) of the title nd as a brown oil.

] Analytical Data: LC-MS: (ES, m/z): RT=0.600 min, LCMS45, m/z=405 [M+1].

Step 4: sis of 6-methoxy(oxanyl)[3-(pyrrolidin yl)propoxy]quinolinol Into a 100-mL round-bottom ﬂask, was placed N-[4-methoxy[3-(pyrrolidin- 1-yl)propoxy]phenyl](oxanyl)oxopropanamide (1 g, 2.47 mmol, 1.00 equiv), sulfuric acid (5 mL). The ing solution was stirred for 0.5 h at 50 0C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 960 mg (98%) of the title compound as a gray solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.837 min, LCMS07, m/z=387 [M+1].

] Step 5: Synthesis of 2-chloromethoxy(oxanyl)[3-(pyrrolidin yl)propoxy]quinoline: Into a 50-mL round-bottom ﬂask, was placed 6-methoxy(oxanyl)[3- (pyrrolidinyl)propoxy]quinolinol (50 mg, 0.13 mmol, 1.00 equiv), phosphoroyl trichloride (2 mL). The resulting solution was stirred for 2 h at 110 0C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 38 mg (73%) of the title compound as a gray solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.758 min, LCMS45, m/z = 405 [M+1]. 1H NMR: (300 MHz, Chloroform-d) 5 7.39 (s, 1H), 7.17 (d, J = 13.9 Hz, 2H), 4.30 — 4.12 (m, 4H), 4.02 (s, 3H), 3.82 — 3.61 (m, 2H), 3.49 — 3.34 (m, 1H), 2.83 — 2.51 (m, 6H), 2.32 — 1.68 (m, 10H).

Step 6: Synthesis of 6-methoxy-N-methyl(oxanyl)[3-(pyrrolidin poxy]quinolinamine: Into a 10-mL vial, was placed 2-chloromethoxy(oxanyl)[3- (pyrrolidinyl)propoxy]quinoline (300 mg, 0.74 mmol, 1.00 equiv), MeNHz-HZO (5 g). The resulting solution was stirred for 48 h at 100 0C. The resulting mixture was concentrated under vacuum. The crude product (165.1 mg) was puriﬁed by Prep-HPLC with Method D TFA. This resulted in 165.1 mg (43%) of the title compound triﬂuoroacetic acid as a solid.

Example 152: Synthesis of nd 906 Compound 906: sis of (ZS)(2-meth0xy[[4-methyl (methylamino)pyrimidin-2—yl]amino]phenoxy)(pyrrolidinyl)propanol \NH cl) NH "r1 A9 Cl N r1 NMO NH CINWO NJ\\N C] L 2 ; H 6H TFA,IPA OH Step 1: Synthesis of -(5-aminomethoxyphenoxy)(pyrrolidin yl)propanol: Synthesis as for Compound 1038 starting with (2R)(2-methoxy nitrophenoxymethyl)oxirane and using pyrrolidine in place of azetidine.

] Step 2: Synthesis of (2S)(2-methoxy[[4-methyl (methylamino)pyrimidinyl] phenoxy)-3 -(pyrrolidinyl)propanol: Into a 20-mL bottom ﬂask, was placed (2R)(5-amino methoxyphenoxy)(pyrrolidinyl)propanol (267 mg, 1.00 mmol, 1.00 equiv), 2-chloro- N,6-dimethylpyrimidinamine (157 mg, 1.00 mmol, 0.99 equiv), triﬂuoroacetic acid (342 mg, 3.03 mmol, 3.02 equiv), IPA (10 mL). The resulting on was stirred for 1 h at 8 0C.

The solids were collected by ﬁltration. The crude product was puriﬁed by Prep-HPLC with Method B TFA. This resulted in 12.3 mg of the title compound as a white solid.

Example 153: Synthesis of Compound 1038 Compound 1038: Synthesis of (2R)(azetidinyl)(2-methoxy[[4- methyl(methylamino)pyrimidinyl]amino]phenoxy)propanol "m mm "D "3 Pd/C,H2 w/xo No2 C/NMo N02 5H mm 0‘ HCI3 KIN/30 2 \NH \NH m | HO o CI N 01> "’I FL NJ\\N F TFA,IPA LNMO H Step 1: Synthesis of (2R)—1-(azetidiny1)(2-methoxy nitrophenoxy)propanol: Into a 40-mL round-bottom ﬂask, was placed (2R)(2-methoxy nitrophenoxymethyl)oxirane (1 g, 4.44 mmol, 1.00 equiv), ethanol (10 mL), chloroform (10 mL), azetidine (507 mg, 8.88 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 75 0C in an oil bath. The resulting mixture was concentrated under . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2). This ed in 650 mg (52%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): 4 min, LCMS07 I m/z= 283.15 [M+1].

Step 2: Synthesis of (2R)(5-aminomethoxyphenoxy)—3-(azetidin yl)propanol: Into a 100-mL round-bottom ﬂask, was placed -(azetidinyl)(2- methoxynitrophenoxy)propanol (600 g, 2.13 mol, 1.00 equiv), ethyl acetate (50 mL), Palladium carbon, hydrogen. The resulting solution was d for 1 h at 20 0C. The solids were ﬁltered out. This resulted in the title compound 400 mg (75%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 5min, LCMS15: m/z=253.15 [M+1].

Step 3: Synthesis of (2R)—1-(azetidinyl)(2-methoxy[[4-methy1 (methylamino)pyrimidiny1]amino]phenoxy)propanol: Into a 20-mL round-bottom ﬂask, was placed (2R)(5-amino methoxyphenoxy)—3-(azetidiny1)propanol (400 mg, 1.59 mmol, 1.00 , triﬂuoroacetic acid (538 mg, 4.76 mmol, 3.00 equiv), IPA (8 mL), 2-chloro-N,6- dimethylpyrimidinamine (199 mg, 1.26 mmol, 0.80 equiv). The resulting solution was stirred for 2 h at 80 0C in an oil bath. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. This resulted in 294.3 mg (38%) of the title compound as a triﬂuoroacetic acid as a pink solid.

Example 154: Synthesis of Compound 965 Compound 965: Synthesis of 2-N-[3-([[2-(azetidin yl)ethyl]amino]methyl)meth0xyphenyl]N-methylpyrimidine-2,4—diamine O O/ O/ pb’NOZ N/\/N HzN—\_N:> Raney-Ni H —.©/\N/\/NljH N02 NHZ N/ HN/ mI o w on El DNA/N N \N TFA/IPA Step 1: Synthesis of [2-(azetidinyl)ethyl][(2-methoxy nitrophenyl)methyl]amine: Into a 250-mL round-bottom ﬂask, was placed tidinyl)ethanamine (500 mg, 4.99 mmol, 1.00 equiv), 2-methoxynitrobenzaldehyde (905 mg, 5.00 mmol, 1.00 equiv) in DCE (50 mL) and stirred for 15 min at 25 0C. Then NaBH(OAc)3 (6.36 g) was added and stirred for 2 h at 25 0C. The resulting on was extracted with 3x30 mL of dichloromethane and the organic layers combined and trated under vacuum. This resulted in 500 mg (38%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.726min, LCMS07: m/z = 266 [M+1].

Step 2: sis of 3-((2-(azetidinyl)ethylamino)methyl) ybenzenamine: Into a 100-mL round-bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed Raney-Ni (100 mg), [2-(azetidinyl)ethyl][(2-methoxy- -nitrophenyl)methyl]amine (400 mg, 1.51 mmol, 1.00 equiv), methanol (50 mL). The resulting solution was stirred for 2 h at 25 degrees. The resulting solution was d and concentrated under vacuum. This resulted in 200 mg (56%) of the title compound as yellow Analytical Data: LC-MS: (ES, m/z): RT = 0.285min, : m/z = 236 [M+1].

Step 3: Synthesis of 2-N-[3-([[2-(azetidinyl)ethyl]amino]methyl) methoxyphenyl]N-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom ﬂask, was placed 3-([[2-(azetidin yl)ethyl]amino]methyl)methoxyaniline (100 mg, 0.42 mmol, 1.00 equiv), 2-chloro-N,6- dimethylpyrimidinamine (67 mg, 0.43 mmol, 1.00 equiv), triﬂuoroacetic acid (97 mg, 0.86 mmol, 2.02 equiv), IPA (10 mL). The resulting solution was stirred for 3 h at 80 0C. The resulting solution was extracted with 3X10 mL of dichloromethane and the organic layers combined and concentrated under . The crude product was puriﬁed by Prep-HPLC with Method C NH4HCO3. This resulted in 75.8 mg (52%) of the title compound as a light brown solid.

Example 155: HPLC Methods for Compound Puriﬁcation Method A. Column: IntelFlash-l, C18 silica gel; Detector, UV 254 nm A. Mobile phase, H20/ACN ] A MeOH. Mobile phase, methanol A Grad. (IntelFlash-l): Mobile phase, H20/ACN=100/0 increasing to N=30/70 within 30 min A 1:1. Mobile phase, ACN/H20=1/1 ADCM/MeOH. Mobile phase, DCM/MeOH AEA/PE. Mobile phase, EA/PE ] Method B. Column, XBridge Prep C18 OBD Column, 30x100mm,5um; Detector, UV 254 nm B HCl. Mobile phase, Water (0.05% HCl) and ACN (Gradient) B TFA. Mobile phase, Water (0.05% TFA) and ACN (Gradient) Method C. Column, SunFire Prep C18 OBD Column, 19x150mm 5um 10nm; Detector, UV 254/220nm C HCl. Mobile phase, Water (0.05% HCl) and ACN (Gradient) C TFA. Mobile phase, Water (0.1% TFA) and CAN (Gradient) C NH3. Mobile phase, Water (0.05% NH3-H20) and ACN (Gradient) C. NH4HCO3. Mobile Phase, Water with 10mmol NH4HCO3 and ACN (Gradient) WO 81177 ] Method D. Column, XSelect CSH Prep C18 OBD Column, 19x250mm, 5um; Detector, uv 254nm D HCl. Mobile phase, Water (0.05% HCl) and ACN (Gradient); D TFA. Mobile phase, Water (0.06% TFA) and ACN (Gradient); Detector 254 nm.

D NH3. Mobile phase, Water (0.05% NH3-Hﬁ20) and ACN (20.0% ACN up to 60.0% in 7 min), Detector, UV 220nm ] D NH4HCO3. Mobile Phase, Water with 10mmol NH4HCO3 and CAN (Gradient) Method E. Column: X Select C18, 19x150 mm, 5 um; Mobile Phase A: Water/0.05% HCl, Mobile Phase B: ACN; Detector 254 nm.

Method F. Column: X Bridge RP, 19x150 mm, 5 um; Detector 254 nm.

F HCl. Mobile phase Water (0.05% HCl) and ACN (Gradient) F TFA. Mobile phase Water (0.05% TFA) and ACN (Gradient) Method G. Column: GeminisoNX C18 AXAI Packed, 21.2x150mm 5um; or, UV 254nm.

G HCl Mobile phase, Water (0.05% HCl) and ACN (3.0% ACN up to 10.0% in 10 min) GNH4HCO3. Mobile Phase, Water with 10mmol NH4HCO3 and ACN (Gradient) Method H. : Sunfire Prep C18 OBD Column, 10um, 19x250mm; Mobile phase, Water (0.05% HCl) and methanol (3.0% methanol-up to 20.0% in 8 min); Detector, UV 254nm.

Method Chiral IC. Column: Chiralpak IC, 2x25cm, 5um; Mobile phase, Hex0.1%DEA- and IPA- (hold 25.0% IPA- in 21 min); Detector, UV 220/254nm.

Method Chiral ID. Column: Chiralpak ID-2, 2x25cm, 5um; Mobile phase, Hex(0.1%DEA)- and ethanol- (hold 50.0% ethanol- in 14 min); or, UV 220/254nm Method Chiral IB4. Column: Chiralpak IB4.6x250,5umHPLC Chiral- A(IB)0011BO0CE-LA026; Mobile phase, Hex (0.1%DEA):EtOH=50:50; Detector, 254nm Method Chiral IF. Column: PAK IF, 2x25cm,5um; Mobile phase, Hex(0.2%DEA)- and IPA- (hold 30.0% IPA- in 22 min); Detector, UV 220/254nm Other compounds were synthesized in the similar manner and the terization data are listed in Tables IA and IB below.

Table IA de Data l LC-MS: (ES, m/z): RT = 1.224 min, LCMS: m/z = 358.20 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.71 (s, 1H), 7.48 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H), 2.67 — 2.69 (m, 4H), 2.07 — 2.02(m, 2H), 1.86 — 1.85 (m, 4H).

LC-MS: (ES, m/z): RT = 1.035 min, LCMS: m/z = 505 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.35 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.12 = 6.0 Hz, 2H), 3.82 (s, 3H), 3.34 — 5.84 (m, 2H), 4.10 (t, J — 3.33 (m, 2H), 3.00 — 2.97 (m, 2H), 2.82 — 2.69 (m, 8H), 2.20 (t, J = 9.6 Hz, 2H), 2.09 — 2.05 (m, 2H), 1.89 — 1.86 (m, 4H), 1.78 — 1.75 (m, 2H), 1.70 — 1.60 (m, 1H), 1.35 (q, J = 3.2 Hz, 2H).

LC-MS: (ES, m/z): RT = 1.124rnin, LCMS: m/z = 442 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.36 (s, 1H), 7.13 (d, J = 8.7Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.97 (d, J = 1.9 Hz, 2H), 3.83 (s, 3H), 3.49 — 3.34 (m, 4H), 2.77 — 2.72 (m, 2H), 2.72 — 2.64 (m, 4H), 2.14 — 1.98 (m, 2H), 2.00 — 1.78 (m, 5H), 1.77 — 1.65 (m, 2H), 1.44 — 1.23 (m, 2H).

LC-MS: (ES, m/z): RT = 1.367 min, LCMS: m/z = 523 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.68 (d, J = 6.1 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.19 — 7.15 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.33 — 3.32 (m, 2H), 3.15 — 2.97 (m, 10H), 2.37 — 2.30 (m, 2H), 2.22 — 2.15 (m, 2H), 2.03 — 1.98 (m, 4H), 1.76 — 1.66 (m, 2H), 1.63 — 1.62 (m, 1H), 1.39 — 1.30 (m, 2H).

LC-MS: (ES, m/z): RT = 1.115 min, LCMS: m/z = 428 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.71 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 — 4.07 (m, 3H), 3.99 — 3.82 (m, 2H), 3.83 (s, 3H), 3.57 — 3.50 (m, 2H), 2.81 — 2.71 (m, 2H), 2.66 — 2.65 (m, 4H), 2.12 — 1.93 (m, 4H), 1.92 — 1.80 (m, 4H), 1.57 (m, 2H).

LC-MS: (ES, m/z): RT = 1.321 min, LCMS: m/z = 400.3 [M-HCl+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.53 (d, J = 7.3 Hz, 1H), 7.13 — 6.99 (m, 3H), 6.19 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.87 — 3.78 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.18 (dt, J = 12.2, 7.2 Hz, 2H), 2.40 — 2.29 (m, 2H), 2.28 — 2.16 (m, 2H), 2.15 — 2.04 (m, 2H), 1.45 (s, 9H).

LC-MS: (ES, m/z): RT = 1.013 min, LCMS: m/z = 441 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.52 (d, J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.02 (d, J = 8.7 Hz, 2H), 6.13 (d, J = 6.9 Hz, 1H), 4.11 (t, J = 5.7 Hz, 2H), 3.79 (s, 3H), 3.63 — 3.62 (m, 2H), 3.35 — 3.20 (m, 6H), 3.06 — 2.97 (m, 2H), 2.81 — 2.80 (m, 2H), 2.19 — 2.04 (m, 4H), 2.01 — 1.84 (m, 5H), 1.36 — 1.18 (m, 2H).

LC-MS: (ES, m/z): RT = 1.43 min, LCMS: m/z = 487 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.77 (s, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.33 — 7.17 (m, 2H), 5.99 (d, J = 6.0 Hz, 1H), 4.53 (d, J = 13.3 Hz, 1H), 4.17 (t, J = 5.8 Hz, 2H), 3.94 (d, J = 13.7 Hz, 1H), 3.19 — 2.93 (m, 7H), 2.72 — 2.57 (m, 1H), 2.19 — 2.12 (m, 2H), 2.10 (s, 3H), 2.02 — 1.76 (m, 8H), 1.34 — 1.07 (m, 2H).

LC-MS: (ES, m/z): RT= 1.976 min, LCMS: m/z = 386 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.77 (s, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 6.0 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 2.90 (s, 3H), 2.73 (d, J = 7.5 Hz, 2H), 2.63 — 2.60 (m, 4H), 2.07 — 2.02 (m, 2H), 1.86 — 1.81 (m, 4H).

LC-MS: (ES, m/z): RT =1.509 min, LCMS: m/z = 440 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.57 (d, J = 6.2 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.95 — 6.92 (m, 1H), 6.85 — 6.82 (m, 1H), 6.11 (d, J = 6.4 Hz, 1H), 5.92 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.24 — 3.21 (m, 2H), 3.02 (d, J = 6.4 Hz, 2H), 2.86 — 2.74 (m, 8H), 2.11 — 2.04 (m, 2H), 1.93 — 1.80 (m, 7H), 1.35 — 1.29 (m, 2H). 11 LC-MS: (ES, m/z): RT = 1.776 min, LCMS: m/z = 440 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.58 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 9.6 Hz, 1H), 6.85 — 6.83 (m, 2H), 6.38 (d, J = 5.2 Hz, 1H), 6.11 (d, J = 5.2 Hz, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.60 — 3.58 (m, 2H), 3.33 — 3.28 (m, 4H), 3.13 — 3.00 (m, 4H), 2.91 — 2.72 (m, 2H), 2.20 — 1.97 (m, 4H), 1.90 — 1.85 (m, 5H), 1.42 — 1.23 (m, 2H). 12 LC-MS: RT= 0.918 min, LCMS: m/z = 442.30 [M+1]. 1H NMR (300 MHz, Deuten‘um Oxide, ppm) 5: 8.28 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 7.0, 2.5 Hz, 1H), 7.00 (s, 1H), 4.46 (s, 2H), 4.28 (t, J = 5.6 Hz, 2H), 4.02 (dd, J = 11.8, 4.6 Hz, 2H), 3.90 (s, 3H), 3.72—3.51 (m, 3H), 3.50-3.30 (m, 4H), 3.10-2.97 (m, 2H), 2.24-2.22 (m, 2H), 2.10-2.05 (m, 4H), 1.95-1.91 (m, 2H), 1.72-1.67 (m, 2H). 13 LC-MS: RT: 1.19 min, LCMS: m/z = 496.30 [M+1]. 1H-NMR (400 MHz, Chloroform—d, ppm) 5: 7.88 (d, J = 5.7 Hz, 1H), 6.90 — 6.79 (m, 2H), 6.75 (dd, J = 8.5, 2.4 Hz,1H), 6.11 (dd, J = 57,19 Hz,1H), 5.94 — 5.74 (m, 2H), 4.61 (d, J = 13.5 Hz, 1H), 4.07 (t, J = 6.7 Hz, 2H), 3.88 (s, 3H), 3.82 — 3.79 (m, 1H), 3.49 (dd, J = 14.2, 7.4 Hz, 1H), 3.35 (dd, J = 14.2, 7.0 Hz, 1H), 2.98 (s, 4H), 2.65 (t, J = 7.3 Hz, 2H), 2.60 — 2.39 (m, 5H), 2.09 (s, 5H), 2.03 — 2.01 (m, 1H), 1.84 — 1.60 (m, 6H), 1.21 — 1.15 (m, 2H). 14 LC-MS: (ES, m/z): RT = 2.434 min, LCMS: m/z = 484 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 9.29 (s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.20 (d, J = 5.6 Hz, 1H), 4.43— 4.38 (m, 1H), 4.20 (d, J = 6.6 Hz, 2H), 3.98 (t, J = 6.3 Hz, 2H), 3.86 — 3.73 (m, 1H), 3.71 (s, 3H), 3.07 — 2.99 (m, 1H), 2.56 — 2.52 (m, 2H), 2.50 — 2.42 (m, 5H), 1.98 (s, 4H), 1.88 — 1.83 (m, 2H), 1.79 — 1.66 (m, 6H), 1.29 — 1.06 (m, 2H).

LC-MS: (ES, m/z): RT = 0.957 min, LCMS: m/z = 457 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.90 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.03 — 6.99 (m, 1H), 6.81 (d, J = 8.7 Hz, 2H), 5.80 (d, J = 5.7 Hz, 1H), 4.92 (br s, 1H), 4.18 — 4.13 (m, 1H), 4.12 — 4.01 (t, J = 1.5 Hz, 2H), 3.83 (s, 3H), 3.22 — 3.21 (m, 2H), 3.14 — 3.10 (m, 2H), 2.82 — 2.54 (m, 10H), 1.79 — 1.67 (m, 7H), 1.30 — 1.16 (m, 2H). 16 LC-MS: (ES, m/z): RT = 1.423 min, LCMS: m/z = 457 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.72 (d, J = 4.4 Hz, 4H), 3.32 — 3.35 (m, 2H), 3.16 — 3.09 (m, 2H), 2.68 — 2.49 (m, 8H), 2.02 — 1.99 (m, 2H), 1.85 — 1.77 (m, 3H), 1.24 — 1.12 (m, 2H). 17 LC-MS: (ES, m/z): RT = 2.234 min, LCMS: m/z = 439 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 3.30 —3.28 (m, 2H), 3.13 — 3.10 (m, 2H), 2.92 — 2.87 (m, 4H), 2.66 — 2.60 (m, 4H), 2.07 — 2.05 (m, 1H), 1.85 — 1.79 (m,5H), 1.79 — 1.57 (m, 4H), 1.26 — 1.15 (m, 4H). 18 LC-MS: (ES, m/z): RT = 1.13 min, LCMS: m/z = 469 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.48 (d, J = 13.3 Hz, 1H), 4.02 — 3.85 (m, 3H), 3.81 (s, 3H), 3.16 — 2.99 (m, 1H), 2.85-2.46 (m, 7H), 2.40 (s, 3H), 2.21 — 1.58 (m, 9H), 1.32 — 1.00 (m, 2H). 19 LC-MS: (ES, m/z): RT = 2.264 min, LCMS: m/z = 497 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.34 (s, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.67 (s, 1H), 5.69 (s, 1H), 4.76 (s, 1H), 4.67 — 4.62 (m, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.81— 3.97 (m, 4H), 3.24 (s, 2H), 3.06 — 2.97 (m, 1H), 2.69 (s, 2H), 2.69 — 2.45 (m, 4H), 2.24 (s, 3H), 2.13 — 2.03 (m, 5H), 1.81 — 1.63 (m, 7H), 1.20— 1.88 (m, 2H). 1H NMR (300 MHz, Methanol-d4) 5 7.74 — 7.65 (m, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.94 — 6.84 (m, 1H), 5.93 — 5.84 (m, 1H), 4.23 (d, J = 9.8 Hz, 1H), 4.08 (d, J = 6.8 Hz, 2H), 3.82 (s, 3H), 2.77 (t, J = 7.7 Hz, 2H), 2.66 — 2.64 (m, 4H), 2.14 — 1.94 (m, 2H), 1.91 — 1.81 (m, 4H), 1.39 — 1.02 (m, 6H).

LC-MS: (ES, m/z): RT = 0.801 min, LCMS: m/z = 434 [M+H]. 1H NMR (400 MHz, ol-d4) 5 7.62 (d, J = 7.2 Hz, 1H), 7.42 — 7.27 (m, 5H), 7.17 (s, 1H), 7.10 — 6.96 (m, 2H), 6.24 (d, J = 7.3 Hz, 1H), 4.69 (s, 2H), 4.03 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.82 — 3.77 (m, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.17 — 3.10 (m, 2H), 2.24 — 2.17 (m, 4H), 2.10 — 2.05 (m, 2H).

LC-MS: (ES, m/z): RT = 1.160 min, LCMS: m/z = 416 [M+H]. 1H NMR (400 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.40 (s, 1H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.80 (s, 3H), 3.46 (t, J = 6.1 Hz, 4H), 3.32 (s, 3H), 2.72 — 2.63 (m, 2H), 2.62 — 2.52 (m, 4H), 2.07 — 1.95 (m, 2H), 1.91 — 1.75 (m, 6H). 23 LC-MS: (ES, m/z): RT = 0.643 min, LCMS: m/z = 435 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 8.59 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.70 — 7.64 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.23 — 7.19 (m, 1H), 7.01 — 6.97 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.75 (br s, 1H), 5.93 (d, J = 5.7 Hz, 2H), 4.70 (d, J = 4.8 Hz, 2H), 4.11 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 2.69 — 2.66 (m, 2H), 2.58-2.54 (m, 4H), 2.16 — 2.02 (m, 2H), 1.80 — 1.76 (m, 4H). 24 LC-MS: (ES, m/z): RT = 1.016 min, LCMS: m/z = 435 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.52 — 8.43 (m, 2H), 7.78 (d, J = 6.0 Hz, 1H), 7.42 — 7.39 (m, 2H), 7.23 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.02 (d, J = 5.7 Hz, 1H), 4.68 (s, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 2.70 — 2.65 (m, 6H), 2.04 — 1.94 (m, 2H), 1.91 — 1.88 (m, 4H).

LC-MS: (ES, m/z): RT = 0.528 min, LCMS: m/z = 435 [M+1]. 1H NMR (400 MHz, ol-d4) 5 8.55 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.42 — 7.39 (m, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 4.67 (s, 2H), 3.99 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 2.79 — 2.72 (m, 6H), 2.04 — 1.99 (m, 2H), 1.94 — 1.82 (m, 4H).

LC-MS: (ES, m/z): RT = 1.301 min, LCMS: m/z = 464 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.75 (d, J = 6.0 Hz, 1H), 7.50 (s, 1H), 7.27-7.23 (t, J = 8.1 Hz, 1H), 6.95 — 6.93 (m, 3H), 6.86 — 6.81 (m, 2H), 5.97 (d, J = 4.0 Hz, 1H), 4.62 (s, 2H), 3.92 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.61 (m, 6H), 1.95 (q, J = 7.2 Hz, 2H), 1.87 — 1.80 (m, 4H). 27 LC-MS: (ES, m/z): RT = 1.674 min, LCMS: m/z = 402 [M+1]. 1H NMR (400 MHz, Chloroform—d) 5 7.92 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.03 — 7.01 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.74 (s, 1H), 5.85 (d, J = 5.6 Hz, 1H), 5.06 (br s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.58 (s, 4H), 3.41 (s, 3H), 2.67 (t, J = 7.6 Hz, 2H), 2.55 (br s, 4H), 2.14 — 2.07 (m, 2H), 1.81 — 1.77 (m, 4H).

LC-MS: (ES, m/z): RT = 0.799 min, LCMS: m/z = 464 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.73 (d, J = 6.0 Hz, 1H), 7.56 (br s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.96 — 6.85 (m, 4H), 5.95 (d, J = 6.0 Hz, 1H), 4.58 (s, 2H), 3.92 (d, J = 6.4 Hz, 2H), 3.80 (d, J = 6.4 Hz, 6H), 2.60 — 2.58 (m, 6H), 1.94 (q, J = 7.6 Hz, 2H), 1.85 — 1.82 (m, 4H).

LC-MS: (ES, m/z): RT = 0.991 min, LCMS: m/z = 483 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.61 (d, J = 5.2 Hz, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.19 (d, J = 7.2 Hz, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.51 — 3.46 (m, 9H), 3.41 — 3.32 (m, 2H), 3.06 — 2.99 (m, 2H), 2.31 — 2.25 (m, 2H), 2.15 (s, 4H), 2.10 — 1.95 (m, 3H), 1.62 (, J = 7.6 Hz, 2H), 1.36 (d, J = 6.6 Hz, 6H).

LC-MS: (ES, m/z): RT = 1.999 min, LCMS: m/z = 438 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.93 (d, J = 1.5 Hz, 1H), 7.61 (s, 1H), 7.45 — 7.32 (m, 2H), 7.02 (d, J = 2.5 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.74 (br s, 1H), 5.83 (d, J = 5.7 Hz, 1H), 4.86 (br s, 1H), 4.42 (d, J = 5.1 Hz, 2H), 4.07 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.63 — 2.61 (m, 2H), 2.58 — 2.52 (m, 4H), 2.11 — 2.02 (m, 2H), 1.82 — 1.73 (m, 4H).

LC-MS: (ES, m/z): RT = 1.492 min, LCMS: m/z = 474 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.82 (d, J = 6.0 Hz, 1H), 7.55 — 7.52 (m, 2H), 7.28 (s, 1H), 7.25 — 7.21 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.4Hz, 1H), 6.07 (d, J = 6.0 Hz, 1H), 4.87 (s, 2H), 3.83 (d, J = 5.6 Hz, 2H), 3.75 (s, 3H), 2.60 — 2.56 (m, 6H), 1.87 — 1.82 (m, 6H). 32 LC-MS: (ES, m/z): RT = 1.175 min, LCMS: m/z = 455 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.88 (d, J = 5.7 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.05 — 6.91 (m, 2H), 6.82 (d, J = 9.0 Hz, 1H), 5.83 (d, J = 6.0 Hz, 1H), 5.02 (br s, 1H), 4.11 (t, J = 3.0 Hz, 2H), 3.83 (s, 3H), 3.26 — 3.24 (m, 2H), 2.99 — 2.91 (m, 8H), 2.36 (s, 3H), 2.24 — 2.19 (m, 2H), 2.17 — 2.01 (m, 2H), 1.90 — 1.94 (m, 4H), 1.80 — 1.76 (m, 2H), 1.65 — 1.49 (m, 1H), 1.49 — 1.25 (m, 2H). 33 LC-MS: (ES, m/z): RT = 5.231 min, LCMS: m/z = 517 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.70 (s, 1H), 7.38 (s, 1H), 7.25 — 7.21 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.90 — 6.82 (m, 2H), 5.94 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.71 — 3.68 (m, 2H), 3.43 — 3.35 (m, 2H), 2.85 — 2.81 (m, 2H), 2.73 — 2.66 (m, 6H), 2.11 (q, J = 6.0 Hz, 2H), 1.91 — 1.87 (m, 6H), 1.81 — 1.80 (m, 1H), 1.48 — 1.41 (m, 2H).

LC-MS: (ES, m/z): RT = 1.313 min, LCMS: m/z = 426.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.74 — 7.65 (m, 1H), 7.43 (s, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.1 Hz, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 3.34 — 3.30 (m, 2H), 2.78 — 2.56 (m, 6H), 2.30 — 2.16 (m, 1H), 2.13 — 1.97 (m, 2H), 1.93 — 1.53 (m, 10H),1.36 — 1.22 (m, 2H).

LC-MS: (ES, m/z): RT = 1.203 min, LCMS: m/z = 398.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.71 (d, J = 5.8 Hz, 1H), 7.44 (s, 1H), 7.07 (dd, J = 8.6, 2.5 Hz, 1H), 6.95 — 6.84 (m, 1H), 5.95 — 5.80 (m, 1H), 4.50 (br s, 1H), 4.12 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 2.75 - 2.64 (m, 6H), 2.42 — 2.34 (m, 2H), 2.10 — 1.94 (m, 5H),1.90 — 1.81 (m, 5H). 36 LC-MS: (ES, m/z): RT = 0.843 min, LCMS: m/z = 464 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.27 — 7.22 (m, 2H), 7.00 — 6.81 (m, 4H), 5.96 (d, J = 6.0 Hz, 1H), 4.60 (s, 2H), 3.96 (t, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 2.76 — 2.70 (m, 6H), 2.02 — 1.95 (m, 2H), 1.93 — 1.83 (m, LC-MS: (ES, m/z): RT = 1.015 min, LCMS: m/z = 449 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.45 — 8.35 (m, 2H), 7.70 (t, J = 6.8 Hz, 2H), 7.41 — 7.30 (m, 2H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.89 (d, J = 6.0 Hz, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.66 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.79 — 2.66 (m, 6H), 2.16 — 1.78 (m, 6H).

LC-MS: (ES, m/z): RT = 1.008 min, LCMS: m/z = 429.10 [M-HC1+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.84 — 7.70 (m, 1H), 7.20 (s, 1H), 7.16 — 7.02 (m, 2H), 6.24 (d, J = 7.2 Hz, 1H), 4.25 (t, J = 5.4 Hz, 2H), 3.94 (s, 3H), 3.90 — 3.83 (m, 2H), 3.64 (dd, J = 6.6, 5.0 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.45 (dd, J = 6.6, 5.0 Hz, 2H), 3.26 — 3.08 (m, 2H), 2.41 — 2.19 (m, 4H), 2.19 — 2.05 (m, 2H), 1.90 (s, 3H).

LC-MS: (ES, m/z): RT = 1.005 min, LCMS: m/z = 449 [M-HC1+1]. 1H NMR (400 MHz, Deuterium Oxide) 5 8.36 (d, J = 5.7 Hz, 2H), 7.61 (d, J = 5.9 Hz, 2H), 7.42 (d, J = 7.3 Hz, 1H),7.11— 6.87 (m, 3H), 6.04 (d, J = 7.3 Hz, 1H), 4.05 (t, J = 5.7 Hz, 2H), 3.82 (s, 3H), 3.74 — 3.58 (m, 4H), 3.31 (t, J = 7.5 Hz, 2H), 3.14 — 2.88 (m, 4H), 2.22 — 1.81 (m, 6H).

LC-MS: (ES, m/z): RT = 1.421 min, LCMS: m/z = 464.3 [M-HC1+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.65 — 7.60 (m, 1H), 7.29 (t, J = 7.7 Hz, 2H), 7.24 — 7.20 (m, 1H), 7.08 — 7.01 (m, 2H), 6.97 — 6.94 (m, 3H), 6.26 (d, J = 6.8 Hz, 1H), 4.19 — 4.16 (m, 4H), 3.89 — 3.80 (m, 5H), 3.80 (t, J = 8.9 Hz, 2H), 3.44 (d, J = 6.6 Hz, 2H), 3.17 — 3.07 (m, 2H), 2.22 — 2.01 (m, 4H), 2.07 (d, J = 5.9 Hz, 2H). 41 LC-MS: (ES, m/z): RT = 1.414 min, LCMS: m/z = 415 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.93 (d, J = 5.7 Hz, 1H), 7.40 (s, 1H), 6.92 — 6.89 (m, 1H), 6.88 — 6.76 (m, 2H), 6.57 (br s, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.41 (br s, 1H), 4.15 (t, J = 6.4 Hz, 2H), 4.08 (d, J = 5.2 Hz, 2H), 3.84 (s, 3H), 2.80 — 2.67 (m, 9H), 2.19 (q, J = 6.9 Hz, 2H), 1.86 — 1.84 (m, 4H).

LC-MS: (ES, m/z): RT = 1.67 min, LCMS: m/z = 416.25 [M-HC1+1]. 1H NMR (300 MHz, ium Oxide) 5 7.64 — 7.40 (m, 1H), 7.09 — 6.93 (m, 3H), 6.14 (d, J = 7.3 Hz, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.73 — 3.57 (m, 2H), 3.46 — 3.26 (m, 4H), 3.13 — 2.95 (m, 2H), 2.24 — 2.02 (m, 4H), 2.02 — 1.82 (m, 2H), 1.17 (s, 6H).

LC-MS: (ES, m/z): RT = 1.105 min, LCMS: m/z = 479 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.76 (d, J = 6.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 6.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.95 (d, J = 5.6 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.84 — 3.81 (m, 5H), 3.34 — 3.29 (m, 2H), 2.81 (s, 6H), 2.72 (t, J = 6.0 Hz, 2H), 2.61 (d, J = 6.4 Hz, 4H), 2.08 — 2.01 (m, 2H), 1.85 — 1.83 (m, 4H).

LC-MS: (ES, m/z): RT = 1.063 min, LCMS: m/z = 457.15 [M-HC1+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.62 (t, J = 6.8 Hz, 1H), 7.20 — 7.05 (m, 3H), 6.26 — 6.16 (m, 1H), 4.21 (q, J = 5.5 Hz, 2H), 3.94 — 3.81 (m, 5H), 3.51 — 3.42 (m, 6H), 3.22 — 3.12 (m, 2H), 3.05 (s, 2H), 2.89 (s, 1H), 2.34 — 2.20 (m, 4H), 2.15 — 2.01 (m, 5H), 1.95 — 1.84 (m, 2H).

LC-MS: (ES, m/z): RT = 2.140 min, LCMS: m/z = 456.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.08 — 7.01 (m, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.47 (br s, 2H), 2.76 (t, J = 7.8 Hz, 2H), 2.67 — 2.65 (m, 4H), 2.11 — 2.00 (m, 2H), 1.89 — 1.79 (m, 4H), 1.68 — 1.45 (m, 9H), 1.39 — 1.21 (m, 1H).

LC-MS: (ES, m/z): RT = 1.146 min, LCMS: m/z = 424.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.75 (d, J = 6.0 Hz, 1H), 7.60 — 7.54 (m, 2H), 7.00 (d, J = 8.6, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.98 (d, J = 6.0, 1H), 4.66 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.81 (s, 3H), 2.78 — 2.59 (m, 6H), 2.01 - 1.86 (m, 6H). 47 LC-MS: (ES, m/z): RT = 1.135 min, LCMS: m/z = 483 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.90 (d, J = 5.7 Hz, 1H), 7.25 (d, J = 5.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 5.82 (d, J = 5.7 Hz, 1H), 4.85 (br s, 1H), 4.67 — 4.62 (m, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.83 — 3.80 (m, 4H), 3.26 — 3.25 (m, 2H), 3.07 — 2.98 (m, 1H), 2.72 — 2.50 (m, 7H), 2.17 — 2.02 (m, 5H), 1.83 — 1.76 (m, 7H), 1.24 — 1.12 (m, 2H). 48 LC-MS: (ES, m/z): RT = 1.203 min, LCMS: m/z = 483 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.69 (s, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.53 — 7.50 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.57 (s, 2H), 4.49 — 4.48 (m, 1H), 3.92 — 3.89 (m, 1H), 3.83 (s, 3H), 3.70 (t, J = 5.6 Hz, 2H), 3.45 — 3.30 (m, 2H), 3.12 — 3.06 (m, 1H), 2.88 — 2.85 (m, 2H), 2.79 — 2.72 (m, 4H), 2.64 — 2.62 (m, 1H), 2.09 (s, 3H), 1.89 — 1.95 (m, 1H), 1.92 — 1.77 (m, 6H), 1.25 — 1.12 (m, 2H).

LC-MS: (ES, m/z): RT = 1.815 min, LCMS: m/z = 458.2 [M-HC1+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.62 (d, J = 7.0 Hz, 1H), 7.18 — 7.06 (m, 3H), 6.30 (d, J = 6.9 Hz, 1H), 4.27 — 4.18 (m, 2H), 3.91 (s, 3H), 3.85 — 3.66 (m, 6H), 3.58 (s, 2H), 3.49 (d, J = 6.7 Hz, 2H), 3.19 (d, J = 8.9 Hz, 2H), 2.38 — 2.15(m, 4H), 2.13 — 2.05 (m, 2H), 1.72 — 1.62 (m, 2H), 1.54 — 1.48 (m, 2H).

LC-MS: (ES, m/z): RT = 1.314 min, LCMS: m/z = 426.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.66 (d, J = 6.1 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 6.1 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.91 — 3.82 (m, 4H), 2.81 (t, J = 7.7 Hz, 2H), 7.73 — 7.71 (m, 4H), 2.14 — 1.96 (m, 4H), 1.93 — 1.75 (m, 6H), 1.69 - 1.59 (m, 1H), 1.51 — 1.16 (m, 5H). 51 LC-MS: (ES, m/z): RT = 1.020 min, LCMS: m/z = 471 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.77 (d, J = 5.6 Hz, 1H), 7.18 (s, 1H), 7.14 — 7.11 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.04 (d, J = 6.0 Hz, 1H), 4.26 (s, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.84 — 3.67 (m, 4H), 3.59 — 3.53 (m, 4H), 2.95 — 2.91 (m, 2H), 2.86 — 2.76 (m, 4H), 2.14 — 2.07 (m, 2H), 1.96 — 1.93 (m, 4H). 52 LC-MS: (ES, m/z): RT = 1.220 min, LCMS: m/z = 491 [M+1]. 1H NMR (400 MHz, form—d) 5 7.86 (d, J = 5.6 Hz, 1H), 7.51 — 7.42 (m, 3H), 7.26 — 7.24 (m, 2H), 7.08 — 7.05 (m, 1H), 6.93 (br s, 1H), 6.69 — 6.65 (m, 2H), 5.84 (br s, 1H), .72 (t, J = 4.4 Hz, 1H), 4.02 (t, J = 6.8 Hz, 2H), 3.85 (s, 5H), 3.33 (s, 3H), 2.64 (t, J = 7.6 Hz, 2H), 2.52 — 2.50 (m, 4H), 2.09 — 2.02 (m, 2H), 1.81 — 1.77 (m, 4H).

LC-MS: (ES, m/z): RT = 1.189 min, LCMS: m/z = 436.3 [M-HC1+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.66 (dd, J = 7.4, 2.8 Hz, 1H), 7.49 (d, J = 10.5 Hz, 1H), 7.26 — 6.87 (m, 3H), 6.23 (d, J = 7.5 Hz, 1H), 4.53 (d, J = 7.3 Hz, 4H), 4.09 — 3.98 (m, 2H), 3.78 — 3.58 (m, 5H), 3.38 — 3.28 (m, 2H), 3.12 — 2.96 (m, 2H), 2.21 — 1.89 (m, 6H). 54 LC-MS: (ES, m/z): RT = 1.12 min, LCMS: m/z = 469 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.71 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.51 - 4.42 (m, 1H), 4.10 — 4.06 (m, 3H), 3.98 —3.84 — 3.82 (m, 1H), 3.81 (s, 3H), 3.29 — 3.20 (m, 1H), 2.97 — 2.84 (m, 1H), 2.81 — 2.54 (m, 6H), 2.19 — 1.97 (m, 7H), 1.88 — 1.72 (m, 4H), 1.54 — 1.32 (m, 2H). 55 LC-MS: (ES, m/z): RT = 1.152 min, LCMS: m/z = 497 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.56 (s, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 4.49 — 4.46 (m, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.90 — 3.88 (m, 1H), 3.81 (s, 3H), 3.46 — 3.35 (m, 2H), 3.06 (t, J = 5.6 Hz, 1H), 2.72 (t, J = .6 Hz, 2H), 2.65 — 2.62 (m, 5H), 2.09 (s, 3H), 2.07 — 2.00 (m, 3H), 1.97 (s, 3H), 1.84 — 1.77 (m, 6H), 1.23 — 1.11 (m, 2H).

LC-MS: (ES, m/z): RT = 1.34 min, LCMS: m/z = 449 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.50 (d, J = 1.6 Hz, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.35 — 7.28 (m, 2H), 7.26 (br s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.18 (d, J = 6.1 Hz, 1H), 4.93 — 4.90 (m, 2H), 3.99 — 3.95 (m, 2H), 3.82 (s, 3H), 3.25 — 3.11 (m, 9H), 2.15 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT = 1.18 min, LCMS: m/z = 487.3 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.90 (d, J = 5.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.7 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 6.98 (br s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.81 (d, J = 5.9 Hz, 1H), 5.21 — 4.91 (m, 2H), 4.68 - 4.61 (m, 1H), 4.55 (s, 2H), 3.90 — 3.62 (m, 6H), 3.55 (t, J = 5.5 Hz, 2H), 3.29 - 3.13 (m, 4H), 3.11 — 2.95 (m, 1H), 2.74 (t, J = 5.4 Hz, 2H), 2.54 - 2.41 (m, 1H), 2.09 (s, 3H), 1.85 — 1.75 (m, 3H), 1.19 - 1.15 (m, 2H).

