NZ788114A - Heterocyclic compounds as immunomodulators - Google Patents
Heterocyclic compounds as immunomodulatorsInfo
- Publication number
- NZ788114A NZ788114A NZ788114A NZ78811417A NZ788114A NZ 788114 A NZ788114 A NZ 788114A NZ 788114 A NZ788114 A NZ 788114A NZ 78811417 A NZ78811417 A NZ 78811417A NZ 788114 A NZ788114 A NZ 788114A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- membered
- membered heterocycloalkyl
- Prior art date
Links
- 239000002955 immunomodulating agent Substances 0.000 title abstract 2
- 230000002584 immunomodulator Effects 0.000 title abstract 2
- 229940121354 immunomodulators Drugs 0.000 title abstract 2
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 39
- 201000010099 disease Diseases 0.000 claims abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims 182
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 150
- 125000001424 substituent group Chemical group 0.000 claims 92
- 125000003118 aryl group Chemical group 0.000 claims 76
- 125000000753 cycloalkyl group Chemical group 0.000 claims 72
- 125000001188 haloalkyl group Chemical group 0.000 claims 61
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 58
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 56
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 56
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 52
- 125000005843 halogen group Chemical group 0.000 claims 49
- 150000003839 salts Chemical class 0.000 claims 36
- 239000011780 sodium chloride Substances 0.000 claims 36
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 31
- 125000001072 heteroaryl group Chemical group 0.000 claims 31
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 30
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 28
- 229910052757 nitrogen Inorganic materials 0.000 claims 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 23
- -1 C2-6 l Chemical group 0.000 claims 21
- 229910052799 carbon Inorganic materials 0.000 claims 21
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 16
- 125000000304 alkynyl group Chemical group 0.000 claims 15
- 125000004438 haloalkoxy group Chemical group 0.000 claims 15
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 14
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 14
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 13
- 101710027095 C14orf180 Proteins 0.000 claims 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 13
- 229910052717 sulfur Inorganic materials 0.000 claims 13
- 125000003545 alkoxy group Chemical compound 0.000 claims 12
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims 11
- 229910004664 ORa Inorganic materials 0.000 claims 11
- 241000658540 Ora Species 0.000 claims 11
- 229910052760 oxygen Inorganic materials 0.000 claims 11
- 101710033916 NRAS Proteins 0.000 claims 9
- 125000006376 (C3-C10) cycloalkyl group Chemical compound 0.000 claims 8
- 125000004429 atoms Chemical group 0.000 claims 8
- 125000004432 carbon atoms Chemical group C* 0.000 claims 8
- 125000005842 heteroatoms Chemical group 0.000 claims 8
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 6
- 229910003813 NRa Inorganic materials 0.000 claims 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 6
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims 5
- 101710006116 IL31RA Proteins 0.000 claims 5
- 229910003667 SRa Inorganic materials 0.000 claims 4
- 150000003857 carboxamides Chemical class 0.000 claims 4
- 125000003178 carboxy group Chemical compound [H]OC(*)=O 0.000 claims 4
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 4
- 229910017711 NHRa Inorganic materials 0.000 claims 3
- FHIMYVFGWKCROK-UHFFFAOYSA-N [1,3]thiazolo[5,4-c]pyridine Chemical compound C1=NC=C2SC=NC2=C1 FHIMYVFGWKCROK-UHFFFAOYSA-N 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical compound 0.000 claims 2
- 125000006700 (C1-C6) alkylthio group Chemical compound 0.000 claims 2
- 101700081293 LMX1A Proteins 0.000 claims 2
- 108020005497 Nuclear hormone receptors Proteins 0.000 claims 2
- 102100019764 PDCD1 Human genes 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000003993 interaction Effects 0.000 claims 2
- 101700070830 nhr-12 Proteins 0.000 claims 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims 1
- RSFNGIUFEFLHRD-UHFFFAOYSA-N 1H-pyrrolo[2,3-c]pyridine-2-carboxamide Chemical compound C1=NC=C2NC(C(=O)N)=CC2=C1 RSFNGIUFEFLHRD-UHFFFAOYSA-N 0.000 claims 1
- FJMQXAJQFNWGKL-UHFFFAOYSA-N 2,3-dihydro-1$l^{6}-benzothiepine 1,1-dioxide Chemical compound O=S1(=O)CCC=CC2=CC=CC=C12 FJMQXAJQFNWGKL-UHFFFAOYSA-N 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 241000287523 Ara Species 0.000 claims 1
- 101700087092 RERE Proteins 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000028993 immune response Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 101700068080 nhr-11 Proteins 0.000 claims 1
- 239000000546 pharmaceutic aid Substances 0.000 claims 1
- 230000004936 stimulating Effects 0.000 claims 1
- 230000002730 additional Effects 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 201000009910 diseases by infectious agent Diseases 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
Abstract
Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.
Description
HETEROCYCLIC COMPOUNDS AS MODULATORS
RELATED ATIONS
The present application is a divisional application from New Zealand patent
application no. 749960. The entire disclosures of New Zealand patent application no. 749960
and its corresponding international patent application no. , are
incorporated herein by reference.
FIELD OF THE INVENTION
The present application is concerned with ceutically active compounds. The
disclosure provides compounds as well as their compositions and s of use. The
compounds modulate PD-1/PD-L1 protein/protein interaction and are useful in the treatment
of s diseases including infectious diseases and cancer.
OUND OF THE INVENTION
The immune system plays an important role in controlling and eradicating diseases
such as cancer. However, cancer cells often develop strategies to evade or to suppress the
immune system in order to favor their . One such mechanism is altering the
expression of co-stimulatory and co-inhibitory molecules expressed on immune cells (Postow
et al, J. Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitory immune
checkpoint, such as PD-1, has proven to be a promising and effective ent ty.
Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor
expressed on ted T cells, natural killer T cells, B cells, and macrophages (Greenwald et
al, Annu. Rev. Immunol 2005, 23:515–548 ; Okazaki and Honjo, Trends Immunol 2006,
(4):195-201 ). It functions as an intrinsic negative feedback system to prevent the activation
of T-cells, which in turn s autoimmunity and promotes self-tolerance. In addition, PD-
1 is also known to play a critical role in the suppression of antigen-specific T cell response in
diseases like cancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239–245; Postow
et al, J. Clinical Oncol 2015, 1-9).
[Link]
https://en.wikipedia.org/wiki/Transmembrane
[Link]
https://en.wikipedia.org/wiki/Phosphorylation
[Link]
https://en.wikipedia.org/wiki/Immunoreceptor_tyrosine-based_inhibitory_motif
The structure of PD-1 consists of an ellular immunoglobulin variable-like
domain followed by a transmembrane region and an intracellular domain (Parry et al, Mol
Cell Biol 2005, 9543–9553). The intracellular domain contains two phosphorylation sites
located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor
tyrosine-based switch motif, which suggests that PD-1 negatively regulates T cell receptormediated
signals. PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al, Mol Cell Biol 2005,
9543–9553; Latchman et al, Nat Immunol 2001, 2, 261–268 ), and they differ in their
expression patterns. PD-L1 n is upregulated on hages and dendritic cells in
se to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T
cell receptor and B cell receptor signaling. PD-Ll is also highly expressed on almost all
tumor cells, and the expression is further increased after IFN—y treatment (Iwai et al,
PNAS2002, 99(19): 12293-7, Blank et al, Cancer Res 2004, 64(3): 1 140-5). In fact, tumor PD-
L1 sion status has been shown to be prognostic in multiple tumor types (Wang et al,
Eur J Surg Oncol 2015, Huang et al, Oncol Rep 2015, Sabatier et al, Oncotarget 2015, 6(7):
5449—5464). PD-L2 expression, in contrast, is more restricted and is expressed mainly by
dendritic cells (Nakae et al, J Immunol 2006, 6-73). Ligation of PD-l with its ligands
PD-L1 and PD-L2 on T cells delivers a signal that inhibits IL-2 and IFN—y production, as
well as cell eration induced upon T cell receptor activation (Carter et al, Eur J Immunol
2002, 32(3):634-43, Freeman et al, J Exp Med 2000, :1027-34). The mechanism
involves recruitment of SHP-2 or SHP-1 phosphatases to t T cell receptor ing
such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol 2007, 8, 239—245).
Activation of the PD-1 signaling axis also attenuates PKC-0 activation loop phosphorylation,
which is necessary for the tion ofNF-KB and AP1 ys, and for cytokine
production such as IL-2, IFN—y and TNF (Sharpe et al, Nat Immunol 2007 , 8, 239—245,
Carter et al, Eur J Immunol 2002, 32(3):634-43, Freeman et al, J Exp Med 2000,
unuynnmmo
Several lines of evidence from preclinical animal s indicate that PD-1 and its
ligands negatively regulate immune responses. PDdef1cient mice have been shown to
p lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al,
Immunity 1999, 11:141—151, Nishimura et al, Science 2001, 291:319—322). Using an LCMV
model of chronic infection, it has been shown that PD-1/PD-L1 interaction inhibits
activation, expansion and acquisition of effector functions of virus-specific CD8 T cells
(Barber et al, Nature 2006, 439, 682-7). er, these data support the development of a
therapeutic approach to block the PDmediated inhibitory signaling e in order to
augment or “rescue” T cell response. Accordingly, there is a need for new compounds that
block PD-1/PD-L1 protein/protein interaction.
SUMMARY
The present disclosure provides, inter alia, a compound of Formula (1):
cy N LAEYZJNF?)
\\ 2 n
X\XTX1 3 O
(D
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein constituent variables
are defined herein.
The present sure further es a pharmaceutical composition comprising a
compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof,
and at least one ceutically acceptable carrier or excipient.
The present disclosure further provides methods of modulating or inhibiting PD-
l/PD-Ll n/protein ction, which comprises administering to an individual a
compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof.
The present disclosure further provides methods of treating a disease or disorder in a
patient comprising administering to the patient a therapeutically effective amount of a
compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof
DETAILED DESCRIPTION
1. nds
The present disclosure provides a compound of a (I):
/ G\
Nf—Yl G2
II A \§ 2A
Cy N VY (R5>n
\ Z
¢x3 0
\X2 (1)
or a pharmaceutically acceptable salt or a stereoisomer thereof, n:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is O, S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously
Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered
heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 tuents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-10 cycloalkyl, C3—
10 cycloalkyl-Ci—4 alkyl-, C6—10aryl, C6-10 aryl-Ci—4 alkyl-, 5-10 ed heteroaryl, 4-10
membered heterocycloalkyl, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-C1—4 alkyl-, C2—4 alkenyl, C2.4 alkynyl, halo, CN, 0R1“, Ci.4 haloalkyl, C1—4
haloalkoxy, NH2, -NHR10, -NR10R10, NHORlO, C(O)R1°, C(0)NR10R10, C(O)OR1°,
OC(O)R1°, OC(O)NR1°R10, NR1°C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(=NR10)R10,
C(=NR10)NR10R10, NR10C(=NR10)NR10R10, NR108(O)R10, NR1°S(O)2R1°,
NRIOS(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, n each R10
is independently ed from H, C1—4 alkyl, C2—4 l, C2—4 alkynyl, C1—4 alkoxy, C340
lkyl, C340 cycloalkyl-Ci—4 , C640 aryl, C640 aryl-Ci-4 alkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered aryl)-Ci-4 alkyl-, and (4-
10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C14 alkyl, C2—4 alkenyl, C2—4 alkynyl,
C1-4 alkoxy, C340 cycloalkyl, C340 lkyl-Ci-4 , C640 aryl, C640 aryl-Ci-4 alkyl-, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1—4
alkyl-, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl- of R1, R2, R3 and R10 are each
optionally substituted with l, 2 or 3 ndently selected Rd substituents,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C16 alkyl, C2—6
alkenyl, C2—6 alkynyl, Ci.6 kyl, Ci.6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa,
OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa,
C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa,
NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa,
S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 lkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered
heterocycloalkyl)-Ci.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with l,
2, 3, 4 or 5 Rb substituents,
or two nt R8 substituents on the Cy ring, taken together with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or ered heterocycloalkyl
ring, a fused 5- or 6-membered aryl ring or a fused C3.6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered
heteroaryl ring and fused C3.6 cycloalkyl ring are each optionally substituted with l, 2 or 3
ndently selected Rb substituents,
or two R5 substituents attached to the same carbon atom, taken together with the
carbon atom to which they are attached, form a C36 cycloalkyl ring or 4-, 5-, 6- or 7-
membered heterocycloalkyl ring, wherein the C36 cycloalkyl ring and 4-, 5-, 6- or 7-
membered cycloalkyl ring are each ally substituted with l, 2 or 3 independently
selected Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640
aryl, C340 cycloalkyl, 5-14 ed heteroaryl, 4-10 membered heterocycloalkyl, C640
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-14 membered heteroaryl)-Ci—4 alkyl-, (4-10
membered cycloalkyl)-Ci-4 alkyl-, CN, N02, OR“, SR“, NH2, NHR“, NRHR“,
NHOR“, C(O)R“, C(O)NR“R“, C(O)OR“, OC(O)R“, OC(O)NR“R11,NR11C(O)R“,
NR11C(O)OR11,NR11C(O)NR11R11, C(=NR11)R11, C(=NR11)NR11R11,
NR11C(=NR11)NR11R11,NR11C(=N0H)NR11R11, NR“C(=NCN)NR“R“, NR“S(O)R“,
NR“S(O)2R11, NR“S(O)2NR11R“, S(O)R“, S(O)NR11R“, S(O)2R“, or R“R11,
wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640 aryl,
C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4
alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl- and (4-10
membered heterocycloalkyl)-Ci-4 alkyl- of R9 are each optionally substituted with 1, 2 or 3 Rb
substituents,
each R11 is independently selected from H, C1—6 alkyl, Ci—6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 , (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered cycloalkyl)-Ci-4 , wherein the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10
ed heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of R11
are each optionally substituted with l, 2 or 3 Rb substituents,
each Ra is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 i—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered aryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ra are each optionally substituted with l, 2 or 3 Rd substituents,
each Rb substituent is independently selected from halo, C16 alkyl, Ci.6 kyl, Ci—
6haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
aryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci-4 , CN, OH, NH2, N02,
NHORC, ORG, SRC, C(O)RC, CRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, C(=NRC)NRCRC,
NRC)NRCRC, NRCC(=NOH)NRCRC, NRCC(=NCN)NRCRC, NHRC, NRCRC, NRCC(O)RC,
NRCC(O)ORC, NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC,
S(O)NRCRC, S(O)2RC and S(O)2NRCRC, n the C16 alkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy,
C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl-and (4-
membered heterocycloalkyl)-Ci-4 alkyl- of Rb are each further optionally substituted with
1-3 independently selected Rd substituents,
each RC is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 , (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci—4 alkyl- and (4-10 membered cycloalkyl)—Ci—4 alkyl- of
, (5-10
RC are each optionally substituted with l, 2 or 3 Rf substituents independently selected from
C1-6 alkyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 , (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, g,
OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,
C(=NRg)NRgRg, NRgC(=NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg,
S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and RgRg, n the C1-6
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-
, (5-10
of Rf are each optionally substituted with l, 2 or 3 R11 substituents independently selected
from C1—6 alkyl, Ci—6 haloalkyl, halo, CN, , C3—6 cycloalkyl, 5-6 membered heteroaryl,
4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, C(O)R°, C(O)NR°R°, C(O)OR°,
OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, NR°C(O)OR°,
C(=NR°)NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°,
NR°S(O)2NR°R°, and R°R°, wherein the C16 alkyl, Ci-6 haloalkyl, phenyl, C3—6
cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R11 is optionally
tuted with l, 2 or 3 Rq substituents,
each Rd is independently selected from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10
membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, NH2, NHORe, ORG, SR6, C(O)Re, C(O)NReRe, C(O)ORe,
OC(O)Re, OC(O)NReRe, NHRe, NReRe, )Re, NReC(O)NReRe, NReC(O)ORe,
C(=NRe)NReRe, NReC(=NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re,
S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, n the C1-6 alkyl,
Ci—6 haloalkyl, C640 aryl, 5-10 ed heteroaryl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of RC1 are each
optionally substituted with 1-3 independently selected Rf substituents,
each R6 is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 i—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci—4 alkyl-, and (4-10 membered cycloalkyl)-Ci—4 , wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Re are each optionally tuted with l, 2 or 3 independently ed Rf tuents,
each Rg is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
cycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are
each optionally substituted with 1-3 Rp tuents independently selected from C16 alkyl,
Ci—6 haloalkyl, Ci—6 haloalkoxy, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 i—4 , C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORr, ORr, SRr, , C(O)NRrRr, C(O)ORr,
OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, )NRrRr, NRrC(O)ORr,
C(=NRr)NRrRr, NRrC(=NRr)NRrRr, NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr,
S(O)NRrRr, S(O)2Rr, )2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl,
Ci-6 haloalkyl, C1-6 haloalkoxy, C2-6 l, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered aryl)-Ci-4 alkyl- and (4-10 membered
heterocycloalkyl)-Ci.4 alkyl- of Rp are each optionally substituted with 1, 2 or 3 Rq
substituents,
or any two Ra substituents together with the nitrogen atom to which they are ed
form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted
with 1, 2 or 3 R11 substituents independently selected from C16 alkyl, Ci.6 haloalkyl, C340
cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-
Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-6 membered heteroaryl)-Ci—4 alkyl-, (4-7
membered cycloalkyl)-Ci—4 alkyl-, Ci.6 haloalkoxy, C2—6 alkenyl, C2.6 l, halo, CN,
0R1, SR1, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi,
)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi,
NRiC(=NOH)NRiRi, NRiC(=NCN)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri,
NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C16 alkyl, Ci—6 haloalkyl, C340 cycloalkyl, 4-7
membered cycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-6 membered heteroaryl)-Ci-4 , (4-7 membered
heterocycloalkyl)-Ci.4 alkyl- of R11 are each optionally substituted by l, 2, or 3 Rj substituents
independently selected from C14 alkyl, C3.6 cycloalkyl, C640 aryl, 5- or 6-membered
heteroaryl, 4-6 membered heterocycloalkyl, C2—4 alkenyl, C2.4 alkynyl, halo, Ci.4 haloalkyl,
Ci-4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)0Rk, OC(O)Rk,
OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk,
NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and
S(O)2NRkRk= wherein the C14 alkyl, C3-6 cycloalkyl, C640 aryl, 5- or 6-membered heteroaryl,
4-6 membered heterocycloalkyl, C2—4 alkenyl, C2—4 alkynyl, Ci.4 haloalkyl, and Ci-4haloalkoxy
of Rj are each optionally substituted with l, 2 or 3 Rq tuents,
or two Rh groups attached to the same carbon atom of the 4- to lO-membered
heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C36
cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring s
selected from O, N or S,
each Ri or Rk is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl,
C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ri or Rk are each optionally tuted with 1-3 independently selected Rp substituents,
or any two RC substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Re substituents together with the nitrogen atom to which they are ed
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rg substituents together with the nitrogen atom to which they are ed
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh tuents,
or any two Ri substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered cycloalkyl group ally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rk substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two R0 substituents together with the en atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rr tuents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh tuents,
each R0 or Rr is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C3-6
cycloalkyl, C640 aryl, 4-6 membered heterocycloalkyl, 5 or ered heteroaryl, Ci—4
kyl, C2—4 alkenyl, and C24 alkynyl, wherein the C14 alkyl, Ci—6 haloalkyl, C36
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C2—4
alkenyl, and C24 alkynyl of R1, Rk, R0 or Rr are each optionally substituted with l, 2 or 3 Rq
substituents,
each Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-6 haloalkyl,
C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hio, phenyl, 5-6 membered heteroaryl, 4-6
membered heterocycloalkyl, C3-6 cycloalkyl, NHR12 and NR12R12, wherein the C1-6 alkyl,
phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq
are each optionally substituted with halo, OH, CN, -COOH, NH2, Ci—4 alkoxy, Ci-4 haloalkyl,
Ci.4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered
heterocycloalkyl and each R12 is independently C1-6 alkyl,
I is a single bond or a double bond to maintain ring A being ic, and
the subscript n is an integer of 1, 2, 3 or 4.