LC-MS: (ES, m/z): RT = 1.88 min, LCMS 07: m/z = 414 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 8.00 (d, J = 6.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 6.96 — 6.91 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.75 (s, 1H), 5.96 (d, J = 6.0 Hz, 1H), 4.07 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.78 — 3.70 (m, 4H), 3.61 — 3.44 (m, 4H), 3.66 — 3.64 (m, 2H), 3.54 — 3.62 (m, 4H), 2.12 — 2.05 (m, 2H), 1.78 — 2.03 (m, 4H).

LC-MS: (ES, m/z): RT = 1.245 min, LCMs28: m/z = 510.35 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.57 (d, J = 2.4 Hz, 1H), 7.27 — 7.26 (m, 1H), 6.98 — 6.92 (m, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.63 (s, 1H), 4.84 (s, 1H), 4.54 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 3.52 — 3.42 (m, 4H), 3.26 — 3.10 (m, 4H), 2.85 — 2.60 (m, 8H), 2.24 — 2.17 (m, 2H), 2.01 — 1.93 (m, 4H), 1.94 — 1.57 (m, 7H), 1.39 — 1.27 (m, 2H).

LC-MS: (ES, m/z): RT=1.410 min, LCMs15: m/z = 441 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.32 (d, J = 5.1 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.29 — 7.16 (m, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 2H), 3.24 — 3.20 (m, 2H), 2.90 — 2.71 (m, 9H), 2.14 — 2.02 (m, 4H), 1.97 — 1.87 (m, 4H), 1.54 — 1.38 (m, 2H).

LC-MS: (ES, m/z): RT = 0.645 min, LCMS48: m/z = 410.3 [M+1]. 1H NMR (400 MHZ, Methanol-d4) 5 7.78 — 7.70 (m, 2H), 7.59 (d, J = 7.2 HZ, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 7.2 Hz, 1H), 3.72 — 3.69 (m, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.50 — 3.42 (m, 3H), 3.42 — 3.40 (m, 1H), 340 — 3.30 (m, 2H), 3.03 — 2.97 (m, 2H), 2.05 — 1.94 (m, 3H), 1.56 — 1.47 (m, 2H).

LC-MS: (ES, m/z): RT = 1.477 min, LCMS 15: m/z = 483 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.34 (s, 1H), 7.25 (s, 1H), 7.17 — 7.15 (m, 3H), 4.70 (s, 3H), 4.25 (t, J = 5.6 Hz, 2H), 4.13 — 4.12 (m, 1H), 3.93 (s, 3H), 3.85 — 3.80 (m, 2H), 3.65 (s, 1H), 3.49(t, J = 7.2 Hz, 2H), 3.34 — 3.14 (m, 4H), 2.80 — 2.65 (m, 1H), 2.34 — 2.26 (m, 3H), 2.24 — 2.18 (m, 2H), 2.07 (s, 3H), 2.12 — 2.07 (m, 2H), 1.76 (s, 1H), 1.60 (s, 1H).

LC-MS: (ES, m/z): RT = 1.712 min, LCMS 07: m/z = 442 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.31 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.98 — 3.95 (m, 2H), 3.83 (d, J = 9.8 Hz, 5H), 3.44 (t, J = 2.0 Hz, 2H), 2.93 — 2.84 (m, 2H), 2.80 — 2.75 (m, 5H), 2.17 — 2.05 (m, 2H), 1.98 — 1.85 (m, 6H), 1.51— 1.42 (m, 2H).

LC-MS: (ES, m/z): RT = 1.45 min, LCMS 33: m/z = 441 [M+1]. 1H NMR (400 MHz, ol-d4) 5 8.22 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 5.90 (s, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.82 (dd, J = 10.9, 5.1 Hz, 3H), 3.53 — 3.40 (m, 5H), 3.18 (dd, J = 12.4, 6.5 Hz, 2H), 3.02 (t, J = 12.7 Hz, 2H), 2.38 — 2.16 (m, 4H), 2.17 — 1.94 (m, 5H), 1.52 (t, J =12.7 Hz, 2H).

LC-MS: (ES, m/z): RT = 5.062 min, LCMs33: m/z = 440 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.92 (d, J = 5.7 Hz, 1H), 7.32 — 7.20 (m, 1H), 7.05 — 7.02 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.70 (s, 1H), 5.82 (d, J = 5.8 Hz, 1H), 4.77 (d, J = 6.3 Hz, 1H), 4.02 (t, J = 6.9 Hz, 2H), 3.85 (s, 3H), 3.24 — 3.17 (m, 2H), 3.17 — 3.13 (m, 2H), 2.66 — 2.58 (m, 2H), 2.00 — 1.37 (m, 15H),1.39 — 1.05 (m, 4H).

LC-MS: (ES, m/z): RT = 2.24 min, m/z = 442.10 [M+1]. 1H NMR (300 MHz, CD30D) 5: 8.13 (d, J = 7.0 Hz, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 4.01 — 3.92 (m, 2H), 3.86 (s, 3H), 3.79 (s, 2H), 3.47 — 3.35 (m, 2H), 2.78 — 2.60 (m, 7H), 2.18 — 2.02 (m, 2H), 1.92 — 1.81 (m, 6H), 1.51 — 1.38 (m, 2H).

LC-MS: (ES, m/z): RT = 1.401 min, LCMS 07: m/z = 455 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.30 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 2H), 2.90 — 2.87 (m, 2H), 2.84 — 2.79 (m, 2H), 2.73 (s, 4H), 2.60 — 2.52 (m, 1H), 2.28 (s, 3H), 2.10 — 2.05 (m, 4H), 1.98 — 1.92 (m, 2H), 1.88 (s, 4H), 1.53 — 1.40 (m, 2H).

LC-MS: (ES, m/z): RT = 1.401 min, LCMS 07: m/z = 455 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.31 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.95 — 6.85 (m, 2H), 4.10 (t, J = 6.0 Hz, 2H), 4.02 — 3.98 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H), 3.42 — 3.36 (m, 2H), 2.80 — 2.71 (m, 2H), 2.70 — 2.68 (m, 5H), 2.35 (s, 3H), 2.09 — 2.05 (m, 2H), 1.88 — 1.83 (m, 6H), 1.64 — 1.60 (m, 2H).

LC-MS: (ES, m/z): RT = 1.70 min, LCMS 15: m/z = 440 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.22 — 7.17 (m, 2H), 7.09 — 7.06 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.96 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 8.1 Hz, 1H), 4.09 (t, J = 6.0 Hz, 2H),, 3.81 (s, 3H), 3.56— 3.08 (m, 4H), 2.85 — 2.74 (m, 8H), 2.11 — 2.02 (m, 2H), 2.07 — 2.02 (m, 7H), 1.97— 1.89 (m, 2H).

LC-MS: (ES, m/z): RT = 0.944 min, LCMS27: m/z = 466.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.00 (s, 1H), 7.66 (s, 1H), 7.38 — 7.25 (m, 3H), 6.15 (d, J = 6.6 Hz, 1H), 4.87 — 4.42 (m, 1H), 3.91 — 3.86 (m, 1H), 3.65 — 3.38 (m, 7H), 3.14 — 2.82 (m, 4H), 2.70 — 2.56 (m, 1H), 2.13 — 2.08 (m, 7H), 2.03 — 1.84 (m, 1H), 1.88 — 1.71 (m, 2H), 1.25 — 1.11 (m, 2H).

LC-MS: (ES, m/z): RT = 1.23 min, LCMS 15: m/z = 500 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 10.68 (s, 1H), 9.95 (s, 1H), 8.91 (s, 1H), 8.26 (s, 1H), 7.84 — 7.78 (m, 2H), 7.78 — 7.76 (m, 1H), 7.41 (s, 1H), 7.20 — 7.13 (m, 3H), 6.91 (d, J = 8.7 Hz, 1H), 5.95 (d, J = 6.0 Hz,1H), 4.30 — 4.26 (m, 1H), 3.72— 3.68 (m, 1H), 3.58 (s, 2H), 3.25 (s, 2H), 2.91 — 2.72 (m, 1H), 2.51 — 2.45 (m, 1H), 1.92 (s, 3H), 1.78 — 1.63 (m, 3H), 1.08 —0.99 (m, 2H).

LC-MS: (ES, m/z): RT = 1.238 min, LCMS 28: m/z = 531 [M+1]. lH-NMR: (400 MHz, Methanol-d4) 5 7.66 — 7.57 (m, 1H), 7.43 — 7.23 (m, 5H), 7.11 (s, 3H), 6.31 — 6.22 (m, 1H), 4.25 — 4.17 (m, 1H), 4.17 — 4.13 (m, 1H), 3.97 — 3.85 (m, 4H), 3.85 — 3.72 (m, 1H), 3.72-3.60 (m, 1H), 3.53 — 3.42 (m, 4H), 3.42 — 3.34 (m, 3H), 3.06 — 2.95 (m, 3H), 2.40 — 2.33 (m, 2H), 2.21 — 2.10 (m, 3H), 2.07 — 1.86 (m, 4H), 1.57 — 1.42 (m, 2H).

LC-MS: (ES, m/z): RT = 1.725 min, LCMS 15: m/z = 501 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 5.30 — 5.20 (m, 1H), 4.51 — 4.48 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.93 — 3.90 (m, 1H), 3.82 (s, 3H), 3.32 — 3.28 (m, 2H), 3.08 — 2.94 (m, 3H), 2.77 — 2.63 (m, 4H), 2.48 — 2.46 (m, 1H), 2.31 — 2.12 (m, 1H), 2.10 (s, 3H), 2.09 — 1.93 (m, 4H), 1.86 — 1.78 (m, 2H), 1.25 — 1.15 (m, LC-MS: (ES, m/z): RT = 1.111 min, LCMS 15: m/z = 501 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.69 (s, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.32 — 5.09 (m, 1H), 4.50 — 4.46 (m, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.92 — 3.88 (m, 1H), 3.81 (s, 3H), 3.32 — 3.22 (m, 2H), 3.07 — 2.92 (m, 3H), 2.76 — 2.62 (m, 4H), 2.47 — 2.44 (m, 1H), 2.32 — 2.13 (m, 1H), 2.08 — 1.92 (m, 7H), 1.85 — 1.76 (m, 2H), 1.19 — 1.14 (m, 2H).

LC-MS: (ES, m/z): RT = 1.357 min, LCMS31: m/z = 497.4 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.14 — 7.12 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.52 — 4.48 (m, 1H), 4.05 (t, J = 6.0 Hz, 2H), 3.94 — 3.91 (m, 1H), 3.83 (s, 3H), 3.56 — 3.50 (m, 4H), 3.36 — 3.33 (m, 2H), 3.15 — 3.03 (m, 1H), 2.67 — 2.61 (m, 1H), 2.38 (t, J = 8.0 Hz, 2H), 2.12 — 1.99 (m, 7H), 1.96 — 1.94 (m, 1H), 1.90 — 1.76 (m, 2H), 1.33 — 1.07 (m, 2H).

LC-MS: (ES, m/z): RT = 0.82 min, LCMS 15: m/z = 469 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.90 (d, J = 5.8 Hz, 1H), 7.26 —7.05 (m, 1H), 6.91 — 6.74 (m, 2H), 5.80 (d, J = 6.0 Hz, 1H), 4.79 (s, 1H), 4.67 (d, J = 1.8 Hz, 1H), 4.06 — 4.04 (m, 1H), 3.99 — 3.78 (m, 5H), 3.28 (s, 2H), 3.19 — 2.96 (m, 2H), 2.85 — 2.65 (m, 1H), 2.63 — 2.50 (m, 3H), 2.32 — 2.30 (m, 2H), 2.14 — 2.08 (m, 5H), 1.81 — 1.76 (m, 5H), 1.12 — 1.13 (m, 2H).

LC-MS: (ES, m/z): RT = 1.22 min, LCMS 07: m/z = 496 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.47 (d, J = 2.6 Hz, 1H), 7.68 (s, 1H), 7.26 (dd, J = 8.8, 2.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.1 Hz, 1H), 4.44 (d, J = 13.3 Hz, 1H), 3.88 (s, 4H), 3.35 (s, 2H), 3.06 (td, J = 13.4, 13.0, 2.8 Hz, 1H), 2.88 (t, J = 6.6 Hz, 2H), 2.74 — 2.58 (m, 7H), 2.08 (s, 3H), 1.97 — 1.71 (m, 7H), 1.29 — 1.07 (m, LC-MS: (ES, m/z): RT = 1.554 min, LCMS 28: m/z = 476.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.27 (s, 1H), 7.75 (s, 1H), 7.40 — 7.16 (m, 3H), 6.49 (s, 1H), .97 (d, J = 6.0 Hz, 1H), 4.46 (d, J = 12.9 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.34 — 3.33 (m, 2H), 3.11 — 2.96 (m, 1H), 2.68 — 2.55 (m, 1H), 2.22 (t, J = 8.4, 1H), 2.08 (s, 3H), 1.99 — 1.70 (m, 3H), 1.31 — 1.07 (m, 4H), 1.07 — 0.97 (m, 2H).

LC-MS: (ES, m/z): RT = 3.287 min, LCMS 27: m/z = 476.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.51 (s, 1H), 8.26 (s, 1H), 7.80 — 7.70 (m, 1H), 7.36 — 7.20 (m, 3H), 5.97 (d, J = 6.0 Hz, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.12 — 3.97 (m, 1H), 3.87 (d, J = 13.7 Hz, 1H), 3.50 — 3.36 (m, 2H), 3.14 — 2.97 (m, 1H), 2.60 (t, J = 12.1 Hz, 1H), 2.06 (s, 3H), 2.01 — 1.70 (m, 3H), 1.42 — 1.02 (m, 6H).

LC-MS: (ES, m/z): RT = 1.277 min, LCMS 33: m/z = 398.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.81 (d, J = 6.1 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.1 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.70 — 3.40 (m, 4H), 2.82 — 2.57 (m, 6H), 2.14 — 1.80 (m, 10H).

LC-MS: (ES, m/z): RT = 4.209 min,UFLC05, LCMS 48: m/z = 412.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.82 (d, J = 6.3 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.7, 2.4 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.15 (d, J = 6.3 Hz, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.81 (s, 3H), 3.72 — 3.62 (m, 4H), 2.83 — 2.63 (m, 6H), 2.14 — 1.55 (m, 12H).

LC-MS: (ES, m/z): RT = 1.028 min, LCMS 28: m/z = 443 [M+1]. lH-NMR: (300 MHz, Deuterium Oxide) 5 6.97 — 6.88 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.75-6.67 (m, 1H), 6.03 (s, 1H), 4.32 (s, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.73 (s, 3H), 3.70 — 3.44 (m, 8H), 3.32 (t, J = 7.5 Hz, 2H), 3.12 — 2.90 (m, 4H), 2.45 — 2.29 (m, 2H), 2.19 — 1.99 (m, 4H), 1.99 — 1.74 (m, 4H).

LC-MS: (ES, m/z): RT = 1.102 min, LCMS 28: m/z = 444 [M+1]. : 127 (400 MHz, Methanol-d4) 5 6.94 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.75 — 6.70 (m, 1H), 5.88 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.99 — 3.92 (m, 2H), 3.80 (d, J = 6.4 Hz, 5H), 3.74 (s, 3H), 3.48 — 3.38 (m, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.82 — 2.73 (m, 5H), 2.14 — 2.04 (m, 2H), 1.95 — 2.82 (m, 6H), 1.52 — 1.39 (m, 2H).

LC-MS: (ES, m/z): RT = 1.08 min, LCMS 27: m/z = 450.30 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 12.54 (s, 1H), 8.87 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.30 (d, J = 6.1 Hz, 1H), 4.65 (s, 2H), 4.13 — 3.88 (m, 4H), 3.72 (s, 3H), 2.76 (d, J = 5.9 Hz, 2H), 2.56 (d, J = 7.0 Hz, 2H), 2.49 — 2.38 (m, 6H), 1.92 (t, J = 6.8 Hz, 2H), 1.72 — 1.61 (m, LC-MS: (ES, m/z): RT = 1.15 min, LCMS 33: m/z = 423.24 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.30 (d, J = 5.3 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 = 6.2 Hz, 2H), 3.81 (s, 3H), 2.74 — — 6.78 (m, 2H), 4.04 (t, J 2.51 (m, 6H), 2.45 (s, 6H), 2.09 — 1.93 (m, 2H), 1.89 — 1.73 (m, 4H).

LC-MS: (ES, m/z): RT = 8.151min, m/z = 424.24 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.41 (d, J = 5.2 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 6.98 — 6.85 (m, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 2.78 — 2.57 (m, 9H), 2.46 (s, 3H), 2.15 — 1.96 (m, 2H), 1.93 — 1.76 (m, 4H).

LC-MS: (ES, m/z): RT = 1.14 min, LCMS 33: m/z = 409.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.26 (d, J = 5.3 Hz, 1H), 8.09 (s, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.18 (dd, J = 8.7, 2.5 Hz, 1H), 7.00 — 6.87 (m, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.78 — 2.56 (m, 9H), 2.10 — 1.90 (m, 2H), 1.91 — 1.75 (m, 4H).

LC-MS: (ES, m/z): RT = 1.725 min, LCMSO7: m/z = 441.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.95 — 7.93 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.07 — 7.05 (m, 1H), 6.95 — 6.87 (m, 1H), 6.25 — 6.16 (m, 1H), 4.31 — 4.24 (m, 2H), 4.15 — 4.05 (m, 2H), 3.96 — 3.80 (m, 5H), 3.57 — 3.48 (m, 2H), 3.04 (s, 3H), 2.89 — 2.39 (m, 6H), 2.15 — 2.07 (m, 2H), 1.91 — 1.80 (m, 4H).

LC-MS: (ES, m/z): RT = 2.345 min, LCMs27: m/z = 441.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.91 (d, J = 6.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.12 — 7.08 (m, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.22 (d, J = 6.3 Hz, 1H), 4.33 (s, 2H), 4.08 (t, J = 6.3 Hz, 2H), 4.00 — 3.90 (m, 2H), 3.81 (s, 3H), 3.38 — 3.31 (m, 2H), 2.76 — 2.68 (m, 2H), 2.65 — 2.60 (m, 4H), 2.12 — 1.96 (m, 2H), 1.94 — 1.76 (m, 6H).

LC-MS: (ES, m/z): RT = 1.133 min, LCMS 28: m/z = 478.3 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 58.24 — 8.16 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.16 — 6.92 (m, 3H), 6.60 — 6.46 (m, 1H), 4.65 (s, 1H), 4.48 (s, 1H), 4.18 — 4.04 (m, 3H), 3.95 — 3.80 (m, 4H), 3.73 — 3.65 (m, 2H), 3.38 (t, J = 7.4 Hz, 2H), 3.73 — 3.65 (m, 2H), 3.73 — 3.65 (m, 3H), 2.27 — 1.84 (m, 6H).

LC-MS: (ES, m/z): RT = 0.992 min, LCMS 33: m/z = 449.6 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.53 — 8.43 (m, 2H), 7.92 (d, J = 6.1 Hz, 1H), 7.77 — 7.74 (m, 1H), 7.44 — 7.40 (m, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.7, 2.5 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 4.94 (s, 2H), 3.91 (t, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.10 (s, 3H), 2.69 — 2.57 (m, 6H), 2.00 — 1.78 (m, 6H).

LC-MS: (ES, m/z): RT = 1.07 min, LCMS 33: m/z = 449.6 [M+1]. 1H NMR (300 MHz, Methanol-d4) 58.55 — 8.52 (m, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.82 — 7.76 (m, 1H), 7.39 — 7.21 (m, 3H), 7.02 — 6.91 (m, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.15 (d, J = 6.2 Hz, 1H), 4.97 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.16 (s, 3H), 2.73 — 2.57 (m, 6H), 2.03 — 1.79 (m, 6H).

LC-MS: (ES, m/z): RT = 1.071 min, LCMS 33: m/z = 400 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.99 (d, J = 6.4 Hz, 1H), 7.25 (s, 1H), 7.11 (q, J = 8.8 Hz, 2H), 6.54 — 6.23 (m, 1H), 4.64 (s, 2H), 4.43 (s, 1H), 4.25 — 4.16 (m, 2H), 3.89 — 3.58 (d, 7H), 3.47 (d, J = 6.6 Hz, 2H), 3.15 (d, J = 11.1 Hz, 2H), 2.33 — 2.05 (m, LC-MS: (ES, m/z): RT = 0.676min, LCMS 30: m/z = 469.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.75 (d, J = 13.6 Hz, 1H), 7.13 — 6.98 (m, 3H), 6.56 (dd, J = 14.4, 7.6 Hz, 1H), 4.30-4.20 (m, 2H), 4.13 — 3.94 (m, 2H), 3.91 (s, 3H), 3.88 — 3.73 (m, 6H), 3.71 — 3.57 (m, 2H), 3.55-3.45 (m, 2H), 3.22 - 3.12 (m, 2H), 2.30 (s, 2H), .15 (m, 2H 2.16—2.02 2.00-1.82 , m, 5H , m, 2H.

LC-MS: (ES, m/z): RT = 1.04min, LCMSO7: m/z = 455.15 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.92 (d, J = 6.2 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.22 (d, J = 6.2 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.81 — 3.73 (m, 2H), 3.73 — 3.62 (m, 6H), 2.83 (t, J = 7.7 Hz, 2H), 2.75 (s, 4H), 2.17 (s, 3H), 2.10 (, J = 6.9 Hz, 2H), 1.93 — 1.85 (m, 4H).

LC-MS: (ES, m/z): RT = 1.09 min, LCMS 33: m/z = 416 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 8.77 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.50 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.06 (d, J = 6.1 Hz, 1H), 4.54 (s, 1H), 3.98 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H), 3.45 (t, J = 6.2 Hz, 2H), 3.33 (s, 2H), 3.04 (s, 3H), 2.90-2.60 (m, 6H), 1.99 (, J = 7.0 Hz, 2H), 1.78 (s, 4H), 1.76 — 1.64 (m, 2H).

LC-MS: (ES, m/z): RT =1.15min,LCMS33: m/z = 442 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.69 (d, J = 7.6 Hz, 1H), 7.16 — 7.00 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 4.63 (d, J = 13.3 Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 3.92 - 3.81 (m, 6H), 3.59 (m, 1H), 3.49 (t, J = 7.0 Hz, 3H), 3.16 (s, 2H), 2.31—2.11 (m, 4H), 2.11-2.07 (m, 2H), 1.77 — 1.61 (m, 4H), 1.29 (s, 3H).

LC-MS: (ES, m/z): RT = 1.874 min, LCMS 07: m/z = 442.10 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.80 — 7.69 (m, 1H), 7.31 — 7.01 (m, 3H), 6.71 - 6.47 (m, 1H), 5.20 — 4.99 (m, 1H), 4.28 — 4.14 (m, 2H), 4.06 — 3.98 (m, 2H), 3.91 (s, 3H), 3.85 — 3.71 (m, 2H), 3.62 — 3.51 (m, 1H), 3.55 — 3.36 (m, 3H), 3.21 — 3.09 (m, 5H), 2.34 — 1.85 (m, 8H), 1.81 - 1.68 (m, 2H).

LC-MS: (ES, m/z): RT = 1.255 min, LCMS 28: m/z = 430.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.84 (d, J = 6.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 6.10 (d, J = 6.3 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.66 (t, J = 7.1 Hz, 2H), 3.46 — 3.35 (m, 5H), 3.11 (s, 3H), 2.85 — 2.66 (m, 6H), 2.16 — 2.04 (m, 2H), 1.94 — 1.84 (m, 6H).

LC-MS: (ES, m/z): RT = 1.07 min, LCMS 53: m/z = 400 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 8.31 (d, J = 5.1 Hz, 1H), 7.32 (d, J = 3.9 Hz, 1H), 7.04 — 7.01 (m, 1H), 6.95 — 6.91 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 5.1 Hz, 2H), 4.41 (d, J = 4.8 Hz, 2H), 4.12 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 2.72 — 2.54 (m, 6H), 2.18 — 2.13 (m, 2H), 2.11 (s, 3H), 2.01—1.82(m,4H).

LC-MS: (ES, m/z): RT = 2.06 min, LCMS 33: m/z = 467 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.60 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 7.1 Hz, 2H), 6.21 (d, J = 7.3 Hz, 1H), 4.47 (d, J = 13.3 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 3.91 (d, J = 13.8 Hz, 1H), 3.80-3.70 (m, 2H), 3.51 — 3.39 (m, 4H), 3.23 — 3.05 (m, 3H), 2.65 (t, J = 11.8 Hz, 1H), 2.31 (t, J = 7.6 Hz, 2H), 2.26 (s, 3H), 2.22-2.15 (m, 2H), 2.14 — 1.88 (m, 6H), 1.79—1.70 (m, 2H), 1.34 — 1.06 (m, 2H).

LC-MS: (ES, m/z): RT = 1.212 min, LCMS 33: m/z = 456 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.84 (d, J = 6.2 Hz, 1H), 7.29 (s, 1H), 7.16 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.08 (d, J = 6.2 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 4.00 — 3.89 (m, 2H), 3.82 (s, 3H), 3.58 — 3.35 (m, 4H), 3.11 (s, 3H), 2.80 — 2.60 (m, 6H), 2.14 — 1.98 (m, 3H), 1.92 — 1.78 (m, 4H), 1.62 — 1.52 (m, 2H), 1.42 — 1.26 (m, LC-MS: (ES, m/z): RT = 1.271 min, LCMS 28: m/z = 470.3 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.84 (d, J = 6.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.7, 2.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.19 (d, J = 6.3 Hz, 1H), 4.57 (d, J = 13.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 2.92 — 2.74 (m, 4H), 2.68 (d, J = 6.3 Hz, 4H), 2.08 (d, J = 15.5 Hz, 2H), 1.87 (p, J = 2.9 Hz, 6H), 1.62 (t, J = 12.1 Hz, 1H), 1.40 — 1.25 (m, 2H), 1.18 (s, 6H).

LC-MS: (ES, m/z): RT = 1.11 min, LCMS 33: m/z = 428.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.71 (dd, J = 7.9, 3.1 Hz, 1H), 7.18 — 6.98 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 4.40 = 5.5 Hz, 2H), 4.03 — 4.33 (m, 1H), 4.19 (t, J — 3.97 (m, 2H), 3.91 (s, 3H), 3.86 — 3.80 (m, 2H), 3.74 — 3.54 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.21 — 3.14 (m, 2H), 2.42 — 2.19 (m, 4H), 2.13 — 2.06 (m, 2H), 2.02 — 1.93 (m, 2H), 1.63 — 1.56 (m, 2H).

LC-MS: (ES, m/z): RT = 1.180min, LCMS 07: m/z = 442.25 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.70 (d, J = 7.6 Hz, 1H), 7.15 — 6.98 (m, 3H), 6.59 (d, J = 7.7 Hz, 1H), 4.19 (t, J = 5.5 Hz, 3H), 3.91 (s, 7H), 3.69 — 3.51 (m, 2H), 3.48 (d, J = 7.1 Hz, 2H), 3.42 (s, 3H), 3.29 — 3.08 (m, 2H), 2.31 — 2.25 (m, 4H), 2.10 - 1.70 (m, LC-MS: (ES, m/z): RT = 1.121 min, LCMs28: m/z = 402.2 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.56 (dd, J = 15.3, 7.6 Hz, 1H), 7.14 — 6.93 (m, 3H), 6.42 = 5.7 Hz, 2H), 3.86 = 7.5 Hz, — 6.28 (m, 1H), 4.10 (t, J — 3.58 (m, 9H), 3.36 (t, J 2H), 3.18 — 2.98 (m, 5H), 2.25 — 1.86 (m, 6H).

LC-MS: (ES, m/z): RT = 1.199 min, LCMS 28: m/z = 428.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.75 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 9.7, 4.6 Hz, 3H), 6.57 (dd, J = 12.5, 7.6 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 4.14 — 4.00 (m, 2H), 3.97 — 3.74 (m, 11H), 3.50 (t, J = 7.1 Hz, 2H), 3.18 (s, 2H), 2.42 — 1.88 (m, 8H).

LC-MS: (ES, m/z): RT = 1.72 min, LCMS 33: m/z = 476.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.60-7.80 (m, 1H), .30 (m, 3H), 6.22 (d, J = 7.3 Hz, 1H), .25 (m, 3H), 3.92 (s, 3H), 3.87 — 3.77 (m, 2H), 3.52 — 3.47 (m, 2H), 3.27 — 3.12 (m, 6H), 2.46 — 2.04 (m, 10H).

LC-MS: (ES, m/z): RT = 1.04min, LCMSO7: m/z = 455.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.71 (d, J = 7.6 Hz, 1H), 7.19 — 6.97 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 4.30 — 4.14 (m, 3H), 3.91 (s, 5H), 3.49 (t, J = 7.1 Hz, 2H), 3.35 (s, 1H), 3.17 (q, J = 12.3 Hz, 3H), 2.37 — 2.15 (m, 4H), 2.16 — 1.88 (m, 4H), 1.74 (q, J = 12.3 Hz, 2H).

LC-MS: (ES, m/z): RT = 1.313 min, LCMS 28: m/z = 475.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.69 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.10 — 7.00 (m, 3H), 6.86 (dd, J = 14.2, 8.0 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H), 4.81 (d, J = 12.6 Hz, 2H), 4.20 (q, J = 5.9 Hz, 3H), 3.97 (s, 3H), 3.83 (s, 2H), 3.59 — 3.43 (m, 2H), 3.35 (s, 3H), 3.30 — 3.02 (m, 2H), 2.32 — 2.04 (m, 6H).

LC-MS: (ES, m/z): RT = 1.01 min, LCMS 33: m/z = 450.6 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 8.50-8.60 (m, 1H), 7.64-7.84 (m, 1H), 7.11 — 6.91 (m, 3H), 6.51-6.70 (m, 1H), 4.91 (s, 1H), 4.74 (s, 1H), 4.15 — 4.06 (m, 3H), 3.96 (t, J = .7 Hz, 1H), 3.82 (s, 3H), 3.69 — 3.63 (m, 2H), 3.34 (t, J = 7.5 Hz, 2H), 3.07 — 2.98 (m, 2H), 2.94 - 2.79 (m, 2H), 2.24 — 1.99 (m, 4H), 2.00 — 1.86 (m, 2H).

LC-MS: (ES, m/z): RT = 0.541 min, LCMS 48: m/z = 462.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.96 (s, 1H), 8.66 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 6.2 Hz, 1H), 4.89 (s, 2H), 4.08 - 4.12 (m, 4H), 3.84 (s, 3H), 3.08 (t, J = 5.9 Hz, 2H), 2.82 — 2.73 (m, 2H), 2.71 — 2.62 (m, 4H), 2.14 — 2.02 (m, 2H), 1.92 — 1.79 (m, 4H).

LC-MS: (ES, m/z): RT = 1.112 min, LCMS 15: m/z = 483.30 [M+1]. 1H NMR (300 MHz, Chloroform-d) 5 7.83 (d, J = 5.8 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H),6.71— 6.83 (m, 2H), 6.34 (dd, J = 5.8, 2.1 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 5.83 (s, 1H), 4.64 (d, J = 13.7 Hz, 1H), 4.15 — 4.03 (m, 4H), 3.75 —3.88 (s, 4H), 2.97 —3.14 (m, 1H),2.80— 2.47 (m, 7H), 2.18 —1.96 (m, 6H), 1.93— 1.74 (m, 6H), 1.36 — 1.19 (m, LC-MS: (ES, m/z): RT = 1.143 min, LCMSO7: m/z = 497.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.63 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.83 — 6.79 (m, 1H), 5.81 (d, J = 6.0 Hz, 1H), 4.42 — 4.32 (m, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.84 — 3.78 (m, 4H), 3.38 (s, 3H), 3.16 — 2.94 (m, 3H), 2.73 — 2.60 (m, 7H), 2.08 — 2.00 (m, 5H), 1.85 — 1.80 (m, 5H), 1.71 — 1.55 (m, 2H), 1.12 — 0.90 (m, 2H).

LC-MS: (ES, m/z): RT = 1.56 min, LCMS 27: m/z = 477.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 57.69 (d, J = 6.1 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.21 — 7.05 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 6.76 — 6.58 (m, 3H), 5.91 (d, J = 6.0 Hz, 1H), 4.17 (t, J = 5.9 Hz, 2H), 3.85 — 3.25 (m, 4H), 2.85 (d, J = 11.5 Hz, 2H), 2.24 (s, 3H), 2.16 — 2.06 (m, 2H), 2.05 — 1.90 (m, 2H), 1.75 (d, J = 13.3 Hz, 2H), 1.70 — 1.54 (m, 1H), 1.40 — 1.21 (m, 2H).

LC-MS: (ES, m/z): RT = 1.31 min, LCMS 33: m/z = 505.30 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.70 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.18 — 7.02 (m, 3H), 6.89 (dd, J = 8.8, 1.3 Hz, 1H), 6.73 — 6.56 (m, 3H), 5.92 (d, J = 6.0 Hz, 1H), 4.45 (d, J = 13.3 Hz, 1H), 4.17 — 4.14 (m, 2H), 3.89 — 3.84 (m, 4H), 3.38 — 3.20 (m, 4H), 3.09 — 2.93 (m, 1H), 2.71 — 2.51 (m, 1H), 2.16 — 2.01 (m,5H), 1.95 — 1.68 (m, 3H), 1.23 — 1.00 (m, 2H.

LC-MS: (ES, m/z): RT = 1.106 min, LCMS 33: m/z = 469 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.86 (d, J = 6.2 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 8.7, 2.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.21 (d, J = 6.3 Hz, 1H), 4.42 (d, J = 13.6 Hz, 2H), 4.13 — 3.89 (m, 3H), 3.82 (s, 3H), 3.16 — 3.00 (m, 2H), 2.81 — 2.58 (m, 6H), 2.18 — 1.68 (m, 11H), 1.52 — 1.34 (m, 2H).

LC-MS: (ES, m/z): RT = 1.78min, : m/z = 491.20 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.92 (d, J = 6.1 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.25 (d, J = 6.2 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.85—3.81 (m, 7H), 3.50 - 3.29 (m, 4H), 2.87 (s, 3H), 2.84 — 2.76 (m, 2H), 2.71(d, J = 5.9 Hz, 4H), 2.14 — 2.02 (m, 2H), 1.92 — 1.84 (m, 4H).

LC-MS: (ES, m/z): RT = 1.18 min, LCMS 33: m/z = 496 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 7.57 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.96 — 6.81 (m, 2H), 6.61 (s, 1H), 5.93 (s, 1H), 4.37 (d, J = 13.0 Hz, 1H), 4.05 (t, J = 6.0 Hz, 2H), 3.88-3.78 (m, 4H), 3.61 — 3.53 (m, 2H), 3.47 — 3.22 (m, 4H), 3.07 — 2.90 (m, 6H), 2.44 (t, J = 12.4 Hz, 1H), 2.18-2.08 (m, 2H), 2.01 (d, J = 6.8 Hz, 2H), 1.98 (s, 3H), 1.92-1.82 (m, 3H), 1.61 — 1.51 (m, 2H), 1.20 - 1.10 (m, 1H), 1.09 — 0.96 (m, LC-MS: RT = 2.26min, LCMSO7: m/z = 474 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 9.12 (s, 1H), 8.56 (d, J = 5.4 Hz, 1H), 7.73 — 7.64 (m, 2H), 7.51 (d, J = 5.4 Hz, 1H), 7.47 — 7.37 (m, 2H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.15 (t, J = 6.1 Hz, 2H), 3.89 — 3.85 (m, 5H), 2.84— 2.75 (m, 2H), 2.67 (t, J = 6.2 Hz, 4H), 2.15 -2.08 (m, 2H), 1.90 — 1.81 (m, 4H).

LC-MS: (ES, m/z): RT = 0.61 min, LCMS 32: m/z = 451.4 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.75 (d, J = 6.0 Hz, 1H), 7.65 (dd, J = 9.4, 2.6 Hz, 1H), 7.44 = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.53 (dd, J = — 7.33 (m, 2H), 7.06 (dd, J 9.3, 0.8 Hz, 1H), 5.95 (d, J = 6.0 Hz, 1H), 4.41 (s, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 2.87 — 2.78 (m, 6H), 2.14 — 1.98 (m, 2H), 1.96 — 1.88 (m, 4H).

LC-MS: (ES, m/z): RT = 0.826 min, LCMS 30: m/z = 497 [M+1]. 1H NMR (400 MHz, Chloroform—d) 5 7.70 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 6.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 4.45 - 4.40 (m, 1H), 4.30 (t, J = 6.0 Hz, 2H), 3.90 - 3.86 (m, 1H), 3.77 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 3.42 (t, J = 6.8 Hz, 2H), 3.32 —3.30 (m, 2H), 3.06 (t, J = 1.2 Hz, 1H), 2.80 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 2.8 Hz, 1H), 2.06 (s, 3H), 1.99 - 1.75 (m, 7H), 1.23 - 1.10 (m, 2H).

LC-MS: (ES, m/z): RT = 1.356 min, LCMS 15: m/z = 449.25 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.69 — 8.59 (m, 1H), 8.50 (t, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9, 5.8 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.15 = 8.6, — 7.07 (m, 2H), 7.03 (d, J 2.4 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 4.00 — 3.89 (m, 5H), 3.89 — 3.75 (m, 2H), 3.61 — 3.49 (m, 4H), 3.22 — 3.08 (m, 2H), 2.35 — 2.16 (m, 4H), 2.15 — 2.00 (m, 2H).

LC-MS: (ES, m/z): RT = 1.165 min, LCMS53: m/z = 490.30 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 8.04 —7.96 (m, 1H),7.88 — 7.78 (m, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 9.3 Hz, 1H), 7.13— 6.98 (m, 3H), 6.97 — 6.89 (m, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.10 (t, J = 5.9 Hz, 4H), 3.89 (s, 4H), 3.82 (s, 5H), 3.72 — 3.59 (m, 2H), 3.36 (t, J = 7.5 Hz, 2H), 3.12 — 2.96 (m, 2H), 2.25 — 2.02 (m, 4H), 1.94 (m,2H).

LC-MS: (ES, m/Z): RT = 1.081 min, LCMS 33: m/Z = 462 [M+1]. 1H-NMR: (400 MHz, Methanol-d4) 5 7.99 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.07 — 7.03 (m, 1H), 6.4 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 6.4 Hz, 1H), 4.28 — 4.08 (m, 4H), 4.06 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.20-3.11 (m, 4H), 2.78 — 2.69 (m, 2H), 2.62 (q, J = 4.4 Hz, 4H), 2.11 — 1.99 (m, 2H), 1.90 — 1.80 (m, 4H).

LC-MS: (ES, m/z): RT = 1.068 min, LCMS 07: m/z = 455 [M+1]. lH-NMR: 170 (400 MHz, Methanol-d4) 5 7.86 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.08 — 7.03 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.83 (d, J = 6.0 Hz, 1H), 4.29 (t, J = 8.8 Hz, 2H), 4.25 — 4.20 (m, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.98 — 3.90 (m, 1H), 3.82 (s, 3H), 3.01 (d, J = 8.4 Hz, 6H), 2.81 — 2.75 (m, 2H), 2.72 — 2.62 (m, 4H), 2.11 — 2.02 (m, 2H), 1.92 — 1.80 (m, 4H).

LC-MS: (ES, m/z): RT = 1.74 min, LCMS 53: m/z = 372 [M+1]. 1H NMR (400 MHz, Chloroform—d) 5 7.93 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 6.98 — 6.95 (m, 1H), 6.82 — 6.80 (d, J = 8.8 Hz, 2H), 5.92 (d, J = 6.0 Hz, 1H), 4.09 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.12 (s, 6H), 2.66 — 2.62 (t, J = 8.0 Hz, 2H), 2.54 (d, J = 6.1 Hz, 4H), 2.12 — 2.05 (m, 2H), 1.83 — 1.79 (m, 4H).

LC-MS: (ES, m/z): RT = 2.821 min, LCMSO7: m/z = 497.25 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.83 (d, J = 6.3 Hz, 1H), 7.24 (s, 1H), 7.17 — 7.13 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.07 (d, J = 6.3 Hz, 1H), 4.43 — 4.39 (m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.87 — 3.81 (m, 4H), 3.60 — , 1H), 3.50 — 3.40 (m, 1H), 3.09 — 3.00 (m, 4H), 2.82 — 2.74 (m, 6H), 2.68 — 2.60 (m, 1H), 2.14 — 1.98 (m, 6H), 1.93 — 1.83 (m, 4H), 1.80 — 1.60 (m, 2H), 1.33 — 1.06 (m, 2H).

LC-MS: (ES, m/z): RT = 1.16 min, LCMS 33: m/z =483 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.74 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.07 — 6.94 (m, 2H), 6.67 (dd, J = 7.3, 2.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.61 (d, J = 13.3 Hz, 1H), 4.22 (t, J = 5.5 Hz, 2H), 4.10 (d, J = 6.0 Hz, 3H), 3.92 (s, 3H), 3.93 — 3.71 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.31 — 3.09 (m, 3H), 2.84 (t, J = 12.8 Hz, 1H), 2.38 — 2.18 (m, 8H), 2.18 — 1.88 (m, 4H), 1.55-1.28 (m, 2H).

LC-MS: (ES, m/z): RT = 1.14 min, LCMS 15: m/z = 343 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 8.24 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.04 — 7.00 (m, 1H), 6.93 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 5.1 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 2.68 — 2.60 (m, 4H), 2.39 (s, 3H), 2.17 — 2.07 (m, 2H), 1.92 — 1.76 (m, 4H).

LC-MS: (ES, m/z): RT = 1.15 min, LCMS 15: m/z = 357 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.54 (d, J = 2.4 Hz, 1H), 7.07 — 6.98 (m, 1H), 6.91 (s, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.48 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 2.58 (q, J = 5.2 Hz, 4H), 2.34 (s, 6H), 2.15 — 2.06 (m, 2H), 1.81 — 1.77 (m, 4H).

LC-MS: (ES, m/z): RT= 1.152, LCMS m/z = 357.30 [M+1]. 1H NMR (300 MHz, Methanol-d4, ppm) 5 7.34 (d, J = 2.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 8.6, 2.4 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.99 (d, J = 7.5 Hz, 1H), 5.85 (d, J = 8.0 Hz, 1H), 4.05 (t, J = 6.2 Hz, 2H), 3.80 (s, 3H), 2.87 (s, 3H), 2.72 — 2.65 (m, 2H), 2.61 — 2.57 (m, 4H), 2.07 — 1.97 (m, 2H), 1.87 — 1.75 (m, 4H).

LC-MS: (ES, m/z): RT = 1.04 min, LCMS 33: m/z = 416 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.79 — 7.63 (m, 1H), 7.15 (d, J = 12.9 Hz, 1H), 7.10 — 7.03 (m, 2H), 6.60 - 6.45 (m, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.99 — 3.75 (m, 7H), 3.70 - 3.60 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.35 (d, J = 6.5 Hz, 3H), 3.28 (d, J = 9.7 Hz, 3H), 3.17-3.10 (m, 2H), 2.42 — 2.01 (m, 6H).

LC-MS: (ES, m/z): RT = 1.14 min, LCMS 07: m/z = 456 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.59 (d, J = 7.3 Hz, 1H), 7.14 — 7.01 (m, 3H), 6.18 (d, J = 7.3 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.96 — 3.75 (m, 7H), 3.57 — 3.34 (m, 6H), 3.20— 3.10 (m, 2H), 2.37 — 2.15 (m, 4H), 2.18 — 2.02 (m, 2H), 1.66 — 1.51 (m, 5H), 1.30— 1.15 (m, 2H).

LC-MS: (ES, m/z): RT = 0.572 min, LCMS 32: m/z = 427 [M+1]. lH-NMR: (400 MHz, Methanol-d4) 5 7.86 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.07 — 7.03 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.83 (d, J = 6.0 Hz, 1H), 4.26 (t, J = 8.6 Hz, 2H), 4.22 — 4.15 (m, 2H), 4.11 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.65 — 3.55 (m, 1H), 2.92 (t, J = 7.6 Hz, 2H), 2.85 (d, J = 6.2 Hz, 4H), 2.16 — 2.05 (m, 2H), 1.96 — 1.86 (m, LC-MS: (ES, m/z): RT = 1.462 min, LCMs33: m/z = 409 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.35 (s, 1H), 8.28 (d, J = 6.6 Hz, 1H), 7.83 (s, 1H), 7.54 — 7.44 (m, 1H), 7.22 (s, 1H), 7.20 — 7.10 (m, 2H), 4.23 (t, J = 5.4 Hz, 2H), 3.93 (s, 3H), 3.87 — 3.80 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.25 — 3.10 (m, 2H), 2.35 — 2.23 (m, 3H), 2.21 — 2.20 (m, 4H), 2.18 — 2.05 (m, 2H).

LC-MS: (ES, m/z): RT = 1.070 min, LCMSO7: m/z = 359.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.38 (s, 2H), 7.38 (d, J = 2.5 Hz, 1H), 7.16 — 7.12 (m, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.49 (s, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 2.84 — 2.76 (m, 2H), 2.76 — 2.66 (m, 4H), 2.15 — 1.99 (m, 2H), 1.95 — 1.79 (m, 4H).

LC-MS: (ES, m/z): RT = 2.06 min, LCMS 33: m/z = 483 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 7.90-7.70 (m, 2H), 6.70-6.45 (m, 2H), 6.09 (s, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 3.83 (s, 4H), .50 (m, 3H), 3.29 (t, J = 7.6 Hz, 2H), 3.20-2.90 (m, 5H), 2.20 (t, J = 7.3 Hz, 2H), 2.10-1.95 (m, 5H), 1.94 — 1.83 (m, 3H),1.83— , 2H), 1.33 — 0.85 (m, 2H).

LC-MS: (ES, m/z): RT = 0.714 min, LCMS 32: m/z = 497 [M+1]. lH-NMR: (300 MHz, Chloroform—d) 5 7.92 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.12 — 7.06 (m, 1H), 6.93 — 6.75 (m, 2H), 5.80 (d, J = 6.0 Hz, 1H), 4.89 (s, 1H), 4.69 — 4.50 (m, 1H), 4.18 — 4.05 (m, 1H), 3.91 — 3.70 (m, 5H), 3.35 — 3.16 (m, 2H), 3.10 — 2.90 (m, 1H), 2.66 — 2.42 (m, 6H), 2.41 — 2.19 (m, 2H), 2.09 (s, 3H), 1.93 — 1.68 (m, 7H), 1.31 — 1.02 (m, 5H).

LC-MS: (ES, m/z): RT = 1.00 min, LCMS 15: m/z = 482.4 [M+1]. 1H NMR: (400 MHz, Methanol-d4) 5 7.48 — 7.41 (m, 2H), 7.08 — 7.01 (m, 2H), 6.93 — 6.83 (m, 2H), 4.57 (d, J = 13.4 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 4.02 (d, J = 13.6 Hz, 1H), 3.89 (s, 3H), 3.87 — 3.79 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.37 (s, 1H), 3.26 — 3.09 (m, 3H), 3.08 (d, J = 6.4 Hz, 2H), 2.70-2.80 (m, 1H), 2.35 — 2.02 (m, 9H), 2.02 — 1.84 (m, 3H), 1.39 — 1.14 (m, 2H).

LC-MS: (ES, m/z): RT = 0.962 min, LCMS 53: m/z = 483.35 [M+1]. 1H NMR: (300 MHz, Methanol-d4) 5 8.04 (d, J = 2.4 Hz, 1H), 7.19 (t, J = 1.4 Hz, 1H), 6.93 (d, J = 1.3 Hz, 2H), 5.99 (d, J = 2.5 Hz, 1H), 4.62 — 4.49 (m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 4.01 — 3.91 (m, 1H), 3.83 (s, 3H), 3.20 — 2.98 (m, 3H), 2.81 — 2.55 (m, 7H), 2.14 — 1.98 (m, 5H), 1.95 — 1.75 (m, 7H), 1.35 — 1.05 (m, 2H).

LC-MS: (ES, m/z): RT = 0.997 min, LCMS53: m/z = 390.30 [M+1]. 1H NMR: (300 MHz, DMSO-d6) 5 8.73 (s, 1H), 7.76 (s, 1H), 7.14 (dd, J = 8.7, 2.2 Hz, 1H), 6.91 (s, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.73 (s, 1H), 5.29 — 5.06 (m, 1H),3.96 (t, J = 6.5 Hz, 2H), 3.68 (s, 3H), 2.89 — 2.70 (m, 5H), 2.68 — 2.48 (m, 3H), 2.34 — 2.26 (m, 1H), 2.26 — 2.02 (m, 4H), 1.98 — 1.74 (m, 3H).

LC-MS: RT= 1.025, m/z = 376.30 187 [M+1]. 1H NMR: (300 MHz, Methanol-d4, ppm) 5: 7.54 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.7, 2.5 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 3.93 (t, J = 6.2 Hz, 2H), 3.69 (s, 3H), 2.89 (s, 3H), 2.62 — 2.57 (m, 2H), 2.52 — 2.46 (m, 4H), 1.96 — 1.87 (m, 2H), 1.77 — 1.72 (m, 4H).

LC-MS: (ES, m/z): RT = 0.955 min, LCMS 28: m/z = 358.2 [M+1]. lH-NMR: 1H NMR (300 MHz, Methanol-d4) 5 8.03 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.00 — 6.89 (m, 2H), 6.37 (d, J = 2.5 Hz, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.86 — 3.75 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.17 (d, J = 10.8Hz, 2H), 2.96 (s, 3H), 2.35 — 2.01 (m, 6H).

LC-MS: (ES, m/z): RT = 0.871 min, LCMS 53: m/z = 442.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.24 (d, J = 6.3 Hz, 1H), 7.25 — 7.11 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 6.76 — 6.67 (m, 1H), 4.40 — 4.32 (m, 2H), 4.20 (t, J = 5.5 Hz, 2H), 4.07— 4.10 (m, 2H), 3.90 (s, 3H), 3.88 — 3.77 (m, 2H), 3.62 — 3.37 (m, 5H), 3.25 — 3.09 (m, 2H), 2.34 — 2.17 (m, 4H), 2.15 — 2.03 (m, 4H), 1.86 — 1.66 (m, 2H).

LC-MS: (ES, m/z): RT = 0.840 min, LCMS 07: m/z = 474.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.88 (d, J = 20.6 Hz, 1H), 8.29 — 8.16 (m, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.03 = 7.5 Hz, 1H), 7.14 — 7.90 (m, 2H), 7.68 (d, J — 6.96 (m, 3H), 6.37 — 6.29 (m, 1H), 4.82 (s, 2H), 4.28 — 4.12 (m, 2H), 3.90 (s, 3H), 3.86 — 3.73 (m, 2H), 3.48 (t, J = 7.1 Hz, 2H), 3.15 (t, J = 8.3, 2H), 2.37 — 1.99 (m, 6H).

LC-MS: (ES, m/z): RT = 1.253 min, LCMSO7: m/z = 441.10 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 10.63 (s, 1H), 9.77 (s, 1H), 9.60 (t, J = 4.1 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.20 — 7.00 (m, 3H), 6.23 (d, J = 7.2 Hz, 1H), 4.60 — 4.48 (m, 1H), 4.39 (t, J = 8.3 Hz, 1H), 4.16 — 4.00 (m, 4H), 3.85 — 3.56 (m, 6H), 3.36 — 3.26 (m, 2H), 3.10 — 2.96 (m, 2H), 2.22 — 1.73 (m, 9H).

LC-MS: (ES, m/z): RT = 0.987 min, LCMS 33: m/z = 439 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.63 — 7.48 (m, 3H), 7.11 (d, J = 7.2 Hz, 3H), 6.30 (t, J = 2.1 Hz, 1H), 6.15 (d, J = 7.3 Hz, 1H), 4.40 (t, J = 6.0 Hz, 2H), 4.19 (t, J = 5.5 Hz, 2H), 3.95 — 3.77 (m, 7H), 3.48 (t, J = 7.1 Hz, 2H), 3.19 — 3.01 (m, 2H), .15 (m, 4H), 2.10-2.00 (m, 2H).

LC-MS: (ES, m/z): RT = 1.00 min, LCMS 15: m/z = 386 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.57 (s, 2H), 7.39 (s, 1H), 7.13 (d, J = 6.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.76 — 2.72 (m, 2H), 2.69 — 2.64 (m, 4H), 2.14 (s, 3H), 2.12 — 2.00 (m, 2H), 1.88 — 1.81 (m, 4H).

LC-MS: (ES, m/z): RT = 1.007 min, LCMS 15: m/z = 497 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.32 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.55 — 4.39 (m, 2H), 3.97 — 3.87 (m, 1H), 3.82 (s, 3H), 3.32 — 3.30 (m, 1H), 3.29 — 3.25 (m, 1H), 3.09 (t, J = 1.2 Hz, 1H), 2.80 — 2.75 (m, 1H), 2.70 — 2.56 (m, 6H), 2.09 (s, 3H), 2.05 — 1.76 (m, 9H), 1.32 (d, J 6.0 Hz, 3H), 1.28 — 1.15 (m, 2H).

LC-MS: (ES, m/z): RT = 0.902 min, LCMS 30: m/z = 483.36 [M+H]. 1H NMR (300 MHz, Methanol-d4) 5 8.31 (d, J = 5.4 Hz, 1H), 7.33 — 7.15 (m, 2H), 7.02 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 5.4 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.93 — 3.76 (m, 8H), 3.66 (t, J = 6.8 Hz, 2H), 3.51 — 3.40 (m, 6H), 3.29 — 3.11 (m, 5H), 2.36 — 2.01 (m, 9H).

LC-MS: (ES, m/Z): RT = 1.207 min, LCMSlS: m/Z = 381.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.14 (s, 1H), 7.15 — 7.10 (m, 1H), 7.03 — 7.00 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.79 — 6.78 (m, 1H), 6.62 — 6.59 (m, 1H), 4.18 (s, 3H), 4.05 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.75 (t, J = 7.5Hz, 2H), 2.68 — 2.63 (m, 4H), 2.13 — 1.97 (m, 2H), 1.93 — 1.77 (m, 4H).

LC-MS: (ES, m/z): RT = 1.06 min, LCMS 53: m/z = 519.3 [M+1]. 1H NMR (300 MHZ, Methanol-d4) 5 7.61 (d, J = 7.3 HZ, 1H), 7.19 — 6.99 (m, 3H), 6.20 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.80 — 3.71 (m, 4H), 3.55 — 3.38 (m, 4H), 3.32 — 3.18 (m, 2H), 2.84 (s, 3H), 2.80 — 2.65 (m, 2H), 2.38 — 2.01 (m, 6H), 1.89 — 1.72 (m, 3H), 1.39 — 1.24 (m, 2H).

LC-MS: (ES, m/z): RT = 0.98 min, LCMS 33: m/z = 381 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 9.14 (s, 1H), 7.63 (dd, J = 8.9, 0.7 Hz, 1H), 7.32 — 7.20 (m, 2H), 7.07 — 6.97 (m, 1H), 6.96 — 6.85 (m, 2H), 4.19 (t, J = 5.6 Hz, 2H), 4.02 (s, 3H), 3.89 —3.79 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.25 — 3.10 (m, 2H), 2.36 — 2.02 (m, LC-MS: (ES, m/z): RT = 0.78 min, LCMS 48: m/z = 368.2 [M+1]. 1H NMR (300 MHz, ol-d4) 5 8.99 (s, 1H), 8.47 (dd, J = 6.5, 1.0 Hz, 1H), 7.49 — 7.31 (m, 2H), 7.12 — 6.89 (m, 3H), 4.20 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.88 — 3.78 (m, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.26 — 3.09 (m, 2H), 2.37 — 1.99 (m, 6H).

LC-MS: (ES, m/z): RT = 0.99 min 202 , LCMS 33: m/z = 383.21 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.76 (s, 1H), 7.24 — 7.07 (m, 3H), 6.54 (s, 1H), 4.24 (t, J = .5 Hz, 2H), 3.95 (s, 3H), 3.90 — 3.77 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.25 — 3.10 (m, 2H), 2.60 (d, J = 0.5 Hz, 3H), 2.39 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT = 1.17 min, LCMS 33: m/z = 513.30 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.70 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.19 — 4.03 (m, 6H), 3.82 (s, 3H), 3.30 (s, 2H), 2.89 — 2.61 (m, 8H), 2.06 (m, 2H), 1.92 — 1.72 (m, 7H), 1.32 — 1.06 (m, 5H).

LC-MS: (ES, m/z): RT = 1.285 min, LCMS 07: m/z = 444.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.70 (s, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 8.7, 2.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 4.02 — 3.92 (m, 2H), 3.82 (s, 3H), 3.76 — 3.69 (m, 4H), 3.48 — 3.37 (m, 2H), 3.32 (d, J 1.6 Hz, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.71 — 2.57 (m, 4H), 1.99 — 1.79 (m, 1H), 1.74 — 1.64 (m, 2H), 1.43 — 1.24 (m, 2H).

LC-MS: (ES, m/z): RT= 0.970 min, LCMS 33, m/z =372 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 57.20 — 6.90 (m, 3H), 5.91 (s, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.72 — 3.60 (m, 2H), 3.40 — 3.28 (m, 2H), 3.10 — 2.95 (m, 2H), 2.84 (s, 3H), 2.29 — 1.85 (m, 9H).

LC-MS: (ES, m/z): RT = 0.96 min , LCMS 33: m/z = 357.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.53 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.91 (m, 2H), 6.44 — 6.34 (m, 1H), 6.02 (d, J = 2.2 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.88 — 3.78 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 — 3.09 (m, 2H), 2.89 (s, 3H), 2.37 — 1.99 (m, 6H).

LC-MS: (ES, m/z): RT =1.540 min, LCMS 15: m/z = 328 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.74 (d, J = 5.2 Hz, 1H), 7.49 (s, 1H), 7.17 — 7.11 (m, 2H), 6.55 — 6.52 (m, 1H), 5.95 (d, J = 6.0 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 2.95 (s, 3H), 2.74 (t, J = 8.0 Hz, 2H), 2.66 (d, J = 5.6 Hz, 4H), 2.07 — 2.00 (m, 2H), 1.91 — 1.88 (m, 4H).

LC-MS: (ES, m/z): RT = 1.07min, LCMSO7: m/z = 372.10 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.52 (s, 1H), 7.35 — 7.21 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.10 (s, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.94 — 3.78 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.17 (q, J = 8.1 Hz, 2H), 3.04 (s, 3H), 2.40 — 2.16 (m, 7H), 2.11 - 2.06 (m, 2H).

LC-MS: (ES, m/z): RT = 0.963 min, LCMS 53: m/z = 357.25 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.41 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 — 6.89 (m, 2H), 6.31 (s, 1H), 5.83 (s, 1H), 4.21 (t, J = 5.6 Hz, 2H) 3.91 (s, 3H), 3.88 — 3.77 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 — 3.09 (m, 2H), 2.86 (s, 3H), 2.37 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT = 0.918 min, LCMS33: m/z = 374 [M+1]. lH-NMR: (300 MHz, Methanol-d4) 5 7.70 (d, J = 6.0 Hz, 1H), 7.47 (s, 1H), 7.10 — 7.02 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.80 (s, 3H), 3.75 — 3.64 (m, 4H), 2.92 (s, 3H), 2.64 — 2.41 (m, 6H), 2.08 — 1.91 (m, 2H).

LC-MS: (ES, m/z): RT= 0.997, m/z = 392.20 [M+1]. 1H NMR (300 MHz, Chloroform—d, ppm) 5: 7.87 (s, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.05 — 7.00 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 5.32 (d, J = 5.0 Hz, 1H), 4.11 (t, J = 5.5 Hz, 2H), 3.94 — 3.76 (m, 4H), 3.58 — 3.40 (m, 1H), 3.34 — 3.29 (m, 2H), 3.22 — 2.95 (m, 5H), 2.49 — 2.40 (m, 2H), 2.15 (s, 4H).

LC-MS: (ES, m/z): RT =0.906 min, LCMS 33: m/z = 344 [M+1]. lH-NMR-PH- EPI-K0: (300 MHz, Methanol-d4) 5 7.74 (d, J = 6.0 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.20 — 7.06 (m, 2H), 6.63 — 6.52 (m, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.14 — 4.07 (m, 1H), 4.06 — 3.86 (m, 2H), 2.94 (s, 3H), 2.83 — 2.77 (m, 1H), 2.74 — 2.56 (m, 5H), 1.92 — 1.72 (m, 4H).

LC-MS: (ES, m/z): RT = 1.40 min, LCMs15: m/z = 344 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 8.03 (s, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.04 — 7.01 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.76 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.29 (s, 2H), 2.72 — 2.67 (m, 6H), 2.16 — 2.07 (m, 2H), 1.94 — 1.78 (m, 4H).

LC-MS: (ES, m/z): RT = 1.25 min, : m/z = 423.2 [M+1]. 1HNMR (300 MHz, Chloroform—d) 5 8.38 (d, J = 5.7 Hz, 1H), 7.29 (d, J = 5.7 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.00 (d, J = 0.9 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.68 — 2.49 (m, 9H), 2.30 (s, 3H), 2.12 — 2.04 (m, 2H), 1.79 (s, 4H).

LC-MS: (ES, m/z): RT = 0.864 min, LCMSO7: m/z = 372.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.67 (s, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.19 — 7.17 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.26 — 4.19 (m, 4H), 3.90 (s, 3H), 3.86 — 3.80 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.21 — 3.14 (m, 2H), 2.79 (s, 3H), 2.31 — 2.27 (m, 2H), 2.25 — 2.21 (m, 2H), 2.17 — 2.02 (m, 2H).

LC-MS: (ES, m/z): RT = 1.465min, LCMSO7: m/z = 483.15 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.75 (d, J = 6.1 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.25 — 7.18 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.01 (d, J = 6.1 Hz, 1H), 4.49 (d, J = 13.3 Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 3.87 (s, 4H), 3.45 (t, J = 6.8 Hz, 6H), 3.30 (d, J = 6.4 Hz, 2H), 3.15 — 3.03 (m, 1H), 2.64 - 2.63 (m, 1H), 2.32 — 2.21 (m, 2H), 2.20 — 2.07 (m,7H), 1.98 — 1.76 (m, 3H), 1.38 — 1.06 (m, 3H).

LC-MS: (ES, m/z): RT =1.25min,LCMSO7: m/z = 381.05 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.82 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.94 — 6.82 (m, 4H), 4.18 (t, J = 5.5 Hz, 2H), 3.93 — 3.78 (m, 8H), 3.49 (t, J = 6.9 Hz, 2H), 3.20 - 3.13 (m, 2H), 2.29 - 2.19 (m, 4H), 2.13 - 2.06 (m, 2H).

LC-MS: (ES, m/z): RT = 0.96 min, LCMSO7: m/z = 382.05 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 9.15 (s, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 8.7, 2.5 Hz, 1H), 7.03 — 6.91 (m, 2H), 4.26 (t, J = 5.5 Hz, 2H), 4.06 (s, 3H), 3.89 — 3.60 (m, 5H), 3.52 (t, J = 7.0 Hz, 2H), 3.27 — 3.11 (m, 2H), 2.40 — 2.03 (m, 6H).

LC-MS: (ES, m/z): RT = 0.663 min, LCMS 32: m/z = 383 [M+1]. lH-NMR: 219 (300 MHz, ol-d4) 5 8.84 (s, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.31 — 2.25 (m, 1H), 7.06 (d, J = 8.7 Hz, 1H), 4.23 (t, J = 5.4 Hz, 2H), 3.90 (d, J = 0.9 Hz, 6H), 3.88 — 3.78 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.20 — 2.13 (m, 2H), 2.36 — 2.27 (m, 2H), 2.27 — 2.16 (m, 2H), 2.15 — 2.00 (m, 2H).

LC-MS: (ES, m/z): RT = 1.016 min, LCMS 33: m/z = 368 [M+1]. lH-NMR: (300 MHz, Methanol-d4) 5 8.37 (s, 1H), 7.56 — 7.50 (m, 1H), 7.14 — 6.95 (m, 4H), 6.48 — 6.40 (m, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.88 (s, 3H), 2.79 — 2.70 (m, 2H), 2.70 — 2.58 (m, 4H), 2.12 — 2.00 (m, 2H), 1.90 — 1.78 (m, 4H).

LC-MS: (ES, m/z): RT = 1.81 min, LCMS 53: m/z = 381.25 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 10.80 (s, 1H), 8.09 (s, 1H), 7.61 — 7.44 (m, 1H), 7.21 (s, 1H), 7.04 (dd, J = 9.2, 2.1 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.6, 2.5 Hz, 1H), 4.11 (s, 3H), 4.01 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H), 3.62 — 3.47 (m, 2H), 3.32 — 3.20 (m, 2H), 3.07 — 2.90 (m, 2H), 2.23 — 1.80 (m, 6H).

LC-MS: (ES, m/z): RT = 1.33 min, LCMS 33:m/z = 381.20 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 8.16 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.98 — 6.73 (m, 5H), 4.11 (s, 3H), 4.01 (t, J = 5.8 Hz, 2H), 3.72 (s, 3H), 3.64 — 3.50 (m, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.06 — 2.91 (m, 2H), 2.17 — 1.99 (m, 4H), 2.00 — 1.87 (m, 2H).

LC-MS: (ES, m/Z): RT = 1.02 min 223 ; LCMS 33: m/Z = 382.22 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.01 (d, J = 9.8 Hz, 1H), 7.74 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.46 — 7.31 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.89 — 3.70(m, 5H), 3.52 (t, J = 7.0 Hz, 2H), 3.20 (s, 2H), 2.61 (m, 3H), 2.42 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT = 1.02 min, LCMS 33: m/z = 409 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.52 (s, 1H), 8.23 (s, 1H), 8.14 (d, J = 6.7 Hz, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.22 — 7.12 (m, 3H), 4.23 (t, J = 5.6 Hz, 2H), 4.02 (s, 3H), 3.93 (s, 3H), .80 (m, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.23 — 3.12 (m, 2H), 2.36 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT =1.13min,LCMS33: m/z = 438 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.82 (s, 1H), 7.73 (s, 1H), 7.38 — 7.30 (m, 2H), 7.09 (d, J = 8.6 Hz, 3H), 6.93 (t, J = 8.1 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.13 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.87 — 3.76 (m, 2H), 3.46 (t, J = 7.1 Hz, 2H), 3.19-3.12 (m, 2H), 2.31 — 2.16 (m, 4H), 2.16 — 2.03 (m, 2H).

LC-MS: (ES, m/z): RT = 1.032 min, LCMS 53: m/z = 441.35 [M+1]. 1H NMR (300 MHZ, Deuterium Oxide) 5 7.70 - 7.31 (m, 2H), 7.30 — 7.09 (m, 2H), 6.13 (d, J = 6.1 Hz, 1H), 4.01 — 3.81 (m, 5H), 3.72 — 3.52 (m, 2H), 3.52 — 3.16 (m, 8H), 3.12 — 2.91 (m, 2H), 2.24 — 1.75 (m,7H), 1.73 — 1.44 (m, 2H), 1.38 — 1.02 (m, 2H).

LC-MS: (ES, m/z): RT = 1.00min, LCMSO7: m/z = 442.27 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.22 (d, J = 3.0 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.49 (dd, J = 8.8, 3.0 Hz, 1H), 5.98 (d, J = 6.0 Hz, 1H), 4.12 — 3.86 (m, 7H), 3.49 — 3.33 (m, 4H), 2.78 — 2.58 (m, 6H), 2.09 — 1.93 (m, 3H), 1.94 — 1.74 (m, 6H), 1.46 — 1.25 (m, 2H).

LC-MS: (ES, m/z): RT = 0.918 min, LCMS 53: m/z = 441.35 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.05 — 7.92 (m, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.53 — 7.23 (m, 2H), .60 (m, 1H), 4.09 — 3.89 (m, 5H), 3.79 — 3.68 (m, 2H),3.63 — 3.51 (m, 2H), 3.50 — 3.36 (m, 6H), 3.22 — 3.07 (m, 2H), 2.44 — 1.85 (m, 7H), 1.85 — 1.62 (m, 2H), 1.49 — 1.25 (m, 2H).

LC-MS: (ES, m/Z): RT = 0.96 min, LCMS 53: m/Z = 376.2 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.92 — 7.83 (m, 1H), 7.49 — 7.35 (m, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 6.1 Hz, 1H), 5.13 (s, 2H), 4.16 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 3.13 — 2.88 (m, 6H), 2.82 (t, J = 7.3 Hz, 2H), 2.72 — 2.62 (m, 1H), 2.36 — 2.00 (m, 4H).

LC-Ms: (ES, m/z): RT = 0.94 min, LCMS 53: m/z = 362.2 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.91 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.10 — 6.95 (m, 2H), 6.84 (d, J = 8.7 Hz, 1H), 5.86 (d, J = 6.0 Hz, 1H), 5.10 — 4.92 (m, 2H), 4.10 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.79 — 3.62 (m, 2H), 3.28 — 3.05 (m, 2H), 2.99 (d, J = 5.1 Hz, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.06 — 1.89 (m, 2H).

LC-MS: (ES, m/z): RT =1.35mm,LCMs 07: m/z = 358 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.70 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.37 — 7.29 (m, 1H), 7.13 — 6.89 (m, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.21 (t, J = 8.2, 2H), 3.93 — 3.78 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.24 — 3.12 (m, 2H), 3.03 (s, 3H), 2.36 — 2.16 (m, 4H), 2.15 - 2.05 (m, 2H).

LC-MS: (ES, m/z): RT = 0.987 mm, LCMS 33: m/z =360 [M+1]. 1H NMR (300 MHz, Methanol-d4) 57.51—7.69 (m, 20 (t, J = 10.2 Hz, 1H), 6.78 - 6.92 (m, 1H) 6.08 (s, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.78-3.62 (m, 2H), 3.43-3.35 (m,2H), 3.16 - 3.02(m, 2H), 3.00 (s, 3H), 2.34 (s, 3H), 2.32 — 2.17 (m, 4H), 2.11 — 1.98 (m, LC-MS: RT= 1.076, m/z= 383.25 [M+1]. 1H NMR (300 MHz, Methanol-d4, ppm) : 8.37 (s, 1H), 7.21 — 7.10 (m, 3H), 4.21 (t, J = 5.5 Hz, 2H), 3.97 (s, 3H), 3.91 — 3.79 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.24 — 3.09 (m, 5H), 2.34 — 2.15 (m, 6H).

LC-MS: (ES, m/z): RT = 1.07 mm, LCMS 33: m/z = 426 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.15 (s, 1H), 7.41 — 6.89 (m, 3H), 4.21 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), .80 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.23 — 3.08 (m, 5H), 2.36 — 2.17 (m, 4H), 2.15 - 2.05 (m, 2H).

LC-MS: (ES, m/z): RT = 1.01 mm, LCMS 07: m/z = 426 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.51 — 7.92 (m, 1H), 7.21 — 7.03 (m, 3H), 4.19 (t, J = 5.5 Hz, 2H), 3.95 — 3.76 (m, 5H), 3.49 (t, J = 7.1 Hz, 2H), 3.20 — 3.10 (m, 2H), 2.93 (s, 3H), 2.37 — 2.14 (m, 4H), 2.10 — 1.98 (m, 2H).

LC-MS: RT= 1.035, m/z = 390.30 [M+1]. 1H NMR (300 MHz, Methanol-d4, ppm) : 7.54 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 3.00 (s, 3H), 2.89 — 2.70 (m, 6H), 2.21 (d, J = 2.9 Hz, 3H), 2.12 — 2.03 (m, 2H), 1.93 — 1.87 (m, 4H).

LC-MS: 237 (ES, m/z): RT = 0.938 mm, LCMS 28: m/z = 360.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.58 (d, J = 7.3 Hz, 1H), 7.32 — 7.19 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.17 (d, J = 7.3 Hz, 1H), 4.50 — 4.36 (m, 2H), 4.22 — 3.98 (m, 2H), 3.92 — 3.72 (m, 5H), 3.72 — 3.62 (m, 4H), 3.43 — 3.30 (m, 2H), 3.03 (s, 3H).

LC-MS: (ES, m/z): RT = 1.356 mm, LCMS 07: m/z = 426 [M+1]. lH-NMR: (400 MHz, Methanol-d4) 5 7.69 (s, 1H), 7.13 — 7.05 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.10 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.98 (s, 3H), 2.78 — 2.68 (m, 2H), 2.64 (q, J = 4.8 Hz, 4H), 2.8 — 2.00 (m, 2H), 1.91 — 1.78 (m, 4H).

LC-MS: (ES, m/z): RT = 0.911 mm, LCMs33: m/z = 341 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.53 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.20 — 7.16 (m, 1H), 6.19 (d, J = 7.2 Hz, 1H), 4.23 (t, J = 8.4 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.28 (t, J = 8.1 Hz, 2H), 3.13 — 2.99 (m, 5H), 2.97 (s, 6H).

LC-MS: (ES, m/z): RT = 1.044 mm, LCMSO7: m/z = 386.15 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.61 (s, 1H), 7.08 — 7.05 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), .81 (s, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 2.80 — 2.71 (m, 2H), 2.71— 2.61 (m, 4H), 2.47 (q, J = 7.6 Hz, 2H), 2.12 — 2.00 (m, 2H), 1.92 — 1.80 (m, 4H), 1.25 (t, J = 7.6 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.17 mm, LCMS 33: m/z = 464.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.43 (d, J = 5.1 Hz, 1H), 7.63 — 7.44 (m, 5H), 7.39 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H), 4.35 (s, 2H), 4.26 (t, J = 5.6 Hz, 2H), 4.07 (dd, J = 12.0, 4.6 Hz, 2H), 3.84 (s, 3H), 3.69 (t, J = 6.8 Hz, 2H), 3.53 — 3.40 (m, 3H), 2.29 — 2.21 (m, 2H), 2.14 — 2.05 (m, 2H), 1.80 — 1.65 (m, 2H).

LC-MS: (ES, m/z): RT = 1.067 mm, LCMS 33: m/z = 483 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.87 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.93 — 6.82 (m, 2H), 6.12 (d, J = 2.5 Hz, 1H), 4.27 (d, J = 12.9 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.92 — 3.58 (m, 6H), 3.34 (t, J = 7.5 Hz, 2H), 3.16 — 2.95 (m, 5H), 2.59 (dd, J = 141,113 Hz, 1H), 2.25 — 1.60 (m, 12H), 1.20 — 0.90 (m, 2H).

LC-MS: (ES, m/z): UFLC 06:RT = 6.901 min, LCMS 53: m/z = 440.3 [M+1]. 1H NMR (300 MHz, Deuteﬁum Oxide) 5 7.42 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 1.6 Hz, 2H), 6.85 — 6.71 (m, 1H), 6.05 (dd, J = 7.4, 1.7 Hz, 1H), 4.64 — 4.56 (m, 1H), 4.33 (t, J = 12.7, 2.3 Hz, 2H), 4.08 — 3.97 (m, 2H), 3.96 — 3.82 (m, 2H), 3.77 (s, 3H), 3.46 — 3.25 (m, 2H), 3.25 — 3.12 (m, 2H), 2.89 — 2.72 (m, 5H), 2.46 — 2.31 (m, 2H), 1.88 — 1.72 (m, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.25 — 1.06 (m, 2H).

LC-MS: (ES, m/z): RT = 0.95min, LCMs33: m/z = 346 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.66 (d, J = 7.3 Hz, 1H), 7.45 (dd, J = 6.3, 3.0 Hz, 1H), 7.22 (m, 1H), 6.93 (m, J = 9.2, 3.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.72 (d, J = 5.8 Hz, 2H), 3.50 — 3.33 (m, 2H), 3.15 (t, J = 13.0 Hz, 2H), 3.02 (s, 3H), 2.24 (m, 4H), 2.16 — 2.02 (m, 2H).

LC-MS: (ES, m/z): RT = 1.004 min, LCMS 07: m/z = 344.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.65 (d, J = 7.3 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 1.3 Hz, 2H), 6.20 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.29 — 3.02 (m, 2H), 2.34 — 2.01 (m, 6H).

LC-MS: (ES, m/z): RT = 0.907 min, LCMS 07: m/z = 358.05 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.01 (d, J = 2.5 Hz, 1H), 7.25 — 7.14 (m, 1H), 6.94 (d, J =13 Hz, 2H), 5.96 (d, J = 2.4 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.84 (s, 3H), 2.78 (s, 5H), 2.70 (s, 4H), 2.12 — 1.99 (m, 2H), 1.90 — 1.80 (m, 4H).

LC-MS: (ES, m/z): RT = 1.41 min, LCMS 07: m/z = 358 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.44 (d, J = 2.5 Hz, 1H), 7.30 — 7.13 (m, 3H), 7.07 — 6.98 (m, 1H), 4.22 (t, J = 5.5 Hz, 2H), 4.02 — 3.77 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.22— 3.12 (m, 2H), 3.03 (s, 3H), 2.37 — 2.02 (m, 6H).

LC-MS: (ES, m/z):RT = 0.871 min, LCMS 07: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.03 (s, 1H), 7.77 (d, J = 6.9 Hz, 1H), 7.27 (s, 1H), 6.81 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 4.53 (s, 2H), 4.00 (s, 3H), 3.89 — 3.75 (m, 2H), 3.49 (t, J = 7.0 Hz, 2H), 3.18 — 3.10 (m, 2H), 3.00 (s, 3H), 2.40 — 2.39 (m, 2H), 2.30 — 2.06 (m, 4H).

LC-MS: (ES, m/z): RT = 0.577 min, LCMS 30: m/z = 368.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.30 (s, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.26 — 7.07 (m, 4H), 4.23 (t, J = 5.6 Hz, 2H), 3.96 (s, 3H), 3.82 (s, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.21 — 3.15 (m, 2H), 2.38 — 2.23 (m, 2H), 2.21 — 2.14 (m, 4H).

LC-MS: (ES, m/z): RT = 0.974 min, LCMS 33: m/z = 367.21 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.90 (d, J = 7.1 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 6.81 - 6.69 (m, 2H), 4.21 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.90 — 3.76 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 — 3.10 (m, 2H), 2.37 — 2.04 (m, 6H) LC-MS: (ES, m/z): RT = 1.07 min, LCMS 53: m/z = 374.2 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.94 (d, J = 5.7 Hz, 1H), 7.40 (t, J = 2.2 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.08 — 7.04 (m, 1H), 6.99 (s, 1H), 6.55 — 6.51 (m, 1H), 5.84 (d, J = 5.7 Hz, 1H), 5.30 — 5.05 (m, 1H), 4.66 (d, J = 7.8 Hz, 1H), 4.06 (t, J = 6.3 Hz, 3H), 3.03 = 6.3 Hz, 6H). — 2.64 (m, 5H), 2.57 — 2.42 (m, 1H), 2.32 — 1.95 (m, 4H), 1.28 (d, J LC-MS: (ES, m/z): RT = 0.943 min, LCMS 28: m/z = 344 [M+1]. lH-NMR: (300 MHz, Methanol-d4) 5 7.74 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.22 — 7.09 (m, 2H), 6.64 — 6.52 (m, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.18-4.06 (m, 1H), 4.04 — 3.89 (m, 2H), 2.94 (s, 3H), 2.84 — 2.78 (m, 1H), 2.77 — 2.57 (m, 5H), 1.96 — 1.74 (m, 4H).

LC-MS: (ES, m/Z): RT = 0.943 min, LCMS 28: m/Z = 344 [M+1]. 1H-NMR: (300 MHz, Methanol-d4) 5 7.74 (d, J = 5.7 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.22 — 7.05 (m, 2H), 6.61 — 6.52 (m, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.19 — 4.06 (m, 1H), 4.05 — 3.90 (m, 2H), 2.94 (s, 3H), 2.84 — 2.96 (m, 1H), 2.76 — 2.57 (m, 5H), 1.93 — 1.75 (m, 4H).

LC-MS: (ES, m/z): RT = 0.83min, : m/z = 414 [M+1]. 1H NMR (300 MHZ, Methanol-d4) 5 7.75 (d, J = 6.7 Hz, 1H), 7.21 (s, 1H), 7.16 — 7.04 (m, 2H), 6.41 (d, J = 6.5 Hz, 1H), 4.39-4.36 (m, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.99-3.92 (m, 4H), 3.89 — 3.64 (m, 5H), 3.51-3.42 (m, 3H), 3.27 — 3.09 (m, 2H), 2.60-2.07 (m, LC-MS: (ES, m/z): RT =1.22min, LCMS 33: m/z = 382 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.20 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.7, 2.4 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 9.1Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 4.09 (s, 3H), 3.90 (s, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.25 — 3.09 (m, 2H), 2.39 — 2.04 (m, 6H).

LC-MS: (ES, m/z): RT = 0.871 min, LCMS 33: m/z = 382 [M+1]. 1H NMR (Methanol-d4, ppm): 5 8.75 (s, 1H), 8.59 (s, 1H), 7.19 — 6.98 (m, 4H), 4.23 (t, J = .6 Hz, 2H), 3.98 — 3.76 (m, 8H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 — 3.10 (m, 2H), 2.38 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT= 1.801 min, LCMS 31, m/z = 482.5 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.57 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 17.2 Hz, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.53 — 4.24 (m, 1H), 4.07 — 3.82 (m, 5H), 3.82 — 3.50 (m, 2H), 3.49 — 3.35 (m, 4H), 3.30 — 3.15 (m, 1H), 2.96 (d, J = 4.1 Hz, 4H), 2.25 — 1.18 (m, 15H).

LC-MS: (ES, m/z): RT = 1.069 min, m/z = 468.35 [M+1]. 1H NMR (300 MHz, Deuteﬁum Oxide) 5 7.37 (d, J = 7.3 Hz, 1H), 6.99 — 6.84 (m, 2H), 6.82 — 6.70 (m, 1H), 5.97 (d, J = 7.5 Hz,1H), 4.15 — 3.92 (m, 3H), 3.88 — 3.61 (m, 7H), 3.37 — 3.13 (m, 2H), 3.12 — 2.98 (m, 2H), 2.81 (s, 3H), 2.05 — 1.81 (m, 2H), 1.85— 1.23 (m, 9H), 1.22 — 0.91 (m, 2H).

LC-MS: (ES, m/z): RT = 0.720 min, LCMS 32: m/z = 388 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 2.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.25 (s, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.87 (s, 3H), 2.77 — 2.68 (m, 2H), 2.62 (d, J = 5.7 Hz, 4H), 2.08-2.00 (m, 2H), 1.88-1.80 (m, LC-MS: (ES, m/z): RT = 0.964 min 262a , m/z = 334 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.59 (d, J = 6.2 Hz, 1H), 5.91 (d, J = 6.6 Hz, 1H), 3.91 (d, J = 8.6 Hz, 1H), 3.73 — 3.39 (m, 3H), 3.35 — 3.18 (m, 4H), 2.92 (s, 3H), 2.38 — 2.25 (m, 1H), 2.17 — 1.78 (m, 10H), 1.50 — 1.20 (m, 5H).

LC-MS: (ES, m/z): RT = 0.964 min, m/z = 334 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.59 (d, J = 6.2 Hz, 1H), 5.87 (d, J = 6.6 Hz, 1H), 3.91 — 3.69 (m, 1H), 3.73 — 3.39 (m, 3H), 2.85 (s, 3H), 2.78 — 2.61 (m, 6H), 2.32 — 2.21 (m, 1H), 2.00 — 1.75 (m, 9H),1.50 — 1.11 (m, 4H).

LC-MS: (ES, m/z): RT = 1.07min, LCMS07: m/z = 408.15[M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.12-8.09 (m,1H), 7.84-7.80 (m, 1H), 7.61 — 7.53 (m, 1H), .46 (m, 1H), 7.25 (s, 1H), 7.20 — 7.07 (m, 2H), 4.22 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.89 — 3.78 (m, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.19-3.14 (m, 5H), 2.36 — 2.16 (m, 4H), 2.10-2.07 (m, 2H).

LC-MS: (ES, m/z): RT=0.695min, LCMS 40, m/z =367 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.35 (d, J = 2.4 Hz, 1H), 7.75 — 7.60 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 3.96 (t, J = 6.1 Hz, 2H), 3.90 — 3.80 (m, 2H), 3.73 (t, J = 6.7 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 3.27 — 3.08 (m, 4H), 3.06 (s, 3H), 2.29 — 1.98 (m, 4H).

LC-MS: (ES, m/z): RT = 2.07min, LCMSO7: m/z = 366.20 [M+1]. 1H NMR (300 MHz, 6) 5 10.96 (s, 1H), 9.38 (s, 1H), 7.70 (s, 1H), 7.31 — 7.15 (m, 1H), 6.90 (dd, J = 7.7, 3.0 Hz, 3H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 — 6.65 (m, 1H), 6.55 (t, J = 2.5 Hz, 1H), 3.99 (t, J = 5.8 Hz, 2H), 3.74 (s, 3H), 3.62 (s, 2H), 3.34-3.26 (m, 2H), 3.06-3.03 (m, 2H), 2.19 — 1.98 (m, 4H), 1.93 — 1.79 (m, 2H).

LC-MS: (ES, m/z): RT = 1.021 min, LCMS 33: m/z = 367 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.51 — 7.38 (m, 2H), 7.24 — 7.04 (m, 4H), 6.92 (d, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 13.2 Hz, 2H), 2.36 — 2.02 (m, 6H).

LC-MS: (ES, m/z): RT= 1.04 267 min, LCMS 45: m/z = 328 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.88-7.86 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H), 6.11 (s, 1H), 4.83 (s, 2H), 4.01 — 3.91 (m, 2H), 3.84-3.68 (m, 2H), 3.59 — 3.49 (m, 2H), 3.28 — 3.13 (m, 2H), 2.95 (s, 3H), 2.25 — 2.01 (m, 4H).

LC-MS: (ES, m/z): RT= 0.94 min, LCMS 28: m/z = 328 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.71 (d, J = 6.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 7.4, 1.1 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 6.0, 2.0 Hz, 1H), 4.59 (s, 2H), 3.81-3.63 (m, 2H), 2.87 (s, 3H), 2.85-2.72 (m, 2H), 2.70 — 2.58 (m, 4H), 1.85-1.68 (m, 4H).