In some embodiments, ed herein is a compound of Formula (I), or a
ceutically acceptable salt or a stereoisomer f, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is O, S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously
Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered
heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 substituents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-10 cycloalkyl, C3—
cycloalkyl-Ci—4 alkyl-, C6-10 aryl, C6-10 aryl-Ci-4 alkyl-, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci—4 alkyl-, C2—4 alkenyl, C2.4 alkynyl, halo, CN, 0R1“, Ci.4 haloalkyl, Ci—4
haloalkoxy, NH2, -NHR10, -NR10R10, , C(O)R1°, C(0)NR10R10, 1°,
OC(O)R1°, OC(O)NR10R1°, O)R10, NR1°C(O)OR1°, NR1°C(O)NR1°R10, C(=NR10)R1°,
C(=NR10)NR10R10, =NR10)NR10R10, NR108(O)R10, NR1°S(O)2R1°,
O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10
is independently selected from H, C14 alkyl, C2—4 alkenyl, C2—4 alkynyl, Ci—4 alkoxy, C340
cycloalkyl, C340 cycloalkyl-Ci—4 alkyl-, C640 aryl, C640 aryl-Ci-4 alkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-
membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C14 alkyl, C2—4 alkenyl, C2—4 alkynyl,
C1-4 alkoxy, C340 cycloalkyl, C340 cycloalkyl-Ci-4 alkyl-, C640 aryl, C640 aryl-Ci-4 alkyl-, 5-10
ed heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-Ci-4
alkyl-, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl- of R1, R2, R3 and R10 are each
optionally substituted with l, 2 or 3 independently selected Rd substituents,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C16 alkyl, C2—6
alkenyl, C2—6 l, Ci.6 haloalkyl, Ci.6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 i—4 , C340
lkyl-Ci—4 alkyl-, (5-14 membered aryl)-Ci—4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa,
OC(O)R"‘, RaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa,
C(=NRa)Ra, )NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa,
NRaC(=NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa,
a, and RaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-14 ed heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered
heterocycloalkyl)-Ci.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with l,
2, 3, 4 or 5 Rb tuents,
or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl
ring, a fused 5- or 6-membered heteroaryl ring or a fused C3.6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered
heteroaryl ring and fused C3.6 cycloalkyl ring are each optionally substituted with l, 2 or 3
independently selected Rb substituents,
or two R5 substituents ed to the same carbon atom, taken together with the
carbon atom to which they are attached, form a C36 cycloalkyl ring or 4-, 5-, 6- or 7-
membered heterocycloalkyl ring, wherein the C36 cycloalkyl ring and 4-, 5-, 6- or 7-
membered heterocycloalkyl ring are each optionally substituted with l, 2 or 3 independently
selected Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 l, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640
aryl, C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-14 membered heteroaryl)-Ci—4 alkyl-, (4-10
membered heterocycloalkyl)—Ci-4 alkyl-, CN, N02, OR“, SR“, NH2, NHR“, NRHR“,
NHOR“, C(O)R11, C(O)NR11R“, C(O)OR11, OC(O)R11, OC(O)NR11R11, O)R11,
O)OR11,NR11C(O)NR11R11, C(=NR11)R11, C(=NR11)NR11R11,
NR11C(=NR11)NR11R11,NR11C(=N0H)NR11R11, NR“C(=NCN)NR“R“, NR“S(O)R“,
NR“S(O)2R11, )2NR11R“, S(O)R“, S(O)NR11R“, S(O)2R“, or S(O)2NR“R11,
wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640 aryl,
C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4
alkyl-, C340 cycloalkyl-Ci-4 , (5-14 membered heteroaryl)-Ci-4 alkyl- and (4-10
membered heterocycloalkyl)—Ci—4 alkyl- of R9 are each optionally substituted with 1, 2 or 3 Rb
substituents,
each R11 is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci—4 alkyl-, (5-10
ed heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)—Ci-4 alkyl- of R11
are each optionally tuted with 1, 2 or 3 Rb substituents,
each Ra is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 , (5-10 membered
aryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
ed heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)—Ci—4 alkyl- of
, (5-10
Ra are each optionally substituted with 1, 2 or 3 Rd substituents,
each Rb tuent is independently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci—
6haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)—Ci-4 alkyl-, CN, OH, NH2, N02,
NHORC, ORG, SRC, C(O)RC, C(O)NRCRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, C(=NRC)NRCRC,
NRCC(=NRC)NRCRC, NRCC(=NOH)NRCRC, NRCC(=NCN)NRCRC, NHRC, NRCRC, )RC,
)ORC, NRCC(O)NRCRC, )RC, NRCS(O)2RC, )2NRCRC, S(O)RC,
S(O)NRCRC, S(O)2RC and S(O)2NRCRC, wherein the C16 alkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy,
C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl-and (4-
membered heterocycloalkyl)-Ci-4 alkyl- of Rb are each further optionally substituted with
1-3 independently selected Rd substituents,
each RC is ndently ed from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci—6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 membered
aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
RC are each optionally substituted with 1, 2 or 3 Rf substituents ndently selected from
C1-6 alkyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C2-6 l, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg,
OC(O)Rg, RgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,
C(=NRg)NRgRg, NRgC(=NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg,
S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg, wherein the C1-6
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-
, (5-10
of Rf are each optionally substituted with 1, 2 or 3 R11 substituents independently selected
from C1—6 alkyl, Ci.6 haloalkyl, halo, CN, phenyl, C3.6 cycloalkyl, 5-6 membered heteroaryl,
4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, C(O)R°, C(O)NR°R°, C(O)OR°,
OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, NR°C(O)OR°,
C(=NR°)NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°,
NR°S(O)2NR°R°, and S(O)2NR°R°, wherein the C16 alkyl, Ci-6 haloalkyl, phenyl, C3—6
cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered cycloalkyl of R11 is optionally
substituted with 1, 2 or 3 Rq substituents,
each Rd is independently selected from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10
membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, NH2, NHORe, ORG, SR6, C(O)Re, C(O)NReRe, C(O)ORe,
OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe,
C(=NRe)NReRe, NReC(=NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re,
S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl,
Ci—6 haloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of RC1 are each
optionally substituted with 1-3 independently selected Rf substituents,
each R6 is independently selected from H, C1—6 alkyl, Ci—6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 ed
cycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci.4 , (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Re are each optionally substituted with l, 2 or 3 independently ed Rf substituents,
each Rg is independently ed from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
cycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10
ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10
ed heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are
each optionally substituted with 1-3 Rp tuents independently selected from C16 alkyl,
Ci-6 kyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr,
OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, )Rr, NRrC(O)NRrRr, NRrC(O)ORr,
C(=NRr)NRrRr, NRrC(=NRr)NRrRr, NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr,
rRr, S(O)2Rr, NRrS(O)2Rr, )2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl,
C1-6haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 ed heteroaryl)-Ci-4 alkyl- and (4-10 membered
heterocycloalkyl)-Ci.4 alkyl- of Rp are each optionally substituted with 1, 2 or 3 Rq
substituents,
or any two Ra substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, 7-, 8-, 9- or bered cycloalkyl group ally substituted
with 1, 2 or 3 R11 substituents independently selected from C16 alkyl, Ci.6 kyl, C340
cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-
Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-6 membered heteroaryl)-Ci—4 alkyl-, (4-7
ed heterocycloalkyl)-Ci—4 alkyl-, Ci.6 koxy, C2—6 alkenyl, C2—6 alkynyl, halo, CN,
0R1, SR1, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi,
NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, )NRiRi, NRiC(=NRi)NRiRi,
NRiC(=NOH)NRiRi, NRiC(=NCN)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri,
NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7
membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-6 membered heteroaryl)-Ci-4 alkyl-, (4-7 membered
heterocycloalkyl)-Ci.4 alkyl- of R11 are each optionally substituted by l, 2, or 3 Rj substituents
independently selected from C1—4 alkyl, C3.6 cycloalkyl, C640 aryl, 5- or 6-membered
heteroaryl, 4-6 ed heterocycloalkyl, C2—4 alkenyl, C2.4 alkynyl, halo, Ci.4 haloalkyl,
Ci—4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)0Rk, OC(O)Rk,
OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(0)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk,
NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, )2Rk, NRkS(O)2NRkRk, and
S(O)2NRkRk= wherein the C14 alkyl, C3-6 cycloalkyl, C640 aryl, 5- or 6-membered heteroaryl,
4-6 membered heterocycloalkyl, C2—4 alkenyl, C2—4 alkynyl, Ci.4 haloalkyl, and Ci-4haloalkoxy
of Rj are each optionally substituted with l, 2 or 3 Rq substituents,
or two Rh groups attached to the same carbon atom of the 4- to 10-membered
heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C36
cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members
selected from O, N or S,
each Ri or Rk is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl,
C2—6 l, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
aryl)-Ci—4 , and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ri or Rk are each optionally substituted with 1-3 independently selected Rp substituents,
or any two RC substituents together with the nitrogen atom to which they are ed
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with l, 2, or 3
independently selected Rh substituents,
or any two Re substituents er with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with l, 2, or 3
independently selected Rh substituents,
or any two Rg substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Ri substituents together with the nitrogen atom to which they are ed
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rk tuents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
ndently selected Rh substituents,
or any two R0 substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rr substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
each R0 or Rr is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C3-6
cycloalkyl, C640 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, Ci—4
haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein the C14 alkyl, Ci.6 kyl, C3—6
cycloalkyl, C640 aryl, 4-6 membered cycloalkyl, 5 or ered heteroaryl, C2—4
alkenyl, and C24 alkynyl of R0 or Rr are each optionally substituted with l, 2 or 3 Rq
substituents,
each Rq is independently selected from OH, CN, -COOH, NH2, halo, Ci.6 haloalkyl,
C1—6 alkyl, Ci—6 , Ci.6 haloalkoxy, Ci.6 alkylthio, , 5-6 membered heteroaryl, 4-6
membered heterocycloalkyl, C3—6 cycloalkyl, NHR12 and NR12R12, wherein the C16 alkyl,
phenyl, C3-6 lkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq
are each optionally substituted with halo, OH, CN, -COOH, NH2, Ci—4 alkoxy, Ci-4 haloalkyl,
Ci.4 haloalkoxy, phenyl, C340 cycloalkyl, 5-6 ed heteroaryl and 4-6 membered
heterocycloalkyl and each R12 is independently C16 alkyl,
I is a single bond or a double bond to maintain ring A being aromatic; and
the subscript n is an integer of 1, 2, 3 or 4.