LC-MS: (ES, m/z): RT = 0.985 min, LCMS 07: m/z = 375 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.62 (d, J = 5.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 — 6.90 (m, 2H), 5.96 (d, J = 7.2 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.85-3.75 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 — 3.09 (m, 2H), 2.92 (s, 3H), 2.37 — 2.02 (m, LC-MS: (ES, m/z): RT=1.529 min, LCMS 33, m/z =346.0 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.49 (d, J = 7.4 Hz, 1H), 7.43 — 7.34 (m, 1H), 7.25 — 7.05 (m, 2H), 3.95 — 6.88 (m, 1H), 6.36 — 5.98 (m, 1H), 5.13 — 4.98 (m, 1H), 4.96 — 4.80 (m, 1H), 4.57 — 4.33 (m, 2H), 4.10 — 3.90 (m, 1H), 3.89 — 3.59 (m, 2H), 3.47 — 3.22 (m, 2H), 2.94 (s, 3H), 2.28 — 1.83 (m, 4H).

LC-MS: (ES, m/z): RT = 1.348 min, LCMS 27: m/z = 364 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.64 (d, J = 7.3 Hz, 1H), 7.46 — 7.27 (m, 3H), 6.97 — 6.84 (m, 1H), 6.22 (d, J = 7.3 Hz, 1H), 4.48 (t, J = 12.2 Hz, 2H), 4.23 — 4.06 (m, 2H), 3.78 — 3.33 (m, 4H), 3.06 (s, 3H), 2.17 (s, 4H).

LC-MS: (ES, m/z): 21min, LCMS 30, m/z =342 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.68 — 7.58 (m, 3H), 7.53 — 7.40 (m, 1H), 7.30 — 7.20 (m, 1H), 6.21 (d, J = 7.3 Hz, 1H), 4.58 (q, J = 6.4 Hz, 1H), 3.75 — 3.54 (m, 4H), 3.48 — 3.34 (m, 2H), 3.22 — 2.99 (m, 5H), 2.20 — 1.99 (m, 4H), 1.53 (d, J = 6.5 Hz, 3H).

LC-MS: (ES, m/z): RT=0.969min, LCMS 15, m/z =360 [M+1].1H NMR (300 MHz, Methanol-d4) 5 7.57 (d, J = 7.3 Hz, 1H), 7.22 (s, 1H), 7.10 (d, J = 1.9 Hz, 2H), 6.19 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.51 — 3.28 (m, 6H), 3.03 (s, 3H), 2.36 — 2.20 (m, 2H), 1.39 (t, J = 7.3 Hz, 6H).

LC-MS: (ES, m/z): RT=0.651min, LCMS 07, m/z =388.4 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.1 Hz, 1H), 7.52 — 7.43 (m, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.18 — 3.90 (m, 3H), 3.81 (s, 3H), 3.29 (s, 3H), 2.93 (s, 3H), 2.83 — 2.48 (m, 6H), 2.18 — 1.94 (m, 3H), 1.88 — 1.76 (m, 1H).

LC-MS: (ES, m/z): RT = 0.57min, LCMS48: m/z = 426 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.56 (d, J = 7.3 Hz, 1H), 7.20 (s, 1H), 7.04-7.10 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.19 (t, J = 5.4 Hz, 3H), 3.99 - 3.87 (m, 5H), 3.69-3.42 (m, WO 81177 4H), 3.03 (s, 3H), 2.51 — 2.26 (m, 4H).

LC-MS: (ES, m/z): RT = 0.934 min, LCMS 07: m/z = 374 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 5.9 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), .30 (m, 1H), 4.14 — 4.03 (m, 2H), 3.82 (s, 3H), 2.97 — 2.47 (m, 9H), 2.24 — 1.92 (m, 3H), 1.80-1.70 (m, 1H).

LC-MS: (ES, m/z): RT = 1.021 min, LCMS 33: m/z = 383 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, 1H), 7.20 (s, 1H), 7.09 (d, 2H), 6.18 (d, 1H), 4.35-4.10(m, 3H), 4.10-3.92 (m, 4H), 3.90-3.48 (s, 5H), 3.03 (s, 3H), 2.87- 2.36 (s, 2H), 2.32 (s, 2H).

LC-MS: (ES, m/z): RT = 2.22 min, LCMS 27: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.80-7.70 (m, 1H), 7.50 (s, 1H), 7.10 — 7.00 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.96 (d, J = 7.2 Hz, 1H), 4.15-4.05 (m, 2H), 3.80 (s, 3H), 3.15-3.05 (m,1H), 2.95 (s, 3H), 2.50 — 2.40 (m, 4H), 2.35 — 2.20 (m, 2H), 2.20 — 2.10 (m, 1H), 1.85 — 1.55 (m, 4H).

LC-MS: (ES, m/z): RT = 0.92min, LCMSO7: m/z = 344.10 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.52 (s, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.04 (d, J = 5.8 Hz, 2H), 3.82 (s, 3H), 3.21 — 3.08 (m, 1H), 2.94 (s, 3H), 2.94-2.83(m, 1H), 2.59 (d, J = 1.3 Hz, 3H), 2.40 (q, J = 9.0 Hz, 1H), 2.19 — 2.06 (m, 1H), 1.90-1.82 (m, 2H), 1.77-1.68 (m, 1H). 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 7.3 Hz, 1H), 7.29 — 7.18 (m, 1H), 7.09 (d, J = 1.0 Hz, 2H), 6.18 (d, J = 7.3 Hz, 1H), 4.30 — 4.12 (m, 2H), 3.94 — 3.49 (m, 6H), 3.30-3.20(m, 2H), 3.03 (s, 3H), 2.48 — 2.03 (m, 5H), 1.90 — 1.70 (m, 1H), 1.51 (d, J = 6.5 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.412 min, LCMS 34: m/z = 273 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.73 (s, 2H), 8.26 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H), 3.53 (, J = 7.3 Hz, 2H), 3.20 (s, 3H), 1.30 (t, J = 7.3 Hz, 3H).

LC-MS: (ES, m/z): RT =1.055 min, LCMS 28: m/z = 372 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.48 (s, 1H), 7.08 (d, J = 6.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.02 (d, J = 8.8 Hz, 1H), 2.93 (s, 3H), 2.87 (s, 1H), 2.79 (d, J = 8.0 Hz, 2H), 2.68 (s, 1H), 2.34 — 2.28 (m, 1H), 2.21 (d, J = 8.0 Hz, 1H), 2.13 — 2.01 (m, 3H), 1.45 (d, J :80 Hz, 1H), 1.09 (d, J = 6.8 Hz, 3H).

LC-MS: (ES, m/z): RT = 0.978 min, LCMs15: m/z = 370.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.50 — 7.44 (m, 1H), 7.08 — 7.06 (m, 1H), 6.89 (d, J = 8.6 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 — 4.02 (m, 2H), 3.82 (s, 3H), 3.08 (d, J = 9.2 Hz, 2H), 2.93 (s, 3H), 2.68 (t, J = 7.6 Hz, 2H), 2.46 (d, J = 9.2 Hz, 2H), 2.01 — 1.95 (m, 2H), 1.49 — 1.41 (m, 2H), 0.68 (q, J = 4.1 Hz, 1H), 0.43 (q, J = 7.2 Hz, 1H).

LC-MS: (ES, m/z): RT=0.590min, LCMS 30, m/z =374 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.22 — 4.09 (m, 1H), 4.09 — 3.91 (m, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 2.90 — 2.65 (m, 6H), 1.92 — 1.78 (m, 4H).

LC-MS: (ES, m/z): RT=0.592min, LCMS 30, m/z =374 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.0 Hz, 1H), 7.53 (s, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.23 — 3.90 (m, 3H), 3.85 (s, 3H), 2.94 (s, 3H), 2.89 — 2.64 (m, 6H), 1.92 — 1.78 (m, 4H).

LC-MS: (ES, m/z): RT = in, LCMS 27: m/z = 390 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.35 — 7.23 (m, 2H), 5.85 (s, 1H), 4.02 (t, J = 6.1 Hz, 2H), 3.87 (s, 3H), 2.94 (s, 3H), 2.84 — 2.75 (m, 2H), 2.72 — 2.62 (m, 4H), 2.20 (s, 3H), 2.03 — 1.81 (m, 6H).

LC-MS: (ES, m/z): RT = 1.013 min, LCMs15: m/z = 390 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.10 (s, 1H), 6.86 (d, J = 12.4 Hz, 1H), 5.85 (s, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 2.93 (s, 3H), 2.71 — 2.66 (m, 2H), 2.59 (s, 4H), 2.19 (s, 3H), 2.05 — 1.96 (m, 2H), 1.93 — 1.77 (m, 4H).

LC-MS: (ES, m/z): RT = 0.529 min, LCMS48: m/z = 373.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.00 (s, 1H), 6.73 (s, 1H), 6.16 (d, J = 1.2 Hz, 1H), 4.28 (t, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.86 — 3.76 (m, 2H), 3.47 (t, J = 7.2 Hz, 2H), 3.22 — 3.10 (m, 2H), 3.04 (s, 3H), 2.47 — 2.42 (m, 3H), 2.41 — 2.29 (m, 2H), 2.26 — 2.24 (m, 2H), 2.24 — 2.19 (m, 2H).

LC-MS: (ES, m/z): RT = 1.019 min, LCMs15: m/z = 368.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.05 (s, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 3.3 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.35 — 7.30 (m, 1H), 7.11 (s, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.98 (d, J = 1.1 Hz, 3H), 3.88 — 3.78 (m, 2H), 3.50 (t, J = 7.3 Hz, 2H), 3.24 — 3.13 (m, 2H), 2.43 — 2.36 (m, 2H), 2.28 — 2.23 (m, 2H), 2.19 — 2.04 (m, 2H).

LC-MS: (ES, m/z): RT =0.958min, LCMS 28: m/z = 358 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.92 (s, 1H), 7.70 (s, 1H), 6.59 (s, 1H), 6.45 (d, J = 9.1 Hz, 1H), 6.00 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.89 — 3.74 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.24 — 3.08 (m, 2H), 2.93 (s, 3H), 2.46 — 2.30 (m, 2H), 2.23 (q, J = 9.0, 2H), 2.09 — 2.06 (m, 2H).

LC-MS: (ES, m/z): RT = 1.30 min, LCMS 53: m/z = 372.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.95 (d, J = 1.3 Hz, 1H), 6.61 (s, 1H), 6.26 (s, 1H), 5.91 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.87 — 3.76 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.22 — 3.10 (m, 2H), 2.92 (s, 3H), 2.55 — 2.45 (m, 3H), 2.40 — 2.16 (m, 4H), 2.16 — 2.00 (m, 2H).

LC-MS: (ES, m/z): RT =1.30 min, LCMS 53: m/z = 372.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.95 (d, J = 1.3 Hz, 1H), 6.61 (s, 1H), 6.26 (s, 1H), 5.91 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.87 — 3.76 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.22 — 3.10 (m, 2H), 2.92 (s, 3H), 2.55 — 2.45 (m, 3H), 2.40 — 2.16 (m, 4H), 2.16 — 2.00 (m, 2H).

LC-MS: (ES, m/z): RT = 2.72 min, LCMS 33: m/z = 372.3 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.95 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 6.66 (s, 1H), 4.92 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.83 — 3.78 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.19 — 3.14 (m, 2H), 3.00 (s, 3H), 2.61 — 2.41 (m, 3H), 2.40 — 2.30 (m, 4H), 2.26 — 2.21 (m, 2H).

LC-MS: (ES, m/z): RT = 1.107 min, : m/z = 390 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.95 (s, 1H), 6.62 (s, 1H), 6.07 (d, J = 6.5 Hz, 1H), 4.29 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.16 (q, J = 8.6 Hz, 2H), 2.97 (s, 3H), 2.51 (d, J = 3.2 Hz, 3H), 2.39 — 2.37 (m, 2H), 2.21 (q, J = 6.7 Hz, 2H), 2.14 — 2.02 (m, 2H).

LC-MS: (ES, m/z): RT = 1.802 min , m/z = 382.2 [M+1]. 1H NMR (300 MHz, Deuten‘um Oxide) 5 6.97 — 6.72 (m, 2H), 6.46 — 6.15 (m, 2H), 6.01 — 5.82 (m, 1H), 3.75 — 2.65 (m, 11H), 2.29 — 1.66 (m, 9H).

LC-MS: (ES, m/z): RT = 2.10 min, LCMS 53: m/z = 319.2 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 8.74 (s, 1H), 7.70 (s, 1H), 7.20 (q, J = 8.7 Hz, 1H), 6.93 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.75 (s, 1H), 4.08 — 3.98 (m, 2H), 3.73 — 3.62 (m, 5H), 3.32 (s, 3H), 2.82 (d, J = 4.5 Hz, 3H), 2.11 (s, 3H).

LC-MS: (ES, m/z): RT = 1.221 min, LCMS 33: m/z = 333 [M+H1]. 1H NMR (400 MHz, Methanol-d4) 5 7.60 (s, 1H), 7.06-7.02 (m, 1H), 6.89 (d, J = 8.7 Hz, 1H), .81 (d, J = 0.8 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.82 (s, 3H), 3.61 (t, J = 6.2 Hz, 2H), 3.37 (s, 3H), 2.93 (s, 3H), 2.19 (s, 3H), 2.10-2.04 (m, 2H).

UPLC: (ES, m/z): RT = 2.42 min, UPLC 07: m/z = 382 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.26 (d, J = 2.0 Hz, 1H), 7.12 — 7.06 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 4.19 (t, J = 5.8 Hz, 2H), 3.81 — 3.72 (m, 2H), 3.55 — 3.46 (m, 2H), 3.22 — 3.12 (m, 2H), 3.03 (s, 3H), 2.39 — 2.28 (m, 5H), 2.23 — 2.03 (m, 5H), 0.99 — 0.91 (m, 2H), 0.70 — 0.63 (m, 2H).

LC-MS: (ES, m/z): RT = 1.167 min, LCMS 28: m/z = 368 [M+1]. : (400 MHz, Methanol-d4) 5 7.58 (d, J = 7.3 Hz, 1H), 7.18 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.18 (d, J = 7.3 Hz, 1H), 4.18 (t, J = 5.7 Hz, 2H), 3.74 (s, 2H), 3.54 — 3.45 (m, 2H), 3.25 — 3.12 (m, 2H), 3.05 (s, 3H), 2.36 — 3.28 (m, 2H), 2.22 — 2.12 (m, 5H), 1 — 0.90 (m, 2H), 0.73 — 0.60 (m, 2H).

LC-MS: (ES, m/z): RT =1.160min, LCMS 33: m/z =412 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.67 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.45 — 7.27 (m, 2H), 6.24 (d, J = 7.3 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.75 — 3.69 (m, 2H), 3.50 = 8.4 Hz, 2H), 3.07 (s, 3H), 2.31 — 3.39 (m, 2H), 3.15 (q, J — 2.29 (m, 2H), 2.20 (d, J = 9.1 Hz, 2H), 2.07 (t, J = 6.6 Hz, 2H).

LC-MS: (ES, m/z): RT=12min, LCMS 31, m/z =358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.22 (dd, J = 8.7, 2.4 Hz, 1H), 7.12 — 6.99 (m, 2H), 6.01 (d, J = 1.0 Hz, 1H), 4.67 — 4.49 (m, 1H), 3.86 (s, 3H), 3.60 — 3.44 (m, 1H), 3.11 — 2.95 (m, 5H), 2.87 (s, 6H), 2.50 — 2.27 (m, 5H).

LC-MS: (ES, m/z): RT = n, LCMs33: m/z = 372 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.36 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.81 (s, 1H), 4.68-4.65 (m, 1H), 3.82 (s, 3H), 2.93 (s, 3H), 2.78 = 6.9 Hz, 2H), 2.36 (s, 6H), 2.36-2.13 (m, 4H), 1.99 — 2.69 (m, 2H), 2.62 (d, J — 1.79 (m, 2H).

LC-MS: (ES, m/z): RT= 0.83 min, LCMS 45: m/z = 404 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.26 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.7, 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.90-3.80 (m, 5H), 3.50 (t, J = 7.1 Hz, 2H), 3.07 (s, 5H), 2.78-2.56 (m, 2H), 2.37 — 2.02 (m, 6H), 1.33 (t, J = 7.6 Hz, 3H).

LC-MS: (ES, m/z): RT=1.780min, LCMS 31, m/z =398 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.34 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.7, 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 5.86 (s, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.89 (s, 3H), 3.87 — 3.78 (m, 2H), 3.49 (t, J = 7.0 Hz, 2H), 3.25 — 3.09 (m, 2H), 3.00 (s, 3H), 2.35 — 2.16 (m, 4H), 2.15 — 2.02 (m, 2H), 1.99 — 1.86 (m, 1H), 1.32 — 1.11 (m, 2H), 1.09 — 0.95 (m, LC-MS: (ES, m/Z): RT = 0.758 min, LCMS 332 m/z = 368 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.71-8.59 (m,1H), 8.31-8.19 (m, 1H), .00(m, 2H), 7.65-7.55(m, 1H),7.61 — 7.50 (m, 1H), 6.88— 6.75 (m, 1H), 4.30 (s, 2H), 3.90 (s, 3H), 3.89-3.75 (m, 2H), 3.42 (s, 2H), 3.20-3.09 (m, 2H), 2.30 (s, 2H),2.28 — 2.02 (m, 4H).

LC-MS: (ES, m/Z): RT = 0.96min, LCMS33: m/Z = 359.00 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.08 (s, 1H), 8.01 (s, 1H), 6.68 (s, 1H), 6.18 (s, 1H), 4.28 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.95-3.75 (m, 2H), 3.48 (t, J = 7.4 Hz, 2H), 3.17 (s, 2H), 2.98 (s, 3H), 2.42 — 2.30 (m, 2H), 2.26-2.23 (m, 2H), 2.08 (t, J = 6.5 Hz, 2H).

LC-MS: (ES, m/z): RT=0.836min, LCMS 15, m/z =359.2 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 8.08 — 7.92 (m, 2H), 7.09 (s, 1H), 6.26 (d, J = 2.4 Hz, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.73 — 3.56 (m, 2H), 3.36 (d, J = 17.0 Hz, 5H), 3.10 — 2.95 (m, 2H), 2.32 — 1.78 (m, 6H).

LC-MS: (ES, m/z): RT = 0.888min, LCMS 33: m/z = 359 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.40 (s, 1H), 7.92 (s, 1H), 6.70 (s, 1H),6.10-5.90 (m, 1H), 4.31 (t, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.85-3.75 (m, 2H), 3.47 (t, J = 7.4 Hz, 2H), .15 (m, 2H), 3.05-2.95 (m, 3H), .30 (m, 2H), 2.22 (s, 2H), 2.10-2.00 (m, 2H).

LC-MS: (ES, m/z): RT = 0.918 min, LCMS 33: m/z = 373 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.99 (s, 1H), 6.67 (s, 1H), 6.00 (s, 1H), 4.28 (s, 2H), 3.94 (s, 3H), 3.80 (s, 2H), 3.47 (s, 2H), 3.21 — 3.08 (m, 2H), 2.99 (s, 3H), 2.59 (s, 3H), 2.35 (s, 2H), 2.22 (s, 2H), 2.08 (s, 2H) LC-MS: (ES, m/z): RT = 0.958 min, LCMS 33: m/z = 383 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.14 (s, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.09 — 6.98 (m, 2H), 4.36 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.90-3.80 (m, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.19 (s, 2H), 2.83 (s, 3H), 2.45-2.35 (m, 2H), 2.30-2.20 (m, 2H), 2.15-2.05 (m, 2H).

LC-MS: (ES, m/z): RT = 1.196 min, m/z = 398.3[M+1]. 1H NMR (300 MHz, Deuten‘um Oxide) 57.22 — 7.12 (m, 1H), 7.07 — 6.92 (m, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.75 — 3.58 (m, 2H), 3.33 (t, J = 7.5 Hz, 2H), 3.11 — 2.95 (m, 2H), 2.89 (s, 3H), 2.72 (t, J = 7.7 Hz, 2H), 2.55 — 2.42 (m, 2H), 2.23 — 1.89 (m, 8H).

LC-MS: (ES, m/z): RT=1.021min, LCMS 31, m/z =358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.18 (dd, J = 8.7, 2.4 Hz, 1H), 7.14 — 6.96 (m, 2H), 6.04 — .96 (m, 1H), 4.13 — 3.96 (m, 1H), 3.87 (s, 3H), 3.37 — 3.34 (m, 1H), 3.04 — 2.97 (m, 3H), 2.91 — 2.75 (m, 8H), 2.71 — 2.59 (m, 2H), 2.31 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.115 min 330 , m/z = 372.0 [M+1]. 1H NMR (300 MHz, Deuten‘um Oxide) 5 7.19 — 7.06 (m, 1H), 6.96 — 6.29 (m, 2H), 5.86 — 5.40 (m, 1H), 3.95 — 3.76 (m, 1H), 3.76 — 3.38 (m, 5H), 2.79 — 2.43 (m, 9H), 2.41 — 2.25 (m, 2H), 2.25 — 2.02 (m, 2H), 1.97 — 1.83 (m, 3H).

LC-MS: (ES, m/z): RT = 0.99min, LCMs33: m/z =372 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.24 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 4.83 — 4.75 (m, 1H), 3.83 (s, 3H), 2.92 (s, 3H), 2.68 (d, J = 4.7 Hz, 3H), 2.53 — 2.24 (m, 10H), 2.19 (s, 3H).

LC-MS: (ES, m/z): RT = 2.247 min, m/z = 373.2 [M+1]. 1H NMR (300 MHz, Deuten‘um Oxide) 5 7.76 — 7.65 (m, 1H), 7.53 — 7.09 (m, 1H), 6.07 — 5.83 (m, 1H), 4.17 — 3.95 (m, 2H), 3.91 — 3.80 (s, 3H), 3.74 — 3.48 (m, 2H), 3.38 — 3.23 (m, 2H), 3.11 — 2.94 (m, 2H), 2.94 — 2.74 (m, 3H), 2.26 — 2.00 (m, 7H), 1.97 — 1.82 (m, 2H).

LC-MS: (ES, m/z): RT = 1.032 min, LCMS 28: m/z = 355 [M+1]. lH-NMR-PH- EPI-K—351-100: (300 MHz, Methanol-d4) 5 12.19 (s, 1H), 7.90 (d, J = 7.1 Hz, 1H), 7.64 — 7.49 (m, 1H), 7.35 —7.25 (m, 1H), 7.21 —7.13 (m, 1H), 6.32 (s, 1H), 4.76 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.93 — 3.85 (m, 2H), 3.74 —3.66 (m, 2H), 3.53 — 3.45 (m, 2H), 3.24 — 3.08 (m, 2H), 2.25 — 2.11 (m, 2H), 2.11 — 1.96 (m, 2H), 1.53 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT=0.955min, LCMS 40, m/z =358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.42 — 7.29 (m, 1H), 7.27 — 6.99 (m, 2H), 6.06 — 5.98 (m, 1H), 4.52 — 4.04 (m, 6H), 3.95 — 3.86 (m, 3H), 3.49 (q, J = 7.3 Hz, 2H), 3.40 — 3.33 (m, 1H), 3.05 — 2.95 (m, 3H), 2.31 (s, 3H), 1.37 — 1.21 (m, 3H).

LC-MS: (ES, m/z): RT= 0.90 335 min, LCMS 33:m/z = 368 [M+1]. lH-NMR: nol-d4, ppm): 5 8.27 (dd, J = 7.3, 2.2 Hz, 1H), 8.12 — 8.00 (m, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.09 = 5.5 Hz, 2H), 3.97 (s, 3H), 3.92-3.77 — 6.98 (m, 2H), 4.30 (t, J (m, 2H), 3.49 (t, J = 7.3 Hz, 2H), 3.24 — 3.09 (m, 2H), 2.43 — 2.01 (m, 6H).

LC-MS: (ES, m/z): RT= 1.73 min, LCMS 53Im/z = 382 [M+]. 1H-NMR: (Methanol-d4, ppm):5 8.14 (s, 1H), 7.48 — 7.35 (m, 3H), 6.92 (d, J = 3.5 Hz, 1H), 4.50-4.40 (m, 2H), 4.05 (s, 3H), 3.92-3.75 (m, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.22- WO 81177 3.05 (m, 2H), 2.74 (s, 3H), 2.47 — 2.36 (m, 2H), 2.22 — 2.09 (m, 4H).

LC-MS: (ES, m/z): RT =0.859 min, LCMS 33: m/z = 326 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.45 (d, J = 0.9 Hz, 1H), 8.09 (s, 1H), 7.84 (dd, J = 9.0, 0.8 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.22 (dd, J = 8.9, 1.8 Hz, 1H), 6.26 (d, J = 7.3 Hz, 1H), 4.99 — 4.87 (m, 2H), 3.29 — 3.17 (m, 2H), 3.10 (s, 3H), 2.92 (s, 6H), 2.48 (s, LC-MS: (ES, m/z): RT = 0.598 min, m/z = 312.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.53 (d, J = 0.9 Hz, 1H), 8.13 — 8.06 (m, 1H), 7.93 — 7.77 (m, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.26 (dd, J = 9.0, 1.8 Hz, 1H), 6.27 (d, J = 7.3 Hz, 1H), .00 (t, J = 6.7, 5.1 Hz, 2H), 3.88 (t, J = 5.9 Hz, 2H), 3.12(s, 3H), 3.09 — 3.01(m, LC-MS: (ES, m/z): RT = 0.942 min, LCMs33: m/z = 344 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.61 — 7.37 (m, 3H), 7.12 — 7.08 (m, 1H), 6.19 — 6.17 (m, 1H), 4.70 — 4.62 (m, 2H), 4.45 (d, J = 5.4 HZ, 1H), 3.97 — 3.84 (m, 3H), 3.84 — 3.70 (m, 2H), 3.34 — 3.11 (m, 2H), 3.09 — 2.92 (m, 6H), 2.57 — 2.33 (m, 1H), 2.34 — 2.09 (m, 1H).

LC-MS: (ES, m/z): RT = 0.95min, LCMSO7: m/z = 358.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.55 (dd, J = 7.3, 1.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 4.7, 1.3 HZ, 2H), 6.18 (d, J = 7.3 HZ, 1H), 4.20 — 4.07 (m, 2H), 3.96-3.84 (m, 4H), 3.75-3.70 (m, 1H), 3.38 (d, J = 7.4 Hz, 2H), 3.30 — 3.05 (m, 2H), 3.19-2.89 (m, 4H), 2.53 — 2.25 (m, 1H), 2.23 — 1.94 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H).

LC-MS: (ES, m/z):RT = 0.981 min, LCMS 33: m/z = 372 [M+1].

LC-MS: (ES, m/z): RT = 0.94 min, LCMS 07: m/z = 388 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.57 (d, J = 7.3 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J = 9.4 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.16 (d, J = 7.3 Hz, 1H), 4.19 — 4.00 (m, 2H), 4.00 — 3.65 (m, 7H), 3.58 — 3.35 (m, 6H), 3.32 — 3.14 (m, 1H), 3.03-2.85 (m, 4H), 2.41— 1.90 (m, 2H).

LC-MS: (ES, m/z): RT=1.285min, LCMS 40, m/z =370 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 7.3 Hz, 1H), 7.29 — 6.99 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.23 — 4.00 (m, 2H), 3.98 — 3.41 (m, 7H), 3.03 (s, 5H), 2.62 — 1.60 (m, 2H), 1.11— 0.89 (m, 4H).

LC-MS: (ES, m/z): RT = 0.919 min, LCMSO7: m/z = 358.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.57 (d, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.13 — 7.01 (m, 2H), 6.26 — 6.13 (m, 1H), 4.09 — 4.04 (m, 1H), 3.99 — 3.84 (m, 4H), 3.75 — 3.71 (m, 1H), 3.57 — 3.53 (m, 1H), 3.07 — 2.90 (m, 8H), 2.42 (s, 1H), 2.10 — 1.89 (m, 3H), 1.59 — 1.40 (m, 1H).

LC-MS: (ES, m/z): RT = 0.969 min, LCMSO7: m/z = 372.20 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.58 (s, 1H), 7.08 — 7.06 (m, 1H), 6.88 (d, J = 8.4Hz, 1H), .81 (s, 1H), 3.96 — 3.94 (m, 1H), 3.90 — 3.79 (m, 4H), 3.16 — 3.14 (m, 1H), 2.93 (s, 4H), 2.36 (d, J = 2.8 Hz, 3H), 2.18 (s, 5H), 2.00 — 1.97 (m, 1H), 1.92 — 1.76 (m, 2H), 1.72 — 1.67 (m, 1H), 1.23 — 1.09 (m, 1H).

LC-MS: (ES, m/z): RT = 1.020 min, LCMS53: m/z = 360.2 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.65 — 7.29 (m, 1H), 7.18 — 6.82 (m, 3H), 7.06 (s, 2H), 6.20 — 5.87 (m, 1H), 4.60 — 4.37 (m, 2H), 4.25 — 3.88 (m, 4H), 3.88 — 3.68 (m, 4H), 3.48 — 3.25 (m, 2H), 2.98 — 2.68 (m, 3H), 2.10 — 1.82 (m, 2H).

LC-MS: (ES, m/z): RT = 1.77 min, LCMS 07: m/z = 344.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.50 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 3.96 — 3.86 (m, 2H), 3.82 (s, 3H), 2.94 (s, 3H), 2.86 (d, J = 9.1 Hz, 1H), 2.81 — 2.73 (m, 1H), 2.67 (t, J = 7.1 Hz, 2H), 2.56 (, WO 81177 J = 7.7 Hz, 1H), 2.43 (s, 3H), 2.20 — 2.04 (m, 1H), 1.69 — 1.67 (m, 1H).

LC-MS: (ES, m/z): RT = 1.71 min, LCMS 07: m/z = 344.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.74 (s, 1H), 7.55 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 5.97 (d, J = 6.0 Hz, 1H), 3.96 — 3.83 (m, 2H), 3.82 (s, 3H), 2.94 (s, 3H), 2.88 (d, J = 9.1 Hz, 1H), 2.84 — 2.72 (m, 1H), 2.66 (t, J = 7.1 Hz, 2H), 2.57 (q, J = 7.7 Hz, 1H), 2.41 (s, 3H), 2.22 — 2.01 (m, 1H), 1.68 — 1.64 (m, 1H).

LC-MS: (ES, m/z): RT = 1.64 min, LCMS 53: m/z = 358.3 [M+1]. 1H NMR (300 MHz, Chloroform—d) 5 7.54 (d, J = 2.5 Hz, 1H), 7.21 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 5.73 (d, J = 0.8 Hz, 1H), 4.94 (s, 1H), 4.00 (d, J = 6.5 Hz, 2H), 3.84 (s, 3H), 3.35 — 2.57 (m, 8H), 2.49 (s, 3H), 2.28 (s, 3H), 2.16 — 2.13 (m, 1H), 1.73 — 1.71 (m, 1H).

LC-MS: (ES, m/z): RT = 1.15 min, LCMS 53: m/z = 358.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.60 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 3.96 — 3.90 (m, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 2.85 — 2.83 (m, 1H), 2.82 — 2.70 (m, 1H), 2.71 — 2.60 (m, 2H), 2.53 — 2.49 (m, 1H), 2.41 (d, J :11 Hz, 3H), 2.18 (s, 3H), 2.16 — 2.03 (m, 1H), 1.67 — 1.60 (m, Hz, 1H).

LC-MS: (ES, m/z): RT in, LCMs33: m/z = 372 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 7.41 (s, 1H), 7.19 — 6.95 (m, 2H), 6.03 (s, 1H), 4.1—3.92 (m, 2H), 3.85—3.7 (m, 3H), 3.63-3.52 (m, 1H), 3.32 — 2.98 (m, 4H), 2.95 — 2.72 (m, 5H), 2.42 — 2.05 (m, 4H), 1.98-1.67 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT=0.774min, LCMS 40, m/z =372 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 7.3 Hz, 1H), 7.28 — 6.98 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.19 — 3.99 (m, 2H), 3.89 (s, 4H), 3.78 — 3.65 (m, 1H), 3.46 — 3.36 (m, 1H), 3.30 — 3.10 (m, 3H), 3.08 — 2.87 (m, 4H), 2.53 — 1.91 (m, 2H), 1.89 — 1.71 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, Methanol-d4) 5 7.69 — 7.63 (m, 1H), 7.57 — 7.55 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.57 — 4.45 (m, 2H), 4.24 — 4.21 (m, 1H), 3.83 (s, 3H), 2.92 (s, 3H), 2.85 — 2.67 (m, 3H), 2.55 — 2.51 (m, 1H), 2.38 (s, 3H), 2.24 — 2.10 (m, 4H), 1.96 — 1.94 (m, 1H).

LC-MS: (ES, m/z): RT = 0.979 min, LCMS 45: m/z = 384.2 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.65 — 7.33 (m, 1H), 7.24 — 7.12 (s, 1H), 7.03 — 6.89 (m, 2H), 6.19 — 5.98 (m, 1H), 4.08 — 3.52 (m, 7H), 3.39 — 2.80 (m, 8H), 2.38 — 2.07 (m, 1H), 2.05 — 1.72 (m, 1H), 1.12 — 0.95 (m, 1H), 0.70 — 0.53 (m, 2H), 0.29 — 0.21 (m, LC-MS: (ES, m/z): RT = 0.94min, LCMSO7: m/z = 358.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 787—75 (m, 1H), 7.29 — 7.01 (m, 3H), 6.38-6.11 (m, 1H), 4.43 (t, J = 9.4 Hz, 1H), 4.27 — 4.10 (m, 3H), 4.08 — 4.00 (m, 1H), 3.94 (d, J = 2.2 Hz, 3H), 3.79 (t, J = 9.8 Hz, 1H), 3.50-3.41 (m, 2H), 3.10—2.9 (m, 4H), 22—202 (m, 2H), 1.41 (d, J = 7.1 Hz, 1H), 1.30 (d, J = 6.7 Hz, 2H).

LC-MS: (ES, m/z): RT = 0.97min, LCMSO7: m/z = 372.20 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 79—754 (m, 1H), 7.29 — 7.05 (m, 3H), 6.4-6.16 (m, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.62 — 3.49 (m, 1H), 3.48 — 3.39 (m, 1H), 3.29-3.19 (m, 1H), 3.17—2.9 (m, 7H), 2.31-2.27 (m, 2H), 1.31 — 1.15 (m, 1H), 0.83-0.80 (m, 2H), 0.59 — 0.39 (m, 2H).

LC-MS: (ES, m/z): RT= 0.96 min, LCMS 45: m/z = 374 [M+1]. lH-NMR: nol-d4, ppm): 5 7.57 (d, J = 7.3 Hz, 1H), 7.24 — 7.03 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.65-4.60 (m, 1H), 4.33 (s, 3H), 4.16-4.10 (m, 2H), 4.08 — 3.90 (m, 4H), 3.59-3.45 (m, 2H), 3.40-3.35 (m, 3H), 3.03 (s, 3H), 2.25—2.11 (m, 2H).

LC-MS: (ES, m/z): RT = 1.34 min, LCMS 33: m/z = 368 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.53 (d, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.07 (s, 2H), 6.25 — 6.12 (m, 2H), 5.14 (s, 2H), 3.89 (s, 3H), 3.02 (s, 3H), 2.15-2.05 (m, 1H), 1.19 — 1.03 (m, 2H), 1.04 — 0.89 (m, 2H).

LC-MS: (ES, m/z): RT =1.111 min, LCMS 33: m/z = 440 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.62 (s, 1H), 7.10 — 7.04 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), .96 (s, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.42 — 3.38 (m,1H), 3.31-3.28 (m, 1H), 2.94 (s, 3H), 2.80 — 2.70 (m, 2H), 2.68 — 2.60 (m, 4H), 2.10-2.02 (m, 2H), .80 (m, 4H).

LC-MS: (ES, m/z): RT=0.996min, LCMS 31, m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 7.3 Hz, 1H), 7.24 — 7.00 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.62 — 4.47 (m, 1H), 4.29 — 4.10 (m, 3H), 4.08 — 3.89 (m, 4H), 3.58 — 3.33 (m, 2H), 3.03 (s, 3H), 2.69 — 2.54 (m, 1H), 2.43 — 2.23 (m, 1H), 2.22 — 2.07 (m, 2H), 1.62 (d, J = 6.6 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.02min, LCMs33: m/z = 372 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 8.1-7.8 (m, 1H), 7.71 (s, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.76 (dd, J = 9.0, 3.0 Hz, 1H), 6.4-6.2 (m, 1H), 4.14 — 3.93 (m, 4H), 3.63 — 3.49 (m, 2H), 3.32 = 6.9 Hz, 3H). — 3.19 (m, 2H), 3.08 — 2.85 (m, 5H), 2.19 — 1.83 (m, 6H), 1.32 (t, J LC-MS: (ES, m/z): RT = 1.06min, : m/z = 386 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 7.96 — 7.89 (m, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.70 (dd, J = 9.0, 3.0 Hz, 1H), .09 (m, 1H), 4.11-3.98 (m, 4H), 3.62-3.56 (m, 2H), 3.31 — 3.19 (m, 2H), 3.08 — 2.85 (m, 5H), 2.39 — 2.24 (m, 3H), 2.19 — 1.76 (m, 6H), 1.36 (t, J = 6.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.34 min, LCMS 33: m/z = 368 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.64 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.01 (d, J = 6.5 Hz, 1H), 5.14 (s, 2H), 3.84 (s, 3H), 2.95 (s, 3H), 2.35-2.25 (m, 1H), 1.35 — 1.13 (m, 4H).

LC-MS: (ES, m/z): RT= 1.15 min, LCMS 53: m/z = 372 [M+1]. : (Methanol-d4, ppm): 5 7.27 (s, 1H), 7.16 — 6.97 (m, 2H), 6.01 (s, 1H), 3.95-3.90 (m, 2H), 3.86 (s, 3H), 3.65 — 3.53 (m, 2H), 3.01-2.95 (m, 5H), 2.90 (s, 3H), 2.31 (s, 3H), 2.22 — 2.11 (m, 3H), 1.87-1.56 (m, 2H).

LC-MS: (ES, m/z): RT= 1.08 min, LCMSS3zm/z = 412 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.27 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.04 — 5.97 (m, 1H), 3.96 (d, J = 5.4 Hz, 2H), 3.85 (d, J = 3.7 Hz, 3H), 3.76 (d, J = 12.4 Hz, 2H), 3.17 — 2.97 (m, 6H), 2.32 — 2.20 (m, 5H), 1.91- 1.76 (m, 2H), 1.33-1.05 (m, 1H), 0.87 — 0.74 (m, 2H), 0.56-0.36 (m, 2H).

LC-MS: (ES, m/z): RT = 0.957 min, LCMs15: m/z = 330.2 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 8.80 — 8.58 (m, 2H), 7.69 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.84 (s, 1H), 4.11 (d, J = 6.2 Hz, 2H), 4.06 (d, J = 9.7 Hz, 2H), 3.91 — 3.71 (m, 6H), 3.28 — 3.18 (m, 1H), 2.86 (s, 3H), 2.16 (s, 3H).

LC-MS: (ES, m/z): RT = 1.54 min, LCMS 28: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 5.8 Hz, 1H), 7.51 (s, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.08 — 3.90 (m, 2H), 3.82 (s, 3H), 2.98 — 2.62 (m, 6H), 2.37 (d, J = 2.5 Hz, 3H), 2.30-2.20 (m, 2H), 2.10- 2.00 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.56 min, LCMS 28: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.51 (s, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.09 — 3.90 (m, 2H), 3.82 (s, 3H), 2.94 (s, 4H), 2.90-2.80 (m, 2H), 2.39 (d, J = 4.9 Hz, 3H), 2.27 (d, J = 8.3 Hz, 2H), 2.08 (s, 1H), 1.18 (d, J = 6.8 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.400 min, LCMS 33: m/z = 359 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.53 (d, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J = 2.7 Hz, 2H), 6.16 (d, J = 7.3 Hz, 1H), 4.20 — 4.00 (m, 3H), 3.91 — 3.73 (m, 5H), 3.03 (s, 3H), 1.85 — 1.49 (m, 9H).

LC-MS: (ES, m/z): RT= 0.831 min, LCMS 32, m/z = 402.4 [M+1]. 1H NMR (400 MHz, Deuterium Oxide) 5 7.15 (d, J = 2.1 Hz, 1H), 7.09 — 6.90 (m, 2H), 6.02 (d, J = 1.7 Hz, 1H), 4.27 (s, 2H), 4.14 — 3.98 (m, 2H), 3.77 (s, 3H), 3.70 — 3.55 (m, 2H), 3.32 (d, J = 4.4 Hz, 5H), 3.08 — 2.92 (m, 2H), 2.83 (s, 3H), 2.24 — 1.73 (m, 6H).

LC-MS: (ES, m/z): RT = 0.930 min, LCMSO7: m/z = 344.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.33 — 7.29 (m, 1H), 7.26 — 7.04 (m, 2H), 6.02 (d, J = 1.2 Hz, 1H), 4.63 — 4.40 (m, 2H), 4.26 — 4.03 (m, 4H), 3.93 (d, J = 1.5 HZ, 3H), 3.32 — 3.31 (m, 1H), 3.08 — 2.95 (m, 6H), 2.32 (s, 3H).

LC-MS: (ES, m/z): RT =0.957 min, LCMS 07: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.35 (d, J = 14.3 Hz, 1H), 7.27 — 7.14 (m, 1H), 7.09 (q, J = 8.8 Hz, 1H), 6.01 (d, J = 1.1 Hz, 1H), 4.54 — 4.35 (m, 2H), 4.31 — 4.08 (m, 4H), 3.92 (s, 3H), 3.70 — 3.47 (m, 2H), 3.47 (s, 1H), 3.01 (s, 3H), 2.48 — 2.24 (m, 3H), 1.28 (t, J = 7.3 HZ, 3H).

LC-MS: (ES, m/z): RT = 1.067 min, LCMs15: m/z = 384.2 [M+1].1H NMR (400 MHz, ol-d4) 5 7.36 — 7.06 (m, 3H), 5.99 (s, 1H), 4.53 — 4.35 (m, 2H), 4.32 — 4.07 (m, 4H), 3.91 (s, 3H), 3.36 (d, J = 7.0 Hz, 2H), 3.18 (d, J = 7.3 Hz, 1H), 3.03 — 2.95 (m, 3H), 2.31 (s, 3H), 1.09 — 1.06 (m, 1H), 0.77 — 0.72 (m, 2H), 0.50 — 0.41 (m, 2H).

LC-MS: (ES, m/Z): RT = 1.99 min, LCMS 33: m/Z = 398.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.33 — 7.17 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 5.98 (s, 1H), 4.26 — 3.86 (m, 6H), 3.80 — 3.46 (m, 2H), 2.99 (d, J = 11.3 Hz, 6H), 2.51 — 2.12 (m, 9H), 1.97 (, J = 9.4 Hz, 2H).

LC-MS: (ES, m/z): RT = 0.85 min, LCMS 33: m/z = 359.0 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 10.65 (s, 1H), 9.28 (s, 1H), 7.31 (s, 2H), 6.89 (d, J = 8.7 Hz, 1H), 5.59 (s, 1H), 3.96 (t, J = 6.5 Hz, 2H), 3.73 (s, 3H), 2.54 (d, J = 7.1 Hz, 2H), 2.42 — 2.39 (m, 4H), 2.05 (s, 3H), 1.89 — 1.84 (m, 2H), 1.68 — 1.63 (m, 4H).

LC-MS: (ES, m/z): RT = 0.88 min, LCMS 33: m/z = 359.0 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 9.19 (s, 1H), 7.67 — 7.41 (m, 1H), 7.05 (q, J = 8.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.63 (s, 1H), 3.99 (t, J = 6.5 Hz, 2H), 3.72 (s, 3H), 2.57 (t, J = 7.1 Hz, 2H), 2.48 (s, 5H), 2.09 (s, 3H), 1.91 — 1.85 (m, 2H), 1.77 — 1.45 (m, 4H).

LC-MS: (ES, m/z): RT = 1.226 min, LCMs34: m/z = 400 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.35 — 7.29 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.98 (d, J = 1.1 Hz, 1H), 5.01 — 4.91 (m, 3H), 4.79 — 4.77 (m, 2H), 4.69 (s, 1H), 4.13 — 4.11 (m, 2H), 3.90 (s, 4H), 3.80 — 3.50 (m, 2H), 3.04 — 2.97 (m, 4H), 2.40 — 2.30 (m, 1H), 2.30 (d, J = 0.9 Hz, 3H), 2.17 (s, 1H).

LC-MS: (ES, m/z): RT = 1.18min, LCMs33: m/z = 427 [M+1]. 1H NMR (300 MHz, DMSO-d6) 510.86—10.48 (m, 2H), 8.04-7.95 (m, 1H), 7.45 (d, J = 15.1 Hz, 1H), 7.08-6.91 (m, 2H), 5.04 (s, 1H), 4.07 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.74— 3.25 (m, 8H), 3.10-2.97 (m, 2H), 2.91 — 2.79 (m, 3H), 2.19 (q, J = 7.4, 6.8 Hz, 2H), 2.06 — 1.81 (m, 8H).

LC-MS: (ES, m/z): RT =1.016min, LCMS 07: m/z = 442 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.30 — 7.12 (m, 2H), 7.05 (q, J = 4.9 Hz, 1H), 6.05 — 5.97 (m, 1H), 4.09 — 4.75 (m, 2H), 4.05 — 3.75 (m, 6H), 3.72 (m, 1H), 3.40 (q, J = 2.3 Hz, 3H), 3.28 — 3.00 (m, 5H), 2.99 — 2.89 (m, 1H), 2.54 — 2.41 (m, 1H), 2.31 (d, J = 0.9 Hz, 3H), 1.88 — 1.81 (m, 1H), 1.80 — 1.78 (m, 1H), 1.75 — 1.73 (m, 1H), 1.72 — 1.57 (m, 2H), 1.29 — 1.25 (m, 2H).

LC-MS: (ES, m/z): RT = 1.245 min, LCMS 33: m/z = 345 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.26 (s, 1H), 7.03 (d, 2H), 6.29-5.99 (m, 1H), 4.30(s, 1H), 4.11-3.82 (m, 7H), 3.00(s, 3H), 2.42-2.22 (m,3H), 2.18-1.81(m, 4H).

LC-MS: (ES, m/z): RT =1.25min,LCMS33: m/z = 331 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.76-7.50 (m, 1H), 7.16-7.11 (m, 1H), 7.10 — 7.01 (m, 2H), 6.39-6.1 (m, 1H), 4.2-4.02 (m, 2H), 3.93 — 3.83 (m, 5H), 3.52 — 3.44 (m, 1H), 3.06- 2.95 (m, 3H), 0.67 — 0.55 (m, 2H), 0.52 (dd, J = 6.8, 4.6 Hz, 2H).

LC-MS: (ES, m/z): RT =0.764min, LCMS48: m/z = 412 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.33 (s, 1H), 7.24 — 7.20 (m, 1H), 7.04 (q, J = 3.5 Hz, 1H), .99 (q, J = 1.2 Hz, 1H), 4.10 — 4.06 (m, 2H), 4.01 — 3.86 (m, 4H), 3.86 — 3.57 (m, 2H), 3.54 — 3.38 (m, 1H), 3.23 — 3.18 (m, 1H), 3.00 (d, J = 12.0 Hz, 4H), 2.53 — 1.96 (m, 7H), 1.94 — 1.65 (m, 6H).

LC-MS: (ES, m/z): RT=3.213min, LCMS 28, m/z =426.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.35 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.7, 2.5 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.86 (d, J = 19.0 Hz, 5H), 3.49 (t, J = 7.0 Hz, 2H), 3.25 — 2.88 , 2.44 — 1.98 (m, 8H), 1.98 — 1.56 (m, LC-MS: (ES, m/z): RT= 1.1001nin, LCMS 28, m/z = 442.2 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.16 (d, J = 1.8 Hz, 1H), 7.11 — 6.92 (m, 2H), 5.93 (s, 1H), 4.18 — 3.92 (m, 4H), 3.80 (s, 3H), 3.74 — 3.58 (m, 2H), 3.57 — 3.27 (m, 4H), 3.15 — 2.62 (m, 6H), 2.28 — 1.52 (m, 10H).

LC-MS: (ES, m/z): RT = 0.998 min, LCMS 33: m/z = 383 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.64 (s, 1H), 8.14 (s, 1H), 7.20(s, 1H), 7.03 (s, 1H), 4.35 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.82 (s, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.18 (s, 2H), 2.73 (s, 3H), 2.45-2.35 (m, 2H), 2.30-2.20 (m, 2H), .05 (m, 2H).

LC-MS: (ES, m/z): RT = 0.63 min, LCMS 53: m/z = 388.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.29 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.09 — 6.99 (m, 1H), 5.99 (s, 1H), 4.20 — 4.02 (m, 2H), 4.00 — 3.63 (m, 7H), 3.61 — 3.41 (m, 3H), 3.26 — 3.19 (m, 1H), 3.01 — 2.98 (m, 4H), 2.31 — 2.26 (m, 4H), 2.23 — 1.99 (m, LC-MS: (ES, m/z): RT =1.069min, LCMSO7: m/z =468 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.36 — 7.11 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 5.99 (s, 1H), 4.13 (s, 2H), 4.04 — 3.52 (m, 9H), 3.50 — 3.35 (m, 3H), 3.30 — 3.16 (m, 1H), 3.04 (d, J = 3.6 Hz, 2H), 2.31 (s, 5H), 1.88 — 1.82 (m, 1H), 1.73 — 1.52 (m, 2H), 1.44 — 1.18 (m, 2H), 1.13 — 0.68 (m, 4H).

LC-MS: (ES, m/z): RT=0.986 min, LCMS 07, m/z =372.20 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.46 — 6.91 (m, 3H), 6.02 (s, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.75 — 3.45 (m, 2H), 3.18 — 2.76 (m, 7H), 2.53 — 2.12 (m, 5H), 1.31 — 0.86 (m, 4H).

LC-MS: (ES, m/z): RT = 1.128 min, LCMS 33: m/z = 456 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.96 (s, 1H),6.52-6.61 (m, 1H),6.20-6.40 (m, 1H), 5.90-6.08 (m, 1H), 4.28 (t, J = 5.6 Hz, 2H), 4.05 — 3.90 (m,5H), 3.81 (s, 2H), 3.52 — 3.41 (m, 4H), 3.21-3.11 (s, 4H), 2.59-2.40 (m, 3H), 2.35 (t, J = 6.6 Hz, 2H), 2.22 (s, 2H), 2.10 (s, 2H), 1.93 (s, 1H), 1.74 (s, 2H), 1.40 (s, 2H).

LC-MS: (ES, m/z): RT = n, LCMs28: m/z = 374 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.29 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 8.7, 2.6 Hz, 1H), 7.06- 7.04 (m, 1H), 62-599 (m, 1H), 4.76 — 4.52 (m, 2H), 4.39 — 4.11 (m, 4H), 4.05-3.85 (m, 4H), 3.61-3.43 (m, 2H), 3.05-2.9 (m, 3H), 2.45-2.23 (m, 3H), 2.20-2.06 (m, LC-MS: (ES, m/z): RT = 1.64min, LCMs33: m/z = 384 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.40 — 7.27 (m, 2H), 7.12-6.95 (d, J = 9.1 Hz, 1H), .97 (m, 1H), 4.89-4.67 (m, 1H), 3.90 (d, J = 4.4 Hz, 3H), 3.77-3.45 (m, 4H), 3.09-2.94 (m, 4H), 2.40 (s, 1H), 2.33-2.23 (m, 4H), 2.14-1.9 (m, 2H), 1.25-0.9 (m,4H).

LC-MS: (ES, m/z): RT = 0.962min, LCMS28: m/z = 359 [M+1]. 1H NMR (300 MHz, ol-d4) 5 8.05 (s, 1H), 7.09 (s, 1H), 6.30 (s, 1H), 4.60 — 4.24 (m, 2H), 4.12 — 3.62 (m, 5H), 3.44 — 3.34 (m, 1H), 3.28 — 2.95 (m, 8H), 2.78 (s, 3H), 2.60 — 2.30 (m, 1H), 2.27 — 1.85 (m, 1H).

LC-MS: (ES, m/z): RT = 1.062 min, LCMS 53: m/z = 368.2 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 13.63 (s, 1H), 8.74 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.45 — 7.19 (m, 1H), 7.19 — 6.95 (m, 1H), 6.95 — 6.66 (m, 1H), 5.87 (d, J = 5.8 Hz,1H), 4.88 (s, 2H), 3.69 (s, 3H), 2.82 (s, 3H), 2.04 (dd, J = 9.7, 5.2 Hz, 1H), 1.13 — 0.97 (m, 2H), 0.90 (d, J = 5.9 Hz, 5H).

LC-MS: (ES, m/z): RT = 1.114 min 480 , m/z = 368.3 [M+1]. 1H NMR (300 MHz, Deuteiium Oxide) 5 8.75 — 8.38 (m, 1H), 7.28 (dd, J = 7.3, 4.6 Hz, 1H), 7.17 — 7.00 (m, 1H), 6.86 — 6.66 (m, 2H), 6.12 —5.89 (m, 1H), 4.98 — 4.75 (m, 2H), 3.75 — 3.42 (m, 4H), 2.85 — 2.46 (m, 3H), 1.09 — 0.93 (m, 4H).

LC-MS: (ES, m/z): RT = 1.03 min, LCMS 33: m/z = 384.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.37 (d, J = 2.5 Hz, 1H), 7.13 (q, J = 8.7, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.94 (s, 1H), 4.05 — 4.01 (m, 2H), 3.86 (s, 3H), 3.48 (t, J = 9.9 Hz, 1H), 3.30 — 3.12 (m, 2H), 2.98 (s, 3H), 2.88 (q, J = 7.2 Hz, 1H), 2.55 (d, J = 8.4 Hz, 1H), 2.27 (s, 4H), 1.93 — 1.91 (m, 6.9 Hz, 1H), 0.80 (q, J = 5.1 Hz, 4H).

LC-MS: (ES, m/z): RT = 1.20 min, LCMS 27: m/z = 384.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.49 (s, 1H), 7.09 (q, J = 8.7 Hz, 1H), 7.00 — 6.91 (m, 1H), .87 (d, J = 2.9 Hz, 1H), 4.09 — 3.96 (m, 2H), 3.84 (s, 3H), 3.26 — 2.69 (m, 8H), 2.22 (s, 5H), 1.79 — 1.69 (m, 1H), 0.63 (, J = 7.7 Hz, 4H).

LC-MS: (ES, m/z): RT =1.16min, LCMS28: m/z = 400 [M+1]. 1H NMR (300 MHZ, Deuterium Oxide) 5 7.27 (s, 1H), 6.92 (s, 2H), 5.84 (s, 1H), 4.14 — 4.02 (m, 2H), 3.75 (s, 3H), 3.26 (d, J = 7.8 Hz, 6H), 2.75 (s, 3H), 2.62 — 2.52 (m, 1H), 2.21 — 2.05 (m, 2H), 1.97 (s, 4H), 1.10 (d, J = 6.9 Hz, 6H).

LC-MS: (ES, m/z): RT = 0.902 min, LCMS33: m/z = 382 [M+1]. 1H NMR (400 MHZ, Methanol-d4) 5 8.08 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.21 — 7.19 (m, 1H), 6.94 (d, J = 8.8 Hz,1H), 6.83 (d, J = 0.8 , 4.14 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.82 — 2.73 (m, 2H), 2.66 (d, J = 4.8 Hz, 4H), 2.50 (d, J = 0.8 Hz, 3H), 2.16 — 2.04 (m, 2H), 1.89 — 1.85 (m, 4H).

LC-MS: (ES, m/z): RT = 0.969 min, LCMS 33: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.25 (s, 1H), 7.20 — 7.11 (m, 1H),7.07 — 6.95 (s, 1H), 6.03 — .96 (m, 1H), 4.39 — 4.28 (m, 2H), 4.25 — 4.08 (m, 4H), 3.95 (s, 3H), 3.64 — 3.48 (m, 2H), 3.01 (s, 3H), 2.65 — 2.51 (m, 1H), 2.52 — 2.38 (m, 1H), 2.41 - 2.22 (m, 3H), 2.14 — 2.00 (m, 2H).

LC-MS: (ES, m/z): RT =1.471min,m/z = 406.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.45 (d, J = 2.4 Hz, 1H), 7.41 — 7.21 (m, 1H), 6.23 - 6.07 (m, 1H), 4.23 (q, J = 5.9 Hz, 2H), 3.90 — 3.70 (m, 5H), 3.53 — 3.42 (m, 2H), 3.18 (m, 2H), 3.02 (s, 3H), 2.46 — 2.03 (m, 9H).

LC-MS: (ES, m/z): RT = 2.041 min, LCMS33: m/z = 370 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.29 — 7.09 (m, 3H), 6.29 — 5.89 (m, 1H), 4.17 (t, J = 5.7 Hz, 2H), 3.82 — 3.70 (m, 2H), 3.53 — 3.41 (m, 2H), 3.18 — 3.04 (m, 2H), 3.04 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 2.45 — 2.17 (m, 7H), 2.17 — 2.03 (m, 2H), 1.29 — 1.14 (m, LC-MS: (ES, m/z): RT= 1.120 min, LCMS 28, m/z =398.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.30 (d, J = 2.4 Hz, 1H), 7.25 — 7.18 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 4.04 — 3.85 (m, 4H), 3.62 — 3.36 (m, 4H), 3.29 — 3.25 (m, 1H), 3.01 (s, 3H), 2.51 — 1.89 (m, 7H), 0.95 — 0.60 ﬁn,4H) LC-MS: (ES, m/z): RT = 0.98min, LCMs33: m/z = 360 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.27 (s, 1H), 7.16 (dd, J = 8.7, 2.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.98 (s, 1H), 4.11 (t, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.35 — 3.30 (m, 2H), 2.97 — 2.88 (m, 9H), 2.30 (s, 3H), 2.06 - 1.89 (m, 4H).

LC-MS: (ES, m/z): RT = 1.140 min, LCMS27: m/z = 372 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.25 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 5.98 (s, 1H), 4.16 — 4.13 (m, 1H), 4.13 — 4.05 (m, 1H), 3.87 (s, 4H), 3.79 — 3.62 (m, 1H), 3.54 — 3.42 (m, 1H), 3.26 — 3.05 (m, 1H), 3.04 — 2.77 (m, 7H), 2.75 — 2.55 (m, 1H), 2.35 (s, 3H), 2.10 — 1.75 (m, 3H).

LC-MS: (ES, m/z): RT= 1.03 504 min, LCMS 15Im/z = 386 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.34 — 7.26 (m, 1H), 7.16 (dd, J = 8.9, 2.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.02 (s, 1H), 4.35-4.18 (m, 2H), 3.98 — 3.78 (m, 4H), 3.74-3.65 (m, 1H), 3.65-3.50 (m, 1H), .08 (m, 2H), 3.05-2.99 (m, 3H), 2.30-2.40 (m, 6H), 2.24 — 2.05 (m, 2H), 1.93-1.75 (m, 1H), .51 (m, 3H).

LC-MS: (ES, m/z): RT in,LCMS33: m/z = 384 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.37 — 7.17 (m, 2H), 7.11 — 7.01 (m, 1H), 5.98 (s, 1H), 4.17 (d, J = 5.4 Hz, 2H), 3.91 — 3.81 (m, 5H), 3.51 - 3.77 (m, 4H), 3.00 (s, 3H), 2.44 — 2.17 (m, 5H), 2.03 = 7.6 Hz, 1H), 0.73-0.58 (m, 1H). - 1.89 (m, 2H), 0.92 (q, J LC-MS: (ES, m/z): RT = 1.023min, LCMs33: m/z = 380 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.06 (s, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.38 (d, J = 0.9 Hz, 1H), 7.26 (d, J = 0.9 Hz, 1H), 7.01 (s, 1H), 4.30 (t, J = 5.4 Hz, 2H), 3.99 (s, 3H), 3.97 — 3.80 (m, 2H), 3.48 — 3.40 (m, 4H), 2.35 — 2.33 (m, 2H), 1.91 — 1.89 (m, 2H), 1.01 — 0.87 (m, 1H), 0.73 — 0.62 (m, 1H).

LC-MS: (ES, m/z): RT = 0.97 min, LCMS 53: m/z = 358.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.23 (t, J = 3.1 Hz, 1H), 7.15 (t, J = 8.9 Hz, 1H), 7.01 (t, J = 1.3 Hz, 1H), 6.01 — 5.96 (m, 1H), 4.45 — 4.25 (m, 2H), 4.09 (q, J = 5.8 Hz, 3H), 3.97 (q, J = 9.3 Hz, 1H), 3.87 (d, J = 2.1 Hz, 3H), 3.27 — 3.06 (m, 1H), 2.99 (d, J = .0 Hz, 4H), 2.92 (s, 2H), 2.30 (d, J = 0.9 Hz, 3H), 2.25 — 2.11 (m, 2H).

LC-MS: (ES, m/z): RT = 1.102 min, LCMS53: m/z = 402 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.93 (s, 1H), 6.62 (s, 1H), 6.09 (d, J = 6.5 Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.89 — 3.87 (m, 2H), 3.50 — 3.38 (m, 4H), 2.96 (s, 3H), 2.50 (d, J = 3.1 Hz, 3H), 2.37 — 2.26 (m, 2H), 1.95 — 1.86 (m, 2H), 0.91 (q, J = 7.7 Hz, 1H), 0.69 — 0.62 (m, 1H).

LC-MS: (ES, m/z): RT = 1.075 min, LCMs28: m/z = 370 [M+1]. lH-NMR: (300 MHz, Methanol-d4) 5 7.25-6.95 (m, 3H), 6.10 — 5.86 (m, 1H), 4.49 — 3.93 (m, 6H), 3.79 (s, 3H), 3.34 — 2.98 (m, 2H), 2.82 (s, 3H), 2.14 (s, 3H), 0.93 — 0.62 (m, 4H).

LC-MS: (ES, m/z): RT = 1.197 min, LCMS 27: m/z = 385 [M+1]. lH-NMR: (300 MHz, Methanol-d4) 5 7.95 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.05 (t, J = 6.2 Hz, 2H), 3.91 (s, 3H), 3.08 (d, J = 9.1 Hz, 2H), 2.91 (s, 3H), 2.74 — 2.64 (m, 2H), 2.50 — 2.44 (m, 2H), 2.18 (s, 3H), 2.04 — 1.94 (m, 2H), 1.49 — 1.41 (m, 2H), 0.70 — 0.32 (m, 1H), 0.46 — 0.38 (m, 1H).

LC-MS: (ES, m/z): RT =0.870min, LCMS 33: m/z = 371 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.44 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 5.98 (s, 1H), 4.20 (q, J = 6.2 Hz, 2H), 3.71 = 7.5 Hz, 2H), 2.41 — 3.41 (m, 6H), 3.00 (s, 3H), 2.83 (q, J — 2.25 (m, 5H), 2.20 — 2.09 (m, 4H), 1.26 (t, J = 7.6 Hz, 3H).

LC-MS: (ES, m/z): RT=1.041 min, LCMS 53, m/z =398 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.29 (d, J = 2.4 Hz, 1H), 7.20 — 6.98 (m, 2H), 6.01 (s, 1H), 4.12 — 3.81 (m, 6H), 3.75— 3.63 (m, 1H), 3.24 — 3.08 (m, 2H), 3.01 (s, 3H), 2.94 — 2.81 (m, 1H), 2.46 — 2.35 (m, 1H), 2.31 (d, J = 0.9 Hz, 3H), 2.14 — 1.78 (m, 3H), 1.63 — 1.43 (m, 1H), 1.17 — 0.95 (m, 4H).

LC-MS: (ES, m/z): RT = 1.094min, : m/z = 398.2 [M+1]. 1H NMR (400 MHz, Deuterium Oxide) 5 7.28 — 6.78 (m, 3H), 6.19 — 5.72 (m, 1H), 3.96 (dd, J = 9.8, 4.7 Hz, 1H), 3.85 (dd, J = 9.8, 7.4 Hz, 1H), 3.80 — 3.70 (m, 4H), 3.58 (d, J = 13.7 Hz, 1H), 3.10 — 2.89 (m, 2H), 2.82 (s, 3H), 2.72 — 2.62 (m, 1H), 2.38 — 2.04 (m, 4H), 1.95 (s, 3H), 1.83 (d, J = 13.1 Hz, 1H), 1.70 — 1.56 (m, 1H), 1.44 — 1.20 (m, 1H), 0.94 — 0.75 (m, 4H).

LC-MS: (ES, m/z): RT = 1.22min, m/z = 385 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.59 (s, 1H), 7.48-7.05 (m, 1H), 4.37 (t, J = 5.4 Hz, 2H), 4.20 — 3.80 (m, 4H), 3.92 — 3.72 (m, 2H), 3.50 (t, J = 7.3 Hz, 2H), 3.25 — 3.10 (m, 5H), 2.61 — 1.60 (m, 14H).

LC-MS: (ES, m/z): RT = 1.27 min, LCMS 53: m/z = 399.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.54 (s, 1H), 7.31— 7.20 (m, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.03 (s, 3H), 3.84 — 3.82 (m, 2H), 3.71 — 3.44 (m, 3H), 3.18 (s, 5H), 2.40 — 2.36 (m, 2H), 2.32 — 2.03 (m, 4H), 2.04 — 1.51 (m, 9H), 1.39 — 1.40 (m, 1H).

LC-MS: (ES, m/z): RT = 0.932min, LCMS28: m/z = 454.3 [M+1]. 1H-NMR: (CDC13, ppm): 1H NMR (300 MHz, Deuterium Oxide) 5 7.43-7.31 (m, J = 11.7 Hz, 1H), 7.09 (s, 1H), 4.30-4.20 (m, 2H), 3.83-3.90 (m, 3H), 3.80 (s, 3H), 3.71 — 3.60 (m, 3H), 3.56 (d, J = 10.7 Hz, 2H), 3.30-3.39 (m, 3H), 3.24 — 3.11 (m, 2H), 3.11— 2.94 (m, 2H), 2.80-2.90 (m, 3H), 2.30-2.20 (m, 3H), 2.20 — 2.02 (m, 7H), 2.00 — 1.84 (m, 4H).

LC-MS: (ES, m/z): RT= 0.69 min, LCMS 15:m/z = 504 [M+1]. : (Methanol-d4, ppm): 5 7.55 (s, 1H), 7.33 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.26 - 4.15 (m, 4H), 4.05 (s, 3H), 3.98 - 3.89 (m, 1H), 3.85 — 3.81 (m, 2H), 3.71- 3.70 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.34 - 3.32 (m, 1H), 3.32 - 3.30 (m, 3H), 2.98 (s, 3H), 2.45 — 2.03 (m, 14H).

LC-MS: (ES, m/z): RT=4.170min , m/z =468 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.76 (s, 1H), 7.29 (s, 1H), 4.60 — 4.22 (m, 3H), 4.12 — 3.89 (m, 4H), 3.88 — 3.76 (m, 2H), 3.75 — 3.62 (m, 2H), 3.61 — 3.39 (m, 3H), 3.23 — 3.05 (m, 2H), 2.96 (s, 3H), 2.45 — 1.58 (m, 19H).

LC-MS: (ES, m/z): RT = 0.666min, m/z = 368.2 [M+1]: 1H NMR (300 MHz, ol-d4) 5 8.60 (s, 1H), 7.83 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 6.85 (s, 1H), 6.30 (d, J = 6.8 Hz,1H), 4.38 (s, 2H), 3.78 (s, 2H), 3.55 (s, 2H), 3.21 (s, 2H), 3.14 (s, 3H), 2.41 (s, 2H), 2.22 - 2.10 (m, 4H).

LC-MS: (ES, m/z): RT = 1.64 min, LCMS 27: m/z = 208.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.64 (d, J = 6.9 Hz, 1H), 6.07 (d, J = 6.9 Hz, 1H), 4.55 — 4.45 (m, 1H), 3.96 — 3.92 (m, 1H), 3.63 — 3.51 (m, 1H), 3.49 — 3.33 (m, 2H), 2.95 (s, 3H), 2.27 — 2.17 (m, 1H), 1.97 — 1.91 (m,1H), 1.89 — 1.69 (m, 2H).

LC-MS: (ES, m/z): RT = 1.21 min, LCMS 27: m/z = 208.0 542 [M--1]. 1H NMR (300 MHz, Methanol-d4) 5 7.67 (d, J = 6.0 Hz, 1H), 5.76 (d, J = 6.0 Hz, 1H), 4.69 — 4.57 (m, 2H), 2.95 — 2.83 (m, 6H), 1.89 — 1.85 (m, 2H), 1.37 — 1.25 (m, 2H).

LC-MS: (ES, m/z): RT = 1.15 min, LCMS 07: m/z = 181.1 543 [M--1]. 1H NMR (300 MHz, Methanol-d4) 5 7.61 (d, J = 6.0 Hz, 1H), 5.77 (d, J = 6.0 Hz, 1H), 3.34 (t, J = 4.5 Hz,1H), 3.32 (t, J =15 Hz,1H), 2.87 (s, 3H), 1.63 — 1.53 (m, 2H), 1.48 — 1.36 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT = 0.86min, LCMS15: m/z = 250 [M+1]. 1H-NMR (300 MHz, Methanol-d4) 5 7.67 (d, J = 6.0 Hz, 1H), 5.75 (d, J = 6.0 Hz, 1H),4.07-3.88 (m, 2H), 3.76-3.54(m, 2H), 2.86 (s, 3H), 1.74 — 1.30 (m, 8H), 1.04-0.80 (m, 3H).

LC-MS: (ES, m/z): RT = 1.31 min, LCMS 27: m/z = 222.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.67 (d, J = 6.0 Hz, 1H), 5.76 (d, J = 6.0 Hz, 1H), 3.86 — 3.80 (m, 1H), 3.69 — 3.58 (m, 1H), 3.57 — 3.48 (m, 2H), 2.88 (s, 3H), 1.76 — 1.55 (m, 4H), 1.14 (s, 3H).

LC-MS: (ES, m/z): RT = 0.67 min, LCMS 27: m/z = 222.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.67 (d, J = 6.0 Hz, 1H), 5.76 (d, J = 6.0 Hz, 1H), 3.92 — 3.84 (m, 2H), 3.71 — 3.62 (m, 2H), 2.87 (s, 3H), 1.61 — 1.49 (m, 4H), 1.22 (s, 3H).

LC-MS: (ES, m/z): RT = 0.98 min, LCMs28: m/z = 208.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.62 (s, 1H), 5.89 (d, J = 6.3 Hz, 1H), 4.31 (t, J = 7.2 Hz, 1H), 3.70 — 3.55 (m, 1H), 2.91 (s, 3H), 2.68 — 2.56 (m, 1H), 2.18 — 2.12 (m, 2H), 1.99 — 1.88 (m, 2H), 1.62 — 1.55 (m, 1H).

LC-MS: (ES, m/z): RT = 1.12 min, LCMS 27: m/z = 278.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.62 (d, J = 7.2 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H), 4.14 — 4.02 (m, 2H), 3.79 — 3.71 (m, 1H), 3.68 — 3.54 (m, 1H), 3.34 — 3.32 (m, 2H), 3.24 — 3.01 (m, 3H), 2.00— 1.91 (m, 4H), 1.72 — 1.65 (m, 2H), 1.52 — 1.39 (m, 5H), 1.02 (t, J: 7.3 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.13 min, LCMS 27: m/z = 278.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.68 (s, 1H), 5.78 (d, J = 6.0 Hz, 1H), 4.32 — 4.25 (m, 2H), 3.67 — 3.27 (m, 2H), 2.87 (s, 3H), 2.71 — 2.65 (m, 2H), 1.65 (t, J = 5.1 Hz, 4H), 1.59 — 1.49 (m, 2H), 1.49 — 1.39 (m, 2H), 1.29 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.04 min, LCMs33: m/z = 387 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.18 (d, J = 2.0 Hz, 1H), 7.08 — 6.95 (m, 2H), 6.04-5.89 (m, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.85 — 3.77 (m, 3H), 3.68 (t, J = 8.1 Hz, 1H), 3.35— 3.25 (m, 1H), 3.05-2.98 (m, 1H), 2.84 (d, J = 2.1 Hz, 3H), 2.69 (s, 3H), .19 (m, 3H), 2.19-2.07 (m, 6H), 1.72 (, J = 9.3 Hz, 2H).

LC-MS: (ES, m/z): RT = 0.681min, LCMS 27: m/z = 306 [M+1]. 1H—NMR (300 MHz, Methanol-d4) 5 8.27 (s, 2H), 4.20 — 4.03 (m, 3H), 3.74 — 3.69 (m, 2H), 3.55 — 3.37 (m, 4H), 3.25 — 3.06 (m, 4H), 2.33 — 2.13 (m, 6H), 2.07 — 2.03 (m, 2H), 1.93 — 1.73 (m, 2H).

LC-MS: (ES, m/z): RT = 0.87 min, LCMS 33: m/z = 307 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.24 (s, 2H), 4.17 — 3.94 (m, 4H), 3.92 — 3.66 (m, 2H), 3.49 — 3.36 (m, 2H), 3.30 (d, J = 7.0 Hz, 2H), 3.27 — 2.88 (m, 6H), 2.50 — 2.22 (m, 1H), 2.19 — 1.86 (m, 2H), 1.71 — 1.58 (m, 2H), 1.33 — 1.08 (m, 2H).

LC-MS: (ES, m/z): RT= 1.24 554 min, LCMS 28zm/z = 291 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.94 - 7.78 (m, 1H), 7.56 (t, J = 3.1 Hz, 1H), 7.19 — 7.11 (m, 1H), 4.20 — 3.98 (m, 3H), 3.92 — 3.65 (m, 2H), 3.58 - 3.44 (m 2H), 3.32 — 3.14 (m, 3H), 3.14 — 2.93 (m, 5H), 2.53 — 2.24 (m, 3H), 2.20 — 1.81 (m, 3H).

LC-MS: (ES, m/z): RT = 0.80 min, LCMS 53: m/z = 292.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.20 (s, 2H), 4.17 — 3.95 (m, 3H), 3.94 — 3.66 (m, 2H), 3.46 (, J = 3.8 Hz, 2H), 3.29 — 2.83 (m, 8H), 2.48 — 1.97 (m, 4H), 1.85 — 1.73 (m, 2H).

LC-MS: (ES, m/z): RT =0.763min, LCMs33: m/z = 318 [M+1]. 1H—NMR (400 MHz, Methanol-d4) 5 8.20 (s, 2H), 4.04 — 3.99 (m, 3H), 3.76 (s, 2H), 3.46 — 3.41 (m, 3H), 3.15 — 3.05 (m, 3H), 2.95 — 8.83 (m, 2H), 2.50 — 2.00 (m, 4H), 1.95 —1.76 (m, 2H), 1.13 — 0.90 (m, 4H).

LC-MS: (ES, m/z): RT =1.315min, LCMS 28: m/z =319 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.09 (s, 2H), 3.94-3.89 (m, 5H), .49 (m, 2H), 2.97 — 2.93 (m, 1H), 2.90 — 2.52 (m, 4H), 2.15 — 1.91 (m, 3H), 1.83 — 1.48 (m, 4H), 0.59 — 0.40 (m, 4H).

LC-MS: (ES, m/z): RT = 1.030 min, LCMS 33: m/z = 372 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.40 — 7.29 (m, 1H), 7.27 — 7.11 (m, 1H), 7.11 — 6.99 (m, WO 81177 1H), 6.29 —5.99 (m, 1H), 4.45 — 4.08 (m, 6H), 3.90 (s, 3H), 3.88 — 3.55 (m, 1H), 3.21 — 3.11 (m, 1H), 3.09 — 2.91 (m, 3H), 2.44— 2.28 (m, 3H), 1.40 -1.21 (m, 6H).

LC-MS: (ES, m/z): RT = 1.05 min, LCMS 53: m/z = 398 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.59 (s, 1H), 7.09 — 6.96 (m, 1H), 6.90 (q, J = 8.7, 1H), 5.81 (s, 1H), 3.99 — 3.96 (m, 2H), 3.83 (d, J = 1.1 Hz, 3H), 3.30 — 2.96 (m, 2H), 2.94 (s, 3H), 2.80 (q, J = 8.0 Hz, 3H), 2.63 (s, 1H), 2.19 (s, 3H), 2.17 — 1.97 (m, 5H), 1.89 — 1.68 (m, 3H).

LC-MS: (ES, m/Z): RT = 0.926 min, LCMS 332 m/z = 382 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.64 — 7.50 (m, 1H), 7.21 — 7.09 (m, 3H), 6.90 (s, 1H), 4.28 - 4.18 (m, 2H), 3.96 (s, 3H), 3.88 — 3.71 (m, 2H), 3.57 - 3.48 (m, 2H), 3.21 — 3.08 (m, 2H), 2.53 (s, 3H), 2.31 - 2.10 (m, 6H).

LC-MS: (ES, m/z): RT = 0.999 min, LCMSO7: m/z = 386.25 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.59 (s, 1H), 7.12 — 7.05 (m, 1H), 6.90 — 6.86 (m, 1H), 5.80 (s, 1H), 4.00 — 3.91 (m, 2H), 3.81 (d, J = 1.7 Hz, 3H), 3.10 — 2.92 (m, 4H), 2.77 — 2.70 (m, 3H), 2.55 — 2.44 (m, 2H), 2.17 — 2.06 (m, 4H), 1. 70 — 1.66 (m, 1H), 1.22 — 1.10 (m, 6H).

LC-MS: (ES, m/z): RT = 1.000 min, LCMs33: m/z = 372 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.60 (s, 1H), 7.09 — 7.06 (m, 1H), 6.89 (d, J = 8.7 Hz, 1H), .81 (d, J = 0.8 Hz, 1H), 4.04 — 3.90 (m, 2H), 3.82 (s, 3H), 2.94 (s, 4H), 2.75 — 2.72 (m, 2H), 2.72 — 2.49 (m, 4H), 2.18 (s, 3H), 2.12 — 2.09 (m, 1H), 1.71 — 1.66 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT=1.784min, LCMS 33, m/z =384 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.37 — 7.26 (m, 1H), 7.27 — 7.03 (m, 2H), 6.00 (d, J = 1.1 Hz, 1H), 4.48 — , 7H), 3.97— 3.84 (m, 3H), 3.32— 3.26 (m, 1H), 2.99 (s, 3H), 2.43 — 2.14 (m, 7H), 2.00 — 1.88 (m, 2H).

LC-MS: (ES, m/z): RT= 0.96 min, LCMS 27zm/z = 400 [M+1]. lH-NMR: (Methanol-d4, ppm): 5 7.59 (s, 1H), 7.15-7.01 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), .82 (s, 1H), 4.13 (d, J = 6.2 Hz, 2H), 4.00 — 3.58 (m, 7H), 3.57 — 3.44 (m, 2H), 3.31 — 3.14 (m, 3H), 2.94-2.92 (m, 4H), 2.19 (s, 3H), 2.10 — 1.90 (m, 1H), 1.82-1.71 (m, 1H).

LC-MS: (ES, m/z): RT =1.073min, LCMS53: m/z = 456.4 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.29 — 6.72 (m, 3H), 6.22 — 5.67 (m, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.90 — 3.70 (m, 5H), 3.68 — 3.58 (m, 2H), 3.41 — 3.18 (m, 4H), 3.12 (d, J = 6.9 Hz, 2H), 3.06 — 2.92 (m, 2H), 2.02 — 1.62 (m, 10H),1.63 — 1.32 (m, 2H), 1.26 — 1.00 (m, 2H).

LC-MS: (ES, m/z): RT=1.553 min, LCMSS3, m/z=400 [M+1]. 1H NMR: (300 MHz, Methanol-d4) 5 7.45 (d, J = 4.3 Hz, 2H), 6.82 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 4.17 — 3.97 m, 5H 3.90 — 3.69 m, 4H 3.67 — 3.37 m, 3H 3.16 , , , s, 5H ,2.47 — 1.75 m, 10H.

LC-MS: (ES, m/z): RT=0.825 min,LCMSS3, m/z=413 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.60 (s, 1H), 7.49 (s, 1H), 6.89 (s, 1H), 4.36 (t, J = 5.6 Hz, 2H), 4.06 (s, 3H), 3.91 — 3.64 (m, 5H), 3.58 —3.41(m, 4H), 3.26 — 3.07 (m, 5H), 2.98 (s, 3H), 2.47 — 1.99 m, 10H .

LC-MS: (ES, m/z): RT = 1.078 min, LCM328: m/z = 373.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.04 — 7.88 (m, 1H), 7.69 — 7.49 (m, 1H), 6.07 (s, 1H), 4.20 — 4.10 (m, 2H), 4.06 — 3.91 (m, 2H), 3.91 — 3.65 (m, 2H), 3.48 — 3.24 (m, 2H), 3.24 — 3.12 (m, 1H), 3.12 — 2.92 (m, 6H), 2.54 — 2.43 (m, 1H), 2.43 — 2.24 (m, 3H), 2.25 — 1.90 (m, 1H), 1.43 (t, J = 9 Hz, 3H).

LC-MS: (ES, m/z): RT=1.325min, LCMS 28, m/z =321.3 [M+1]. 1H NMR (400 MHz, D20-d6) 57.30 (d, J = 4.2, 1H), 6.25 (s, 1H), 4.05 — 3.50 (m, 8H), 3.48 — 3.38 (m, 2H), 3.30 — 2.80 (m, 8H), 2.40 — 1.70 (m, 6H).

LC-MS: (ES, m/z): RT = 0.15min, LCMs28; m/z =368.20 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 8.14 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 3.3 Hz, 1H), 7.27 — 7.13 (m, 2H), .01 (m, 1H),4.57-4.41 (m, 2H), 4.45—4.35 (m, 1H), 4.30 — 4.17 (m, 2H), 4.16-4.09 (m, 1H), 4.01 (d, J = 9.7 Hz, 3H), 3.53 — 3.47 (m, 2H), 3.4335 (m, 1H), 2.73 (s, 3H), 1.31 — 1.26 m, 3H LC-MS: (ES, m/z): RT = 0.886 min, LCMS33: m/z = 383 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 9.27 (s, 1H), 8.81 (s, 1H), 6.99 (d, J = 1.5 Hz, 1H), 6.08 (d, J = 1.1 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.83 — 3.73 (m, 2H), 3.62 — 3.50 (m, 2H), 3.25 — 3.15 (m, 2H), 3.07 s, 3H 2.48 —2.31 , m, 5H 2.30 — 2.15 , m, 2H 2.15 — 2.00 , m, 2H.

LC-MS: (ES, m/z): RT=0.876 min,LCMSS3, m/z=453 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.52 (s, 1H), 7.47 (s, 1H), 6.82 (s, 1H),4.32 (t, J = 5.5 Hz, 2H), 4.03 (s, 3H), 3.91 — 3.64 (m, 9H), 3.49 (t, J = 7.2 Hz, 2H), 3.45 — 3.32 (m, 2H), 3.24 — 3.08 (m, 2H), 2.98 (s, 3H), 2.46 — 1.95 (m, 14H).

LC-MS: (ES, m/z): RT = 2.127min; LCMS33: m/z = 383 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 9.30 (d, J = 2.9 Hz, 1H), 8.39 (s, 1H), 6.82 (s, 1H), 6.20 (s, 1H), 4.61 (t, J = .9 Hz, 2H), 3.77 (s, 2H), 3.60 — 3.51 (m, 2H), 3.21 — 3.19 (m, 5H), 2.51 — 2.38 (m, 5H), 2.23 , J = 7.7 Hz, 2H 2.14 — 2.05 , m, 2H.

LC-MS: (ES, m/z): RT = 0.868 min, : m/z = 345.1 [M+1].

LC-MS: (ES, m/z): RT = 0.903 min, LCMSO7: m/z = 359.20 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.97 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 5.82 (d, J = 0.9 Hz, 1H), 4.04 — 3.87 (m, 5H), 2.92 (s, 3H), 2.86 — 2.75 (m, 2H), 2.75 — 2.59 (m, 2H), 2.57 — 2.47 (m, 1H), 2.40 s, 3H 2.21 —2.02 , m, 4H 1.71 — 1.61 , m, 1H.

LC-MS: (ES, m/z): RT = 1.961 min, HPLC05: m/z = 371 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.90—7.75 (m, 1H), 7.72—7.49 (m, 1H), 7.25—7.09 (m, 1H), 6.04 — 5.97 (m, 1H), 4.34 (s, 2H), 3.97 (s, 3H), 3.70 — 3.43 (m, 8H), 2.99 (s, 3H), 2.49—2.25 (m, 3H), 2.21— 2.03 (m, 4H).

LC-MS: (ES, m/z): RT=1.001 min, , m/z=388 [M+1]. 1H NMR: (300 MHz, Methanol-d4) 5 7.61 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.18 — 4.08 (m, 1H), 4.08 — 3.90 (m, 2H), 3.83 (s, 3H), 3.01 — 2.73 m, 4H 2.70 — 2.55 m, 5H 2.17 1.83-1.79 , , s, 3H , m, 4H.

LC-MS: (ES, m/z): RT = 1.509min; LCMs15: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.97 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.33 — 3.28 (m, 4H), 2.91 (s, 3H), 2.67 (q, J = 8.1, 2H 2.21 — 2.05 1.77 — 1.86 , m, 5H , m, 6.2 Hz, 2H.

LC-MS: (ES, m/z): RT = in, LCMSO7: m/z = 357 [M+1]. 1H NMR: (400 MHz, Methanol-d4) 5 7.61 — 7.53 (m, 2H), 6.92 (d, J = 8.6 Hz, 1H), 5.80 (s, 1H), 3.86 (s, 3H), 3.74 (s, 2H), 3.22 (t, J = 6.8 Hz, 4H), 2.91 (s, 3H), 2.57 — 2.56 (m, 4H), 2.18 (s, 3H), 2.09 — 2.05 m, 2 .