In some embodiments, provided herein is a compound of Formula (I), or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is O, S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not aneously
Cy is C640 aryl, C340 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered
heterocycloalkyl, each of which is optionally tuted with l to 5 independently selected
R8 substituents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C340 lkyl, C3—
cycloalkyl-Ci—4 alkyl-, C640 aryl, C640 aryl-Ci-4 alkyl-, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, (5-10 ed heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci—4 , C2—4 alkenyl, C2.4 alkynyl, halo, CN, 0R1“, Ci.4 haloalkyl, Ci—4
koxy, NH2, , -NR10R10, NHORlO, C(O)R1°, C(0)NR10R10, C(O)OR1°,
OC(O)R10, OC(O)NR1°R10, NR1°C(O)R10, NR10C(O)OR1°, NR10C(O)NR1°R10, C(=NR10)R1°,
C(=NR10)NR10R10, NR10C(=NR10)NR10R10, NR108(O)R10, NR1°S(O)2R1°,
NRIOS(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10
is independently selected from H, C1—4 alkyl, C2—4 alkenyl, C2—4 l, Ci—4 alkoxy, C340
cycloalkyl, C340 cycloalkyl-Ci—4 alkyl-, C640 aryl, C640 aryl-Ci-4 alkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-
membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C14 alkyl, C2—4 alkenyl, C2—4 alkynyl,
C1-4 alkoxy, C340 cycloalkyl, C340 lkyl-Ci-4 alkyl-, C640 aryl, C640 aryl-Ci-4 alkyl-, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-Ci-4
alkyl-, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl- of R1, R2, R3 and R10 are each
optionally substituted with l, 2 or 3 independently ed Rd substituents,
R4, R5, R6, R7 and R8 are each independently ed from H, halo, C16 alkyl, C2—6
alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci.6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa,
OC(O)R"‘, OC(O)NRaRa, NHRa, NRaRa, )Ra, NRaC(O)ORa, NRaC(O)NRaRa,
C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa,
NRaC(=NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa,
S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 l, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 lkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 , and (4-10 ed
cycloalkyl)-Ci.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with l,
2, 3, 4 or 5 Rb substituents,
or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl
ring, a fused 5- or 6-membered heteroaryl ring or a fused C3.6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered aryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or ered
heteroaryl ring and fused C3.6 cycloalkyl ring are each optionally substituted with l, 2 or 3
independently selected Rb substituents,
or two R5 substituents attached to the same carbon atom, taken together with the
carbon atom to which they are attached, form a C36 cycloalkyl ring or 4-, 5-, 6- or 7-
membered heterocycloalkyl ring, wherein the C36 cycloalkyl ring and 4-, 5-, 6- or 7-
membered heterocycloalkyl ring are each optionally substituted with l, 2 or 3 independently
selected Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6 haloalkyl, Ci-6 koxy, C640
aryl, C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-14 membered heteroaryl)-Ci—4 alkyl-, (4-10
membered heterocycloalkyl)-Ci-4 , CN, N02, OR“, SR“, NH2, NHR“, NRHR“,
NHOR“, C(O)R11, C(O)NR11R“, C(O)OR“, OC(O)R“, OC(O)NR11R11, O)R11,
NR11C(O)OR11,NR11C(O)NR11R11, C(=NR11)R11, C(=NR11)NR11R11,
NR11C(=NR11)NR11R11, NR“C(=NOH)NR11R11, NR“C(=NCN)NR“R“, NR“S(O)R“,
NR“S(O)2R11, NR“S(O)2NR11R“, S(O)R“, S(O)NR11R“, S(O)2R“, or S(O)2NR“R11,
wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640 aryl,
C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4
alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl- and (4-10
membered heterocycloalkyl)-Ci-4 alkyl- of R9 are each optionally substituted with 1, 2 or 3 Rb
substituents,
each R11 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-10 membered
aryl)-Ci-4 alkyl-, and (4-10 membered cycloalkyl)-Ci-4 , wherein the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 , (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered cycloalkyl)-Ci-4 alkyl- of R11
are each optionally substituted with l, 2 or 3 Rb substituents,
each Ra is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci-4 , wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ra are each optionally substituted with l, 2 or 3 Rd substituents,
each Rb substituent is ndently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci—
lkoxy, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, (4-10 membered cycloalkyl)-Ci-4 alkyl-, CN, OH, NH2, N02,
NHORC, ORG, SRC, C(O)RC, C(O)NRCRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, C(=NRC)NRCRC,
NRCC(=NRC)NRCRC, NRCC(=NOH)NRCRC, NCN)NRCRC, NHRC, NRCRC, )RC,
NRCC(O)ORC, NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC,
S(O)NRCRC, S(O)2RC and S(O)2NRCRC, wherein the C16 alkyl, Ci-6 haloalkyl, Ci.6 koxy,
C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed heterocycloalkyl, C6-
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl-and (4-
membered heterocycloalkyl)-Ci-4 alkyl- of Rb are each further optionally substituted with
1-3 independently selected Rd substituents,
each RC is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 ed
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
RC are each optionally substituted with l, 2 or 3 Rf substituents independently selected from
C1-6 alkyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered aryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg,
OC(O)Rg, RgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,
C(=NRg)NRgRg, NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg,
S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, )2NRgRg, and S(O)2NRgRg, wherein the C1-6
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci—4 alkyl-
, (5-10
of Rf are each optionally substituted with l, 2 or 3 R11 substituents independently ed
from C1—6 alkyl, Ci.6 haloalkyl, halo, CN, phenyl, C3.6 cycloalkyl, 5-6 membered heteroaryl,
4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, , C(O)NR°R°, C(O)OR°,
OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, NR°C(O)OR°,
C(=NR°)NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°,
NR°S(O)2NR°R°, and S(O)2NR°R°, wherein the C16 alkyl, Ci-6 haloalkyl, phenyl, C3—6
cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R11 is optionally
substituted with l, 2 or 3 Rq substituents,
each Rd is independently selected from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10
membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-10 ed heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 , CN, NH2, NHORe, ORG, SR6, C(O)Re, eRe, C(O)ORe,
e, ReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe,
C(=NRe)NReRe, NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re,
S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl,
Ci—6 haloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered cycloalkyl)-Ci-4 alkyl- of RC1 are each
optionally substituted with 1-3 independently selected Rf substituents,
each R6 is independently ed from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 cycloalkyl, 5-10 membered
aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci—4 alkyl- and (4-10 membered heterocycloalkyl)—Ci—4 alkyl- of
, (5-10
Re are each optionally substituted with 1, 2 or 3 ndently selected Rf tuents,
each Rg is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 l, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
aryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci—4 alkyl-, (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are
each optionally substituted with 1-3 Rp substituents independently selected from C1—6 alkyl,
C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 , (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr,
OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr,
C(=NRr)NRrRr, NRrC(=NRr)NRrRr, NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, ,
S(O)NRrRr, S(O)2Rr, )2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl,
C1-6 haloalkyl, C1-6 koxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl- and (4-10 membered
heterocycloalkyl)-Ci.4 alkyl- of Rp are each optionally tuted with 1, 2 or 3 Rq
substituents,
or any two Ra substituents er with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted
with 1, 2 or 3 R11 tuents independently selected from C16 alkyl, Ci.6 haloalkyl, C340
cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-
Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-6 membered heteroaryl)-Ci—4 alkyl-, (4-7
membered cycloalkyl)-Ci—4 alkyl-, Ci.6 haloalkoxy, C2—6 alkenyl, C2—6 alkynyl, halo, CN,
0R1, SR1, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi,
)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRi)NRiRi,
NRiC(=NOH)NRiRi, NCN)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri,
NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C16 alkyl, Ci.6 kyl, C340 cycloalkyl, 4-7
membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci—4 alkyl-, (5-6 membered aryl)-Ci—4 alkyl-, (4-7 membered
heterocycloalkyl)-Ci.4 alkyl- of R11 are each optionally substituted by l, 2, or 3 Rj substituents
independently selected from C1—4 alkyl, C3.6 cycloalkyl, C640 aryl, 5- or 6-membered
aryl, 4-6 membered heterocycloalkyl, C2—4 l, C2.4 alkynyl, halo, Ci.4 haloalkyl,
Ci.4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(0)NRkRk, C(O)0Rk, k,
OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk,
NRkC(=NRk)NRkRk, S(O)Rk, S(0)NRkRk, S(O)2Rk, )2Rk, NRkS(O)2NRkRk, and
S(O)2NRkRk= wherein the C14 alkyl, C3-6 cycloalkyl, C640 aryl, 5- or 6-membered heteroaryl,
4-6 membered heterocycloalkyl, C2—4 alkenyl, C2—4 alkynyl, Ci.4 haloalkyl, and Ci-4haloalkoxy
of Rj are each optionally substituted with l, 2 or 3 Rq substituents,
or two Rh groups attached to the same carbon atom of the 4- to 10-membered
heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C36
cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members
selected from O, N or S,
each Ri or Rk is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 l,
C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 ed heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ri or Rk are each optionally substituted with 1-3 independently selected Rp substituents,
or any two RC tuents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Re substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rg substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered cycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Ri substituents together with the en atom to which they are attached
form a 4-, 5-, 6-, or 7-membered cycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents, or 1, 2, or 3 independently ed Rq substituents,
or any two Rk substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or ered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents, or 1, 2, or 3 independently selected Rq substituents,
or any two R0 substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh tuents, or 1, 2, or 3 independently selected Rq substituents,
or any two Rr substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
ndently selected Rh substituents, or 1, 2, or 3 independently selected Rq substituents,
each R0 or Rr is independently ed from H, C1-6 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, Ci—4
haloalkyl, C2—4 alkenyl, and C24 alkynyl, n the C14 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or ered heteroaryl, C2—4
alkenyl, and C24 alkynyl of R0 or Rr are each optionally substituted with l, 2 or 3 Rq
substituents,
each Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-6 haloalkyl,
C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6
membered heterocycloalkyl, C3-6 cycloalkyl, NHR12 and NR12R12, wherein the C1-6 alkyl,
phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 ed heteroaryl of Rq
are each optionally substituted with halo, OH, CN, -COOH, NH2, Ci—4 alkoxy, Ci-4 haloalkyl,
Ci.4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered
cycloalkyl and each R12 is independently C1-6 alkyl,
m is a single bond or a double bond to maintain ring A being aromatic; and
the subscript n is an integer of 1, 2, 3 or 4.
In some embodiments, provided herein is a compound of Formula (I), or a
ceutically acceptable salt or a stereoisomer thereof, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is O, S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously
Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to bered heteroaryl, or 4- to lO-membered
heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 substituents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-6 cycloalkyl, C2—4
alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, Ci.4 koxy, NH2, -NH-
C1-4 alkyl, -N(C1-4 alkyl)2, NHORlO, C(O)R1°, C(O)NR1°R1°, 10, OC(O)R10,
0C(0)NR10R10, NR10C(O)R10, NR10C(0)0R10, NR10C(0)NR10R10, C(=NR10)R10,
C(=NR10)NR10R10, NR10C(=NR10)NR10R10, NR1°S(O)R1°, NR1°S(O)2R1°,
NRIOS(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10
is independently selected from H and C14 alkyl ally substituted with l or 2 groups
independently selected from halo, OH, CN and C14 alkoxy, and wherein the C14 alkyl, C3-6
cycloalkyl, C2—4 l, C2—4 alkynyl and C14 alkoxy of R1, R2 and R3 are each optionally
substituted with l or 2 tuents independently selected from halo, OH, CN and C14
alkoxy,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci—4 alkyl-, C3-10
cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa,
OC(O)Ra, RaRa, NHRa, NRaRa, )Ra, )ORa, NRaC(O)NRaRa,
C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa,
NRaC(=NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa,
S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10
cycloalkyl, 5-14 membered heteroaryl, 4-10 ed heterocycloalkyl, C6-10 aryl-C1—4 alkyl-
C3—io cycloalkyl-C1-4 , (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C1.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with l,
2, 3, 4 or 5 Rb substituents,
or two adjacent R8 substituents on the Cy ring, taken er with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl
ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered
heteroaryl ring and fused C3-6 lkyl ring are each optionally substituted with l, 2 or 3
independently selected Rb substituents,
or two R5 substituents attached to the same carbon atom, taken together with the
carbon atom to which they are attached, form a C3-6 cycloalkyl ring or 4-, 5-, 6- or 7-
membered heterocycloalkyl ring, wherein the C3-6 cycloalkyl ring and 4-, 5-, 6- or 7-
membered heterocycloalkyl ring are each ally substituted with l, 2 or 3 independently
ed Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10
aryl, C3—io cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10
aryl-C1—4 alkyl-, C3-10 lkyl-C1.4 alkyl-, (5-14 membered heteroaryl)-C1—4 alkyl-, (4-10
membered cycloalkyl)-C1-4 alkyl-, CN, N02, OR“, SR“, NH2, NHR“, NRHR“,
NHOR“, C(O)R“, C(O)NR“R“, C(O)OR“, OC(O)R“, OC(O)NR“R11, NR11C(O)R11,
NR11C(O)OR11,NR11C(O)NR11R11, C(=NR11)R11, C(=NR11)NR11R11,
NR11C(=NR11)NR11R11,NR11C(=N0H)NR11R11, NR11C(=NCN)NR11R11, NR“S(O)R11,
NR“S(O)2R11, NR“S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, or R11R11,
wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl,
C3-1o cycloalkyl, 5-14 membered heteroaryl, 4-10 membered cycloalkyl, C6-10 i—4
alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10
membered heterocycloalkyl)-C1-4 alkyl- of R9 are each optionally substituted with 1, 2 or 3 Rb
substituents,
each R11 is ndently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of R11
are each optionally substituted with l, 2 or 3 Rb substituents,
each Ra is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
l, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 i—4 , C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ra are each optionally substituted with l, 2 or 3 Rd substituents,
each Rb substituent is independently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci—
6haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, CN, OH, NH2, N02,
NHORC, ORG, SRC, C(O)RC, C(O)NRCRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, C(=NRC)NRCRC,
NRCC(=NRC)NRCRC, NRCC(=NOH)NRCRC, NRCC(=NCN)NRCRC, NHRC, NRCRC, NRCC(O)RC,
NRCC(O)ORC, NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC,
S(O)NRCRC, C and S(O)2NRCRC, wherein the C16 alkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy,
C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl-and (4-
10 ed heterocycloalkyl)-Ci-4 alkyl- of Rb are each further optionally tuted with
1-3 independently selected Rd substituents,
each RC is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10 ed
cycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
aryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
RC are each ally substituted with l, 2 or 3 Rf tuents independently selected from
C16 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)0Rg,
OC(O)Rg, RgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,
)NRgRg, NRgC(=NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg,
S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg, wherein the C1-6
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci—4 alkyl-
, (5-10
of Rf are each ally substituted with l, 2 or 3 R11 substituents independently selected
from C1—6 alkyl, Ci—6 haloalkyl, halo, CN, , C3—6 cycloalkyl, 5-6 membered aryl,
4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, C(O)R°, C(O)NR°R°, C(O)OR°,
OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, NR°C(O)OR°,
C(=NR°)NR°R°, NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°,
NR°S(O)2NR°R°, and S(O)2NR°R°, wherein the C16 alkyl, Ci-6 haloalkyl, , C3—6
cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R11 is optionally
substituted with l, 2 or 3 Rq substituents,
each Rd is independently ed from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10
membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 lkyl-Ci—4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, NH2, NHORe, ORG, SR6, C(O)Re, C(O)NReRe, C(O)ORe,
OC(O)Re, ReRe, NHRe, NReRe, NReC(O)Re, )NReRe, NReC(O)ORe,
C(=NRe)NReRe, NReC(=NRe)NReRe, NOH)NReRe, NReC(=NCN)NReRe, S(O)Re,
S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl,
Ci—6 haloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of RC1 are each
ally substituted with 1-3 independently ed Rf substituents,
each R6 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci—6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 ed heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Re are each ally substituted with l, 2 or 3 independently selected Rf substituents,
each Rg is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-10 ed
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, n the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are
each optionally substituted with 1-3 Rp substituents independently selected from C16 alkyl,
Ci—6 haloalkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed
heteroaryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)—Ci.4 alkyl-, halo,
, (5-10
CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, r, OC(O)Rr, OC(O)NRrRr, NHRr,
NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, )NRrRr, NRrC(=NRr)NRrRr,
NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr,
NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10 ed
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci—4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of Rp is optionally
substituted with l, 2 or 3 Rq substituents,
or any two Ra substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted
with 1, 2 or 3 R11 substituents ndently ed from C16 alkyl, Ci.6 haloalkyl, C340
cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C340
cycloalkyl-Ci-4 alkyl-, (5-6 membered heteroaryl)-Ci-4 alkyl-, (4-7 membered
heterocycloalkyl)-Ci—4 alkyl-, Ci.6 haloalkyl, C2—6 alkenyl, C2.6 alkynyl, halo, CN, 0R1, SR1,
NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri,
NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, NRiC(=NOH)NRiRi,
NRiC(=NCN)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and
S(O)2NRiRi, wherein the C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7 membered
heterocycloalkyl, C640 aryl, 5-6 ed heteroaryl, C340 cycloalkyl-Ci—4 alkyl-, (5-6
membered aryl)-Ci—4 alkyl-, (4-7 membered heterocycloalkyl)-Ci—4 alkyl- of R11 are each
optionally tuted by l, 2, or 3 Rj substituents independently selected from C14 alkyl, C3-6
cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, C2—4 alkenyl, C2.4 alkynyl, halo, Ci—4
haloalkyl, Ci.4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(0)NRkRk, C(O)0Rk,
OC(O)Rk, RkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(0)NRkRk, )0Rk,
C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(0)NRkRk, S(O)2Rk, NRkS(O)2Rk,
NRkS(O)2NRkRk, and S(O)2NRkRk,
or two Rh groups attached to the same carbon atom of the 4- to 10-membered
heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C3-6
lkyl or 4- to 6-membered cycloalkyl having 1-2 heteroatoms as ring members
selected from O, N or S,
or any two RC substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh tuents,
or any two Re substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or ered heterocycloalkyl group optionally substituted with l, 2, or 3
independently ed Rh substituents,
or any two Rg substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or ered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Ri substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered cycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rk substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two R0 substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered cycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rr substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with l, 2, or 3
independently selected Rh substituents,
each R1, Rk, R0 or Rr is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, Ci—4
haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein the C14 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C2—4
l, and C24 alkynyl of R1, Rk, R0 or Rr are each optionally substituted with l, 2 or 3 Rq
substituents,
each Rq is ndently selected from OH, CN, -COOH, NH2, halo, C1-6 haloalkyl,
C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hio, phenyl, 5-6 membered heteroaryl, 4-6
membered heterocycloalkyl, C3-6 cycloalkyl, NHR12 and NR12R12, n the C1-6 alkyl,
phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq
are each optionally substituted with halo, OH, CN, -COOH, NH2, Ci—4 alkoxy, Ci-4 haloalkyl,
Ci.4 haloalkoxy, phenyl, C3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R12 is
independently C1-6 alkyl,
I is a single bond or a double bond to maintain ring A being aromatic, and
the subscript n is an integer of 1, 2, 3 or 4.