LC-MS: (ES, m/z): RT=0.97min, LCMs28, m/z=374.21 [M+1]. lH-NMR: (Methanol-d4) 7.30 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H),7.10-7.01 (m, 1H), 6.25—5.92 (m, 1H), 4.40 — 4.15 (m, 5H), 4.13 — 3.98 (m, 2H), 3.92—3.88 (m, 3H), 3.54 (dd, J = 12.9, 3.2 Hz, 1H), 3.45—3.38 (m, 1H), 3.06—2.93 (m, 3H), 2.78—2.56 (m, 1H), 2.52—2.39 (m, 1H), 2.31 d, J: 1.0 Hz, 3H.

Table IB LC-MS: (ES, m/z): RT=1.015 min,LCM828, m/z=369 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.25 (d, J = 0.9 Hz, 1H), 8.18 (dd, J = 9.1, 1.0 Hz, 1H), 7.94 (s, 1H), 7.18 (d, J = 9.1 Hz, 1H), 6.83 (s, 1H), 4.24 (t, J = 5.6 Hz, 2H), 4.11 (s, 3H), 3.86 — 3.76 (m, 2H), 3.47 dd, J = 8.1, 6.8 Hz, 2H 3.23 — 3.08 m, 2H 2.40 — 2.02 1.29 , , m, 6H , s, 1H.

LC-MS: (ES, iii/z): RT=0.541min LCMS 32, III/Z =416 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.66 (s, 1H), 7.52 (s, 1H), 4.38 (t, J = 5.5 Hz, 2H), 4.12 (s, 3H), 4.02 — 3.90 652 (In, 1H), 3.90 — 3.79 (m, 2H), 3.77 — 3.68 (In, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.42 — 3.32 (In, 2H), 3.24 — 3.10 (In, 2H), 2.99 (s, 3H), 2.79 — 2.73 (In, 3H), 2.68 — 2.52 (In, 2H), 2.45 — 2.34 m, 2H 2.30—2.02 , m, 6H .

LC-MS: (ES, iii/z): RT = 1.488 min; LCMS53: III/Z = 370 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.59 (s, 1H), 8.23 (d, J = 8.1, 1H), 8.16 (s, 1H), 7.84 (d, J = 8.8, 1H), 7.42 (d, J = 8.8, 1.0 Hz, 1H), 4.65 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.86 — 3.63 (In, 2H), 3.48 (t, J = 7.6 Hz, 2H), 3.18 (q, J = 9.0 Hz, 2H), 2.42 — 2.31 (m, 2H), 2.22 (q, J = 9.4 Hz, 2H), 2.08 d, J = 3.7 Hz, 2H.

LC-MS: (ES, iii/z): RT = 0.99min, LCMs28; m/z = 427.31 [M+1]. 1H NMR (300 MHz, Deuterium Oxide) 5 7.55 (s, 1H), 7.26 (s, 1H), 4.36 (t, J = 5.6 Hz, 2H), 4.18-3.95 (m, 4H), 3.76 — 3.43 (In, 5H), 3.42 — 3.12 (In, 4H), 3.1-2.96 (m, 2H), .81 (m, 3H), 2.35 — 2.15 (In, 6H), 2.13 — 1.79 (In, 4H) , 1.41 — 1.19 (In, 6H).

LC-MS: (ES, iii/z): RT = 1.087 min, LCMS 31, m/z = 398.27 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.80 — 7.68 (m, 2H), 7.53 (d, J = 2.2 Hz, 1H), 4.48 — 4.31 (111,2H), 4.16 (d, J = 2.6 Hz, 3H), 4.14 — 3.79 (In, 2H), 3.80 — 3.65 (m, 3H), 3.57 — 3.35 (In, 5H), 3.27 — 3.05 m, 2H 3.00 , s, 3H 2.93 , s, 3H 2.62 — 1.96 1.49 — 1.35 , m, 6H , m, 3H.

LC-MS: (ES, iii/z): RT = 1.047 min, LCMS 30, m/z = 426.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.76 — 7.64 (m, 2H), 7.57 (s, 1H), 4.47 — 4.25 (m, 2H), 4.19 — 3.80 (In, 5H), 3.84 — 3.59 (In, 4H), 3.56 — 3.12 (m,6H), 2.92 (s, 3H), 2.63 — 1.93 (In, 7H), 1.52 — : (ES, iii/z): RT = 0.786 min; LCMSO7: III/Z = 385 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.67 (d, J = 5.7 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 4.61 — 4.41 (In, 2H), 4.40 — 4.24 (In, 2H), 4.26 — 3.87 (m, 7H), 3.83 — 3.56 (m, 2H), 3.49 (q, J = 7.3 Hz, 3H), 3.35 (d, J = 2.5 Hz, 1H), 2.98 (s, 3H), 2.83 (d, J = 1.5 Hz, 3H), 2.55 — 2.29 (m, 2H), 2.20 (d, J = 8.2 LC-MS: (ES, iii/z): RT=0.856 min,LCMs28, m/z=427 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.95 (s, 1H), 7.69 (s, 1H), 4.76 (t, J = 5.7 Hz, 2H), 4.14 (s, 3H), 4.04 — 3.90 (In, 1H), 3.79 (s, 2H), 3.74 — 3.58 (In, 3H), 3.54 — 3.35 (In, 4H), 3.16 (s, 2H), 2.89 (s, 3H), 2.47— 1.96 m, 10H 1.46 , d, J = 6.7 Hz, 6H.

LC-MS: (ES, iii/z): RT = 0.815 min; LCMs15: III/Z = 399 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.43 (s, 1H), 7.19 (s, 1H), 4.23 — 4.06 (m, 2H), 4.02 (s, 3H), 3.62 — 3.49 (In, 1H), 3.09 (d, J = 5.9 Hz, 2H), 2.99 — 2.91 (In, 1H), 2.89 — 2.42 (m, 9H), 2.42 — 2.25 (In, 5H 2.26 —2.01 , m, 3H 1.99 — 1.80 , m, 2H 1.81—1.70 , m, 1H 1.16 , t, J = 7.3 Hz, 3H.

LC-MS: (ES, : RT = 1.013 min, LCMS 28, m/z=451.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 8.41 (s, 2H), 7.57 (s, 1H), 7.41 (d, J = 2.2 Hz, 1H), 4.39 (t, J = 5.5 Hz, 2H), 4.09 (s, 3H), 4.02 —3.92 (In, 1H), 3.90 — 3.80 (In, 2H), 3.78 — 3.68 (m, 2H), 3.64 — 3.47 (In, 2H), 3.43 — 3.33 (In, 2H), 3.26 — 3.10 (In, 2H), 2.99 (s, 3H), 2.52 — 2.34 (In, 4H), 2.33 — 217 m 4H 2.15—202 m 2H 2 a LC-MS: (ES, iii/z): RT = 0.920 min, LCMS 30, III/Z = 331 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.49 (s, 1H), 7.24 (s, 1H), 4.41 — 4.33 (m, 2H), 4.02 (s, 3H), 3.84 (s, 2H), 3.54 — 3.45 (In, 2H), 3.16 (s, 5H), 2.89 (s, 3H), 2.45 — 2.33 (In, 2H), 2.23 (s, 2H), 2.13 — : (ES, iii/z): RT = 0.898 min, LCMS 07; m/z = 386 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.47 (s, 1H), 7.39 (s, 1H), 4.38 (t, J = 5.6 Hz, 2H), 4.30 (t, J = 5.2 Hz, 4H), 4.03 (s, 3H), 3.85 (d, J = 9.8 Hz, 2H), 3.55 — 3.39 (In, 6H), 3.25 — 3.15 (In, 2H), 2.89 (s, , d, J = 7.8, 4.9 Hz, 2H.

LC-MS: (ES, : RT = 0.88min, LCMS33: m/z = 399.27 [M+1]. 1H NMR (400 MHz, Deuterium Oxide) 5 .45 (m, 1H), 7.26 (d, J = 1.4 Hz, 1H), 4.44 — 4.05 (In, 3H), 4.02— 3.89(m, 3H), 3.72 — 3.59 (m, 2H), 3.57 — 3.31 (In, 5H), 3.10 — 2.97 (m, 3H), 2.95 — 2.79 LC-MS: (ES, m/z): RT = 0.89n11n, : n1/z = 385.28 [M+1]. 1H NMR (400 MHz, Deuterium Oxide) 5 7.54 (s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 4.89—4.78 (n1, 1H), 4.36 (t, J = 745 5.6 Hz, 2H), 4.25—4.17 (n1, 1H), 4.12—3.95 (n1, 3H), 3.89 — 3.76 (m, 1H), 3.72 — 3.61 (m, 2H), 3.52—3.41 (m, 1H), 3.39 — 3.34 (n1, 2H), 3.32—3.21 (n1, 1H), 3.11—2.95 (n1, 5H), 2.94— 2.79 n1, 4H 2.37 — 2.19 n1, 2H 2.14—2.01 , n1, 3H 2.01—1.82 , , n1, 2H.

HPLC: (ES, m/z): RT = 4.51n11n, HPLC07: n1/z =414.28 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.58—7.42 (m, 1H), 7.29 (s, 1H),4.45-4.31 (n1, 2H), 4.21—4.01 (m, 4H), 3.95 — 3.57 (n1, 4H), 3.57 — 3.43 (n1, 3H), 3.26 — 3.05 (n1, 6H), .98 (n1, 3H), 2.47— 2.32 n1, 2H 2.31 — 2.02 , n1, 7H 1.93—1.82 , n1, 1H.

LC-MS: (ES, n1/z): RT= 0.94 n11n, LCMS 28: n1/z = 468 [M+1]. lH-NMR: (Methanol-d4, ppm);5 7.69 (d, J = 8.1 Hz, 2H), 7.56 (s, 1H), 4.44 (t, J = 5.5 Hz, 2H), 4.21 — 4.10 (m, 5H), 4.09— 3.9,6(m 1H), 3.87——3.,81(m 4H), 3.64— 3.3,8(m 7H), 3.26— 3.10(m, 2H), 2.93(s, LCMs. (ES, n1/z). RT—— 1. 316 n11n, . n1/z—— 454 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.68 (d, J: 6.4 Hz, 2H), 7.54 (s, 1H), 4.43 (t, J: 5.5 Hz, 2H), 4.28 (d, J—— 8.1 Hz, 1H), 4.14 (s, 6H), 3.62— 3.96 (m, 3.42 — 3.58 (m, 4H), 3.25 —3.09 (n1, 2H), , 6H), LCMS. (ES, n1/z). RT:0. 887 n11n,L,CMS53 n1/z=483 [M+1]. 1H NMR (300 MHz, old4) 5 7.46 (s, 2H), 5 6.87 (s, 1H),4.33 (t, J: 5.5 Hz, 2H), 4.18— 4.07 (n1, 2H), 4.03 (s, 3H), 3.90 — 3.69 (m, 5H), 3.61 — 3.34 (n1, 7H), 3.17 (s, 5H), 2.44 — 1.99 (n1, 12H), 1.98— 1.79 n1, 2H.

LC-MS: (ES, n1/z): RT=0.877 n11n,LCMS53, n1/z=469 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.46 (s, 2H), 6.88 (s, 1H), 4.38 — 4.20 (m, 3H), 4.19 — 3.99 (m, 5H), 3.97 — 3.56 (m, 7H), 3.55 — 3.36 (n1, 4H), 3.17 (s, 5H), 2.55 — 2.01 (n1, 12H).

HPLC: (ES, m/z): RT=3.82 n11n, HPLC07: n1/z = 471 [M+1]. lH-NMR: (Methanol-d4): 5 7.59 (s, 1H), 7.29 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.28 — 3.95 (n1, 7H), 3.96 — 3.59 (n1, 6H), 3.54 — 3.38 (n1, 4H), 3.27 — 3.08 (n1, 5H), 2.68 — 2.01 (m, 12H).

LC-MS: (ES, m/z): RT = 1.130 n11n, LCMS 28, n1/z = 387 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.50 (s, 1H), 7.31 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.05 — 3.98 (n1, 7H), 3. 91 —3. 78 (n1, 6H), 3. 50 (t, J—— 7.2 Hz, 2H), 3.23— 3.11 (n1, 2H), 2.91 (s, 3H), 2.45 —2.34 LCMS. (ES, n1/z). RT= 1.107 n11n, LCMS53. n1/z=424.3 [M+1]. 1HNMR (300 MHz, Methanold4)5787 (s 1H), 766 (s 1H), 7.5,0(s 1H), 4.60— 4.3,8(m 4H), 4.12(s, 3H), 398 (s 4H), 3.90— 3. 76 (n1 2H), 3.31 —3.69 (m,6H), 3.25—3.10(m, 2H), 2.85 (s, 3H), LCMS. (ES, n1/z). RT—— 1. 025 n11n, LCMs 33. n1/z—— 352 [M+1]. 1H NMR (300 MHz, Methanold4.,)5778(d J= 2.7,Hz 1H), d J= 2.7,Hz 1H), 692 (d J: 9.0,Hz1H), .81 (d, J = 0.9 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 2H), 2.91 (s, 3H), 2.85 — 2.72 (n1, 4H), 2.22 —2.15 n1, 3H 1.97— 1.81 , n1, 4H.

LC-MS: (ES, m/z): RT = 1.399 min; LCMS53: n1/z = 455 [M+1]. 1H NMR (400 MHz, ol—d4) 5 7.33 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.7, 1H), 6.92 (d, J = 8.7 Hz, 1H), .80 (s, 1H), 4.10 (t, J = 6.0 Hz, 3H), 3.82 (s, 3H), 2.99 (s, 1H), 2.88 — 2.34 (n1, 7H), 2.29 (s, 3H), 2.17 (s, 3H), 2.13 — 2.01 (n1, 3H), 1.95 (s, 2H), 1.91 — 1.75 (m, 5H), 1.69 (d, J = 3.6 Hz, 1H), 1.31 (d, J = 10.8 Hz, 1H).

LC-MS: (ES, n1/z): RT = 1.041 min; LCMSO7: n1/z = 442 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.54 (s,1H), 7.03 — 6.94 (m,1H), 6.89 (d, J = 5.6 Hz, 1H), 5.81 (s, 1H), 4.11 (t, J = 7.2 Hz, 4H), 3.83 (d, J = 6.1 Hz, 4H), 3.45 (t, J = 3.2 Hz, 1H), 3.22 — 3.13 (m, 1H), 2. 76 (d, J = 8.9 Hz, 6H), 2.14 (s, 3H), 2.05 (s, 3H), 1.86 (d, J = 7.6 Hz, 5H), 2.73 — LCMS. (ES, n1/z). RT= 1.15 n11n, LCMs28. n1/z=428 [M+1]. lH-NMR. (Methanol-d4, ppm)5.,742(d J= 2.5,Hz 1H), 7.1,1(dd J: 8.7, 2.5,Hz 1H), 6.8,8(d J= 8.7,Hz1H), .82 (d, J = 0.8 Hz, 1H), 4.56 (s, 1H), 4.12 — 3.77 (n1, 8H), 3.68 — 3.53 (n1, 1H), 2.80 — 2.57 LC-MS: (ES, m/z): RT = 0.924 n11n, LCMS 07: n1/z = 409 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 4.41 (t, J = 5.4 Hz, 2H), 4.18 (s, 3H), 3.92 — 3.82 (n1, 1H), 3.81 (d, J = 10.9 790 Hz, 2H), 3.73 (d, J = 11.2 Hz, 2H), 3.51 (q, J = 9.9, 8.4 Hz, 4H), 3.19 (d, J = 14.4, 7.7 Hz, 2H), 3.01 (d, J = 2.7 Hz, 3H), 2.41 (q, J = 6.1 Hz, 2H), 2.33 — 2.18 (n1, 4H), 2.19 — 2.06 (n1, LC-MS: (ES, m/z):RT = 1.673 min; LCMSS3: n1/z=367 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 8.01 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 5.94 (s, 1H), 4.23 (t, J—— 6.0 Hz, 2H), 2.93 (s, 3H), 2. 86— 2.81 (n1, 2H), 2.73 — 2.70 (n1, 4H), 2.20 LCMS. (ES, m/z:) RT: 1. 706 n11n,LCMS53, n1/z=383 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.56 (d, J: 2.5 Hz, 1H), 7.42 (d, J: 2.5 Hz, 1H), 6.00 (s, 1H), 4.28 (t, J = .5 Hz, 2H), 3.62 — 3.38 (n1, 6H), 2.99 (s, 3H), 2.33 — 2.05 (n1, 9H).

LC-MS: (ES, m/z): RT = 0.958 n11n, n1/z = 382.15 [M+1]. 1H NMR (400 MHz, Chloroform-d) 5 8.85 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 5.6 Hz, 1H), 7.59 — 7.49 (n1, 1H), 7.1,7(d J=2.7,Hz 1H), 7.11 (dd, J=8.6, 2.6,Hz1H),6.8,8(d J=8.7,Hz 1H), 6.5,6(s 1H), 4.15 (t, J: 6.2,Hz 2H), s 3H), 3.8,6(s 3H), 3.11 (s, 6H), 2.42— 2.2,6(n1 2H), LCMS. (ES, n1/z). RT: 0.8 n11n, n1/z—— 383.25 [M+1]. 1H NMR (400 MHz, Methanol- d4) 5 9.74 (s, 1H), 8.79 (d, J: 6.5, 1.0 Hz, 1H), 8.50 (d, J: 6.4 Hz, 1H), 7.91 (s, 1H), 7.26 (s, 1H), 4.53 (t, J = 5.7 Hz, 2H), 4.43 (s, 3H), 3.99 (s, 3H), 3.87 — 3.76 (n1, 2H), 3.51 (t, J = 7. 4 Hz, 2H), 3.26 — 3.11 (n1, 2H), 2.49 — 2.38 (n1, 2H), 2.29 — 2.17 (n1, 2H), 2.16 — 2.01 (n1, LCMs. (ES, n1/z). RT: 0.982n11n, LCMS33. n1/z—— 331 [M+1]. 1H NMR (300 MHz, Methanold4)5700(d J= 8.7,Hz1H),6.9,0(d J= 2.3,Hz 1H), 6.83 (dd, J: 85, 2.5Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 3.91 —3.73 (n1, 5H), 3.49 (t, J = 7.0 Hz, 2H), 3.25 — 3.02(n1, 2H), 2.34 (s, 3H), 2.29 — 2.04 (n1, 7H).

LC-MS: (ES, n1/z): RT = 1.218 n11n, LCMs28: n1/z = 344 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 6.98 — 6.90 (n1, 2H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 4.18 (t, J = 5.5 Hz, 2H), 3.87— 3.74 (n1, 5H), 3. 69 (s, 3H), 3.48 (t, J = 6.9 Hz, 2H), 3.22 —3.11 (n1, 2H), 2.32 — LCMS. (ES, n1/z). RT: 1.103 n11n, LCMSl5: n1/z—— 399 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.98 (d, J: 2.2 Hz, 1H), 7.85 (s, 1H), 5.83 (d, J: 0.8 Hz, 1H), 4.21 — 3.65 (n1, 5H), 3.13 — 2.76 (n1, 5H), 2.76 — 2.49 (n1, 3H), 2.39 (d, J = 9.7, 6.2 Hz, 1H), 2.19 (s, 3H ,2.15 — 1.86 n1, 5H 1.86— 1.53 , n1, 3H.

LC-MS: (ES, n1/z): RT = 1.478 min; LCMSO7: n1/z = 402 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.18 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.02 (d, J = 1.1 Hz, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.78 (s, 2H), 3.58 — 3.39 (n1, 2H), 3.23 (s, 2H), 3.06 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 2.30 — 2.13 (n1, 4H), 2.07 (d, J = 8.8 Hz, LCMs. (ES, n1/z). RT: 2.007 n11n, LCMS53. n1/z—— 372 [M+1]. 1H NMR (300 MHz, old4) 5 7.48 (d, J: 2.4 Hz, 1H), 7.12 (d, J: 8.7, 2.4 Hz, 1H), 6.89 (d, J: 8.7 Hz, 1H), 5.77 (d, J = 0.8 Hz, 1H), 4.15 (s,1H), 4.08 — 1,1H), 3.98 — 3.92 (n1,1H), 3.8 (s, 3H), 3.31 — 3.19 (n1,2H),3. 18 — 3.00 (n1, 2H), 2.81 — 2.70 (n1, 1H), 2.23 — 2.07 (n1, 4H), 1.82 d, J: 6.8 Hz, 1H 1.23 , d, J: 6.5 Hz, 6H.

LC-MS: (ES, m/z): RT=1.843min LCMS 31, n1/z =372 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.49 — 7.43 (n1, 2H), 6.83 (s, 1H), 4.35 — 4.27 (n1, 1H), 4.27 — 4.18 (n1, 1H), 4.17 — 4.08 (n1, 2H), 4.02 (s, 3H), 3.83 — 3.72 (n1, 2H), 3.66 — 3.51 (n1, 3H), 3.46 — 3.28 (n1, 2H), 3.18 (s, 3H), 3.07 — 2.95 (n1, 1H), 2.43 — 2.29 (n1, 1H), 2.14 — 2.00 (n1, 1H), 1.98— 1.82 n1, 4H.

LC-MS: (ES, m/z): RT=0.672min LCMS 32, n1/z =386 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.27 (s, 1H), 7.19 (s, 1H), 6.55 (s, 1H), 4.15 — 3.99 (n1, 4H), 3.94 (s, 3H), 3.80 — 3.69 (n1, 2H), 3.52 — 3.36 (n1, 1H), 2.99 (s, 3H), 2.96 — 2.90 (n1, 1H), 2.89 — 2.76 (n1, 1H), 2.76 — 2.66 (n1, 2H), 2.63 — 2.55 (n1, 1H), 2.44 (s, 3H), 2.24 — 2.10 (n1, 1H), 1.95 — LC-MS: (ES, m/z): 83 min,LCM828, m/z=308 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.45 (s, 1H), 6.44 (s, 1H), 4.12 — 3.92 (m, 7H), 3.90 — 3.80 (m, 1H), 3.63 — 3.33 (m, 5H), 3.25 (dd, J = 11.9, 7.0 Hz, 1H), 2.97 — 2.77 (m, 1H), 2.35 — 2.18 (m,1H), 2.10— 1.90 m, 3H 1.70 —1.50 , m, 2H.

LC-MS: (ES, m/z): RT = n, LCMS33: m/z = 322.21 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.50 (s, 1H), 6.64 (s, 1H),4.31-4.15 (m, 1H), 4.14 — 3.95 (m, 7H), 3.71 — 3.55 (m, 2H), 3.54 — 3.42 (m, 2H), 3.41 — 3.35 (m, 1H), 3.28—3.21 (m, 1H), 3.10 (s, 3H), 2.95 — 2.87 (m, 1H), 2.41—2.22 (m, 1H), 2.09 — 1.92 (m, 3H), 1.80 — 1.70 (m, 2H).

LC-MS: (ES, m/z): RT=0.991 min,LCMSS3, m/z=441 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.46 (d, J = 6.9 Hz, 2H), 6.79 (s, 1H), 4.82 — 4.68 (m, 1H), 4.33 (t, J = 5.5 Hz, 2H), 4.19 — 4.06 (m, 1H), 4.02 (s, 3H), 3.91 — 3.75 (m, 2H), 3.71 — 3.35 (m, 4H), 3.16 s, 5H 2.93 , td, J = 13.0, 2.6 Hz, 1H 2.45— 1.96 m,11H, 1.85 — 1.55 , m, 2H.

LC-MS: (ES, m/z): RT =1.842min, LCMs15, m/z = 384 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.46 (s, 1H), 7.37 (s, 1H), 7.25 (d, J = 1.2 Hz, 1H), 4.33 (t, J = 5.5 Hz, 2H), 4.02 (s, 3H), 3.91 — 3.82 (m, 6H), 3.51 (t, J = 7.2 Hz, 2H), 3.23 — 3.10 (m, 2H), 2.73 (d, J = 1.0 Hz, 3H), 2.46 — 2.31 (m, 2H), 2.27 — 2.20 (m, 2H), 2.15 — 2.04 (m, 2H), 1.87 — 1.78 (m, HPLC: (ES, m/z): RT = 8.367 min; HPLC07: m/z = 467 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.55 — 7.46 (m, 2H), 7.09 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 4.03 (s, 3H), 3.92 — 3.66 (m, 9H), 3.55 — 3.32 (m, 3H), 3.20 — 3,12 (m, 2H), 2.97 (s, 4H), 2.44 — 2.00 (m, 10H 1.82 , s, 6H.

LC-MS: (ES, m/z): RT = 1.246 min; LCMs15: m/z = 398 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.20 (d, J = 8.8 Hz, 2H), 6.52 (s, 1H), 4.18 (t, J = 6.1 Hz, 2H), 3.92 (s, 3H), 3.24 — 3.04 (m, 1H), 2.98 (s, 3H), 2.85 — 2.71 (m, 2H), 2.73 — 2.53 (m, 4H), 2.26 — 2.07 (m, 2H ,2.07— 1.90 m, 4H 1.90— 1.74 , m, 5H 1.72— 1.45 , m, 4H 1.45 — 1.24 m, 1H.

LC-MS: (ES, m/z): RT=2.004 min,LCM828, m/z=358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.53 (s, 1H), 7.46 (s, 1H), 6.85 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.02 (s, 3H), 3.93 — 3.79 (m, 2H), 3.68 (p, J = 6.8 Hz, 1H), 3.53 (t, J = 7.2 Hz, 2H), 3.20 (s, 5H), 2.50 — 2.02 m, 6H 1.42 , d, J = 6.8 Hz, 7H.

LC-MS: (ES, m/z): RT = 0.695 min, LCMS 30, m/z =317 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.42 (s, 1H), 7.19 (s, 1H), 6.90 (d, J = 1.1 Hz, 1H), 4.37 (t, J = 5.6 Hz, 2H), 4.03 (s, 3H), 3.92 — 3.78 (m, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.27 — 3.11 (m, 2H), 2.77 (s, 3H 248—233 m 2H 232—203 m 4H LC-MS: (ES, m/z): RT = 1.047 min; LCMSO7: m/z = 331 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.53 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 4.42 (t, J = 5.5 Hz, 2H), 4.34 (s, 3H), 4.08 (s, 3H), 3.90 — 3.80 (m, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.22 — 3.17 (m, 2H), 2.94 s, 3H 2.45 — 2.39 , m, 2H 2.30 — 2.17 , m, 2H 2.16 — 2.08 , m, 2H.

LC-MS: (ES, m/z): RT=1.815 min, , m/z=387 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.59 (s, 1H), 7.31 (d, J = 1.1 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 4.41 (t, J = .7 Hz, 2H), 4.18 — 4.05 (m, 5H), 3.90 — 3.75 (m, 5H), 3.52 (t, J = 7.2 Hz, 2H), 3.25 — 3.14 m, 2H 2.48 — 2.36 , m, 2H 2.31 — 2.02 , m, 4H 2.00 — 1.83 , m, 4H.

LC-MS: (ES, m/z): RT = 1.008 min, LCMS 07: m/z = 414 [M+1]. 1H NMR (400 MHz, D20) 5 7.19 — 7.07 (m, 2H), 7.01 — 6.93 (m, 1H), 4.31 — 4.21 (m, 2H), 3.91 (td, J = 10.3, 9.5, 4.7 Hz, 5H), 3.73 (d, J = 10.9, 5.2 Hz, 2H), 3.38 (d, J = 37.3, 8.9 Hz, 4H), 3.16 — 2.98 (m, 5H), 2.81 (s, 2H), 2.36 — 2.24 (m, 2H), 2.15 (d, J = 9.6, 5.6 Hz, 2H), 2.07 — 1.88 (m, 3H), 1.61 — 1.52 (m, 2H), 1.35 (q, J = 11.6 Hz, 2H).

LC-MS: (ES, m/z): RT=1.339 min,LCMSlS, m/z=454 [M+1]. 1H NMR (400 MHz, ol-d4) 5 7.51 (s, 1H), 7.47 (s, 1H), 7.05 (s, 1H), 4.33 (t, J = 5.5 Hz, 2H), 4.18 — 4.09 (m, 2H), 4.03 (s, 3H), 3.91 — 3.73 (m, 8H), 3.70 — 3.55 (m, 1H), 3.50 (t, J = 7.2 Hz, 2H), 3.17 (dd, J = 11.5, 6.7 Hz, 2H), 2.44 — 2.33 (m, 2H), 2.30 — 2.16 (m, 2H), 2.16 — 2.02 (m, 2H), 2.02 — 1.87 (m, 4H), 1.86 — 1.72 (m, 6H).

LC-MS: (ES, m/z): RT=1.172 min,LCM828, m/z=414 [M+1]. 1H NMR (400 MHz, Deuterium Oxide) 57.30 — 7.10 (m, 2H), 6.72 — 6.60 (m, 1H), 4.30 — 4.10 (m, 2H), 4.07 — 3.99 (m, 2H), 3.90 — 3.85 (m, 3H), 3.75 — 3.60 (m, 4H), 3.45 — 3.30 (m, 3H), 3.30 — 3.20 LC-MS: (ES, n1/z): RT=1.099 n11n,LCMs28, n1/z=428 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.61 (s, 1H), 7.45 (s, 1H), 6.83 (s, 1H), 4.36 (t, J = 5.5 Hz, 2H), 4.30 — 4.20 826 (n1, 1H), 4.17 — 4.07 (m, 2H), 4.02 (s, 3H), 3.89 — 3.75 (m, 4H), 3.60 — 3.45 (n1, 3H), 3.20 — 3.10 (n1, 2H) 2.42— 2.30 (m, 2H), 2.30 — 2.17 (m, 2H), 2.17 — 2.02 (m, 2H), 1.96 — 1.81 111, 4H,1.40 d, J=6.,3Hz 6H.

LCMS: (ES, n1/z): RT—— 1. 385 n11n, LCMSO7: n1/z—— 495 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.49— 7.41 (m, 2H), 6.87 (s, 1H), 4.33 (t, J: 5.5 Hz, 2H), 4.03 (s, 3H), 3. 85— 3. 79 (n1, 4H), 3. 72— 3.66 (n1, 1H), 3.58 —3.36 (n1, 6H), 3.17 (s, 5H), 2.92 —2.86 (n1, LCMs: (ES, n1/z): RT—— 1. 462 n11n, LCMSO7: n1/z—— 481 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.46— 7.41 (m, 2H), 7.43 (s, 1H), 4.32 (t, J: 5. 5 Hz, 2H), 4. 01 (s, 3H), 3.86 — 3.77 (n1, 2H), 3.69 — 3.60 (n1, 2H), 3.52 — 3.42 (n1, 5H), 3.24 — 3.01 (n1, 7H), 2.39 — 2.35 n1, 2H 2.28 — 1.92 , n1, 8H .

LC-MS: (ES, n1/z): RT = 0.858 min; LCMSO7: n1/z = 457 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.22 — 7.17(m, 2H), 6.53 (s, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3. 63— 3.57(m, 2H), 3.3,7(s 3H), 3.23— 3. 06 (n1 3H), 297 (s 3H), 2.83—2.60 (m, 8H), LCMS: (ES, n1/z): RT—— 1. 012 n11n, LCMs28: n1/z—— 353.2 [M——1]. 1H NMR (300 MHz, Methanold4) 5 8.47 (s, 1H), 8.02 (s, 1H), 6.01 (s, 1H), 4.41 (s, 2H), 4.01 (s, 3H), 3.91 — 3.32 (m, 4H), 2.95 (s, 3H), 2.32 (s, 3H), 2.21 — 2.01 (m, 4H).

LC-MS: (ES, n1/z): RT = 0.981 n11n, LCMSl5: n1/z = 338.3 [M--1]. 1H NMR (300 MHz, Methanol—d4) 5 7.74 (d, J = 2.7 Hz, 1H), 7.65 — 7.55 (m, 1H), 6.94 (d, J = 9.0 Hz, 1H), 5.81 (s,1H), 4.33— 4.32 (n1, 1H), 3. 84 (s, 3H), 3.32— 3.31 (m, 1H), 3.30 — 3.07 (m, 1H), 2.90 LCMS: (ES, n1/z): RT—— 1. 003 n11n, LCMS 33: n1/z—— 352 [M+1]. 1H NMR (400 MHz, Methanold4) 5 7.64— 7.45 (m, 2H), 7. 06 (d, J: 8. 8 Hz, 1H), 5.99 5.96 (n1, 1H), 3. 89 (s, 6H), 3.45 (s, 1H), 3.27 (s, 1H), 2.99 (s, 6H), 2.63 (s, 1H), 2.44 — 2.14 (m, 4H).

LC-MS: (ES, n1/z): RT = 1.655 n11n, LCMs28: n1/z = 352.2 [M+1]. 1H NMR (300 MHz, ol—d4) 5 7.78 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 5.81 (s, 1H), 3.84 (s, 3H), 3.44 (t, J = 6.9 Hz, 1H), 3.03 — 2.88 (m, 4H), 2.30 — 2.92 (n1, 4H), 2.35 — 2.08 n1, 4H 2.00 — 1.92 2 n1, 3H.

LC-MS: (ES, n1/z): RT = 1.18n11n, LCMS33: n1/z = 400.14 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.50 (d, J = 2.5 Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.16 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.12—3.02 (m, 2H),3.01-2.91(m, 7H 2.49 s, 3H 2.23—2.12 , , n1, 2H 2.04 — 1.87 , n1, 4H.

LC-MS: (ES, n1/z): 33n11n, LCMSl5, 66.3 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.66 (d, J = 7.4 Hz, 2H), 7.14 (d, J = 9.5 Hz, 1H), 6.02 (s, 1H), 4.32 (s, 2H), 3.93 (s, 3H), 3.72 (s,3H), 3.57 (d, J = 1.6 Hz, 3H), 2.99 (s, 3H), 2.32 (s, 3H), 1.88 LCMS: (ES, n1/z): RT: 1. 256 n11n, LCMS53: n1/z=454 [M+1]. lH-NMR (300 MHz, Methanold4) 57.68— 7.64 (n1, 2H), 7.52 (s, 1H), 4.42 (t, J: 6.0 Hz, 2H), 4.28 4.22 (n1, 1H), 4.18— 398 (n1 6H), 3.97— 3. 62 (n1, 6H), 3.52—3.39 (m, 4H),3.22—3.08 (n1, 2H), LCMS: (ES, n1/z): RT: 0. 813 n11n, LCMS53: n1/z—— 454 [M+1]. 1H NMR (300 MHz, Methanold4) 57.38 (s, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 4.23 (t, J: 6.0 Hz, 2H), 4.06— 3.88 (n1, 5H), 3.87 — 3.65 (m, 2H), 3.43 — 3.32 (n1, 1H), 3.26 — 3.08 (n1, 4H), 3.02 — 3.00 (n1, 2H), 2.91 — 2.71 (n1, 4H), 2.64 (s, 3H), 2.59—2.38 (m, 2H), 2.27 — 2.09 (n1, 3H), 2.05 — 1.80 LCMS: (ES, n1/z): RT—— 1. 406 n11n, : n1/z—— 469 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.23— 7.18 (m, 2H), 6.65 (s, 1H), 4.18 (t, J: 6.1 Hz, 2H), 4.06— 3.88 (n1, 5H), 3.87 — 3.65 (n1, 2H), 3.24 — 2.92 (n1, 7H), 2.81 — 2.75 (m, 2H), 2.80 — 2.30 (m, 6H), LC-MS: (ES, n1/z): RT = 1.405 min; LCMSO7: n1/z = 469 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.25 — 7.16 (n1, 2H), 6.64 (s, 1H), 4.21 (t, J = 6.1 Hz, 2H), 4.05 — 3.87 (n1, 5H), 3.87 — 3.65 (n1, 2H), 3.24 — 2.86 (n1, 7H), 2.81 — 2.75 (n1, 2H), 2.70 — 2.33 (n1, 6H), 2.26 — 2.08 n1, 3H 2.06 — 1.72 , n1, 9H.

LC-MS: (ES, m/z): RT = 1.182 n11n, LCMS 28: n1/z = 427 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.64 (d, J = 2.5 Hz, 1H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.72 (s, 1H), 4.24 (t, J = 5.5 Hz, 2H), 4.11 — 4.01 (n1, 2H), 3.95 — 3.79 (n1, 5H), 3.73 — 3. 54 (n1, 2H), 3. 53— 3.46 (n1, 2H), 3.23— 3. 14 (n1, 2H), 3. 06— 2.83 (n1, 1H), 2.43 (s, 3H), LCMS. (ES, n1/z). RT=1.383n11n, , n1/z=378.2 [M+1]. . 5824 (d J: 2.7 Hz, 1H), 7.65 (s, 1H), 7.45— 7.17 (n1, 4H), 6.03 (d, J—— 1.3 Hz,2H), 5.09 (s, 1H), 4.65 (s, 2H), 4.01 (d, J = 1.6 Hz, 3H), 2.99 (s, 3H), 2.32 (d, J = 1.0 Hz, 3H).

LC-MS: 75n11n, LCMSl5, n1/z=365.3 [M+1]. lH-NMR: 5 8.51 — 8.39 (n1, 3H), 7.86 — 7.76 (n1, 3H), 7.16 (dd, J = 9.0, 1.2 Hz, 1H), 5.84 (s, 1H), 4.05 (s, 3H), 2.95 (s, 3H), 2.21 (s, 3H).

LC-MS: (ES, m/z): RT = 0.939 n11n, LCMS 27: n1/z = 385 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 8.19 (dd, J = 21.0, 2.9 Hz, 1H), 7.69 (dd, J = 8.9, 2.9 Hz, 1H), 7.22 (d, J = 9.0,Hz 1H), 6.27— 5.9,7(n1 1H), 4.25— 4.10(n1, 1H), 4.0,0(s 3H), 3.6,2(d J=12.8Hz, LCMs. (ES, n1/z). RT—— 1. 864 n11n, LCMS 07. n1/z—— 382 [M+1]. 1H NMR (400 MHz, Methanold4) 5 8.26 (d, J—— 10.6 Hz, 2H), 8.38 (d, J—— 12.4 Hz, 1H), 7.76— 7. 64 (n1, 1H), 7.32 — 7.22 (n1, 1H), 6.04 (q, J = 1.0 Hz, 1H), 4.34 (q, J = 14.2, 10.4 Hz, 2H), 4.07 (d, J = .2 Hz, 3H 3.00 , d, J = 9.2 Hz, 3H 2.33 , s, 3H 1.59 — 1.49 , n1, 3H.

LC-MS: (ES, n1/z): RT=1.300n11n, LCMSl5, n1/z=378.2 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.93 — 7.82 (n1, 2H), 7.63 — 7.39 (n1, 3H), 7.31 (d, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.1, 2.0 Hz, 1H), 6.03 (s, 1H), 4.59 (s, 1H), 3.94 (s, 3H), 3.03 (s, 3H), 2.32 (s, 3H).

LC-MS: (ES, n1/z): RT=1.375n11n, LCMSl5, n1/z=378.3 [M+1]. 1H NMR (300 MHz, DMSO-d6) 5 10.28 (s, 1H), 8.83 (s, 1H), 8.68 — 8.57 (n1, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7. 72 (s, 1H), 7.39— 7.10 (n1, 6H), 6.08 (s, 1H), 4.51 (d, J = 6.1 Hz, 2H), 3.92 (s, 3H), 2.96 LCMS. (ES, m/z:) RT:0.963n11n, LCMs28, n1/z=389.2 [M+1]. 1H NMR (300 MHz, old4) 5 8.03 (s, 1H), 7.57 (d, J: 2.3 Hz, 1H), 6.04 (d, J—— 1.5 Hz, 1H), 4.43— 4.31 (n1,1H), 4.14— 398 (n1 2H), 378 (d J=10.2,Hz 3H), 347 (d J: 9.6 Hz, 2H),3.23 LCMS. (Es, n1/z). RT:0. 947111111, LCMs28, n1/z=389.2 [M+1]. 1H NMR (300 MHz, Methanold.4)5805 (s, 1H), 758 (s 1H), 6.07— 600 (n1 1H), 4.43— 4.31 (n1, 1H), 4.09 (d, J=48,Hz 2H), 4.01 (s, 3H), 3. 81—3. 71 (n1, 2H), 3. 52— 3.39 (n1, 2H), 3.24 (s, 2H), LCMS. (ES, n1/z). RT:0. 897n11n, LCMs28, n1/z=445.3 [M+1]. 1H NMR (300 MHz, old4)58.13 (s, 1H), 7.62 (d,J 2.3 Hz, 1H), 6.24 (s, 1H), 4.44 4.20 (n1, 2H), 4.17— 4.03 (n1, 2H), 399 (s 3H), 3.94— 3.37(n1, 8H), 3.35—3.15 (n1, 3H), 2.47 (s, 4H), LCMS. (ES, n1/z). RT=1.373n11n, LCMs28, 45.2 [M+1]. 1H NMR (300 MHz, Methanold4) 58.14(d, J: 2.1 Hz, 1H), 7.61 (s, 1H), 6.23 (s, 1H), 4.44— 4.20 (n1, 2H), 4.11 (dd, J=5. 1, 2. 5 Hz, 2H), 3.99 (s 3H), 3.94—3.38(n1, 8H),3.24 (s, 3H), 2.47 (s, 3H), LCMS. (ES, n1/z). RT=0.962 n11n, LCMs 07, n1/z=389 [M+1]. 1H NMR (400 MHz, Chloroformd.)5833(s,1H), 782 (s 1H), 5.80 (s 1H), 428 (d J: 244, 95, 4.8Hz, 2H), 4.16 (d, J = 9.9, 5.5 Hz, 1H), 3.88 (s, 3H), 3.01 — 2.87 (n1, 6H), 2.779 (d, 3H) , 2.30 (s, LC-MS: (ES, m/z): RT=0.962 min, LCMS27, m/z=389 [M+1]. 1H NMR (400 MHz, Chloroform-d) 5 8.33 (s, 1H), 7.82 (s, 1H), 5.80 (s, 1H), 4.28 (d, J = 24.4, 9.5, 4.8 Hz, 2H), 4.16 (d, J = 9.9, 5.5 Hz, 1H), 3.88 (s, 3H), 3.01 — 2.87 (n1, 6H), 2.779 (d, 3H) , 2.30 (s, 3H), 1.94 — 1.86 (In, 4H), 1.21 (s, 1H).

LC-MS: (ES, m/z): RT = 0.983 min; LCMS33: n1/z = 444 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.94 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 5.83 (s, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.92 (s, 3H), 3.64 (t, J = 6.8 Hz, 2H), 2.85 — 2.75 (m, 2H), 2.71 (d, J = 4.6 Hz, 7H 2.48 , t, J = 6.8 Hz, 2H 2.17 , s, 3H 2.09 —2.07 , n1, 2H 1.95 — 1.79 , n1, 4H.

LC-MS: (ES, m/z): RT = 1.38 n11n, LCMS 33; m/z = 485.3 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.96 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.99 (d, J = 5.7 Hz, 5H), 3.84 (t, J = 8.4 Hz, 2H), 3.75 — 3.55 (m, 4H), 3.48 (t, J = 7.2 Hz, 2H), 3.17 (q, J = 9.3 Hz, 2H), 2.92 — 2.79 (m, 1H), 2.67 (s, 3H), 2.38 (s, 3H), 2.28 — 2.07 (m, 6H).

LC-MS: (ES, m/z): 59 n11n, LCMs27, n1/z=403 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 7.46 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.21 — 7.13 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 5.97 (d J: 11Hz, 1H), 4.13 (t, J: 5.5 Hz, 2H), 3.83 (s, 3H), 3.16 (t, J: 7.0 Hz, LCMs. (ES, n1/z). RT:2.388 mln, LCMso7, n1/z=417 [M+1]. 1H NMR (300 MHz, Methanold4) 5 7.30 (s, 1H), 7.22 (d, J: 2.5 Hz, 1H), 7.16— 7.04 (m, 1H), 6.98 (d, J: 8.8 Hz, 1H), 5.97 (d, J = 0.9 Hz, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 3.08 t, J = 7.1 Hz, 2H 2.97 , d, J = 4.8 Hz, 3H 2.34 —2.19 , n1, 5H.

LC-MS: (ES, m/z): 83n11n, LCMSl5, n1/z=479.3 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.40 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.7, 2.5 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.85 (s, 1H), 4.20 — 4.10 (m, 2H), 3.90 — 3.75 (m, 5H), 3.36 (s, 1H), 3.32 (d, J = 3.6 Hz, 1H 3.08 — 2.91 , n1, 6H 2.65 , s, 3H 2.23 — 2.07 2.05 — 1.89 , n1, 5H , n1, 4H.

LC-MS: (ES, m/z): RT=1.072n11n, LCMs28, n1/z=493.3 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 7.39 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.85 (s, 1H), 4.22 — 4.11 (m, 2H), 3.88 — 3.77 (m, 5H), 3.34 — 3.24 (m, 2H), 3.10 — 2.97 n1, 6H 2.81 , s, 6H 2.18 , d, J = 9.3 Hz, 5H 2.04 — 1.93 , n1, 4H.

LC-MS: (ES, m/z): RT = 1.798 n11n, LCMS33: n1/z = 415 [M+1]. 1H NMR (300 MHz, Methanol—d4) 5 8.15 (s, 1H), 8.01 (s, 1H), 6.77 (s, 1H), 6.41 (s, 1H), 4.32 — 4.29 (m, 2H), 3.96 (s, 3H), 3. 88— 3. 76 (m, 4H), 3.73— 3. 70 (m, 2H), 3.48— 4.44 (m, 4H), 3.26 —3.10 LCMS. (ES, n1/z). RT—— 1. 221 mln, LCMs33. n1/z—— 326 [M+1]. 1H NMR (300 MHz, Methanold4) 5 8.51 (s, 1H), 7.30 (d, J: 5.6 Hz, 2H), 4.25 (t, J: 6.1 Hz, 2H), 3.98 (s, 3H), 2.86 — 2.71 (m, 5H), 2.70 — 2.59 (m, 4H), 2.21 — 2.12 (m, 2H), 1.94 — 1.77 (m, 4H).

LC-MS: (ES, m/z): RT=0.715n11n LCMS30, n1/z =319 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 8.28 (d, J = 9.7 Hz, 1H), 7.53 — 7.41 (m, 2H), 4.37 (t, J = 5.5 Hz, 2H), 4.04 (s, 3H), 3.94 — 3.75 (m, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.25 — 3.09 (m, 2H), 2.77 (d, J = 2.6 Hz, 3H 2.46 — 2.33 , n1, 2H 2.31 — 2.01 , n1, 4H.

LC-MS: (ES, m/z): 90n11n LCMS 07, n1/z =334 [M+1]. 1H NMR (400 MHz, Methanol—d4) 5 8.08 (d, J = 11.2 Hz, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 3.98 (s, 3H), 3.90— 3. 80 (m, 2H), 3. 51 (t, J: 7.2 Hz, 2H), 3.27—3.11 (m, 5H), 2.44— LCMS. (ES, n1/z). RT=1.28n11n, LCMs33. n1/z=329.19 [M+1]. 1H NMR (400 MHz, Methanold4) 5 7.18 (s, 1H), 6.90 (s, 1H), 6.57 (s,1H), 3.94 (s, 3H), 3.88— 3.76 (m, 2H), 3. 73— 3. 64 (m, 2H), 3.15—3.04 (m, 4H), 2.78 (s, 3H), 2.61 (d, J = 1.0 Hz, 3H), 2.32 —2.13 LCMS. (ES, n1/z). RT= 1.447 n11n, LCMSO7, n1/z=368 [M+1]. 1H NMR (400 MHz, Methanold.,4)5777(s1H),7.5,1(dd J: 90, 2.8,Hz 1H), 6.9,2(d J= 9.0,Hz 1H), 5.82 (s,1H), 3. 83 (s, 3H), 3. 76 (t,J=4.7 Hz, 4H),3.57 (s, 2H), 2.92 (s, 3H), 2.70 (dd,J=5.7, LC-MS. (ES, m/z): RT: 1. 720 min, LCMS28, m/z=388 [M+1]. 1H NMR (300 MHZ, old4)5766 7.58(m,1H),7.08(dd, J: 8.7 2.5Hz, 1H), 6.91 (d, J: 8.7Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 4.19-4.11 (In, 1H), 4.04 (dd, J = 9.7, 4.4 Hz, 1H), 3.96 (dd, J = 9.7, 6.3 Hz, 1H), 3.84 (s, 3H), 2.93 (s, 3H), 2.82 (dd, J = 12.6, 4.4 Hz, 1H), 2.75 — 2.59 (111, 5H), 2.19 (s, 3H), 1.91 — 1.75 (111, 4H).

LC-MS: (ES, m/z): RT=1.001 , LCMS28, 111/z=388 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.61 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5. 79 (d, J—— 0.8 Hz, 1H), 4. 18— 4.08 (111, 1H), 4. 08— 3.90 (111, 2H), 3.83 (s, 3H), 3.01 LCMS. (ES, 111/z). RT: 1. 01111111, LCMs33. 360. 15[M+1]. 1H-NMR. (Methanol-d4) 7.72 (d, J: 5.8 Hz, 1H), 7.50 (d, J: 2.5 Hz, 1H), 7.09 (dd, J: 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.05 — 3.90 (111, 3H), 3.85 (s, 3H), 3.44 (t, J = 7.2 Hz, 4H), 2.94 (s, 3H), 2.82 (dd, J = 12.5, 3.7 Hz, 1H), 2.74 — 2.63 (111, 1H), 2.25—2.10(111, LC-MS: (ES, m/z): RT=0.94min, LCMS28 2 m/z=360.12 [M+1]. : (Methanol- d4) 5 7.67-7.45 (111, 1H), 7.32 — 7.02 (111, 3H), 6.44 — 6.10 (111, 1H), 4.43 — 4.15 (111, 5H), 4.10— 3.99 (111, 2H), 3.923. 78 (111, 3H), 3. 61 — 3.47 (111, 1H), 345—335 (111, 1H), 312% LCMS. (ES, 111/z). RT: 0.614 111111, LCMS32. 111/z—— 359 [M+1]. 1H NMR (400 MHz, Methanold4)5796(d J= 2.2,Hz 1H), 7.79 771 (111 2H), 5.9,4(d J= 6.0,Hz 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 2.93 (s,3H),2.91— 2.65 (111, 6H), 2.14 — 2.03 (111, 2H), 1.95 — 1.82 (111, 4H).

LC-MS: (ES, m/z): RT = 0.961 min; LCMS27: m/z = 345 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.96 (d, J = 2.2 Hz, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.03 — 3.90 (m, 5H), 2.94 (s, 3H), 2.91 — 2.62 (m, 4H), 2.68 — 2.44(m, 1H), 2.41 (s, 3H ,2.32 —2.05 m, 1H 1.75 — 1.62 , m, 1H .

LC-MS: (ES, m/z): RT: 0.96 min, LCMS 27: m/z = 345 [M+1]. 1H-NMR: (Methanol-d4, ppm): 5 7.97 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 6.20 (d, J—— 7.3 Hz, 1H), 4.45— 4.30 (m, 2H), 4.24— 4. 07 (m, 4H), 4. 03 (s, 3H), 3.45 (t, J = 6.9 Hz, LCMs. (ES, m/z). R—T— 1. 076 111111, LCMs27.111/z—— 371 [M+1]. 1H NMR (400 MHz, Methanold4) 5 8.03— 7.86 (111, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 5.94 (d, J: 6.0 Hz, 1H), 4.04 — 3.90 (111, 5H), 3.24 — 2.96 (111, 1H), 2.94 (s, 3H), 2.88 — 2.64 (111, 3H), 2.65 — 2.56 (111, 1H), 2.21 — 1.89 (111, 1H), 1.76 (d, J = 5.5 Hz, 1H), 1.69 — 1.62 (111, 1H), 0.56 — 0.41 (111, LC-MS: (ES, m/z): RT = 1.124 min; LCMS39: m/z = 318 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.72 (s, 1H), 7.47 (s, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.99 — 6.73(m, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 2.93 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H 2.44 , s, 3H 2.03 , , J = 6.4 Hz, 2H.

LC-MS: (ES, m/z): RT: 0.90 min, LCMS 28: m/z = 319 [M+1]. 1H-NMR: (Methanol-d4, ppm): 5 7.97 (d, J = 2.2 Hz, 1H), 7.81 — 7.71 (m, 2H), 5.95 (d, J = 6.0 Hz, 1H), 4.15 (t, J = .9 Hz, 2H), 3.95 (s, 3H), 2.98 — 2.80 (m, 5H), 2.55 (s, 3H), 2.20 — 2.03 (m,2H).

LC-MS: (ES, m/z): RT=0.837 111111, LCMS 07, 344.0[M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.60 — 7.53 (111, 1H), 7.25 (s, 1H), 7.16 — 7.03 (111, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.28 (t, J = 8.5, 4.2 Hz, 1H), 4.15 — 4.04 (111, 2H), 3.91 (d, J = 2.0, 1.1 Hz, 3H), 3.23 d, J = 12.7, 8.4 Hz, 1H 3.03 , s, 4H 2.80 , s, 3H.

LC-MS: (ES, m/z): RT = 1.006 111111, LCMS28: 111/z = 388 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.57 (d, J = 7.3 Hz, 1H), 7.28 — 7.00 (111, 3H), 6.18 (d, J = 7.3 Hz, 1H), 4.31 — 4.10 (111, 2H), 4.02 (dq, J = 8.0, 3.8 Hz, 1H), 3.90 (s, 3H), 3.80 — 3.70 (111, 2H), 3.59 (s, 4H), 3.49 (dd, J = 13.2, 3.2 Hz, 1H), 3.24 (s, 2H), 3.04 (s, 3H), 2.21 (s, 2H), 2.11 (d, J = LC-MS: (ES, m/z): RT = 0.997 111111, LCMS28: 111/z = 388 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 7.3 Hz, 1H), 7.27 — 7.00 (111, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.30 — 4.09 (111, 2H), 4.08 — 3.95 (111, 1H), 3.89 (s, 3H), 3.74 (s, 2H), 3.58 (s, 4H), 3.48 (dd, J = 13.2, 3.2 Hz, 1H 3.24 , t, J = 8.6 Hz, 2H 3.04 , s, 3H 2.24 — 2.03 , 111, 4H.

LC-MS: (ES, m/z): RT = 0.966 min, LCMs28: m/z = 348 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.20 — 7.03 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.29 (dd, J = 10.4, 4.3 Hz, 1H), 4.16 (dd, J = 10.4, 3.6 Hz, 1H), 3.91 (s, 4H), 3.56 s, 3H 3.39 , td, J = 10.8, 8.8, 5.6 Hz, 2H 3.03 , s, 3H 2.80 , s, 3H.

LC-MS: (ES, m/z): RT = 1.437 min, LCMS 07: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.57 (d, J = 3.2 Hz, 1H), 7.33 — 7.28 (m, 3H), 6.19 (d, J = 2.4 Hz, 1H), 4.13 — 4.10 (m, 2H), 4.00 — 3.78 (m, 4H), 3.72 — 3.68 (m, 1H), 3.44 — 3.35 (m, 2H), 3.29 — 3.10 (m, 1H),3.16 — 3.09(m, 1H) 3.03 (s, 4H), 2.53 — 1.93 (m, 2H), 1.41 — 1.39 (m, 3H).

LC-MS: (ES, m/z): RT = 1.369 min, LCMS 33: m/z = 370 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.56 (d, J = 2.4 Hz, 1H), 7.21 (s, 1H), 7.08 (d, J = 1.2 Hz, 2H), 6.18 (d, J = 1.8 Hz, 1H), 4.20 — 4.05 (m, 2H), 4.02 — 3.79 (m, 4H), 3.78 — 3.67 (m, 1H), 3.61 — 3.58 (m, 1H), 3.53 — 3.36 (m, 1H), 3.13 (s, 1H), 3.03 (s, 4H), 2.26 — 2.23 (m, 2H), 1.04-1.01(m, LC-MS: (ES, m/z): RT = 1.86 min, LCMS 531m/z = 360 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.3 Hz, 1H), 7.51 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.14 — 3.87 (m, 4H), 3.82 (s, 3H), 3.71 (t, J = 2.4 Hz, 1H), 3.04 — 2.90 (m, 4H), 2.74 (q, J = 1.8 Hz, 1H), 2.35 (s, 3H), 2.29 — 2.07 (m, 1H) 2.05 —2.00 m, 1H .

LC-MS: (ES, m/z): RT = 0.92 min, LCMS 331m/z = 374 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.15 — 3.88 (m, 4H), 3.86 — 3.65 (m, 4H), 3.09 — 3.05 (m, 1H), 2.94 (s, 3H), 2.89 — 2.77 (m, 1H), 2.50 (q, J = 7.2 Hz, 2H), 2.26 — 1.97 m, 2H 1.15 , t, J = 7.2 Hz, 3H.

LC-MS: (ES, m/z): RT = 1.86 min, LCMS 531m/z = 346 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.71 (d, J = 6.3 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.09 (q, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.12 — 3.99 (m, 4H), 3.84 (s, 3H), 3.69 — 3.64 (m, 1H), 3.10 — 3.08 (m, 1H), 2.97 (s, 3H), 2.90 — 2.71 (m, 3H).

LC-MS: (ES, m/z): RT = 0.912 min; LCMS33: m/z = 360 [M+1].1H NMR (300 MHz, Methanol-d4) 5 7.55 (d, J = 7.3 Hz, 1H), 7.22 (s, 1H), 7.18 — 6.99 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.26 — 4.09 (m, 4H), 3.89 (s, 4H), 3.70 — 3.68(m, 1H), 3.51 — 3.50 (m, 1H), 3.22 — 3.20 m, 2H 3.02 , d, J: 7.7 Hz, 6H.

LC-MS: (ES, m/z): RT = 0.931 min; LCMS33: m/z = 374 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.72 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.94 (d, J = 6.1 Hz, 1H), 4.20 — 4.05 (m, 1H), 4.04 — 3.90 (m, 3H), 3.84 (s, 3H), 3.74 — 3.72 (m, 1H), 3.15 — 3.04 (m, 1H), 2.95 (s, 3H), 2.86 — 2.84 (m, 1H), 2.52 , J = 7.2 Hz, 2H 2.29 —2.00 , m, 2H 1.16 , t, J = 7.2 Hz, 3H.

LC-MS: (ES, m/z): RT = 0.907 min; : m/z = 346 [M+1]. 1H NMR (300 MHz, ol-d4) 5 7.72 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.05 — 4.03 (m, 1H), 4.00 — 3.84 (m, 3H), 3.82 (s, 3H), 3.67 — 3.64 (m, 1H), 3.12 — 3.01 (m, 1H), 2.94 (s, 3H), 2.88 — 2.79 (m, 2H), 2.72 — 2.68 (m, 1H).

LC-MS: (ES, m/z): RT = 1.509min; LCMs15: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.97 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.33 — 3.28 (m, 4H), 2.91 (s, 3H), 2.67 (q, J = 8.1, 2H 2.21 — 2.05 , m, 5H 1.77 — 1.86 , m, 6.2 Hz, 2H.

LC-MS: (ES, m/z): RT = 0.611min, LCMS 32, m/z = 374.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.58 (d, J = 7.3 Hz, 1H), 7.32 — 7.26 (m, 1H), 7.21 — 7.05 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.50 — 4.19 (m, 4H), 4.06 — 3.92 (m, 5H), 3.57 (d, J = 13.3 Hz, 1H), 3.39 d, J = 13.3 Hz, 1H 3.04 , s, 3H 2.75 — 2.60 , m, 1H 2.50 —2.35 , m, 1H 1.36 , s, 3H.

LC-MS: (ES, m/z): RT=0.982 min, LCMS 28, m/z =332.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) 5 7.58 (d, J = 7.3 Hz, 1H), 7.29 — 7.17 (m, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.17 (d, J = 7.3 Hz, 1H), 4.60 — 4.49 (m, 1H), 3.92 (s, 3H), 3.32 — 3.25 (m, 2H), 3.02 (s, 3H), 2.78 (s, 3H), 2.17 — 2.00 (m, 2H), 1.37 (d, J = 6.1 Hz, 3H).

LC-MS: (ES, m/z): RT=1.00min, LCMS28 : m/z=358.14 [M+1]. 1H-NMR(Methanol-d4) 1014 5 7.95—7.52 (m, 1H), .89 (m, 3H), 6.44 — 6.10 (m, 1H), 4.59—4.37 (m,1H), 4.35 — 4.09 (m, 5H), 3.97-3.88 (m, 3H), 3.75—3.52 (m, 1H), 3.12—2.94 (m, 3H), 2.71 — 2.57 (m, 1H), 2.48-2.27 m, 1H 2.26-2.01 , m, 2H 1.34 , d, J = 6.5 Hz, 3H .

LC-MS: (ES, m/z): RT = 6.569 min; : m/z = 343[M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.80 — 7.55 (m, 3H), 7.19 (d,1H), 6.19 (d, J = 7.3 Hz, 1H), 4.36 (s, 2H), 4.12 — 3.92 (m, 4H), 3.67 — 3.31 (m, 4H), 3.02 (s, 3H), 2.46 — 2.29 (m, 1H), 2.24 —1.98(m, LC-MS: (ES, m/z): RT = 8.458 min; LCMS53: m/z = 343[M+1]. 1H NMR (300 MHz, Methanol-d4) 5 7.82 — 7.55 (m, 3H), 7.19 (d, J = 8.9 Hz, 1H), 6.19 (d, J = 7.3 Hz, 1H), 4.36 (s, 2H), 4.10 — 3.92 (m, 4H), 3.64 — 3.35 (m, 5H), 3.02 (s, 3H), 2.38 (m, 1H), 2.22 — 1.98 MHz, Methanol-d4) 5 8.67 — 8.62 (m, 1H), 8.02 (d, J = 2.6 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 4.35 (s, 2H), 4.06 (d, J = 7.1 Hz, 3H), 3.71 — 3.55 (m, 4H), 3.48 (s, 4H), 2.99 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 2.18 — 2.10 (m, 4H).

LC-MS: (ES, m/z): RT = 0.868 min, LCMS28: m/z =357 [M+1]. 1H NMR (400 MHz, DMSO-d6) 5 8.83 (s, 1H), 7.82 — 7.74 (m, 2H), 7.68 (d, J = 8.9 Hz, 1H), 7.10 (s, 1H), 6.96 (d, J = 8.9 Hz, 1H), 5.89 (d, J = 5.9 Hz, 1H), 3.95 (s, 2H), 3.79 (s, 3H), 2.96 — 2.78 (m, 7H 2.77 — 2.69 m, 4H 1.84 — 1.72 , , m, 4H.

Example 156: Bioactivity Assays ALS AND ENT: Recombinant puriﬁed human EHMT2 93 (55 uM) synthesized by Viva was used for all experiments. Biotinylated histone peptides were synthesized by Biopeptide and HPLC-puriﬁed to > 95% purity. Streptavidin Flashplates and seals were purchased from PerkinElmer and 384 Well V-bottom Polypropylene Plates were from Greiner. 3H-labeled S- adenosylmethionine (3H-SAM) was obtained from American Radiolabeled Chemicals with a speciﬁc activity of 80 l. Unlabeled SAM and S—adenosylhomocysteine (SAH) were obtained from American Radiolabeled Chemicals and Aldrich respectively.

Flashplates were washed in a Biotek ELX-405 with 0.1% Tween. 384-we11 Flashplates and 96-well ﬁlter binding plates were read on a TopCount microplate reader (PerkinElmer).

Compound serial dilutions were performed on a Freedom EVO (Tecan) and spotted into assay plates using a Thermo Scientiﬁc Matrix ate (Thermo Scientiﬁc). Reagent ils were added by Multidrop Combi (Thermo Scientiﬁc). -231 cell line was purchased from ATCC (Manassas, VA, USA).

RPMI/Glutamax medium, Penicillin-Streptomycin, Heat Inactivated Fetal Bovine Serum, and D-PBS were purchased from Life Technologies (Grand Island, NY, USA). Odyssey blocking buffer, 800CW goat anti-mouse IgG (H+L) antibody, and Licor Odyssey Infrared Scanner were purchased from Licor Biosciences, Lincoln, NE, USA. H3K9me2 mouse monoclonal antibody (Cat #1220) was purchased from Abcam (Cambridge, MA, USA). 16% Paraformaldehyde was purchased from Electron Microscopy Sciences, Hatﬁeld, PA, USA).MDA-MB-231 cells were maintained in complete growth medium (RPMI supplemented with 10% v/v heat inactivated fetal bovine serum) and cultured at 37°C under % C02, UNC0638 was purchased from Sigma-Aldrich (St. Louis, MO, USA).

General Procedure for EHMT2 Enzyme Assay on Histone Peptide Substrate. 10-point curves of test compounds were made on a Freedom EVO (Tecan) using serial 3-fold dilutions in DMSO, beginning at 2.5 mM (ﬁnal top concentration of compound was 50 uM and the DMSO was 2%). A 1 [LL aliquot of the tor dilution series was spotted in a polypropylene 384-well V-bottom plate er) using a Thermo Scientiﬁc Matrix PlateMate (Thermo Scientiﬁc). The 100% inhibition control consisted of 1 mM ﬁnal concentration of the t inhibitor S-adenosylhomocysteine (SAH, Sigma-Aldrich).

Compounds were ted for 30 minutes with 40 [LL per well of 0.031 nM EHMT2 (recombinant puriﬁed human EHMT2 913-1193, Viva) in 1X assay buffer (20 mM Bicine [pH 7.5], 0.002% Tween 20, 0.005% Bovine Skin Gelatin and 1 mM TCEP). 10 [LL per well of substrate mix comprising assay buffer, 3H-SAM beled S—adenosylmethionine, American Radiolabeled Chemicals, speciﬁc activity of 80 Ci/mmol), unlabeled SAM (American Radiolabeled Chemicals), and peptide representing histone H3 residues 1-15 containing C-terminal biotin ded to a C-terminal amide-capped lysine, synthesized by Biopeptide and HPLC-puriﬁed to greater than 95% purity) were added to initiate the reaction (both substrates were present in the ﬁnal reaction mixture at their respective KIn values, an assay format referred to as "balanced ions"). Reactions were incubated for 60 minutes at room temperature and quenched with 10 [LL per well of 400 uM unlabeled SAM, then transferred to a ll streptavidin late (PerkinElmer) and washed in a Biotek ELx- 405 well washer with 0.1% Tween after 60 minutes. 384-well Flashplates were read on a TopCount microplate reader (PerkinElmer).

General ure for MDA-MB-231 HEK9me2 l Western Assay.

Compound (100 nL) was added directly to 384-well cell plate. MDA-MB-231 cells (ATCC) were seeded in assay medium (RPMI/Glutamax supplemented with 10% v/v heat vated fetal bovine serum and 1% Penicillin/Streptomycin, Life Technologies) at a concentration of 3,000 cells per well to a Poly-D-Lysine coated 384-well cell culture plate with 50 [LL per well. Plates were incubated at 37°C, 5% C02 for 48 hours (BD Biosciences 356697). Plates were ted at room temperature for 30 minutes and then ted at 37°C, 5% C02 for onal 48 hours. After the incubation, 50 [LL per well of 8% paraformaldehyde (Electron Microscopy Sciences) in PBS was added to the plates and incubated at room temperature for minutes. Plates were erred to a Biotek 406 plate washer and washed 2 times with 100 uL per well of wash buffer (1X PBS containing 0.3% Triton X-100 (v/v)). Next, 60 [LL per well of y blocking buffer (Licor Biosciences) was added to each plate and incubated for 1 hour at room temperature. Blocking buffer was removed and 20 [LL of monoclonal primary antibody 0t-H3K9me2 (Abcam) diluted 1:800 in Odyssey buffer with 0.1% Tween 20 (v/v) were added and plates were incubated overnight (16 hours) at 4 °C.

Plates were washed 5 times with 100 uL per well of wash buffer. Next 20 uL per well of secondary antibody was added (1:500 800CW donkey anti-mouse IgG (H+L) antibody (Licor Biosciences), 1:1000 DRAQS (Cell Signaling logy) in y buffer with 0.1% Tween 20 (v/v)) and incubated for 1 hour at room temperature. The plates were washed 5 times with 100 uL per well wash buffer then 2 times with 100 uL per well of water. Plates were allowed to dry at room temperature then imaged on a Licor Odyssey Infrared Scanner (Licor Biosciences) which measured integrated intensity at 700nm and 800nm ngths.

Both 700 and 800 channels were scanned.

% Inhibition Calculation. First, the ratio for each well was determined ‘ {3E2 mains: mamas mam-e" a 133—219? maxim-mum .s' Each plate included fourteen control wells of DMSO only ent (Minimum Inhibition) as well as fourteen control wells (background wells) for m inhibition treated with control compound UNC0638 (Background wells).

] The average of the ratio values for each well was calculated and used to determine the percent inhibition for each test well in the plate. Control compound was serially d three-fold in DMSO for a total of 10 test concentrations beginning at 1 uM.

Percent inhibition was calculated as: t Inhibition = 100- ng-zrrmmlﬁsg- Basia} \l a we ) mstmuwﬁﬁimmgg 3mm}! IC50 curves were generated using triplicate wells per concentration of compound. The IC50 is the concentration of compound at which measured methylation is inhibited by 50% as olated from the dose response curves. IC50 values were calculated using a non-linear regression (variable slope—four parameter fit model) with by the following formula: < Top - Bottom % inhibition = Bottom +—n) (1 + (1C50/[1D ) where Top is fixed at 100% and Bottom is ﬁxed to 0%, [I] = tration of inhibitor, 1C50 = half maximal inhibitory concentration and n = Hill Slope.

The IC50 values are listed in Tables II-VII below ("A" means IC50 <100nM; "B" means IC50 ranging between 100 nM and 1 11M; "C" means IC50 ranging between >1 "M and 10 11M; "D" means IC50 >10 HM; "ND" means not determined).

Table 11 Compound EHMT21CW No. (IC50 BM) (IC50 HM) (IC50 pM) B B 2 B B B B —— B B -- B B —— c 7 c B -- c B —-_ B 21 A B B 22 A A B 24 A A B Compound EHMT2 PEP EHMTl PEP EHMT2 ICW N0. (IC50 uM) (IC50 HM) (IC50 pM) B 55 oooooooooooooooowwwwwwwwwwwwww Compound EHMT21CW N0. (IC50 uM) (IC50 HM) (IC50 pM) 57 C C C 58 D D \ 60 C C \ 61 D D \ ///// ///////////// /UUUUUUUUUUUUUUUUUUUUUUUUUUUUU nd EHMT2 PEP EHMTl PEP EHMT2 ICW (IC50 uM) (IC50 HM) (IC50 pM) /// DUO /// DUO 101 //// UUUU 116 /////////////U/UUUUUUUUUUUUUUU 117 / WO 81177 "W" "MW N0. (IC50 11M) (IC50 HM) (IC50 HM) 119 D \D 120 C \D 122 \D 123 \D 125 C C \D 126 D D 148 UUOUUUUUUUUUUUUUUUUUUUU WO 81177 Compound EHMT2 PEP EHMTl PEP EHMT2 ICW N0. (IC50 uM) (IC50 HM) (IC50 pM) 149 D 179 UUJDUODUUOUUOWUUUUUUUOUUUUUUUUU WO 81177 "W" "MW N0. (IC50 HM) (IC50 HM) (IC50 MM) 181 D 182 D 184 D D D 185 C C D 187 C C C 188 B B D 191 A A B 192 B B C nd EHMT2 PEP EHMTl PEP EHMT2 ICW N0. (IC50 uM) (IC50 HM) (IC50 pM) 213 ND 243 UUOwUUUWUUUUWOOUUOOUUUUUUUUUUU WO 81177 "W" EHMT2" N0. (IC50 HM) (IC50 HM) (IC50 MM) 245 B B C 248 A A B 251 D D D Table III Compound EHMT2 PEP EHMTl PEP EHMT2 ICW (IC50 N0. (IC50 M) (IC50 M) M) 256 D D 2U 257 C 260 DUO 261 U I262a and 262b UUUUUU UUUUUU 263 > A 2U 0|.264 D 265 D 267 D 268 DO D 0|271270 A 272 03 003 273 U U UOUUJUUOUU WO 81177 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 WO 81177 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 WO 81177 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 No. (IC50 M) (IC50 M) M) 435 C C O l.436 O 437 439 UJUUJ 440 UUJU 441 B 442 >UJU A 443 D 445 UJ>U 446 >UJD> 449 OJUU> 451 030 452 U O>UUJUU UUJOUJUUJOUUJUOU Table IV EHMT2 PEP EHMT1 PEP EHMT21CW Compound No.

(IC50 M) (IC50 M) (IC50 M) 453 D 458 UJ>OU 461 >>0 462 > EHMT2 PEP EHMTl PEP CW C m0 p0"ndN0' (IC50 M) (IC50 M) (IC50 M) 465 >03 466 C1 468 O 473 OOU 475 03 477 03 478 C 480 U 481 > 482 E 483 D> 485 >- 486 C1 487 O 488 03 489 O 490 >- 491 03 492 03 494 >- 496 00303 497 03 498 O 502 O EHMT2 PEP EHMTl PEP EHMTZICW C m0 p0"ndN0' (IC50 M) (IC50 M) (IC50 M) 504 03 |!|506 507 >- 508 O lillgllgl 509 E > 510 US > 512 >- 514 03 515 O IHI 516 (3 517a mi 517b 03030 |:| 518 C (3 519 m r) |||520 > 521 O 522 r) 523 O 524 >- 526 > 527 > 528 03 529 >- |€||E|Iallillillillillillil 530 > > 532 > > 533 > 534 O 535 >- 536 >- IHIIHIIEIIHI Tabk V Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 M) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW (IC50 M) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 M) (IC50 M) (IC50 M) 596 C C Table VI nd EHMT2 PEP EHMT1 PEP EHMT2 ICW No. IC50 ("M) IC50 ("M) IC50 ("M) 630 UUJUCDUJOOUUUOOUJOUUJUJUUJ U>U>>OOOUUUJUJ>OUUJ>UUJ UUUWOOUUUUUOOOOOOUU WO 81177 Compound EHMT2 PEP EHMTl PEP EHMT2 ICW N0 IC50 (11M) IC50 (11M) IC50 (11M) Compound EHMT2 PEP EHMTl PEP EHMT2 ICW No IC50 (11M) IC50 (11M) IC50 (11M) 664 C C Compound EHMT2 PEP EHMTl PEP EHMT2 ICW No IC50 (11M) IC50 (11M) IC50 (11M) 753 A A C WO 81177 Compound EHMT2 PEP EHMTl PEP EHMT2 ICW No IC50 (11M) IC50 (11M) IC50 (11M) 809 A A Compound EHMT2 PEP EHMTl PEP EHMT2 ICW No IC50 (11M) IC50 (11M) IC50 (11M) 864 A A WO 81177 Compound EHMT2 PEP EHMTl PEP EHMT2 ICW No IC50 (11M) IC50 (11M) IC50 (11M) 906 A A Compound EHMT2 PEP EHMTl PEP EHMT2 ICW N0. IC50 (11M) IC50 (11M) IC50 (11M) 963 >- > 964 >- 965 3> 974 >- 985 >' 986 w 990 C> 1005 C) 1006 >- 1007 C3 1008 >- 1009 <5 1011 (3 1014 U1 1016 w 1019 It 1020 C) 1021 m 1022 {w 1028 $> 1030 >- 1031 >' 1032 >' 1033 C> 1034 U: 1035 m 1036 w>wcoww>>ww>oooooooowcwo>www>w w 1037 {w 1038 $> 1040 w >>UJOOOUJUJUJUJUJUOUUOOOOUJUUJOUJOUJUJ>OUJ Compound EHMT2 PEP EHMTl PEP EHMTZICW N0. IC50 (11M) IC50 (11M) IC50 (11M) 1041 "II- Table VII EIIDITZ EHMT2 PEP EHMTl PEP Com ound N0.p ICVVICSO 111M) IC50 (uM) 1067 UUUJUJUJUUOOUUJ>UJOOO>UJUJUJUJOUJUJ EIIDITZ EHMT2 PEP EHMTI PEP Com ound N0p ° ICVVICSO IC50(111M) IC50(uM) 1098 UJUUOUJUJOUJUJUJUJOOUJUUJUCDOOCDOOUJUOUUUUUg EIIDITZ EHMTZPEP EHNHIPEP Compound No. SO IC50(uDD IC50(uDD 1099 "- 1112 ll:||l%|||:|||i|||H|||H|||H|||:|IIHIIIIHIIHIIIHI 1114 UOOUJUJOUJUJUJOUJOUJUJOUJg 1115 II 1116 22OD 1117 00 ND 1118 ND 1119 III ND Example 157: Bioactivity Assays The following procedure and Figures 1A-1D, 2, and 3 describe the induction of fetal hemoglobin following treatment of cells with EHMT2 inhibitors defined herein.

Cell Culture Peripheral Blood clear Cells (PBMCs) where isolated from whole blood of healthy donors by Ficoll gradients. CD34+ cells were then magnetically ed from the PBMC fraction. Cells were entiated in vitro toward the erythroid lineage for 14 days using the first two weeks of the 3-phase culture method described by Giarratana, et al (Blood 2011). After isolation, cells were seeded at a density of 1X105 cells/mL in phase 1 media. At day 7, cells were split in a ratio of 1 :5 into Phase 2 media.

Drug Treatment Compounds were dissolved in Dimethyl sulfoxide (DMSO), and 1 uM stocks were prepared and diluted in a 1:3 series to generate an nt dose curve. 100 % DMSO served as control. Compound dilutions were added to cells on day 1 as 1:1000 dilutions.

DMSO was y added to control cells for a ﬁnal concentration of 0.001%. Compound dilutions and DMSO were re-added on day 7, after the cell split described above.

Flow cytometry At day 14, around 106 cells were ﬁxed, permeabilized, and stained for cell surface markers , CD71, Human Fetal Hemoglobin, Human Histone 3, and Di- methyl-Lysine 9 Histone 3.

RT-qPCR At day 14, around 106 cells were pelleted. RNA was isolated by traditional spin column methods and gene expression analysis carried out by 2-step RT-qPCR. Standard curves were ted using plasmids encoding each of Human Globin HBA, HBB and HBG and were used to calculate individual globin copy numbers. HBB and HBG were added to ate the total B-Locus Globins copies. Reported results represent % HBG/Total mRNA copies.

Mass Spectrometry At day 14, around 106 cells were pelleted. Protein was isolated, ed, and quantiﬁed by LC-PRM mass spectrometry analysis. Globin-speciﬁc label peptides were used for quantiﬁcation of individual globins. HBB and HBG were added to calculate the total B- Locus Globin protein levels. Reported results represent % HBG/Total protein.

There was good correlation between in-cell Western (ICW) and ﬂuorescence- activated cell sorting (FACs) data for K9 lysine ylation, and between ﬂuorescence- activated cell sorting data for K9 lysine dimethylation and percent of cells containing fetal hemoglobin (HbF+ cells), as shown in Figures 1A-1D. As shown in Figures 2 and 3, all tested compounds showed around 30% be-y per total ins at the mRNA and protein level, with a 1:1 correlation between protein and mRNA data. A good ation between potency, target ment, and induction of HbF+ cells was observed. More potent compounds were shown to have a more sustained induction of be-y, which also correlated with the sustained induction of HbF+ cells as observed by FACs analysis. The data suggests that sickle-cell disease (SCD)-relevant levels of around 30% HbF/ total B-globins might be achievable for all tested EHMT2 inhibitors. The following procedure and Figures 4 and 5 describe the inhibition of MV4-11 human acute monocytic leukemia cells following treatment with an EHMT2 inhibitor deﬁned herein.

MATERIALS AND ENT: MV11 ia cells were purchased from ATCC. IMDM, FBS, and Calcein-AM were purchased from Invitrogen. Flat 96-well plates were purchased from , and Poly-D-Lysine 96-well lates, black/clear were purchased from BD BIOCOAT.

A 3-fold serial dilution of Compound 205 ("3*compounds") was prepared as follows: Compound 205 was dissolved in DMSO to give a 10 mM solution and stored at -20 °C. A 3-fold serial dilution of Compound 205 in DMSO to give solutions ranging in concentration from 5 mM to 0.25 uM.

The 3*compounds solutions were added to the cell plate via the following procedure: 1.2 ul of the compound ons were transferred to a 96-well plate with 200 pl of media in each well, then mixed well by pipetting up and down to give 3*compounds in media. 50 ul of 3*compounds in media were then transferred to the cell plate.

Day 0 In a ﬂat bottom 96-well plate, 100uL of cells were added per well at a density of 1x105 cells/mL. (Note: Only internal wells were used. PBS was placed in all outer wells to avoid evaporation of the internal wells.) 50 [LL of ounds were added to each well, to give a final volume of 150 uL per well.

Days 1-3 The plates were incubated for 96 hours.

Day 4 Cells were pipetted up and down to mix in each well. 20 [LL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 [LL ofHBSS was added to each well of the V-bottom plate and mixed.

Next, 50 uL of cell suspension in the V-bottom plate was aspirated and added to a -lysine coated 96-well plate. To this was added 50 [LL of HBSS containing 2 uM Calcein-AM, to give a final concentration of 1 uM. The cells were allowed to sit at room temperature for 10 s, then fuged to settle the cells on the bottom of the wells.

The plate was then incubated for an additional 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate , and cell numbers were calculated, taking into account the dilution factors. The master plate was split by taking the total viable cell count calculated, and cells were pipetted up and down in each well in order to mix. Then, cell suspension was aspirated from each well and added to a V-bottom plate.

The plate was fuged at 1100 rpm for 5 minutes, then the media was removed, being careful not to disturb the cell .

The pellet was then resuspended in 200 uL fresh media. The cells were mixed in each well by pipetting up and down, then 100 uL of cell sion was ted from each well and added to a new 96-well ﬂat bottom plate, and 50 [LL of 3*compounds solution was added.

Days 4-6 The plates were incubated for 72 hours.

Day 7 Cells were pipetted up and down to mix in each well. 20 [LL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 [LL ofHBSS was added to each well of the V-bottom plate and mixed.

Next, 40 uL of cell suspension in the V-bottom plate was aspirated and added to a poly-D-lysine coated 96-well plate. To this was added 40 [LL of HBSS containing 2 uM Calcein-AM, to give a final concentration of 1 uM. The cells were allowed to sit at room temperature for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

] The plate was then incubated for an additional 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate reader, and cell numbers were ated, taking into account the dilution factors. The master plate was split by taking the total viable cell count calculated, and cells were pipetted up and down in each well in order to mix. Then, 12* of the calculated cell suspension was aspirated from each well and added to a V-bottom plate.

The plate was centrifuged at 1100 rpm for 5 minutes, then the media was removed, being careful not to disturb the cell pellet.

The pellet was then resuspended in 120 uL fresh media. The cells were mixed in each well by pipetting up and down, then 100 uL of cell suspension was aspirated from each well and added to a new 96-well ﬂat bottom plate, and 50 [LL of 3*compounds solution was added.

Days 7—10 WO 81177 The plates were incubated for 96 hours.

Day 11 Cells were pipetted up and down to mix in each well. 20 [LL of the cell suspension was ted from each well and added to a V-bottom plate. 80 [LL of HBSS was added to each well of the V-bottom plate and mixed.

Next, 50 uL of cell suspension in the V-bottom plate was aspirated and added to a poly-D-lysine coated 96-well plate. To this was added 50 [LL of HBSS containing 2 uM Calcein-AM, to give a ﬁnal concentration of 1 uM. The cells were allowed to sit at room temperature for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

The plate was then incubated for an onal 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate reader, and cell numbers were calculated, taking into account the dilution factors. The master plate was split by taking the total viable cell count calculated, and cells were pipetted up and down in each well in order to mix and reduce variation caused by pipetting. Then, 12* of the calculated cell suspension was aspirated from each well and added to a V-bottom plate.

The plate was centrifuged at 1100 rpm for 5 minutes, then the media was d, being careful not to disturb the cell pellet.

The pellet was then ended in 120 uL fresh media. The cells were mixed in each well by pipetting up and down, then 100 uL of cell suspension was aspirated from each well and added to a new 96-well ﬂat bottom plate, and 50 [LL of 3*compounds on was added.

Days 11-13 The plates were incubated for 72 hours.

Day 14 Cells were pipetted up and down to mix in each well. 20 [LL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 [LL ofHBSS was added to each well of the V-bottom plate and mixed.

Next, 40 uL of cell suspension in the om plate was aspirated and added to a -lysine coated 96-well plate. To this was added 40 [LL of HBSS containing 2 uM Calcein-AM, to give a final concentration of 1 uM. The cells were allowed to sit at room temperature for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

The plate was removed and read on an Acumen plate reader, and cell numbers were calculated, taking into account the on factors.

Growth was calculated for days 4, 7, 11, and 14 as follows: the split factor was calculated for day 4 to 7, day 7 to 11, and day 11-14 The split factor is the number of viable cells/mL on Day X (either 4, 7, or 11) divided by the density the cells are being split back to.

For growth of cells from day 4 to 7, the day 7 viable cells/mL density was multiplied by the split factor from day 4.

For growth of cells from day 7 to 11, the day 11 viable cells/mL density was multiplied by the day 4 and day 7 split s.

For growth of cells from day 11 to 14, the day 14 viable cells/mL density was multiplied by the day 4, day 7, and day 11 split factors.

Growth was plotted on semi-log chart (viable cells/mL on Y axis, in log, and days on X axis).

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are ore to be considered in all ts illustrative rather than limiting on the invention described herein.

Scope of the invention is thus ted by the appended claims rather than by the foregoing description, and all changes that come within the g and range of equivalency of the claims are intended to be embraced therein.