In some embodiments, provided herein is a compound of Formula (I), or a
pharmaceutically able salt or a stereoisomer thereof, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is O, S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously
Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered
heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 tuents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-6 cycloalkyl, C2—4
alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 , Ci.4 haloalkyl, Ci.4 haloalkoxy, NH2, -NH-
C1-4 alkyl, -N(C1-4 alkyl)2, NHORIO, C(O)R10, C(O)NR1°R1°, C(O)OR1°, OC(O)R1°,
OC(O)NR1°R1°, NR1°C(O)R1°, O)OR1°, NR10C(0)NR10R10, C(=NR10)R10,
C(=NR10)NR10R10, NR10C(=NR10)NR10R10, NR108(O)R10, NR1°S(O)2R1°,
NRIOS(O)2NR10R10, 0, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10
is independently selected from H and C14 alkyl optionally tuted with l or 2 groups
independently selected from halo, OH, CN and C14 alkoxy, and wherein the C14 alkyl, C3-6
lkyl, C2—4 alkenyl, C2—4 alkynyl and C14 alkoxy of R1, R2 and R3 are each optionally
substituted with l or 2 substituents independently selected from halo, OH, CN and C14
alkoxy,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C16 alkyl, C2—6
alkenyl, C2—6 l, Ci.6 haloalkyl, Ci.6 haloalkoxy, C640 aryl, C340 lkyl, 5-14
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa,
OC(O)R"‘, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa,
C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa,
NRaC(=NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa,
S(O)2Ra, and S(O)2NRaRa, n the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340
cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, and (4-10 ed
heterocycloalkyl)-Ci.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with l,
2, 3, 4 or 5 Rb substituents,
or two adjacent R8 substituents on the Cy ring, taken er with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl
ring, a fused 5- or 6-membered heteroaryl ring or a fused C3.6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring
each have 1-4 heteroatoms as ring s selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered
heteroaryl ring and fused C3.6 cycloalkyl ring are each optionally substituted with l, 2 or 3
independently selected Rb substituents,
or two R5 substituents attached to the same carbon atom, taken together with the
carbon atom to which they are attached, form a C36 cycloalkyl ring or 4-, 5-, 6- or 7-
membered heterocycloalkyl ring, n the C36 cycloalkyl ring and 4-, 5-, 6- or 7-
membered heterocycloalkyl ring are each optionally substituted with l, 2 or 3 independently
selected Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 l, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640
aryl, C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-14 membered aryl)-Ci—4 alkyl-, (4-10
membered cycloalkyl)-Ci-4 alkyl-, CN, N02, OR“, SR“, NH2, NHR“, NRHR“,
NHOR“, , C(O)NR“R“, C(O)OR“, OC(O)R“, OC(O)NR11R11, NR11C(O)R“,
NR11C(O)OR11,NR11C(O)NR11R11, C(=NR11)R11, 1)NR11R11,
NR11C(=NR11)NR11R11, NR“C(=NOH)NR11R11, NR“C(=NCN)NR“R“, NR“S(O)R“,
NR“S(O)2R11, NR“S(O)2NR11R“, S(O)R“, S(O)NR11R“, S(O)2R“, or S(O)2NR“R11,
wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640 aryl,
C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered cycloalkyl, C640 aryl-Ci—4
alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl- and (4-10
ed heterocycloalkyl)-Ci-4 alkyl- of R9 are each ally substituted with 1, 2 or 3 Rb
substituents,
each R11 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
l, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci—4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-, wherein the C16
alkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10
membered cycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci—4 alkyl-, (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of R11
are each optionally substituted with l, 2 or 3 Rb substituents,
each Ra is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 l, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 , and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci—6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
Ra are each optionally substituted with l, 2 or 3 Rd substituents,
each Rb substituent is independently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci—
6haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, CN, OH, NH2, N02,
NHORC, ORG, SRC, C(O)RC, C(O)NRCRC, C(O)ORC, OC(O)RC, RCRC, C(=NRC)NRCRC,
NRCC(=NRC)NRCRC, NRCC(=NOH)NRCRC, NRCC(=NCN)NRCRC, NHRC, NRCRC, NRCC(O)RC,
NRCC(O)ORC, NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC,
S(O)NRCRC, S(O)2RC and S(O)2NRCRC, wherein the C16 alkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy,
C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 , (5-10 membered heteroaryl)-Ci—4 alkyl-and (4-
membered heterocycloalkyl)-Ci-4 alkyl- of Rb are each further ally substituted with
1-3 independently selected Rd substituents,
each RC is independently ed from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
cycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 , wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of
, (5-10
RC are each optionally substituted with l, 2 or 3 Rf substituents independently ed from
C1-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340
cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 , halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg,
OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg,
C(=NRg)NRgRg, NRgC(=NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg,
S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, )2NRgRg, and S(O)2NRgRg, wherein the C1-6
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-
, (5-10
of Rf are each ally substituted with l, 2 or 3 R11 substituents independently selected
from C1—6 alkyl, Ci.6 haloalkyl, halo, CN, , C3.6 cycloalkyl, 5-6 ed heteroaryl,
4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, C(O)R°, C(O)NR°R°, C(O)OR°,
OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, )R°, NR°C(O)NR°R°, NR°C(O)OR°,
C(=NR°)NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°,
NR°S(O)2NR°R°, and S(O)2NR°R°, wherein the C16 alkyl, Ci-6 haloalkyl, phenyl, C3—6
cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R11 is optionally
substituted with l, 2 or 3 Rq substituents,
each Rd is independently selected from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10
membered aryl, C340 cycloalkyl, 4-10 membered cycloalkyl, C640 aryl-Ci—4 alkyl-
C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered
heterocycloalkyl)-Ci.4 alkyl-, CN, NH2, NHORe, ORG, SR6, , eRe, C(O)ORe,
OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe,
C(=NRe)NReRe, NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re,
eRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl,
Ci—6 haloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of RC1 are each
optionally substituted with 1-3 independently selected Rf substituents,
each R6 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 , and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 lkyl, 5-10 membered
aryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci—4 alkyl- and (4-10 membered heterocycloalkyl)—Ci—4 alkyl- of
, (5-10
Re are each optionally substituted with 1, 2 or 3 independently selected Rf substituents,
each Rg is ndently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16
alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10
membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10
membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are
each optionally substituted with 1-3 Rp substituents ndently ed from C16 alkyl,
Ci—6 kyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-
membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)—Ci.4 alkyl-, halo,
, (5-10
CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)0Rr, OC(O)Rr, OC(O)NRrRr, NHRr,
NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(=NRr)NRrRr, NRrC(=NRr)NRrRr,
NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr,
NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 alkyl- and (4-10 membered cycloalkyl)-Ci-4 alkyl- of Rp is optionally
substituted with 1, 2 or 3 Rq tuents,
or any two Ra tuents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, 7-, 8-, 9- or bered heterocycloalkyl group ally substituted
with 1, 2 or 3 R11 substituents ndently selected from C16 alkyl, Ci.6 haloalkyl, C340
cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C340
cycloalkyl-Ci-4 alkyl-, (5-6 ed heteroaryl)-Ci-4 alkyl-, (4-7 membered
heterocycloalkyl)-Ci—4 alkyl-, Ci.6 haloalkyl, C2—6 alkenyl, C2.6 alkynyl, halo, CN, 0R1, SR1,
NHORi, C(O)Ri, iRi, C(O)ORi, i, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri,
NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, NOH)NRiRi,
NRiC(=NCN)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and
S(O)2NRiRi, wherein the C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7 membered
heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C340 cycloalkyl-Ci—4 alkyl-, (5-6
membered heteroaryl)-Ci-4 , (4-7 membered heterocycloalkyl)-Ci.4 alkyl- of R11 are each
optionally substituted by l, 2, or 3 Rj substituents ndently ed from C14 alkyl, C3—6
cycloalkyl, C640 aryl, 5- or 6-membered aryl, C2—4 alkenyl, C2—4 l, halo, Ci—4
haloalkyl, loalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(0)NRkRk, C(O)0Rk,
OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk,
C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(0)NRkRk, S(O)2Rk, NRkS(O)2Rk,
NRkS(O)2NRkRk, and S(O)2NRkRk,
or two Rh groups attached to the same carbon atom of the 4- to lO-membered
heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C3-6
cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members
selected from O, N or S,
or any two RC substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
ndently selected Rh substituents,
or any two Re substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Rg substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents,
or any two Ri substituents together with the en atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents, or 1, 2, or 3 independently selected Rq substituents,
or any two Rk substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered cycloalkyl group optionally substituted with l, 2, or 3
independently selected Rh substituents, or 1, 2, or 3 independently selected Rq substituents,
or any two R0 substituents together with the nitrogen atom to which they are attached
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with l, 2, or 3
independently ed Rh substituents, or 1, 2, or 3 independently selected Rq substituents,
or any two Rr substituents together with the nitrogen atom to which they are ed
form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3
ndently selected Rh substituents, or 1, 2, or 3 independently selected Rq substituents,
each R1, Rk, R0 or Rr is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered aryl, Ci—4
haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein the C14 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C2—4
alkenyl, and C24 alkynyl of R1, Rk, R0 or Rr are each optionally substituted with l, 2 or 3 Rq
substituents,
each Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-6 haloalkyl,
C1-6 alkyl, C1-6 alkoxy, C1-6 koxy, C1-6 alkylthio, phenyl, 5-6 membered aryl, 4-6
membered heterocycloalkyl, C3-6 cycloalkyl, NHR12 and NR12R12, wherein the C1-6 alkyl,
phenyl, C3-6 lkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq
are each ally substituted with halo, OH, CN, -COOH, NH2, Ci—4 , Ci-4 haloalkyl,
Ci—4 haloalkoxy, phenyl, C3—io cycloalkyl and 4-6 membered heterocycloalkyl and each R12 is
independently C1-6 alkyl,
: is a single bond or a double bond to maintain ring A being aromatic, and
the subscript n is an integer of 1, 2, 3 or 4.
In some embodiments, provided herein is a compound having Formula (II):
/Y1/—G\1G2
R1 R3
R2 (II)
or a pharmaceutically acceptable salt or a stereoisomer thereof.
In some embodiments, provided herein is a compound having Formula (111):
(1,21%:#5“? (111)
or a pharmaceutically acceptable salt or a stereoisomer thereof.
In some ments, provided herein is a compound having Formula (IV):
R9 N/N G
Cy “Mam
O R4
R1 R3
R2 (IV)
or a pharmaceutically able salt or a stereoisomer thereof.
In some embodiments, provided herein is a compound having Formula (V):
if}:«$2
or a pharmaceutically acceptable salt or a stereoisomer thereof.
In some embodiments, provided herein is a compound having Formula (VI):
N’NFGCG
Cy <R5>n
R1 Rim/MA
R2 (VI)
or a pharmaceutically able salt or a stereoisomer thereof.
In some embodiments, provided herein is a compound having Formula (VII):
R9 N //<'
Cy “WNileh
R1 R3
R2 (VII)
or a pharmaceutically acceptable salt or a stereoisomer thereof.
In some embodiments, R1, R2 and R3 are each ndently selected from H, C14
alkyl, C3-6 cycloalkyl, C2—4 alkenyl, C2—4 alkynyl, halo, CN, OH, Ci—4 alkoxy, Ci—4 haloalkyl, Ci—
4haloalkoxy, NH2, -4 alkyl, -N(Ci-4 alkyl)2, C(O)R10, C(O)NR10R10, C(O)OR10,
OC(O)R10, R1°R1°, NR10C(O)R1°, NR10C(O)OR10, NRIOS(O)R10, NRIOS(O)2R10,
NRIOS(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10
is independently selected from H and C14 alkyl optionally substituted with l or 2 groups
independently selected from halo, OH, CN and C14 alkoxy, and wherein the C14 alkyl, C3-6
lkyl, C2—4 alkenyl, C2—4 alkynyl and C14 alkoxy of R1, R2 and R3 are each optionally
substituted with l or 2 substituents independently selected from halo, OH, CN and C14
alkoxy.
In some embodiments, R1, R2 and R3 are each independently selected from H, C14
alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, Ci—
4 haloalkoxy, NH2, -NH-Ci-4 alkyl, and 4 alkyl)2.
In some embodiments, R1, R2 and R3 are each ndently ed from H, C14
alkyl, C2—4 alkenyl, C2—4 l, halo, CN, OH, Ci—4 alkoxy, Ci—4 haloalkyl, or 04 haloalkoxy.
In some embodiments, R1 is H, R2 is H or halo, and R3 is H.
In some embodiments, R1, R2, and R3 are H.
In some embodiments, Cy is phenyl, 5- or ered heteroaryl, C3-6 cycloalkyl or
- or 6-membered heterocycloalkyl, each of which is optionally substituted with l to 5
independently selected R8 substituents, or two adjacent R8 substituents on the Cy ring, taken
together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or
7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-6
cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or
6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O
and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring,
fused 5- or ered heteroaryl ring and fused C3-6 cycloalkyl ring are each optionally
substituted with l, 2 or 3 independently selected Rb substituents.
In some embodiments, Cy is phenyl ally substituted with l to 5 R8 substituents.
In some embodiments, Cy is 5- or 6-membered heteroaryl optionally substituted with l to 5
independently selected R8 substituents. In some embodiments, Cy is C3-6 cycloalkyl
optionally substituted with l to 5 ndently selected R8 substituents. In some
embodiments, Cy is 5- or 6-membered heterocycloalkyl optionally substituted with l to 5
independently selected R8 substituents.
In some ments, Cy is phenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 3,6-dihydro-2H-pyranyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-l,4-
benzodioxinyl, l,3-benzodioxinyl, ylindazolyl or l-methylindazolyl, each
of which is optionally substituted with l to 5 R8 substituents.
In some embodiments, R9 is halo, C1-6 alkyl, C2-6 l, C2-6 alkynyl, C1-6 kyl,
Cm haloalkoxy, CN, N02, OR“, SR“, NH2, NHR11,NR“R11, NHOR“, C(O)R11,
C(O)NR“R“, C(O)OR“, OC(O)R“, OC(O)NR“R“, NR11C(O)R11, NR11C(O)OR“,
NR“C(O)NR11R“, NR11S(O)R“, NR“S(O)2R11, NR11S(O)2NR11R11, S(O)R“,
S(O)NR“R11, S(O)2R11, or S(O)2NR11R“, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, and C1-6 haloalkoxy of R9 are each optionally substituted with l, 2 or 3 Rb
substituents.
In some embodiments, R9 is halo, C1-6 alkyl, C2-6 l, C2-6 alkynyl, C1-6 haloalkyl,
C1-6 haloalkoxy, CN, N02, or NH2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, and C1-6 haloalkoxy of R9 are each optionally tuted with l, 2 or 3 Rb
substituents.
In some embodiments, R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,
C1-6 koxy, CN, N02, and NH2.
In some embodiments, R9 is halo, C1-6 alkyl, or CN.
In some embodiments, R9 is CH3, CN or halo. In some embodiments, R9 is CH3. In
other embodiments, R9 is CN. Yet in certain embodiments, R9 is halo such as F, C1 or Br.
In some embodiments, Z is S, CR4, NR4, or N and R4 is independently H or C1-6 alkyl.
In some embodiments, Z is S, CH, NCH3 or N. In certain embodiments, Z is S. In other
embodiments, Z is CH. In some embodiments, Z is N(C1-6 alkyl) such as NCH3. Yet in other
embodiments, Z is N.
In some embodiments, Y1 is C or N and Y2 is C.
In some embodiments, Y1 is C and Y2 is N.
N—/—’Y{ f.' A ‘\
LxZ/yY2 (R5)n
In some embodiments, the moiety: is ed from:
The moiety:
can be XL
N—"\\ A A N
x \ (R5 ,I XV )n
[7"2 (R5)n
The moiety: can be R4
,—G1 G1
\ / \
/—G1 2
Nr—Yl GZ l A
:A‘x\ 2A / <R5>n
LxZ/yY (Ron
The moiety: can be R4
In some ments, (i) Y1 is N, Y2 is C and Z is N, (ii) Y1 is N, Y2 is C and Z is
CR4, (iii) Y1 is C, Y2 is N and Z is N, (iv) Y1 is C, Y2 is N and Z is CR4, (V) Y1 is C, Y2 is C
andZ is S, or (Vi) Y1 is C, Y2 is C andZ is O.
In some embodiments, Y1 is N, Y2 is C and Z is N. In certain embodiments, Y1 is N,
Y2 is C and Z is CR4. In certain ments, Y1 is C, Y2 is N and Z is N. In some
embodiments, Y1 is C, Y2 is N and Z is CR4. In some embodiments, Y1 is C, Y2 is C and Z is
S. Yet in some embodiments, Y1 is C, Y2 is C and Z is O.
In some embodiments, R5 is H.