Preferred aspects of the ion include: membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, 0x0, 9, -SOZR8, -SOzN(R8)2, -NR8C(O)R9, amino, mono- or dialkylamino , or C1-C6 alkoxyl,, or when ring A is a 5-membered heteroaryl containing at least one N atom, R4 is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, each of RZ’, R3’ and R ’ independently is H or C1-C3 alkyl, R5 is selected from the group consisting of H, F, Br, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, )Rb, C3-C3 cycloalkyl, 4- to bered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, C1-C6 alkyl optionally substituted with one or more of halo, ORa or NRaRb, and C2-C6 alkynyl optionally substituted with 4- to 12- membered heterocycloalkyl, wherein said C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl are ally substituted with one or more of halo, C(O)Ra, ORa, NRaRb, 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, or C1- C4 alkyl optionally substituted with one or more of halo, ORa or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are ed form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, R6 is absent when X5 is N and ring A is a 6-membered heteroaryl, or R6 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or R", in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, -SOZR8, -SOzN(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and R6 is not )NR12R13, or R6 and one of R2 or R3 together with the atoms to which they are attached form phenyl or a 5- or ered heteroaryl, or R6 and one of Rz’or R3’ together with the atoms to which they are attached form a 5- or 6-membered aryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=0), C1-C3 alkoxyl, or -Q1-T1, each R7 is ndently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 l, and each T2 independently is H, halo, cyano, ORIO, OR", 1, NRIOR", 10R11, NR10C(O)R11, 5- to lO-membered heteroaryl, C3-C3 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to lO-membered heteroaryl, C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, -SO2R8, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)ORg, or optionally, when B is present, one R7 and R5 together form a C3-C10 alkylene, C2-Cio heteroalkylene, C4-Cio alkenylene, C2-Cio heteroalkenylene, C4-Cio alkynylene or C2- C10 heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, 13, S(O)2NR12R13, or R52, in which RS2 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, or a 5- to bered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered cycloalkyl ning 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered aryl, ORG, C(O)Rc, S(O)2RC, NRCRd, C(O)NRCRd, and )Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R8 and R9 taken together with the en atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of —Q5-T5, wherein each Q5 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 , and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Re, S(O)2Re, S(O)2NReRf, NReRf, C(O)NReRf, and NReC(O)Rf, each of Re and Rf independently being H or C1-C6 alkyl, or —Q5-T5 is oxo, R10 is selected from the group consisting of H and C1-C6 alkyl, R11 is —Q6-T6, in which Q6 is a bond or C1-C6 alkylene, C2-C6 lene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, yl, oxo, or C1-C6 alkoxyl, and T6 is H, halo, ORg, NRth, NRgC(O)Rh, C(O)NRth, C(O)Rg, S(O)2Rg, or RS3, in which each of Rg and Rh independently is H, phenyl, C3-C3 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C3 cycloalkyl, or Rg and Rh together with the nitrogen atom to which they are attached form a 4- to 12-membered cycloalkyl ning 1-4 heteroatoms selected from N, O, and S, and RS3 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O and S, or a 5- to -membered heteroaryl, and RS3 is optionally substituted with one or more —Q7-T7, wherein each Q7 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T7 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR], C(O)Rj, NRij, C(O)NRij, j, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl optionally substituted with one or more halo, or —Q7-T7 is oxo, or R10 and R11 taken together with the nitrogen atom to which they are attached form a 4- to bered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, or C1-C6 alkoxyl, R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 lkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl ning 1-4 atoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, and 11 is 0, 1, 2, 3, or 4, optionally provided that (1) the compound of Formula (I) is not 4-(((2-((1-acetylindolinyl)amino) (triﬂuoromethyl)pyrirnidinyl)amino)methyl)benzenesulfonamide, o-N4-(4-ﬂuorophenyl)-N2-(4-methoxy-3 -(2-(pyrrolidin-l - yl)ethoxy)phenyl)pyrimidine-2,4-diamine, N2-(4-methoxy(2-(pyrrolidin- l -yl)ethoxy)phenyl)-N4-(5 -pentyl)- lH-pyrazol- 3-yl)pyrirnidine-2,4-diamine, 4-((2,4-dichloromethoxyphenyl)arnino)((3-(2-(pyrrolidin-l- yl)ethoxy)phenyl)amino)pyrirnidinecarbonitrile, N—(naphthalenyl)(piperidin-l-ylmethoxy)pyrirnidinarnine, N—(3 ,5 -diﬂuorobenzyl)(3-(pyrrolidin-l -yl)propyl)pyrirnidinarnine, N—(((4-(3-(piperidin-l-yl)propyl)pyrimidinyl)amino)methyl)benzarnide, N—(2-((2-(3-(dimethylamino)propyl)pyrimidinyl)amino)ethyl)benzarnide, 2-(hexahydromethyl- lH-l ,4-diazepin- l -yl)-6,7-dimethoxy-N- [ l -(phenylmethyl) piperidinyl]quinazolinamine, ohexylmethoxy-N—[l-(l-methylethyl)piperidinyl][3-(lpyrrolidinyl )propoxy]quinazolinamine, 3-(1-cyano-l-methylethyl)-N—[3-[(3,4-dihydromethyloxo quinazolinyl)arnino]methylphenyl]benzamide, 6-acetylcyclopentylmethyl[(5-piperazin-l-ylpyridinyl)amino]pyrido[2,3- d]pyrirnidinone, N-[2-[[4-(Diethylarnino)butyl]amino](3,5-dimethoxyphenyl)pyrido[2,3- d]pyrimidinyl]—N'—(1,1-dimethylethyl)urea, or 6-[[2-[[4-(2,4-dichlorophenyl)(5-methyl-lH-irnidazolyl) pyrimidinyl] amino] ethyl] amino] -3 inecarbonitrile, (2) when T is a bond, B is substituted phenyl, and R6 is NRgRg, in which R9 is —Q3- R82, and RS2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6- membered heteroaryl, then B is substituted with at least one substituent selected from (i) —Q2- OR11 in which R11 is —Q6-RS3 and Q6 is optionally substituted C2-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker and (ii) —Q2-NR10R11 in which R11 is —Q6-RS3, (3) when T is a bond and B is ally substituted phenyl, then R6 is not OR9 or NRgR9 in which R9 is optionally tuted naphthyl, (4) when T is a bond and B is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, then R6 is not NRgR9 in which R9 is optionally substituted phenyl, naphthyl, indanyl or l,2,3,4-tetrahydronaphthyl, (5) when T is a bond and B is optionally substituted phenyl or thiazolyl, then R6 is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NRgR9 in which R9 is optionally tuted imidazolyl or 6- to 10-membered heteroaryl, or (6) when T is a C1-C6 ne linker and B is absent or optionally substituted C6-C10 aryl or 4- to 12-membered heterocycloalkyl, or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R6 is not NR8C(O)R13, (7) when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to -membered aryl, or (8) when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl, each ally substituted with one or more C1-C6 alkyl, and R6 and R2 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl. 2. The nd of claim 1, n ring A is a 6-membered heteroaryl, at least one of X1, X2, X3 and X4 is N and X5 is C. 3. The nd of any one of the ing claims, wherein ring A is a 6-membered heteroaryl, two ole, X2, X3 and X4 are N and X5 is C. 4. The compound of any one of the preceding claims, wherein R6 and one of R2 or R3 together with the ring A to which they are attached form a 6,5- fused bicyclic heteroaryl, or R6 and one of R2’ or R3’ er the ring A to which they are attached form a 6,5-fused bicyclic heteroaryl.

. The compound of any one of the preceding claims, wherein at least one of R6, R2, R3, and R4 is not H. 6. The compound of any one of the ing claims, wherein when one or more of RZ’, R3’, and R4’ are present, at least one of R6, RZ’, R3’, and R4’ is not H. 7. The compound of any one of the ing claims, being of Formula (11): X2/ \\x3 AA R7)" R6 x1 T R1 (11), wherein ring B is phenyl or pyridyl, one or both of X1 and X2 are N while X3 is CR4 and X4 is CR5 or one or both of X1 and X3 are N while X2 is CR3 and X4 is CR5, and nis 1,2, or3. 8. The compound of any one of the preceding claims, being of Formula (Hal), (IIa2), (IIa3), (IIa4), or (IIa5): R5 R5 R3 R3 \ N \ \ N \ I A I —‘R )M7 I A I JR )M7 R‘N8 / R7 R‘N8 R7 N N N N N F}9 | Fag I R1 (Hal), R1 (IIa2), R3 N \ N \ l k I —(R7)n_1 ﬁ l :‘Rnn-1 N N N N N N R9 I R9 R 1 (IIa3), R1 (IIa4), or \ N \ N | X | 4R7)", RN8 N/ / R7 R9 T R1 (IIa5). 9. The compound of any one of the preceding claims, n at most one of R3 and R5 is not H.

. The nd of any one of the preceding claims, being of a (IIbl), (IIb2), (IIb3), (IIb4), or (IIbS): R5 R5 R3 R R3 R \ \ \ \ l ' 7 l ' ﬁlm RWYa / a / N [I] RsN R7 N [I] N R9 R9 R1 (Hbl), R1 (1112), R5 R5 R3 R \ N/\ R3 R4 \ N\\ | | —(R7)n_1 | | —(R7)n_1 R? / / 7 R? / / 7 R9 R9 R1 (IIb3), R1 (IIb4), R3 R \ \ N | | —'éR7)n_1 R\Na / / R7 R9 I|\] or R1 (IIbS). 11. The compound of any one of the preceding claims, wherein at most one of R3, R4 and R5 is not H. 12. The compound of any one of the preceding claims, being of Formula (IIcl), (IIc2), (IIc3), (IIc4), or (IIc5): R5 R5 R4 R4 N \ \ N \ \ l /—iR7)n_1 I l /)—(\R7)n-1 Rwy8 )L / 8 N T R\[l\] R7 N N R9 R9 T R1 (IIcl), R1 (IIc2), N N N N R9 I R9 N R1 (IIc3), R1 (IIc4), or N \ \ N )L | —'(R7)n 1 R\Na / / R7 R9 T R1 (IIcS). 13. The compound of any one of the preceding claims, wherein at most one of R4 and R5 is not H. 14. The compound of any one of the preceding claims, being of Formula (IIdl), , (IId3), (IId4), or (IId5): R5 R5 R R N \ \ N \ \ | | 7""7 | ' R8 / R \8 / ZR’M7 \N R7 R7 [I] N T N R9 R2 R9 R2 R1 (Hdl), R1 (11012), R5 R5 R N/\ R4 N \ N \ \\ | | —éR7)n_1 | | —lR7)n_1 RN8 / / RN8 R7 / / R7 R9 R2 T R9 R2 T R1 (IId3), R1 (IId4), or N \ \ N l | —'(R7)n_1 R§N / / R7 {Q9 R2 I R1 (IIdS).

. The nd of any one of the preceding claims, wherein at most one of R2, R4, and R5 is not H. 16. The compound of any one of the preceding , wherein ring A is a 5-membered heteroaryl. 17. The compound of any one of the preceding claims, being of Formula (111): Xz—X3 wherein ring B is phenyl or pyridyl, at least one of X2 and X3 is N, and n is 1 or 2. 18. The compound of any one of the preceding claims, being of Formula (IIIa): N—N \ / | —eR7)n_1 R8 / / ‘N T R7 R9 R2 R1 (IIIa). 19. The compound of any one of the ing claims, n at most one of R4’ and R2 is not H.

. The compound of any one of the preceding claims, wherein the optionally tuted 6,5- fused bicyclic heteroaryl contains 1-4 N atoms. 21. The compound of any one of the preceding claims, wherein T is a bond and ring B is phenyl or pyridyl. 22. The compound of any one of the preceding claims, wherein n is 1 or 2. 23. The compound of any one of the preceding claims, being of Formula (IV): R20 R5 A R7)n R22 N N R23 I wherein ring B is C3-C6 cycloalkyl, each of R20, R21, R22 and R23 independently is H, halo, C1-C3 alkyl, hydroxyl, or C1-C3 alkoxyl, and n is l or 2. 24. The compound of any one of the preceding claims, wherein ring B is cyclohexyl.

. The compound of any one of the preceding claims, wherein R1 is H or CH3. 26. The compound of any one of the preceding claims, wherein n is l or 2, and at least one of R7 is —Q2-OR11 in which R11 is —Q6-RS3 and Q6 is optionally tuted C2-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker. 27. The compound of any one of the preceding claims, wherein n is l or 2, and at least one of R7 is —Q2-NR10R11 in which R11 is —Q6-RS3. 28. The compound of any one of the preceding , wherein Q6 is C2-C6 alkylene, C2- C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl and RS3 is 4- to 7-membered cycloalkyl optionally substituted with one or more —Q7-T7. 29. The nd of any one of the preceding claims, n Q6 is C1-C6 alkylene, C2- C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl and RS3 is C3-C6 cycloalkyl optionally substituted with one or more —Q7-T7 . The compound of any one of the preceding claims, wherein each Q7 is independently a bond or a C1-C3 ne, C2-C3 alkenylene, or C2-C3 alkynylene linker and each T7 is independently H, halo, C1-C6 alkyl, or phenyl. 31. The compound of any one of the preceding claims, wherein Q2 is a bond or a C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene . 32. The compound of any one of the preceding claims, wherein at least one of R7 is *0MQEME)"N \o Flo/\/\CNH 7"»:Oi 0% 7% MW:Mm"m ""0; "ion 3 3 3 3 &N\CNH,& \CN ﬁ/ TNV. 33. The nd of any one of the preceding claims, n n is 2 and the compound r ses another R7 selected from halo and methoxy. 34. The compound of any one of the preceding claims, wherein ring B is selected from phenyl, pyridyl, and cyclohexyl, and the halo or methoxy is at the para-position to NR1.

. The compound of any one of the preceding claims, wherein R6 is NR8R9. 36. The compound of any one of the preceding claims, wherein R9 is —Q3-T3, in which T3 is OR12,NR12C(O)R13, C(O)R13, C(O)NR12R13, R12R13, or R52. 37. The compound of any one of the preceding claims, wherein Q3 is C1-C6 alkylene, C2- C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl. 38. The compound of any one of the preceding claims, wherein RS2 is C3-C6 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more . 39. The compound of any one of the preceding claims, wherein each Q4 is independently a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker ally substituted with one or more of hydroxyl and halo, and each T4 is independently H, halo, C1-C6 alkyl, or phenyl, or -Q4-T4 is oxo. 40. The compound of any one of the preceding claims, wherein R6 or NRSR9 is selected from the group consisting of: WO 81177 ﬁGﬁOUm I2 0 / N f: \ N N l H and F F 3 . 41. The compound of any one of the preceding claims, wherein B is absent and T is unsubstituted C1-C6 alkyl or T is C1-C6 alkyl substituted with at least one R7. 42. The compound of any one of the ing claims, wherein B is 4- to 12-membered heterocycloalkyl and T is unsubstituted C1-C6 alkyl. 43. The nd of any one of the preceding claims, being of Formula (V): H30’O \ x3 R9-o NAN/T‘IEB HIV)" l _ .

R1 (V), wherein ring B is absent or C3-C6 cycloalkyl, X3 is N or CR4 in which R4 is H or C1-C4 alkyl, R1 is H or C1-C4 alkyl, or when B is , T and R1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R7)n, or when B is absent, T is H and n is 0, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 lene linker optionally substituted WO 81177 with one or more of halo, cyano, hydroxyl, amino, mono- or di- mino, or C1-C6 alkoxyl, and each T2 independently is H, halo, OR"), OR", C(O)R11, , C(O)NR10R11, NR10C(O)R11, C3-C3 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C3-C3 cycloalkyl or 4- to 12- ed heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, -S02R8, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)0Rg, R5 is selected from the group consisting of C1-C6 alkyl, C3-C3 cycloalkyl and 4- to 12- membered cycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C3 cycloalkyl and 4- to 12-membered cycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, -C(O)C1-C6 alkyl or C1-C6 alkyl optionally substituted with one or more of halo or ORa, R9 is —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is 4- to 12-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)RC, S(O)2RC, NRCRd, CRd, and NRCC(O)Rd, each of RC and RC1 independently being H or C1-C6 alkyl, or — Q4-T4 is oxo, and nis 0, l or2. 44. The compound of claim 1, being of Formula (VI): R3 o \ N \CH3 R6 N H OMNQ (V1), WO 81177 wherein R5 and R6 are independently ed from the group consisting of C1-C6 alkyl and NR8R9, or R6 and R3 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl. 45. The compound of any one of the preceding claims, wherein R6 is methyl. 46. The compound of any one of the preceding claims, being of Formula (VII): Xz/X\\X34 u m X TMW1 7 R1 (V11), wherein m is l or 2 and n is 0, l, or 2. 47. The compound of any one of the preceding claims, wherein both of X1 and X3 are N while X2 is CR3 and X4 is CR5. 48. The compound of any one of the preceding claims, being of Formula (VIIIa): Xz/nge» / | A :—n-1 R‘N8 \ x1 N R7 R9 FIN (Villa), wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is ed from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo, ORa, or NRaRb, each of R3 and R4 is H, and R5 are independently selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl optionally substituted with one or more of halo or ORa, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered aryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and n at least one of R2 or R3 are not H. 49. The compound of any one of the preceding claims, being of a (VIIIb): x2X\4x3 \CH3 R8EELXkN O/\/\NQ (VIIIb), wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group ting of H, C3-C3 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H, and R5 is selected from the group ting of H, C3-C3 cycloalkyl, and C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R3 are not H. 50. The compound of any one of the preceding , being of Formula (VIIIc): X2X4\X3 O\R10 R1%ka R11 (VIIIc) wherein X1 is N or CR2, X2 is N or CR3, X3 is N or CR4, X4 is N or CR5, R2 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl each of R3 and R4 is H, and R5 is selected from the group consisting of H, C3-C3 cycloalkyl, and C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, and wherein at least one of R2 or R5 are not H. 51. A nd of Formula (IX-1): \ \ x3 ( T1_Q1 V / / x6 N R158 (IX-1), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, n, X6 is N or CH, X7 is N or CH, X3 is N or CR4, R4 is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, each Q1 is ndently a bond or C1-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, each T1 is independently H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or RSI, in which RS1 is C3-C3 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, - SOZRS, -S02N(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and —Q1—T1 is not NR8C(O)NR12R13, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R", ORB, NR12R13, O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which RS2 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered cycloalkyl containing 1-4 atoms ed from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 ndently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd ndently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, n each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally tuted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T8 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, R15a is CN, C(0)H, C(O)R18, OH, ORIS, C1-C6 alkyl,NHR17, C3-C3 cycloalkyl, C6- C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to lO-membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to lO-membered aryl is optionally substituted with one or more —Q9-T9, wherein each Q9 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T9 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q9-T9 is oxo, R16a is -Q11-R16 in which Q11 is a bond, 0, NRa, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and R16 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q 10-T10, wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T10 independently is selected from the group consisting of H, halo, cyano, C(O)H, C(O)R18, S(O)pR18, OH, ORIS, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q10-T10 is oxo, R17 is H or C1-C6 alkyl, each R18 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, p is 0,1, or2, and V is 0, l, or 2. 52. The compound of claim 51, wherein R15a is CN or C(O)R18. 53. The nd of claim 51 or 52, wherein R16a is 16 in which Q11 is a bond, NRa, or C1-C3 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy. 54. The compound of any one of claims 51-53, wherein each Q1 is ndently a bond or C1-C6 alkylene or C2-C6 alkynylene linker optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy. 55. The compound of any one of claims 51-54, wherein each T1 is independently NR8R9, 0R9, or RSI, in which RS1 is ally substituted C3-C3 cycloalkyl or ally tuted 4- to 12-membered heterocycloalkyl.

WO 81177 56. The compound of claim 51, being a compound of Formula (IX): he" \ \ X3 V K / /i x6 N R15 (1X), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein X6 is N or CH, X7 is N or CH, X3 is N or CR4, R4 is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 7- ed heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 lene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 l, and T3 is H, halo, 0R", ORB,NR12R13,NR12C(O)R13, 12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which R52 is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more , wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each ally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, S(O)2RC, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd ndently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, n each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, R15 is C1-C6 alkyl, NHR17, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10- ed heteroaryl, wherein each of said C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is ally substituted with one or more —Q9-T9, wherein each Q9 ndently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T9 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, and 5- to 6- membered heteroaryl, or —Q9-T9 is oxo, R16 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, C3-C3 lkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to bered heteroaryl, each of which is optionally substituted with one or more —Q10- T10, wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T10 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to ered heteroaryl, or — Qlo-T10 is oxo, R17 is H or C1-C6 alkyl, and Vis 0,1, or2. 57. The compound of any one of the preceding claims, wherein each T3 independently is OR12 or ORB. 58. The compound of any one of the preceding claims, wherein each Q3 independently is a bond or C1-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl. 59. The compound of any one of the preceding claims, wherein R15 is C1-C6 alkyl, NHR", or 4- to 12-membered heterocycloalkyl. 60. The compound of any one of the preceding claims, wherein R16 is C1-C6 alkyl or 4- to 12-membered heterocycloalkyl, each ally substituted with one or more —Q10-T10. 61. The compound of any one of the preceding claims, wherein each T10 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, and 4- to 7-membered heterocycloalkyl. 62. The compound of any one of the ing , wherein each Q10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker optionally substituted with a hydroxyl. 63. The compound of any one of the preceding claims, being of Formula (X): H3CO X7 \ \x3 R90 X6 N R1500, wherein X3 is N or CR4, wherein R4 is ed from the group consisting of H, halo, and cyano. 64. The compound of any one of the preceding claims, being of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xi), 0r 0%) WO 81177 R16 R16 H CO3 H CO \ 3 \ N N R15 (Xa), R 09 N R15 (Xb), R16 R16 H CO3 H CO \ \ N 3 \ \ / A / / R 09 R15 (Xe), R 09 N N N N R15 (Xd), H 00 F H CO N 3 \ \ \ / / / R90 N R15 (Xe), R90 N R15 (X3. or H3CO CN R 09 N R15 (Xg). 65. The compound of any one of the preceding claims, n at least one of X1, X2, X3 and X4 is N. 66. The compound of any one of the preceding claims, wherein X2 and X3 is CH, and X1 and X4 is N. 67. The compound of any one of the preceding claims, wherein X2 and X3 is N, X1 is CR2, and X4 is CR5. 68. The compound of any one of the preceding claims, wherein R6 is NRgR9 and R5 is C1. 6 alkyl or R5 and R3 together with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.

WO 81177 69. The compound of any one of the preceding claims, wherein the compound is selected from those in Tables 1-5 and ceutically acceptable salts thereof. 70. The compound of any one of the preceding claims, wherein the compound ts a kinase with an enzyme tion IC50 value of about 100 nM or greater, 1 uM or greater, 10 uM or greater, 100 uM or greater, or 1000 uM or greater. 71. The compound of any one of the preceding claims, wherein the compound inhibits a kinase with an enzyme inhibition IC50 value of about 1 mM or greater. 72. The compound of any one of the preceding claims, wherein the compound inhibits a kinase with an enzyme inhibition IC50 value of 1 uM or r, 2 uM or greater, 5 uM or greater, or 10 uM or greater, wherein the kinase is one or more of the following: AbI, AurA, CHKl, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARKl, MNK2, PKCb2, SIK, and Src. 73. A pharmaceutical composition comprising a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof and a ceutically acceptable carrier. 74. A method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMTl and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a nd of Formula (I): XZ/X\X34 xX‘K /T\">/‘R7’ R6 X1 n N 'B‘ | \ R1 (1), or a tautomer f, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein ring A is phenyl or a 5- or 6-membered heteroaryl, X1 is N, CR2, or NR2’ as valency permits, X2 is N, CR3, or NR3’ as valency permits, X3 is N; CR4; or NR4’ as valency s; X4 is N or CR5; or X4 is absent such that ring A is a 5-membered heteroaryl containing at least one N atom; X5 is C or N as valency permits; B is absent or a ring structure selected from the group consisting of C6-C10 aryl; C3- C10 cycloalkyl; 5- to 10-membered heteroaryl; and 4- to 12-membered heterocycloalkyl containing 1-4 atoms selected from N; O; and S; T is a bond or C1-C6 alkylene; C2-C6 alkenylene; or C2-C6 alkynylene linker optionally substituted with one or more of halo; cyano; hydroxyl; oxo; or C1-C6 alkoxy when B is present; or T is H and n is 0 when B is absent; or T is C1-C6 alkyl ally substituted with (R7)Il when B is absent; or when B is absent; T and R1 together with the atoms to which they are attached ally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl; each of which is optionally substituted with (R7)n; R1 is H or C1-C4 alkyl; each of RZ’; R3’ and R ’ independently is H or C1-C3 alkyl; each of R2; R3; and R4; independently is selected from the group consisting of H; halo; cyano; C1-C6 l; 06-010 aryl; NRaRb; C(O)NRaRb; NRaC(O)Rb; c3—c8 cycloalkyl; 4— to 7- membered heterocycloalkyl; 5- to 6- membered heteroaryl; and C1-C6 alkyl; n C1-C6 alkoxyl and C1-C6 alkyl are ally substituted with one or more of halo; ORa; or NRaRb; in which each of Ra and Rb independently is H or C1-C6 alkyl; or R3 is —Q1-T1; in which Q1 is a bond or C1-C6 alkylene; C2-C6 alkenylene; or C2-C6 alkynylene linker optionally substituted with one or more of halo; cyano; hydroxyl; oxo; or C1-C6 alkoxyl; and T1 is H; halo; cyano; NRSRg; C(O)NR8R9; 0R8; 0R9; or RSI; in which RS1 is C3-C3 cycloalkyl; phenyl; 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; or a 5- or 6-membered heteroaryl and RSl is optionally substituted with one or more of halo; C1-C6 alkyl; yl; oxo; -C(O)R9; 60st; R8)2; -NR8C(O)R9; amino; mono- or di- alkylamino; or C1-C6 alkoxyl; or when ring A is a 5-membered heteroaryl containing at least one N atom; R4 is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; R5 is selected from the group consisting of H; halo; cyano; C1-C6 alkoxyl; C6-C10 aryl; NRaRb; C(O)NRaRb; NRaC(O)Rb; C3-C3 cycloalkyl; 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N; O; and S; optionally substituted with one or more of -C(O)C1-C6 alkyl or C1-C6 alkyl optionally tuted with one or more of halo or ORa; C1-C6 alkyl optionally substituted with one or more of halo; ORa; or NRaRb; and C2-C6 alkynyl optionally substituted with 4- to 12-membered heterocycloalkyl, wherein said C3-C3 cycloalkyl and 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)Ra, ORa, NRaRb, 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene to 7-membered heterocycloalkyl, or C1-C4 alkyl optionally substituted with one or more of halo, ORa or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ er with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered aryl as formed is ally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, R6 is absent when X5 is N and ring A is a 6-membered heteroaryl, or R6 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or RSI, in which R51 is C3-C3 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RSl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R9, -SOZR8, R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and R6 is not NR8C(O)NR12R13, or R6 and one of R2 or R3 together with the atoms to which they are ed form phenyl or a 5- or 6-membered heteroaryl, or R6 and one of Rz’or R3’ together with the atoms to which they are ed form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=0), C1-C3 alkoxyl or -Q1-T1, each R7 is independently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 lene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 ndently is H, halo, cyano, OR"), OR", 1, NRIORH, C(O)NR10R11, NR10C(O)R11, 5- to 10-membered heteroaryl, C3-C3 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C3-C3 lkyl, or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, , cyano, C1-C6 haloalkyl, -SOZRS, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)ORg, or optionally, when B is present, one R7 and R5 together form a C3-C10 alkylene, C2-C10 heteroalkylene, C4-C10 alkenylene, C2-C10 alkenylene, C4-C10 alkynylene or C2- C10 heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, each R8 independently is H or C1-C6 alkyl, each R9 is ndently —Q3-T3, in which Q3 is a bond or Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker ally substituted with one or more of halo, cyano, hydroxyl or C1-C6 l, and T3 is H, halo, OR12, ORB, NRIZRB, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which R52 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to bered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 ne, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to ered heteroaryl, ORG, C(O)Rc, S(O)2RC, S(O)2NRCRd, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and RC1 independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R8 and R9 taken together with the nitrogen atom to which they are ed form a 4- to bered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of —Q5-T5, wherein each Q5 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Re, S(O)2Re, S(O)2NReRf, NReRf, C(O)NReRf, and NReC(O)Rf, each of Re and Rf independently being H or C1-C6 alkyl, or —Q5-T5 is oxo, R10 is selected from the group consisting of H and C1-C6 alkyl, R11 is —Q6-T6, in which Q6 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, yl, oxo, or C1-C6 alkoxyl, and T6 is H, halo, ORg, NRth, NRgC(O)Rh, C(O)NRth, C(O)Rg, S(O)2Rg, or RS3, in which each of Rg and Rh independently is H, phenyl, C3-C3 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C3 cycloalkyl, or Rg and Rh er with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 WO 81177 heteroatoms selected from N, O, and S, and RS3 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to lO-membered heteroaryl, and RS3 is optionally substituted with one or more —Q7-T7, wherein each Q7 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T7 independently is selected from the group ting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR], C(O)Rj, NRij, C(O)NRij, S(O)2Rj, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl optionally tuted with one or more halo, or —Q7-T7 is oxo, or R10 and R11 taken together with the nitrogen atom to which they are ed form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, or C1-C6 alkoxyl, R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, each of which is optionally substituted with one or more —Q8-T8, n each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 lene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, and n is 0, 1, 2, 3, or 4, provided that (l) the compound of Formula (I) is not 2-(hexahydromethyl-1H-1,4-diazepinyl)- 6,7-dimethoxy-N-[ l ylmethyl)piperidinyl] quinazolinamine, or 2-cyclohexylmethoxy-N-[l-(l-methylethyl)piperidinyl][3-(l- pyrrolidinyl)propoxy]quinazolinamine, (2) when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 l, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5 to -membered heteroaryl, or (3) when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C1-C6 alkyl, and R6 and R2 together with the atoms to which they are ed form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to bered heteroaryl. 75. A method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMTl and EHMT2, the method comprising administering to a t in need thereof a therapeutically effective amount of a compound of any one of the preceding claims. 76. The method of any one of the preceding claims, wherein the blood disorder is sickle cell anemia or B-thalassemia. 77. The method of any one of the ing claims, wherein the blood disorder is a hematological cancer. 78. The method of any one of the preceding claims, wherein the logical cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL). 79. The method of any one of the ing claims, wherein a compound of any of Formulae (I)-(Xg) is a selective inhibitor of EHMT2.

Claims

What is claimed is:

1. A compound of Formula (1): X/ \X3 X5 III/7784‘T ”‘~ R7) R6/ \x1 n R1 (1), or a tautomer thereof, or a ceutically acceptable salt of the compound or the tautomer, wherein ring A is phenyl or a 5- or 6-membered heteroaryl, X1 is N, CR2, or NR2’ as valency permits; X2 is N, CR3, or NR3’ as valency s, X3 is N, CR4, or NR4’ as valency permits, X4 is N or CR5, or X4 is absent such that ring A is a 5-membered heteroaryl containing at least one N atom, X5 is C or N as valency permits, B is absent or a ring structure selected from the group consisting of C6-C10 aryl, C3- C10 cycloalkyl, 5- to lO-membered heteroaryl, and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, T is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxy when B is present, or T is H and n is 0 when B is absent, or T is C1-C6 alkyl optionally substituted with (R7)Il when B is absent, or when B is absent, T and R1 together with the atoms to which they are attached ally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally tuted with (R7)n, R1 is H or C1-C4 alkyl, each of R2, R3, and R4, independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, 06-010 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, c3—c8 cycloalkyl, 4— to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-C6 alkyl, wherein C1-C6 l and C1-C6 alkyl are optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R3 is —Q1-T1, in which Q1 is a bond or C1-C6 ne, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 l, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, 0R8, 0R9, or RSI, in which RS1 is C3-C3 cycloalkyl, phenyl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is ally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, 0x0, -C(O)R9, , -SOzN(R8)2, -NR8C(O)R9, amino, mono- or dialkylamino , or C1-C6 alkoxyl,, or when ring A is a 5-membered heteroaryl containing at least one N atom, R4 is a spiro-fused 4- to bered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, each of RZ’, R3’ and R ’ independently is H or C1-C3 alkyl, R5 is selected from the group consisting of H, F, Br, cyano, C1-C6 alkoxyl, C6-C10 aryl, NRaRb, C(O)NRaRb, NRaC(O)Rb, C3-C3 cycloalkyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, C1-C6 alkyl optionally substituted with one or more of halo, ORa or NRaRb, and C2-C6 alkynyl ally substituted with 4- to 12- membered heterocycloalkyl, wherein said C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)Ra, ORa, NRaRb, 4- to 7-membered cycloalkyl, -C1-C6 alkylene to ered heterocycloalkyl, or C1- C4 alkyl optionally substituted with one or more of halo, ORa or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl, or R5 and one of R3 or R4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R5 and one of R3’or R4’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl, R6 is absent when X5 is N and ring A is a ered heteroaryl, or R6 is —Q1-T1, in which Q1 is a bond or C1-C6 alkylene, C2-C6 lene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, NR8R9, C(O)NR8R9, C(O)R9, 0R8, 0R9, or R“, in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, yl, oxo, -C(O)R9, , -SOzN(R8)2, -NR8C(O)R9, NR8R9, or C1-C6 alkoxyl, and R6 is not NR8C(O)NR12R13, or R6 and one of R2 or R3 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl, or R6 and one of Rz’or R3’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=0), C1-C3 alkoxyl, or -Q1-T1, each R7 is ndently oxo (=0) or —Q2-T2, in which each Q2 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, yl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T2 independently is H, halo, cyano, ORIO, OR“, C(O)R11, NRIOR“, C(O)NR10R11, NR10C(O)R11, 5- to lO-membered heteroaryl, C3-C3 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to lO-membered heteroaryl, C3-C3 cycloalkyl or 4- to bered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl optionally substituted with NRXRy, hydroxyl, oxo, N(R8)2, cyano, C1-C6 haloalkyl, -SO2R8, or C1-C6 alkoxyl, each of RK and Ry independently being H or C1-C6 alkyl, and R7 is not H or C(O)ORg, or optionally, when B is present, one R7 and R5 together form a C3-C10 alkylene, C2-Cio alkylene, C4-Cio alkenylene, C2-Cio heteroalkenylene, C4-Cio alkynylene or C2- C10 heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, each R8 independently is H or C1-C6 alkyl, each R9 is independently —Q3-T3, in which Q3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T3 is H, halo, 0R”, ORB, NR12R13, NR12C(O)R13, C(O)NR12R13, C(O)R13, S(O)2R13, S(O)2NR12R13, or R52, in which RS2 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to lO-membered heteroaryl, and RS2 is optionally substituted with one or more —Q4-T4, wherein each Q4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally tuted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Rc, C, NRCRd, C(O)NRCRd, and NRCC(O)Rd, each of RC and Rd independently being H or C1-C6 alkyl, or —Q4-T4 is oxo, or R8 and R9 taken together with the en atom to which they are ed form a 4- to 12-membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of —Q5-T5, wherein each Q5 ndently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 WO 81177 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORG, C(O)Re, S(O)2Re, S(O)2NReRf, NReRf, C(O)NReRf, and NReC(O)Rf, each of Re and Rf independently being H or C1-C6 alkyl, or —Q5-T5 is oxo, R10 is selected from the group consisting of H and C1-C6 alkyl, R11 is —Q6-T6, in which Q6 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T6 is H, halo, ORg, NRth, NRgC(O)Rh, C(O)NRth, C(O)Rg, S(O)2Rg, or RS3, in which each of Rg and Rh independently is H, phenyl, C3-C3 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C3 cycloalkyl, or Rg and Rh together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and RS3 is C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and RS3 is optionally substituted with one or more , wherein each Q7 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T7 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR], C(O)Rj, NRij, ij, S(O)2Rj, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl ally substituted with one or more halo, or —Q7-T7 is oxo, or R10 and R11 taken together with the nitrogen atom to which they are ed form a 4- to 12-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, or C1-C6 alkoxyl, R12 is H or C1-C6 alkyl, R13 is C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally tuted with one or more —Q8-T8, wherein each Q8 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 , and each T8 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C3 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms ed from N, O, and S, and 5- to 6-membered heteroaryl, or —Q8-T8 is oxo, and 11 is 0, 1, 2, 3, or 4, ally provided that (1) the compound of Formula (I) is not 4-(((2-((1-acetylindolinyl)amino) (triﬂuoromethyl)pyrirnidinyl)amino)methyl)benzenesulfonamide, 5-bromo-N4-(4-ﬂuorophenyl)-N2-(4-methoxy-3 -(2-(pyrrolidin-l - yl)ethoxy)phenyl)pyrimidine-2,4-diamine, N2-(4-methoxy(2-(pyrrolidin- l -yl)ethoxy)phenyl)-N4-(5 -(tert-pentyl)- lH-pyrazol- 3-yl)pyrirnidine-2,4-diamine, 4-((2,4-dichloromethoxyphenyl)arnino)((3-(2-(pyrrolidin-l- yl)ethoxy)phenyl)amino)pyrirnidinecarbonitrile, N—(naphthalenyl)(piperidin-l-ylmethoxy)pyrirnidinarnine, N—(3 ,5 -diﬂuorobenzyl)(3-(pyrrolidin-l -yl)propyl)pyrirnidinarnine, N—(((4-(3-(piperidin-l-yl)propyl)pyrimidinyl)amino)methyl)benzarnide, N—(2-((2-(3-(dimethylamino)propyl)pyrimidinyl)amino)ethyl)benzarnide, 2-(hexahydromethyl- lH-l ,4-diazepin- l -yl)-6,7-dimethoxy-N- [ l -(phenylmethyl) piperidinyl]quinazolinamine, 2-cyclohexylmethoxy-N—[l-(l-methylethyl)piperidinyl][3-(lpyrrolidinyl )propoxy]quinazolinamine, 3-(1-cyano-l-methylethyl)-N—[3-[(3,4-dihydromethyloxo quinazolinyl)arnino]methylphenyl]benzamide, 6-acetylcyclopentylmethyl[(5-piperazin-l-ylpyridinyl)amino]pyrido[2,3- rnidinone, N-[2-[[4-(Diethylarnino)butyl]amino](3,5-dimethoxyphenyl)pyrido[2,3- d]pyrimidinyl]—N'—(1,1-dimethylethyl)urea, or 6-[[2-[[4-(2,4-dichlorophenyl)(5-methyl-lH-irnidazolyl) pyrimidinyl] amino] ethyl] amino] -3 -pyridinecarbonitrile, (2) when T is a bond, B is substituted , and R6 is NRgRg, in which R9 is —Q3- R82, and RS2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6- membered heteroaryl, then B is substituted with at least one substituent selected from (i) —Q2- OR11 in which R11 is 3 and Q6 is optionally substituted C2-C6 alkylene, C2-C6 lene, or C2-C6 alkynylene linker and (ii) —Q2-NR10R11 in which R11 is —Q6-RS3, (3) when T is a bond and B is optionally tuted phenyl, then R6 is not OR9 or NRgR9 in which R9 is optionally substituted naphthyl, (4) when T is a bond and B is optionally substituted phenyl, naphthyl, l or 4-tetrahydronaphthyl, then R6 is not NRgR9 in which R9 is optionally substituted phenyl, naphthyl, indanyl or l,2,3,4-tetrahydronaphthyl, (5) when T is a bond and B is optionally substituted phenyl or thiazolyl, then R6 is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NRgR9 in which R9 is optionally substituted imidazolyl or 6- to 10-membered heteroaryl, or (6) when T is a C1-C6 ne linker and B is absent or optionally substituted C6-C10 aryl or 4- to 12-membered heterocycloalkyl, or when T is a bond and B is ally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R6 is not NR8C(O)R13, (7) when X1 and X3 are N, X2 is CR3, X4 is CR5, X5 is C, R5 is 4- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl, and R6 and R3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally tuted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl, or (8) when X2 and X3 are N, X1 is CR2, X4 is CR5, X5 is C, R5 is C3-C3 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C1-C6 alkyl, and R6 and R2 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C6-C10 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

2. The compound of claim 1, wherein ring A is a 6-membered heteroaryl, at least one of X1, X2, X3 and X4 is N and X5 is C.

3. The compound of any one of the ing claims, wherein ring A is a 6-membered heteroaryl, two ole, X2, X3 and X4 are N and X5 is C.

4. The nd of any one of the ing claims, wherein R6 and one of R2 or R3 together with the ring A to which they are ed form a 6,5- fused bicyclic heteroaryl, or R6 and one of R2’ or R3’ together the ring A to which they are attached form a 6,5-fused bicyclic heteroaryl.

5. The compound of any one of the preceding claims, wherein at least one of R6, R2, R3, and R4 is not H.

6. The compound of any one of the ing claims, wherein when one or more of RZ’, R3’, and R4’ are present, at least one of R6, RZ’, R3’, and R4’ is not H.

7. The compound of any one of the preceding , being of Formula (11): X2/ \\x3 AA R7)” R6 x1 T R1 (11), wherein ring B is phenyl or pyridyl, one or both of X1 and X2 are N while X3 is CR4 and X4 is CR5 or one or both of X1 and X3 are N while X2 is CR3 and X4 is CR5, and nis 1,2, or3.

8. The compound of any one of the preceding claims, being of Formula (Hal), (IIa2), (IIa3), (IIa4), or (IIa5): R5 R5 R3 R3 \ N \ \ N \ I A I —‘R )M7 I A I JR )M7 R‘N8 / R7 R‘N8 R7 N N N N N F}9 | Fag I R1 (Hal), R1 (IIa2), R3 N \ N \ l k I —(R7)n_1 ﬁ l :‘Rnn-1 N N N N N N R9 I R9 R 1 (IIa3), R1 (IIa4), or \ N \ N | X | 4R7)“, RN8 N/ / R7 R9 T R1 (IIa5).

9. The compound of any one of the preceding claims, wherein at most one of R3 and R5 is not H.

10. The compound of any one of the preceding claims, being of Formula (IIbl), (IIb2), (IIb3), (IIb4), or (IIbS): R5 R5 R3 R R3 R \ \ \ \ l ' 7 l ' ﬁlm RWYa / a / N [I] RsN R7 N [I] N R9 R9 R1 (Hbl), R1 , R5 R5 R3 R \ N/\ R3 R4 \ N\\ | | —(R7)n_1 | | —(R7)n_1 R? / / 7 R? / / 7 R9 R9 R1 (IIb3), R1 (IIb4), R3 R \ \ N | | —'éR7)n_1 R\Na / / R7 R9 I|\] or R1 (IIbS).

11. The compound of any one of the preceding claims, wherein at most one of R3, R4 and R5 is not H.

12. The compound of any one of the preceding claims, being of a (IIcl), (IIc2), , (IIc4), or (IIc5): R5 R5 R4 R4 N \ \ N \ \ l /—iR7)n_1 I l /)—(\R7)n-1 Rwy8 )L / 8 N T R\[l\] R7 N N R9 R9 T R1 (IIcl), R1 (IIc2), WO 81177 N N N N R9 I R9 N R1 (IIc3), R1 (IIc4), or N \ \ N )L | —'(R7)n 1 R\Na / / R7 R9 T R1 (IIcS).

13. The compound of any one of the preceding , wherein at most one of R4 and R5 is not H.

14. The compound of any one of the preceding claims, being of Formula (IIdl), (IId2), (IId3), (IId4), or (IId5): R5 R5 R R N \ \ N \ \ | | 7““7 | ' R8 / R \8 / ZR’M7 \N R7 R7 [I] N T N R9 R2 R9 R2 R1 (Hdl), R1 (11012), R5 R5 R N/\ R4 N \ N \ \\ | | —éR7)n_1 | | —lR7)n_1 RN8 / / RN8 R7 / / R7 R9 R2 T R9 R2 T R1 (IId3), R1 (IId4), or N \ \ N l | —'(R7)n_1 R§N / / R7 {Q9 R2 I R1 (IIdS).

15. The compound of any one of the preceding claims, wherein at most one of R2, R4, and R5 is not H.

16. The compound of any one of the preceding claims, wherein ring A is a 5-membered aryl.

17. The compound of any one of the preceding claims, being of Formula (111): Xz—X3 wherein ring B is phenyl or pyridyl, at least one of X2 and X3 is N, and n is 1 or 2.

18. The compound of any one of the preceding claims, being of Formula (IIIa): N—N \ / | —eR7)n