In some embodiments, G1 is NR6 and G2 is CR7R7. In some ments, G1 is
CRGR6 and G2 is NR7. In some embodiments, R6 is H or C1-6 alkyl optionally substituted with
1, 2 or 3 Rb substituents. In some embodiments, R7 is H or C1-6 alkyl ally substituted
with 1, 2 or 3 Rb tuents.
In some embodiments, Rb substituent is independently selected from halo, C1-6 alkyl,
01.6 haloalkyl, 01.6 haloalkoxy, CN, OH, NH2, N02, NHORC, ORG, SRC, C(O)RC, C(O)NRCRC,
C(O)ORC, OC(O)RC, OC(O)NRCRC, NHRC, NRCRC, NRCC(O)RC, NRCC(O)ORC,
NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)Rc, S(O)NRCRC, S(O)2RC
and S(O)2NRCRC, wherein the C1-6 alkyl, C1-6 haloalkyl, and C1-6 haloalkoxy of Rb are each
further ally substituted with 1-3 independently selected Rd substituents.
In some embodiments, Rb substituent is independently selected from halo, C1-6 alkyl,
C1-6 haloalkyl, C1-6 haloalkoxy, CN, OH, NH2, N02, ORG, SRC, C(O)RC, C(O)NRCRC,
C, NHRC, NRCRC, and NRCC(O)RC, n the C1-6 alkyl, C1-6 haloalkyl, and C1-6
haloalkoxy of Rb are each further optionally substituted with 1-3 independently selected Rd
substituents.
In some ments, Rb substituent is independently selected from halo, C1-6 alkyl,
C1-6 haloalkyl, C1-6 haloalkoxy, CN, OH, NH2, ORG, C(O)RC, C(O)NRCRC, and C.
In some embodiments, Rb substituent is independently selected from C1-6 alkyl, CN,
OH, and C(O)ORC. In certain embodiments, Rb is C1-6 alkyl such as methyl. In certain
embodiments, Rb is CN. In other embodiments, Rb is OH. In some embodiments, Rb is
C(O)ORC such as C(O)OH or C(O)O(C1-6 alkyl).
In some embodiments, ed herein is a compound of Formula I, or a
pharmaceutically acceptable salt or a stereoisomer f, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is O, S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously
Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered
cycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 substituents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-6 cycloalkyl, C2—4
alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, Ci.4 haloalkoxy, NH2, -NH-
C1-4 alkyl, -N(C1-4 alkyl)2, C(O)R1°, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10,
NR10C(O)R10, O)OR10, NR1°S(O)R10, NR1°S(O)2R10, NR108(O)2NR10R10, S(O)R1°,
S(O)NR1°R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently selected from
H and C14 alkyl optionally substituted with l or 2 groups independently selected from halo,
OH, CN and C14 alkoxy, and wherein the C14 alkyl, C3-6 cycloalkyl, C2—4 alkenyl, C2—4 alkynyl
and C14 alkoxy of R1, R2 and R3 are each optionally substituted with l or 2 tuents
independently selected from halo, OH, CN and C14 alkoxy,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, ORa, SRa, C(O)Ra,
C(0)NRaRa, "‘, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, )Ra, NRaC(O)ORa,
NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NR"‘R"‘,
wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R4, R5, R6, R7 and R8 are each
optionally substituted with l, 2, 3, 4 or 5 Rb tuents,
or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered cycloalkyl
ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered
heteroaryl ring and fused C3-6 cycloalkyl ring are each optionally substituted with l, 2 or 3
independently selected Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN,
N02, OR“, SR“, NH2,NHR11,NR11R11, NHOR“, C(O)R11, C(0)NR11R11, C(O)OR“,
OC(O)R“, OC(O)NR“R“,NR“C(O)R11,NR“C(O)OR“,NR11C(O)NR“R11,NR“S(O)R11,
NR“S(O)2R11, )2NR11R“, S(0)R11, S(O)NR11R“, S(O)2R“, or S(O)2NR“R11,
wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 haloalkoxy of R9 are
each optionally substituted with l, 2 or 3 Rb substituents,
each R11 is independently ed from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and
C2-6 alkynyl,
each Ra is independently selected from H, C1-6 alkyl, C1-6 kyl, C2-6 alkenyl, and
C2-6 alkynyl,
each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, Ci—
shaloalkoxy, CN, OH, NH2, N02, NHORC, ORG, SR9, C(O)RC, C(O)NRCRC, C(O)ORC,
OC(O)RC, OC(O)NRCRC, NHRC, NRCRC, NRCC(O)RC, NRCC(O)ORC, NRCC(O)NRCRC,
NRCS(O)RC, NRCS(O)2RC, )2NRCRC, S(O)RC, S(O)NRCRC, S(O)2RC and S(O)2NRCRC,
wherein the C1-6 alkyl, C1-6 haloalkyl, and C1-6 haloalkoxy of Rb are each further optionally
tuted with 1-3 independently selected Rd substituents,
each RC is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 l, and
C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of RC are
each optionally tuted with l, 2 or 3 Rf tuents independently selected from C1-6
alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg,
C(O)0Rg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg,
)ORg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and
S(O)2NRgRg,
each Rd is independently selected from C16 alkyl, Ci.6 kyl, halo, CN, NH2, ORG,
SR6, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re,
)NReRe, NReC(O)ORe, S(O)Re, S(0)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe,
and S(O)2NReRe,
each R6 is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 , (5-10 membered
heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-,
each Rg is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6
alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered
heteroaryl)-Ci-4 , and (4-10 membered heterocycloalkyl)-Ci—4 ,
: is a single bond or a double bond to maintain ring A being aromatic, and
the subscript n is an integer of 1, 2, 3 or 4.
In some embodiments, provided herein is a compound of Formula I, or a
pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, ed Y1 and Y2 are not simultaneously
Cy is C640 aryl, C340 cycloalkyl, 5- to l4-membered heteroaryl, or 4- to lO-membered
heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 substituents,
R1, R2 and R3 are each independently selected from H, C14 alkyl, C3.6 cycloalkyl, C2—4
l, C2.4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 kyl, Ci.4 haloalkoxy, NH2, -NH-
C1-4 alkyl, and -N(Ci-4 alkyl)2,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, ORa, SRa, C(O)Ra,
C(O)NRaRa, and C(O)ORa, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 l of R4, R5,
R6, R7 and R8 are each optionally tuted with l, 2, 3, 4 or 5 Rb substituents,
or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which
they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl
ring, a fused 5- or ered heteroaryl ring or a fused C3-6 cycloalkyl ring, wherein the
fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or ered heteroaryl ring
each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused
phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered
aryl ring and fused C3-6 cycloalkyl ring are each optionally substituted with l, 2 or 3
ndently selected Rb substituents,
R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN,
N02, or NH2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6
haloalkoxy of R9 are each optionally substituted with l, 2 or 3 Rb substituents,
each Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and
C2-6 alkynyl,
each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, Ci—
shaloalkoxy, CN, OH, NH2, N02, ORG, SRC, C(O)RC, C(0)NRCRC, C(O)ORC, NHRC, NRCRC,
and NRCC(O)RC, wherein the C1-6 alkyl, C1-6 haloalkyl, and C1-6 haloalkoxy of Rb are each
r optionally substituted with 1-3 ndently selected Rd substituents,
each RC is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and
C2-6 alkynyl,
each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, NH2, ORG,
SR6, C(O)Re, C(0)NReRe, C(0)0Re, NHRe, NReRe, and NReC(0)Re,
each R6 is independently ed from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and
C2-6 alkynyl,
I is a single bond or a double bond to maintain ring A being aromatic, and
the subscript n is an integer of 1 or 2.
In some embodiments, provided herein is a compound of Formula I, or a
pharmaceutically able salt or a stereoisomer thereof, wherein:
(i) G1 is NR6 and G2 is CR7R7, or
(ii) G1 is CRGR6 and G2 is NR7,
X1 is N or CR1,
X2 is N or CR2,
X3 is N or CR3,
Z is S, N, NR4 or CR4,
Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously
Cy is phenyl, C340 lkyl, 5- to l4-membered heteroaryl, or 4- to lO-membered
heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected
R8 substituents,
R1, R2 and R3 are each independently selected from H, 04 alkyl, C2—4 alkenyl, C2—4
alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, or Ci.4 haloalkoxy,
R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, ORa, and C(O)OR"‘, wherein
the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R4, R5, R6, R7 and R8 are each optionally
substituted with l or 2 Rb substituents,
or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which
they are attached, form a fused 5-, 6- or 7-membered cycloalkyl ring, or a fused 5- or
6-membered aryl ring, n the fused 5-, 6- or 7-membered heterocycloalkyl ring
and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members
ed from N, O and S and wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring
and fused 5- or 6-membered heteroaryl ring are each optionally substituted with l or 2
independently selected Rb tuents,
R9 is halo, C1-6 alkyl, or CN,
each Ra is independently ed from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and
C2-6 alkynyl,
each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1—
6haloalkoxy, CN, OH, NH2, ORG, C(O)RC, CRC, and C(O)ORC,
each RC is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and
C2-6 alkynyl,
: is a single bond or a double bond to maintain ring A being ic, and
the subscript n is an integer of 1 or 2.
In some embodiments, compounds of Formula (I) or any subformulas as disclosed
herein, when Cy is phenyl, R8 is not 4-aminopiperidin-l-yl, optionally substituted with 1-5
independently selected Rb substituents.
In some embodiments, compounds of Formula (I) or any subformulas as disclosed
herein, when Cy is phenyl, R8 is not —NHC(O)Ra, wherein Ra is 5- or 6-membered
heteroaryl, or 2-pyridonyl, each of which is optionally substituted with 1-5 independently
selected Rd substituents.
In some ments, compounds of Formula (I) or any subformulas as disclosed
, when Cy is phenyl, R8 is not (lO-membered bicyclic heteroaryl)-NH-, optionally
substituted with 1-5 independently selected Rd substituents.
It is further appreciated that certain es of the invention, which are, for clarity,
described in the context of separate ments, can also be provided in ation in a
single embodiment (while the embodiments are intended to be combined as if written in
multiply dependent form). Conversely, various features of the invention which are, for
brevity, described in the context of a single ment, can also be provided separately or
in any suitable subcombination. Thus, it is contemplated as features described as
embodiments of the nds of Formula (I) can be combined in any suitable combination.
At various places in the present specification, certain features of the compounds are
disclosed in groups or in ranges. It is specifically intended that such a disclosure include each
and every individual subcombination of the s of such groups and ranges. For
example, the term "Cl-6 alkyl" is specifically intended to individually disclose (without
limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
The term "n-membered," where n is an integer, typically describes the number of
ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example,
piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of
a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered aryl ring and
1,2,3,4-tetrahydro-naphthalene is an example of a bered cycloalkyl group.
At various places in the present specification, variables defining divalent linking
groups may be described. It is ically intended that each linking substituent include both
the forward and backward forms of the linking substituent. For example, -NR(CR'R")n-
includes both -NR(CR'R")n- and -(CR'R")nNR- and is intended to disclose each of the forms
individually. Where the structure requires a g group, the Markush variables listed for
that group are understood to be linking groups. For example, if the structure requires a
g group and the Markush group tion for that variable lists "alkyl" or "aryl" then it
is understood that the " or "aryl" ents a linking alkylene group or arylene group,
respectively.
The term "substituted" means that an atom or group of atoms formally replaces
hydrogen as a "substituent" attached to another group. The term "substituted", unless
otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or
penta-substitution, where such substitution is permitted. The substituents are independently
selected, and substitution may be at any chemically accessible position. It is to be understood
that tution at a given atom is limited by valency. It is to be understood that substitution
at a given atom results in a ally stable molecule. The phrase "optionally substituted"
means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is
removed and replaced by a tuent. A single divalent substituent, e.g., oxo, can replace
two hydrogen atoms.
The term "Cn-m" indicates a range which includes the endpoints, wherein n and m are
integers and indicate the number of carbons. Examples include Ci—4, C1-6 and the like.
The term "alkyl" employed alone or in combination with other terms, refers to a
saturated hydrocarbon group that may be ht-chained or branched. The term "Cn-m alkyl",
refers to an alkyl group having 11 to m carbon atoms. An alkyl group formally corresponds to
an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the
remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6
carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
es of alkyl es include, but are not limited to, chemical groups such as methyl,
ethyl, yl, isopropyl, n-butyl, tert—butyl, isobutyl, sec-butyl, higher homologs such as 2-
methyl-l-butyl, n-pentyl, 3-pentyl, n-hexyl, l,2,2-trimethylpropyl and the like.
The term "alkenyl" employed alone or in combination with other terms, refers to a
straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or
more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with
one C-H bond replaced by the point of attachment of the l group to the remainder of
the compound. The term "Cn-m alkenyl" refers to an alkenyl group having 11 to m carbons. In
some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
Example alkenyl groups e, but are not d to, ethenyl, n-propenyl, isopropenyl, nbutenyl
, sec-butenyl and the like.
The term "alkynyl" employed alone or in combination with other terms, refers to a
straight-chain or branched hydrocarbon group ponding to an alkyl group having one or
more triple carbon-carbon bonds. An l group formally corresponds to an alkyne with
one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the
compound. The term "Cn-m alkynyl" refers to an alkynyl group having 11 to m carbons.
Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propynyl
and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3
carbon atoms.
The term "alkylene", employed alone or in combination with other terms, refers to a
divalent alkyl linking group. An ne group ly corresponds to an alkane with two
C-H bond replaced by points of attachment of the alkylene group to the der of the
nd. The term "Cn-m alkylene" refers to an alkylene group having 11 to m carbon atoms.
Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, propan-l,3-diyl,
propan-l,2-diyl, butan-l,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-l,3-diyl and
the like.
The term "alkoxy", employed alone or in combination with other terms, refers to a
group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "Cn—m
alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Example
alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t—butoxy
and the like. In some embodiments, the alkyl group has 1 to 6, l to 4, or 1 to 3 carbon atoms.
The term "amino" refers to a group of formula —NH2.
The term "carbonyl", employed alone or in combination with other terms, refers to
a -C(=O)— group, which also may be written as C(O).
The term "cyano" or "nitrile" refers to a group of formula —CEN, which also may be
written as -CN.
The terms "halo" or en", used alone or in combination with other terms, refers
to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom
selected from F, C1, or Br. In some ments, halo groups are F.
The term "haloalkyl" as used herein refers to an alkyl group in which one or more of
the hydrogen atoms has been replaced by a halogen atom. The term "Cn-m haloalkyl" refers to
a Cn-m alkyl group having 11 to m carbon atoms and from at least one up to {2(n to m)+l}
halogen atoms, which may either be the same or different. In some embodiments, the halogen
atoms are fluoro atoms. In some ments, the haloalkyl group has 1 to 6 or 1 to 4 carbon
atoms. e haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHClz, C2Cls and the like.
In some embodiments, the haloalkyl group is a fluoroalkyl group.
The term lkoxy", employed alone or in ation with other terms, refers to
a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term
"Cn-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m
carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some
embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl
group when attached to carbon, or attached to a heteroatom g a sulfoxide or sulfone
group, or an N—oxide group. In some embodiments, heterocyclic groups may be optionally
substituted by 1 or 2 oxo (=0) substituents.
The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a
rbonyl group (C=S) when attached to carbon.
The term "aromatic" refers to a carbocycle or heterocycle having one or more
polyunsaturated rings having aromatic character (l'.e., having (4n + 2) delocalized 7: (pi)
electrons where n is an integer).
The term "aryl," employed alone or in combination with other terms, refers to an
aromatic hydrocarbon group, which may be clic or polycyclic (e. g. 2 fused
, having
rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms.
Aryl groups include, e.g., phenyl, naphthyl, and the like. In some embodiments, aryl groups
have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon
atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the
aryl group is phenyl. In some embodiments, the aryl group is naphthyl.
The term "heteroaryl" or "heteroaromatic," employed alone or in combination with
other terms, refers to a monocyclic or polycyclic ic heterocycle having at least one
heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments,
the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from
nitrogen, sulfur and oxygen. In some ments, any ring-forming N in a heteroaryl
moiety can be an N—oxide. In some embodiments, the heteroaryl has 5-14 ring atoms
including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected
from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-10 ring atoms
including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected
from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms
and 1 or 2 atom ring s independently selected from nitrogen, sulfur and
oxygen. In some embodiments, the heteroaryl is a five-membered or mbered
heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered
or ten-membered fused ic heteroaryl ring. Example aryl groups include, but are
not limited to, pyridinyl yl), dinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,
azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, inyl, isoquinolinyl,
naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and phthyridine),
indolyl, indazolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[l,2-b]thiazolyl,
purinyl, and the like.
A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein
one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
Exemplary f1ve-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl, lyl, azolyl, isoxazolyl, l,2,3-triazolyl, tetrazolyl, 1,2,3-
thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, l,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
triazolyl, l,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein
one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and
pyridazinyl.
The term "cycloalkyl," employed alone or in combination with other terms, refers to a
non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including
cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl that has
n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g.
having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or
7 ring-forming carbons (C34). In some ments, the cycloalkyl group has 3 to 6 ring
members, 3 to 5 ring members, or 3 to 4 ring members. In some ments, the cycloalkyl
group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic.
In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-
forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or
sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments,
cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or exyl. Also included in the
definition of cycloalkyl are moieties that have one or more aromatic rings fused (116., having
a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of
cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring
can be attached through any ring-forming atom ing a ring-forming atom of the fused
aromatic ring. Examples of cycloalkyl groups include ropyl, utyl, entyl,
cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, exadienyl, cycloheptatrienyl,
norbomyl, norpinyl, norcamyl, bicyclo[l.l.l]pentanyl, bicyclo[2. l. l]hexanyl, and the like. In
some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl.
The term "heterocycloalkyl," employed alone or in combination with other terms,
refers to a non-aromatic ring or ring system, which may optionally contain one or more
alkenylene groups as part of the ring structure, which has at least one heteroatom ring
member independently selected from en, sulfur oxygen and phosphorus, and which has
4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term
“heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups.
Heterocycloalkyl groups can include mono- or bicyclic (eg, having two fused or bridged
rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group
having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-
g carbon atoms and heteroatoms of a heterocycloalkyl group can be ally
oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or
S(O)2, N—oxide etc.) or a nitrogen atom can be ized. The heterocycloalkyl group can
be attached through a orming carbon atom or a orming heteroatom. In some
embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some
embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the
definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.€.,
having a bond in common with) to the heterocycloalkyl ring, 6. g., benzo or thienyl
derivatives of piperidine, line, azepine, etc. A heterocycloalkyl group ning a
fused aromatic ring can be attached through any ring-forming atom including a ring-forming
atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl,
azepanyl, dihydrobenzofuranyl, dihydrofuranyl, opyranyl, dihydrobenzodioxinyl,
benzodioxinyl, morpholino, 3-oxa—9-azaspiro[5.5]undecanyl, l-oxaazaspiro[4.5]decanyl,
piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydropyranyl, 4-tetrahydroquinolinyl, tropanyl, and
thiomorpholino.
At certain places, the definitions or embodiments refer to specific rings (e.g., an
azetidine ring, a pyridine ring, etc). Unless otherwise indicated, these rings can be attached
to any ring member provided that the valency of the atom is not exceeded. For example, an
azetidine ring may be attached at any position of the ring, whereas an azetidinyl ring is
ed at the 3-position.
The compounds described herein can be asymmetric (e. g. one or more
, having
stereocenters). All isomers, such as enantiomers and diastereomers, are intended unless
otherwise indicated. Compounds of the present invention that contain asymmetrically
substituted carbon atoms can be isolated in optically active or racemic forms. Methods on
how to e optically active forms from optically inactive starting materials are known in
the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many
geometric isomers of olefins, C=N double bonds and the like can also be present in the
compounds described herein, and all such stable isomers are contemplated in the present
invention. Cis and trans geometric isomers of the compounds of the present invention are
described and may be isolated as a mixture of isomers or as ted isomeric forms.
Resolution of racemic mixtures of compounds can be d out by any of numerous
methods known in the art. One method includes fractional recrystallization using a chiral
resolving acid which is an optically active, orming organic acid. le resolving
agents for fractional recrystallization methods are, e.g., optically active acids, such as the D
and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic
acid, lactic acid or the various optically active camphorsulfonic acids such as [3-
camphorsulfonic acid. Other resolving agents le for fractional crystallization methods
include stereoisomerically pure forms of oc-methylbenzylamine (e.g., S and R forms, or
diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-
methylephedrine, cyclohexylethylamine, aminocyclohexane and the like.
Resolution of racemic mixtures can also be d out by elution on a column packed
with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution
solvent composition can be determined by one skilled in the art.
In some embodiments, the nds of the invention have the (R)-conf1guration. In
other ments, the compounds have the (S)-conf1guration. In compounds with more
than one chiral centers, each of the chiral centers in the compound may be independently (R)
or (5), unless otherwise indicated.
Compounds of the invention also include tautomeric forms. Tautomeric forms result
from the swapping of a single bond with an adjacent double bond er with the
concomitant migration of a proton. Tautomeric forms include ropic tautomers which
are isomeric protonation states having the same empirical formula and total charge. e
prototropic tautomers include ketone — enol pairs, amide - imidic acid pairs, lactam — lactim
pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more
ons of aheterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-
triazole, 1H- and 2H- isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention can also include all isotopes of atoms occurring in the
intermediates or final compounds. es include those atoms having the same atomic
number but different mass numbers. For example, isotopes of en include tritium and
deuterium. One or more constituent atoms of the compounds of the invention can be replaced
or substituted with isotopes of the atoms in natural or non-natural nce. In some
embodiments, the compound includes at least one deuterium atom. For e, one or
more hydrogen atoms in a compound of the t disclosure can be replaced or substituted
by deuterium. In some embodiments, the compound includes two or more deuterium atoms.
In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium
atoms. Synthetic methods for including isotopes into c compounds are known in the
The term, "compound," as used herein is meant to include all stereoisomers,
geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant
to refer to compounds of the inventions, regardless of how they are prepared, e.g.,
synthetically, through biological s (e.g., metabolism or enzyme conversion), or a
combination thereof.
All compounds, and pharmaceutically able salts thereof, can be found together
with other substances such as water and solvents (e.g., hydrates and solvates) or can be
isolated. When in the solid state, the compounds described herein and salts thereof may occur
in various forms and may, 6. g. take the form of solvates, including hydrates. The compounds
may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated
otherwise, reference in the specification to compounds and salts thereof should be understood
as encompassing any solid state form of the compound.
In some embodiments, the compounds of the invention, or salts thereof, are
ntially isolated. By "substantially isolated" is meant that the compound is at least
lly or substantially ted from the environment in which it was formed or detected.
Partial separation can include, e.g., a composition ed in the compounds of the
invention. Substantial tion can include compositions containing at least about 50%, at
least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about
95%, at least about 97%, or at least about 99% by weight of the compounds of the invention,
or salt thereof.
The phrase aceutically acceptable" is employed herein to refer to those
compounds, materials, compositions and/or dosage forms which are, within the scope of
sound l nt, suitable for use in contact with the tissues of human beings and
s without ive toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
The expressions, "ambient ature" and "room temperature," as used herein, are
understood in the art, and refer generally to a temperature, e. g. a reaction temperature, that is
about the temperature of the room in which the reaction is carried out, e. g., a ature
from about 20 0C to about 30 0C.
The present invention also includes pharmaceutically acceptable salts of the
compounds described herein. The term "pharmaceutically acceptable salts" refers to
derivatives of the disclosed nds wherein the parent nd is modified by
converting an existing acid or base moiety to its salt form. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues
such as amines, alkali or organic salts of acidic es such as carboxylic acids, and the
like. The pharmaceutically acceptable salts of the present invention include the non-toxic
salts of the parent compound formed, e. g. from non-toxic inorganic or organic acids. The
pharmaceutically acceptable salts of the present invention can be synthesized from the parent
compound which contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or base forms of these
compounds with a stoichiometric amount of the appropriate base or acid in water or in an
organic solvent, or in a mixture of the two, generally, non-aqueous media like ether, ethyl
acetate, alcohols (e. g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are
preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th Ed,
(Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,
66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and
Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-
oxide forms.
11. Synthesis
Compounds of the invention, ing salts thereof, can be prepared using known
organic sis techniques and can be synthesized according to any of numerous possible
synthetic , such as those in the Schemes below.
The reactions for preparing nds of the invention can be carried out in suitable
solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable
solvents can be substantially non-reactive with the starting materials (reactants), the
intermediates or products at the atures at which the reactions are carried out, e. g.
temperatures which can range from the solvent's freezing temperature to the solvent's boiling
ature. A given on can be carried out in one t or a mixture of more than one
solvent. Depending on the particular reaction step, suitable solvents for a particular reaction
step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and
deprotection of various chemical groups. The need for protection and ection, and the
selection of riate protecting groups, can be readily determined by one skilled in the art.
The chemistry of protecting groups is bed, e. g., in Kocienski, Protecting ,
(Thieme, 2007), Robertson, Protecting Group Chemistry, (Oxford University Press, 2000),
Smith et al., March 's Advanced Organic Chemistry: Reactions, Mechanisms, and ure,
6th Ed. (Wiley, 2007), Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J.
Chem. Educ, 1997, , 1297, and Wuts et al., Protective Groups in Organic Synthesis,
4th Ed, (Wiley, 2006).
Reactions can be monitored according to any suitable method known in the art. For
example, product formation can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e. g., 1H or 13C), infrared spectroscopy, spectrophotometry
(e. g., UV-visible), mass spectrometry or by chromatographic methods such as high
performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
The Schemes below provide general guidance in connection with preparing the
compounds of the ion. One skilled in the art would tand that the preparations
shown in the Schemes can be modified or optimized using general knowledge of organic
chemistry to prepare various compounds of the invention.
Compounds of Formula (I) can be prepared, e. g., using a process as rated in
Schemes 1-3.
Compound of a 1-7 can be synthesized using a process shown in Scheme 1. A
palladium-catalyzed coupling reaction of halo-substituted aromatic amine 1-1 with a
suitable coupling reagent 1-2 (where M is, e. g., -B(OH)2) under standard conditions (such as
Suzuki coupling reaction, e. g. in the presence of a palladium catalyst and a suitable base)
can produce compound 1-3. The reaction of aromatic amine 1-3 with an acid of formula 1-4
using a coupling reagent such as, but not limited to, HATU can give the amide 1-5, which
can be deprotected under acidic conditions (6. g. acid or trifluoroacetic acid) to
, hydrochloric
provide the amine 1-6. The R7 group can be introduced either by direct alkylation with an
alkyl halide or reductive alkylation with an aldehyde or a ketone to give the desired t
of formula 1-7.
Scheme 1
N’Y1 NBOC
\Y2_)\
/—\
R9 R9 HO\n/l\CZ>/ (R )n
R9 N’YJ £309
HaIWNHz CyWNHZ H 2
CyM O C xY (R5)n
’ —> l [um/L
xl 2x3 1-2 x1 x3 1-4 x1 x3 o
x x2 x
1-1 1-3 1'5
H R9
deprotectlon-
R9 N’Yj reductive alkylation CYWNWKKH N61238—R7,Y (R5)n
CyW“W’YZJNRS)” ;
or N-alkylation l1 3
x1 2x3 0 X~x2X 0
1-6 1-7
Alternatively, compound of formula 2-7 can be synthesized using a process shown in
Scheme 2. The reaction of halo-substituted aromatic amine 2-1 with an ester of formula 2-2 in
the ce of a suitable base such as, but not limited to, potassium tert—butoxide or sodium
hydride can furnish the amide 2-3. The Boc protecting group in compound 2-3 can be removed
under acidic conditions (eg, hydrochloric acid or trifluoroacetic acid) to provide the free
amine of formula 2-4. The Cy ring can be installed by the cross-coupling of compound 2-4
With a suitable coupling reagent 2-5 (where M is, e.g., -B(OH)2) under standard conditions
(such as Suzuki coupling on, eg, in the ce of a palladium catalyst and a suitable
base) to give compound of formula 2-6. Finally, the R7 group can be introduced either by direct
tion with an alkyl halide or reductive alkylation with an aldehyde or a ketone to give the
desired t of formula 2-7.
Scheme 2
N’Y NBoc
R0 O/Y _I\(R5)n
Hal \ NH2
| o %2’NOY2_,\,Y (R5) Hal :XJHWKLZ/ZYNO? (R )n x1 x3
X2 2-2
2-1 2-3 24
N’YJ\NH N’Y‘1
C -My TKQY2 re ucuvead t' lkyalonI t'
(R5>n —. <RR5>n2
X1X2X3 or N—alkylation X, X2X3
2-6 2-7
Ester of a 3-3 can be synthesized using a s shown in Scheme 3. The free
amine group in compound 3-1 can be protected with Boc to give the nd of formula 3-
2. Compound 3-2 can be deprotonated by a strong base such as, but not limited to, n-butyl
lithium or lithium bis(trimethylsilyl)amide to generate the corresponding aryl lithium
intermediate, which can further react with a chloroformate or carbon dioxide to give the
desired ester or acid of formula 3-3.
Scheme3
N’Y1 ‘NH (BOC)2O,\rY1 NBoc carbonylation N/Y1NBoc
QYZ\(R5)n —’ QYZ\(Rbn
3-1 Rom/KO)”M2(R5)n
Compound of formula 4 can be synthesized in accordance with the synthetic protocols
set forth in Schemes 1-3, using the appropriate ng materials.
R9 N’Y\1
CyWNfl/YH 2—/\
(R5)n
1 3
x~X2x o
[1]. Uses offhe Compounds
Compounds of the present disclosure can inhibit the activity of PD-l/PD-Ll
protein/protein interaction and, thus, are useful in treating diseases and disorders associated
With activity of PD-l and the diseases and disorders associated with PD-Ll including its
interaction with other proteins such as PD-l and B7-1 (CD80). Advantageously, the
compounds of the present disclosure demonstrate better efficacy and favorable safety and
toxicity es in animal studies. In certain embodiments, the compounds of the present
disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, are useful for
therapeutic administration to enhance, stimulate and/or increase ty in cancer or
chronic infection, including enhancement of response to vaccination. In some ments,
the present disclosure es a method for inhibiting or blocking the PD-l/PD-Ll
protein/protein interaction. The method includes administering to an individual or a patient a
compound of a (I) or any of the formulas as described herein or of a compound as
recited in any of the claims and described , or a pharmaceutically acceptable salt or a
stereoisomer thereof. The compounds of the present disclosure can be used alone, in
combination with other agents or ies or as an adj uvant or neoadj uvant for the ent
of diseases or disorders, including cancer or infection diseases. For the uses described
herein, any of the compounds of the disclosure, including any of the embodiments thereof,
may be used.
The compounds of the present disclosure inhibit the PD-l/PD-Ll protein/protein
interaction, resulting in a PD-l pathway blockade. The blockade of PD-l can enhance the
immune se to cancerous cells and infectious diseases in mammals, including .
In some embodiments, the present disclosure provides treatment of an individual or a patient
in viva using a compound of Formula (I) or a salt or stereoisomer thereof such that growth of
cancerous tumors is inhibited. A nd of Formula (I) or of any of the formulas as
described herein, or a compound as recited in any of the claims and described herein, or a salt
or stereoisomer thereof, can be used to inhibit the growth of cancerous tumors. atively,
a compound of Formula (I) or of any of the formulas as described herein, or a compound as
recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be
used in conjunction with other agents or standard cancer treatments, as described below. In
one embodiment, the present disclosure provides a method for inhibiting growth of tumor
cells in vilro. The method includes contacting the tumor cells in vitro with a nd of
Formula (I) or of any of the formulas as described herein, or of a compound as recited in any
of the claims and described herein, or of a salt or stereoisomer thereof. In another
embodiment, the present sure provides a method for inhibiting growth of tumor cells in
an individual or a patient. The method includes administering to the individual or patient in
need thereof a therapeutically effective amount of a compound of Formula (I) or of any of the
formulas as described herein, or of a compound as d in any of the claims and described
herein, or a salt or a isomer thereof
In some embodiments, provided herein is a method for treating cancer. The method
includes administering to a patient in need thereof, a therapeutically effective amount of a
nd of Formula (I) or any of the formulas as described herein, a compound as recited
in any of the claims and described herein, or a salt thereof. Examples of cancers include
those whose growth may be inhibited using compounds of the disclosure and cancers
typically responsive to immunotherapy.
In some embodiments, the present disclosure provides a method of enhancing,
ating and/or increasing the immune response in a patient. The method includes
administering to the patient in need thereof a therapeutically effective amount of a compound
of Formula (I) or any of the formulas as described , a compound as recited in any of
the claims and described herein, or a salt thereof.
Examples of cancers that are ble using the compounds of the present disclosure
include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head
or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal
cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer,
carcinoma of the fallopian tubes, carcinoma of the trium, endometrial cancer,
carcinoma of the cervix, oma of the vagina, carcinoma of the vulva, Hodgkin's Disease,
non-Hodgkin's ma, cancer of the esophagus, cancer of the small intestine, cancer of
the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of
the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or
acute ias including acute myeloid leukemia, chronic myeloid leukemia, acute
blastic leukemia, chronic cytic leukemia, solid tumors of childhood,
lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of
the renal pelvis, neoplasm of the central s system (CNS), primary CNS lymphoma,
tumor angiogenesis, spinal axis tumor, brain stem , pituitary adenoma, Kaposi's
sarcoma, epidermoid cancer, squamous cell cancer, T -cell lymphoma, environmentally
induced cancers ing those induced by asbestos, and combinations of said cancers. The
compounds of the present disclosure are also useful for the treatment of metastatic cancers,
especially metastatic s that express PD-Ll.
In some embodiments, cancers treatable with compounds of the present sure
include melanoma (e.g., metastatic malignant melanoma), renal cancer (e. g. clear cell
carcinoma), te cancer (e. g. hormone refractory prostate adenocarcinoma), breast
cancer, colon cancer and lung cancer (e. g. non-small cell lung cancer). Additionally, the
sure includes refractory or recurrent malignancies whose growth may be inhibited
using the compounds of the disclosure.
ln some embodiments, cancers that are treatable using the compounds of the present
disclosure include, but are not limited to, solid tumors (e.g., prostate , colon cancer,
esophageal cancer, trial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic
cancer, pancreatic , gastric cancer, breast cancer, lung cancer, cancers of the head and
neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), logical cancers
(6. g. , lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous
leukemia (AML), chronic lymphocytic leukemia (CLL), c myelogenous leukemia
(CML), DLBCL, mantle cell lymphoma, dgkin ma (including relapsed or
refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and
combinations of said s.
PD—l pathway blockade with compounds oftlie present disclosure can also be used
for treating infections such as viral, bacteria, fungus and parasite infections. The t
disclosure provides a method for treating infections such as viral infections. The method
includes administering to a patient in need thereof, a therapeutically effective amount of a
compound of Formula (I) or any of the formulas as described herein, a compound as recited
in any of the claims and described herein, a salt thereof. Examples of viruses causing
infections ble by methods of the t disclosure include, but are not limit to, human
immunodeficiency virus, human omavirus, influenza, hepatitis A, B, C or D viruses,
adenovii'us, poxvirus, herpes simplex viruses, human cytoinegalrwinis, severe acute
respiratory syndrome virus, ebola virus, and measles Virus. In some ments, viruses
causing infections treatable by methods ot‘the present disclosure e, but are not limit to,
hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-l, HAV-6, HSV-II, and CMV, Epstein
Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus,
comovirus, respiratory syncytial virus, irus, rus, measles virus, rubella virus,
parvovirus, ia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus,
poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
The t disclosure provides a method for treating bacterial infections. The
method includes administering to a patient in need f, a therapeutically effective amount
of a compound of Formula (I) or any of the formulas as described herein, a compound as
recited in any of the claims and described herein, or a salt thereof. Non-limiting examples of
pathogenic bacteria causing infections treatable by methods of the disclosure include
chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci,
meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella,
diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and
Lyme's disease bacteria.
The present sure provides a method for ng fungus infections. The method
includes administering to a patient in need thereof, a therapeutically effective amount of a
nd of Formula (I) or any of the formulas as described , a compound as recited
in any of the claims and bed , or a salt thereof. Non-limiting examples of
pathogenic fungi causing ions ble by methods of the disclosure include a
(albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus
(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, hus), Sporothrix schenkii,
Blastomyces itidis, Paracoccidioides brasiliensis, Coccidioides immitis and
Histoplasma capsulatum.
The present disclosure provides a method for treating parasite ions. The method
includes administering to a patient in need thereof, a therapeutically effective amount of a
compound of Formula (I) or any of the formulas as described herein, a compound as recited
in any of the claims and described herein, or a salt thereof. Non-limiting examples of
pathogenic parasites causing infections treatable by methods of the disclosure include
Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia
lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, a microti,
Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and
Nippostrongylus brasiliensis.
The terms "individual" or "patient," used interchangeably, refer to any animal,
ing mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle,
sheep, horses, or primates, and most preferably humans.
The phrase "therapeutically effective amount" refers to the amount of active compound
or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system,
, individual or human that is being sought by a researcher, veterinarian, medical doctor
or other clinician.
As used herein, the term "treating" or "treatment" refers to one or more of (l)
inhibiting the disease, 6. g. a disease, condition or disorder in an individual who is
, inhibiting
experiencing or displaying the ogy or symptomatology of the disease, condition or
disorder (116., arresting further development of the pathology and/or symptomatology), and
(2) ameliorating the disease, eg, ameliorating a disease, condition or er in an
individual who is experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (116., reversing the pathology and/or symptomatology) such as
decreasing the severity of disease.
In some embodiments, the compounds of the invention are useful in preventing or
reducing the risk of developing any of the diseases referred to ; 6. g. or
, preventing
reducing the risk of developing a disease, condition or disorder in an individual who may be
predisposed to the disease, condition or disorder but does not yet experience or display the
pathology or symptomatology of the disease.
Combination Therapies
Cancer cell growth and survival can be impacted by multiple signaling pathways.
Thus, it is useful to combine different enzyme/protein/receptor inhibitors, exhibiting different
preferences in the targets which they modulate the ties of, to treat such conditions.
Targeting more than one signaling pathway (or more than one biological molecule involved
in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell
population, and/or reduce the toxicity of treatment.
The compounds of the present disclosure can be used in combination with one or
more other enzyme/protein/receptor tors for the ent of diseases, such as cancer or
infections. Examples of cancers include solid tumors and liquid , such as blood
cancers. Examples of ions include viral ions, bacterial infections, fungus
infections or parasite infections. For example, the compounds of the present disclosure can
be combined with one or more inhibitors of the ing s for the treatment of :
Aktl, Akt2, Akt3, TGF-BR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK,
ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-lR, IR-R, PDGFocR,
, CSFIR, KIT, ,KDR/FLK-1, FLK-4, flt-1,FGFR1,FGFR2, FGFR3,
FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,VEGF1UFlt2, Flt4, EphAl, EphA2,
EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK
and B-Raf. In some embodiments, the compounds of the present disclosure can be
combined with one or more of the following inhibitors for the treatment of cancer or
infections. Non-limiting examples of inhibitors that can be combined with the compounds of
the present disclosure for treatment of cancer and infections include an FGFR inhibitor
(FGFRl, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and 904), a
JAK inhibitor (JAKl and/or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO
inhibitor (e.g., epacadostat and ), an LSDl inhibitor (e.g., INCB59872 and
INCB60003), a TDO inhibitor, a PI3K-delta tor (e.g., INCB50797 and INCB50465), a
PI3K-gamma inhibitor such as a PI3K-gamma selective inhibitor, a Pim inhibitor, a CSFlR
inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis inhibitor,
an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for
e, omain tors or BET inhibitors such as INCB54329 and INCB57643)
and an ine or antagonist or combinations thereof.
Compounds of the present disclosure can be used in combination with one or more
immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors
against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73,
CD47, 0X40, GITR, CSFlR, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also
known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA,
PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a
stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR and
CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint
molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1,
TIM3, and VISTA. In some embodiments, the compounds provided herein can be used in
combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIRI
inhibitors, CD160 inhibitors, 2B4 tors and TGFR beta inhibitors.
In some embodiments, the inhibitor of an immune checkpoint molecule is D1
antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of PD-1, e.g., an D-l monoclonal antibody. In some embodiments, the D-l
monoclonal dy is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab,
SHR—1210, PDR001, or AMP-224. In some embodiments, the anti-PD-l monoclonal
antibody is nivolumab or pembrolizumab. In some embodiments, the D1 antibody is
pembrolizumab. In some embodiments, the anti PD-1 antibody is SHR-1210.
In some embodiments, the inhibitor of an immune checkpoint le is an inhibitor
of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll
monoclonal antibody is EMS-935559, MEDI4736, MPDL3280A (also known as RG7446),
or MSB0010718C. In some embodiments, the D-Ll monoclonal antibody is
MPDL3280A or MEDI4736.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of CTLA-4, e.g., an anti-CTLA-4 antibody. In some ments, the anti-CTLA-4
antibody is ipilimumab.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is
BMS-986016 or LAG525.
In some embodiments, the tor of an immune checkpoint le is an inhibitor
of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is
TRX518 or MK-4l 66.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor
of 0X40, e.g., an anti-0X40 antibody or OX40L fusion protein. In some embodiments, the
anti-0X40 antibody is MEDIOS62. In some ments, the OX40L fusion protein is
MEDI63 83.
Compounds of the present sure can be used in combination With one or more
agents for the treatment of diseases such as cancer. In some embodiments, the agent is an
alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and
bendamustine. In some embodiments, the proteasome inhibitor is zomib. In some
embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the
immunomodulatory agent is domide (LEN) or pomalidomide (POM).
The compounds of the present disclosure can further be used in ation With
other methods of treating s, for example by chemotherapy, ation therapy, tumor-
targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of therapy
include cytokine treatment (e.g., interferons, GM-CSF, G—CSF, IL-2), CRS-207
immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, oncolytic
Virotherapy and immunomodulating small molecules, including thalidomide or JAKl/2
inhibitor and the like. The compounds can be administered in combination with one or more
ancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of:
abarelix, aldesleukin, zumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic
trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin,
bortezombi, bortezomib, busulfan enous, busulfan oral, calusterone, capecitabine,
carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,
cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,
daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,
doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, ustine,
ide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine,
fludarabine, racil, fulvestrant, gefitinib, abine, gemtuzumab ozogamicin,
goserelin acetate, histrelin acetate, ibritumomab an, idarubicin, ifosfamide, ib
mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole,
leucovorin, leuprolide e, levamisole, lomustine, meclorethamine, rol acetate,
melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,
mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel,
pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,
pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,
nib, streptozocin, nib, sunitinib maleate, tamoxifen, temozolomide, teniposide,
actone, thalidomide, thioguanine, pa, topotecan, fene, tositumomab,
trastuzumab, tretinoin, uracil d, valrubicin, stine, vincristine, vinorelbine,
vorinostat and zoledronate.
Other anti-cancer agent(s) include dy therapeutics such as trastuzumab
(Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-
lBB, antibodies to PD-l and PD-Ll, or antibodies to cytokines (IL-10, TGF-B, etc.).
Examples of dies to PD-l and/or PD-Ll that can be combined with compounds of the
present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus and
parasite infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A,
MEDI-4736 and SHR-lZlO.
The compounds of the present disclosure can further be used in combination with one
or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.
The compounds of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or salts f can be
combined with another immunogenic agent, such as cancerous cells, purified tumor antigens
(including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells
transfected with genes encoding immune stimulating cytokines. Non-limiting examples of
tumor vaccines that can be used include es of melanoma antigens, such as peptides of
gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to
express the ne GM-CSF.
The compounds of Formula (I) or any of the formulas as described herein, a
compound as recited in any of the claims and described herein, or salts thereof can be used in
combination with a vaccination protocol for the treatment of cancer. In some embodiments,
the tumor cells are uced to express GM-CSF. In some embodiments, tumor vaccines
e the proteins from viruses implicated in human cancers such as Human Papilloma
s (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some embodiments, the compounds of the present disclosure can be used in
combination with tumor specific n such as heat shock ns isolated from tumor
tissue itself. In some embodiments, the nds of a (I) or any of the formulas as
described herein, a compound as d in any of the claims and described herein, or salts
thereof can be combined with dendritic cells immunization to activate potent anti-tumor
responses.
The nds of the t disclosure can be used in combination with bispecific
macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to
tumor cells. The compounds of the present disclosure can also be ed with
macrocyclic es that activate host immune responsiveness.
The compounds of the present disclosure can be used in combination with bone
marrow transplant for the treatment of a variety of tumors of hematopoietic origin.
The compounds of Formula (I) or any of the formulas as described , a
compound as recited in any of the claims and described herein, or salts thereof can be used in
combination with vaccines, to stimulate the immune response to pathogens, toxins, and self
antigens. es of pathogens for which this therapeutic approach may be particularly
useful, include pathogens for which there is currently no effective vaccine, or ens for
which conventional vaccines are less than completely effective. These include, but are not
limited to, HIV, tis (A, B, & C), Influenza, Herpes, Giardia, a, Leishmania,
Staphylococcus aureus, Pseudomonas Aeruginosa.
Viruses causing infections treatable by methods of the present disclosure include, but
are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenevirus,
pexvirus, herpes simplex viruses, human gaievirus, severe acute respiratory syndrome
virus, ebola virus, measles virus, herpes virus (e.g., VZV, HSV-l, HAV-6, HSV-II, and
CMV, Epstein Barr , flaviviruses, echovirus, rhinovirus, coxsackie virus, comovirus,
respiratory syncytial virus, mumpsvirus, rotavirus, s virus, rubella virus, parvovirus,
vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,
rabies virus, JC virus and arboviral encephalitis virus.
Pathogenic bacteria causing infections treatable by methods of the disclosure include,
but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci,
streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia,
pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax,
plague, leptospirosis, and Lyme's disease ia.
Pathogenic fungi causing infections treatable by methods of the disclosure include,
but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), coccus
mans, Aspergillus atus, niger, etc.), Genus Mucorales (mucor, absidia,
rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis,
Coccidioides s and Histoplasma capsulatum.
Pathogenic parasites causing infections treatable by methods of the sure
e, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri,
Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium
vivaX, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,
Toxoplasma gondi, and Nippostrongylus brasiliensis.
When more than one pharmaceutical agent is administered to a patient, they can be
administered simultaneously, separately, sequentially, or in combination (6. g., for more than
two agents).
IV. Formulation, Dosage Forms inistration
When employed as pharmaceuticals, the nds of the present disclosure can be
administered in the form of pharmaceutical compositions. Thus the present disclosure
provides a composition comprising a compound of Formula (I) or any of the formulas as
described herein, a compound as d in any of the claims and described herein, or a
pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one
pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a
manner well known in the pharmaceutical art, and can be administered by a variety of routes,
ing upon whether local or systemic treatment is ted and upon the area to be
treated. Administration may be topical (including transdermal, mal, ophthalmic and to
mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (eg, by
inhalation or insufflation of powders or ls, including by nebulizer, intratracheal or
intranasal), oral or eral. Parenteral administration includes intravenous, intraarterial,
subcutaneous, intraperitoneal intramuscular or injection or infusion, or intracranial, e. g. ,
intrathecal or intraventricular, administration. Parenteral administration can be in the form of
a single bolus dose, or may be, eg, by a continuous perfusion pump. Pharmaceutical
compositions and formulations for topical administration may include transdermal s,
ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
tional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like
may be necessary or desirable.
This invention also includes pharmaceutical compositions which contain, as the
active ingredient, the compound of the present disclosure or a pharmaceutically acceptable
salt thereof, in combination with one or more pharmaceutically acceptable carriers or
excipients. In some embodiments, the composition is suitable for topical administration. In
making the compositions of the invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a carrier in the form of, e. g. a
capsule, sachet, paper, or other ner. When the excipient serves as a diluent, it can be a
solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active
ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges,
sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, ls (as a solid or in a
liquid medium), ointments containing, e.g., up to 10% by weight of the active compound,
soft and hard gelatin capsules, itories, sterile inj ectable solutions and e packaged
powders.
In preparing a formulation, the active compound can be milled to provide the
riate particle size prior to combining with the other ingredients. If the active
nd is substantially insoluble, it can be milled to a particle size of less than 200 mesh.
If the active compound is substantially water soluble, the particle size can be adjusted by
milling to provide a substantially uniform distribution in the formulation, eg, about 40
mesh.
The compounds of the invention may be milled using known milling ures such
as wet milling to obtain a particle size appropriate for tablet formation and for other
formulation types. Finely divided (nanoparticulate) preparations of the compounds of the
invention can be prepared by processes known in the art see, e.g.,
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, n, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl
cellulose. The formulations can additionally e: lubricating agents such as talc,
magnesium stearate and l oil, wetting agents, emulsifying and suspending agents,
preserving agents such as methyl- and propylhydroxy-benzoates, sweetening , and
flavoring agents. The compositions of the ion can be formulated so as to provide quick,
sustained or delayed release of the active ient after administration to the patient by
employing procedures known in the art.
In some embodiments, the ceutical composition ses silicified
microcrystalline cellulose (SMCC) and at least one compound described herein, or a
pharmaceutically acceptable salt thereof. In some ments, the fied
microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2%
silicon e W/W.
In some embodiments, the composition is a sustained release composition comprising
at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically acceptable carrier or excipient. In some embodiments, the
composition comprises at least one compound described herein, or a pharmaceutically
acceptable salt thereof, and at least one component selected from microcrystalline cellulose,
lactose drate, hydroxypropyl methylcellulose and polyethylene oxide. In some
embodiments, the composition comprises at least one compound described herein, or a
pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate
and hydroxypropyl methylcellulose. In some embodiments, the composition ses at
least one compound described herein, or a pharmaceutically acceptable salt thereof, and
rystalline cellulose, lactose monohydrate and polyethylene oxide. In some
embodiments, the composition further comprises magnesium te or n dioxide. In
some ments, the microcrystalline cellulose is Avicel PH102TM. In some embodiments,
the lactose monohydrate is Fast-flo 316““. In some embodiments, the hydroxypropyl
methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M
rTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., el K00LVTM).
In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox
WSR 1105““).
In some embodiments, a wet granulation process is used to produce the composition.
In some embodiments, a dry granulation process is used to produce the composition.
The compositions can be ated in a unit dosage form, each dosage containing
from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the
active ient. In some embodiments, each dosage contains about 10 mg of the active
ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient.
In some embodiments, each dosage contains about 25 mg of the active ient. The term
"unit dosage forms" refers to physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in association with a suitable
pharmaceutical excipient.
The components used to formulate the pharmaceutical compositions are of high
purity and are substantially free of potentially harmful contaminants (e.g., at least National
Food grade, generally at least analytical grade, and more typically at least pharmaceutical
grade). Particularly for human consumption, the composition is preferably manufactured or
ated under Good Manufacturing Practice standards as defined in the applicable
regulations of the US. Food and Drug Administration. For example, suitable formulations
may be sterile and/or substantially ic and/or in full compliance with all Good
Manufacturing Practice regulations of the US. Food and Drug Administration.
The active compound may be effective over a wide dosage range and is lly
administered in a therapeutically effective . It will be understood, however, that the
amount of the compound ly administered will usually be determined by a physician,
according to the relevant circumstances, including the ion to be treated, the chosen
route of administration, the actual compound administered, the age, , and response of
the individual patient, the severity of the patient's symptoms and the like.
The therapeutic dosage of a compound of the present invention can vary according to,
e. g., the particular use for which the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the nt of the prescribing
physician. The proportion or concentration of a compound of the invention in a
pharmaceutical composition can vary depending upon a number of factors including dosage,
chemical teristics (6. g. and the route of administration. For example,
, hydrophobicity),
the nds of the invention can be provided in an aqueous physiological buffer solution
ning about 0.1 to about 10% w/v of the compound for parenteral administration. Some
typical dose ranges are from about 1 pig/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight
per day. The dosage is likely to depend on such variables as the type and extent of
progression of the disease or disorder, the overall health status of the particular patient, the
relative biological efficacy of the nd selected, formulation of the excipient, and its
route of administration. Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
For preparing solid compositions such as tablets, the principal active ingredient is
mixed with a pharmaceutical excipient to form a solid preformulation composition
containing a homogeneous mixture of a compound of the present invention. When referring
to these preformulation compositions as homogeneous, the active ingredient is typically
dispersed evenly hout the ition so that the composition can be readily
subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This
solid preformulation is then subdivided into unit dosage forms of the type described above
ning from, e.g., about 0.1 to about 1000 mg of the active ingredient of the present
invention.
The s or pills of the present ion can be coated or otherwise compounded
to provide a dosage form affording the advantage of prolonged action. For example, the
tablet or pill can se an inner dosage and an outer dosage component, the latter being in
the form of an envelope over the former. The two components can be separated by an enteric
layer which serves to resist egration in the stomach and permit the inner component to
pass intact into the duodenum or to be delayed in release. A variety of materials can be used
for such enteric layers or coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose
acetate.
The liquid forms in which the compounds and compositions of the present invention
can be incorporated for administration orally or by injection include aqueous solutions,
suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and r
ceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic ts, or es thereof, and powders.
The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients
as described supra. In some embodiments, the compositions are administered by the oral or
nasal respiratory route for local or systemic effect. Compositions can be zed by use of
inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the
nebulizing device can be attached to a face mask, tent, or intermittent positive pressure
breathing e. Solution, suspension, or powder compositions can be administered orally
or nasally from devices which deliver the ation in an appropriate manner.
Topical formulations can contain one or more conventional carriers. In some
embodiments, ointments can contain water and one or more hydrophobic carriers selected
from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene , white Vaseline, and
the like. Carrier compositions of creams can be based on water in combination with glycerol
and one or more other components, 6. g., glycerinemonostearate, PEG-glycerinemonostearate
and cetylstearyl l. Gels can be formulated using isopropyl alcohol and water, suitably
in combination with other components such as, e.g., ol, hydroxyethyl cellulose, and the
like. In some embodiments, topical formulations contain at least about 0.1, at least about
0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5 wt % of the
compound of the invention. The topical formulations can be suitably packaged in tubes of,
e. g., 100 g which are optionally associated with instructions for the treatment of the select
indication, e.g., psoriasis or other skin condition.
The amount of compound or composition administered to a t will vary
depending upon what is being administered, the purpose of the administration, such as
prophylaxis or therapy, the state of the patient, the manner of administration and the like. In
therapeutic applications, compositions can be administered to a patient already suffering
from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the
disease and its cations. Effective doses will depend on the disease ion being
treated as well as by the judgment of the attending ian depending upon factors such as
the severity of the disease, the age, weight and general condition of the patient and the like.
The compositions administered to a t can be in the form of pharmaceutical
compositions described above. These compositions can be sterilized by conventional
sterilization techniques, or may be e ed. Aqueous solutions can be packaged for use
as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous
carrier prior to administration. The pH of the nd preparations typically will be
between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be
understood that use of certain of the foregoing excipients, carriers or stabilizers will result in
the formation of pharmaceutical salts.
The therapeutic dosage of a compound of the present invention can vary according to,
e. g., the particular use for which the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the nt of the ibing
physician. The proportion or tration of a compound of the invention in a
pharmaceutical composition can vary depending upon a number of factors including dosage,
chemical characteristics (6. g. and the route of administration. For example,
, hydrophobicity),
the compounds of the invention can be provided in an s physiological buffer solution
containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some
typical dose ranges are from about 1 ug/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight
per day. The dosage is likely to depend on such variables as the type and extent of
progression of the disease or er, the overall health status of the particular patient, the
relative biological efficacy of the compound ed, formulation of the excipient, and its
route of administration. Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
V. Labeled Compounds andAssay Methods
The compounds of the present disclosure can further be useful in investigations of
biological processes in normal and abnormal tissues. Thus, r aspect of the present
invention relates to labeled nds of the invention (radio-labeled, fluorescent-labeled,
etc.) that would be useful not only in g techniques but also in assays, both in vitro and
in vivo, for localizing and quantitating PD-l or PD-Ll protein in tissue samples, including
human, and for fying PD-Ll ligands by inhibition binding of a labeled compound.
Accordingly, the t invention includes PD-l/PD-Ll binding assays that contain such
d compounds.
The present invention further includes isotopically-substituted compounds of the
disclosure. An "isotopically-substituted" compound is a compound of the invention where
one or more atoms are replaced or substituted by an atom having an atomic mass or mass
number different from the atomic mass or mass number typically found in nature (1'. e. ,
naturally occurring). It is to be understood that a "radio-labeled" is a compound that has
incorporated at least one isotope that is radioactive (e.g., radionuclide). Suitable
radionuclides that may be orated in compounds of the present ion e but are
not limited to 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 358,
36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the
instant radio-labeled nds will depend on the specific application of that radio-labeled
compound. For example, for in vitro PD-Ll protein labeling and competition assays,
compounds that incorporate 3H, 14C, 82Br, 125I, 131I, 358 or will lly be most useful. For
radio-imaging applications 11C, 18F, 125I, 123I, 124I, 1311, 75Br, 76Br or 77Br will generally be
most useful. In some embodiments the uclide is selected from the group consisting of
3H, 14C, 125I, 358 and 82Br. Synthetic methods for incorporating radio-isotopes into organic
compounds are known in the art.
Specifically, a labeled compound of the invention can be used in a screening assay to
identify and/or te nds. For example, a newly synthesized or identified
compound (l'.e., test compound) which is labeled can be evaluated for its ability to bind a PD-
Ll protein by monitoring its concentration variation when contacting with the PD-Ll protein,
through tracking of the labeling. For example, a test compound ed) can be evaluated for
its ability to reduce binding of another compound which is known to bind to a PD-Ll protein
(i.€., standard compound). Accordingly, the ability of a test nd to compete with the
standard compound for binding to the PD-Ll protein directly correlates to its binding
affinity. Conversely, in some other screening assays, the standard compound is labeled and
test nds are unlabeled. Accordingly, the concentration of the labeled standard
compound is monitored in order to evaluate the competition between the standard compound
and the test compound, and the ve binding affinity of the test compound is thus
ascertained.
VI. Kits
The present sure also includes pharmaceutical kits , 6. g., in the treatment
or prevention of diseases or disorders associated with the activity of PD-Ll including its
ction with other proteins such as PD-l and B7-1 (CD80), such as cancer or infections,
which include one or more containers ning a pharmaceutical composition comprising a
therapeutically effective amount of a compound of a (I), or any of the embodiments
thereof. Such kits can r include one or more of various conventional pharmaceutical kit
components, such as, e. g. containers with one or more pharmaceutically acceptable carriers,
additional containers, etc, as will be readily apparent to those skilled in the art. Instructions,
either as inserts or as labels, indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the components, can also be
included in the kit.
The invention will be described in greater detail by way of ic examples. The
following examples are offered for illustrative purposes, and are not ed to limit the
invention in any manner. Those of skill in the art will y recognize a variety of non-
critical parameters which can be changed or ed to yield essentially the same results.
The compounds of the Examples have been found to inhibit the activity of PD-l/PD-Ll
protein/protein interaction according to at least one assay described herein.
EXAMPLES
Experimental procedures for compounds of the invention are provided below. Open
Access Preparative LCMS Purification of some of the compounds prepared was performed
on Waters mass directed fractionation systems. The basic ent setup, protocols and
l software for the operation of these systems have been described in detail in literature.
See, e.g., Blom, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K.
Blom, J. Combi. Chem, 2002, 4, 295-301, Blom et al., "Optimizing Preparative LC-MS
Configurations and Methods for Parallel Synthesis Purification", J. Combi. Chem, 2003, 5,
670-83, and Blom et al., "Preparative LC-MS ation: Improved Compound c
Method Optimization", J. Combi. Chem, 2004, 6, 874-883.
Example 1
N-[2-cyan0(2,3—dihydr0-1,4-benzodioxinyl)phenyl]-4,5,6,7-
tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide
Step 1: 0-6—(2, 3-dihydr0-1, 4-benzodi0xmyl)benzom'trl'le
gum
A mixture of obromobenzonitrile (1.5 g, 7.6 mmol) (Ark Pharm, cat#AK-
36350), 2,3-dihydro-1,4-benzodioxinylboronic acid (1.4 g, 7.6 mmol) (Combi-Blocks,
cat#BB-8311), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with
dichloromethane (1:1) (0.3 g, 0.4 mmol), Na2CO3 (2.4 g, 22.8 mmol) in 1,4-dioxane (30.0
mL) and water (4.0 mL) was purged with nitrogen. The reaction mixture was heated to 100
0C for 4 h under Vigorous stirring. After being cooled to room temperature, the reaction was
quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl e. The
combined organic layers were washed with brine, dried over Na2804, filtered, and
concentrated under d pressure. The residue was purified by flash chromatography on a
silica gel column eluting with 50% ethyl acetate in hexanes to afford the desired product (1.7
g, 88%). LCMS calculated for C15H13N202 (M+H)+: m/z = 2531, found 253.1.
Step 2: tert-butyl 2—({[2—cyan0(2,3-dl'hydr0-1,4-benzodi0xm
yUphenyl]amin0}carb0nyl)-6, 7—dihydr0[I , 3]thiazolo[5, 4-c]pyrl'dine-5(4H)-carb0xylate
[:NHEJSQ—{fi
2-Amino(2,3-dihydro-1,4-benzodioxinyl)benzonitrile (31 mg, 0.12 mmol) from
Step 1 was added to a solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-
c]pyridinecarboxylic acid (30 mg, 0.10 mmol) (J&WPharmlab, cat#90R0423),
N,N,N',N'-tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate (60 mg, 0.16
mmol) and N,N—diisopropylethylamine (55 uL, 0.32 mmol) in DMF (1.0 mL). The reaction
mixture was stirred at room temperature for 24 h. The reaction was quenched with saturated
aqueous NaHCO3 solution, and ted with ethyl acetate. The ed organic layers
were washed with brine, dried over NazSO4, filtered, and concentrated under reduced
pressure. The crude product was used for next step without further ation. LCMS
calculated for C27H27N4OsS (M+H)+: m/z = 5192, found 519.2.
Step 3: N-[2-cyan0(2, 3-dihydr0-1, 4-ben20dl'0xmyl)phenyl]-4, 5, 6, 7-
tetrahydrofl, 3]thia2010-[5, 4-c]pyridine-2—carbexamide
The crude product from Step 2 was dissolved in ol (0.5 mL), and then treated
with 4.0 M hydrogen chloride in 1,4-dioxane (0.5 mL). After being stirred at 50 0C for 2 h,
the reaction mixture was concentrated and purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for
C22H19N4O3S (M+H)+: m/z = 4191, found 419.2.
Example 2
N-(2-cyanobiphenylyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide
0 M NH
oW0
Step 1: tert-butyl 2-{[(3-br0m0-2—cyan0phenyl)aminojcarb0nyl}-6, 7-
dihydro[I , 3]thia2010[5, 4-c]pyrl'dine-5(4H)-carb0xylate
Br N/QN—fi0
N\n/”\S O
Potassium utoxide (0.15 g, 1.3 mmol) was added to a solution of 5-tert-butyl 2-
ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (0.26 g, 0.88 mmol)
(Aurum Pharmatech, cat#Z-3884), and obromobenzonitrile (0.17 g, 0.88 mmol)
(Ark Pharm, cat#AK-36350) in tetrahydrofuran (4 mL). After being stirred at room
temperature for 3 h, the reaction mixture was quenched with water, and extracted with ethyl
e. The combined organic layers were washed with brine, dried over , filtered,
and concentrated under reduced pressure. The crude product was used for next step t
further purification. LCMS calculated for BrN4O3S (M+H)+: m/z = 4630, found
463.1.
Step 2: r0m0-2—cyan0phenyl)-4, 5, 6, 7-tetrahydr0[1 , 3]thia2010[5, 4-c]pyridme
carboxaml'de
M NH
The crude product from Step 1 was dissolved in ol (2.0 mL), and then treated
with 4.0 M hydrogen de in 1,4-dioxane (2.0 mL). After being stirred at 50 0C for 2 h,
the reaction mixture was neutralized with saturated aqueous Na2CO3 solution, and extracted
with ethyl acetate. The combined organic layers were washed with brine, dried over NazSO4,
filtered, and trated under reduced pressure. The residue was purified by flash
chromatography on a silica gel column eluting with 5% methanol in romethane to
afford the d product (0.20 g, 61% over 2 steps). LCMS calculated for C14H12BrN4OS
(M+H)+: m/z = 3630, found 363.1.
Step 3: N-(2-cyan0blphenylyl)-4, 5, 6, 7-tetrahydr0[1, 3]thia2010[5, 4-c]pyridme
carboxaml'de
A mixture of N-(3-bromocyanophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-
c]pyridinecarboxamide (8.0 mg, 0.02 mmol) from Step 2, phenylboronic acid (5.3 mg,
0.04 mmol), dichloro[1,1’-bis(dicyclohexylphosphino)ferrocene]palladium(II) (0.7 mg, 0.001
mmol), and Na2CO3 (7.0 mg, 0.07 mmol) in tert-butyl alcohol (0.15 mL) and water (0.15
mL) was purged with nitrogen. The reaction mixture was heated to 100 °C for 2 h under
Vigorous stirring. After being cooled to room temperature, the mixture was diluted with
methanol, and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for C20H17N4OS (M+H)+: m/z = 361.1, found
361.2.
Example 3
N-[2-cyan0(1-methyl-1H-indazolyl)phenyl]-4,5,6,7-tetrahydro[1,3]thiaz010[5,4—
c] pyridine-Z-carboxamide
O NCNH
N’ 0 “#9O
This compound was prepared using similar procedures as described for Example 2
with yl-1H-indazoleboronic acid pinacol ester (Aldrich, Cat#: 725323) replacing
phenylboronic acid in Step 3. The reaction mixture was d by PLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C22H19NGOS (M+H)+: m/z = 415.1, found 4152.
Example 4
N-(2-cyan0-2'-fluorobiphenylyl)-4,5,6,7-tetrahydr0[1,3]thiaz010[5,4-c]pyridine
carboxamide
O C”“
F 0 anyO
This compound was prepared using similar procedures as described for Example 2
with (2-fluorophenyl)boronic acid (Aldrich, Cat#: 445223) replacing phenylboronic acid in
Step 3. The reaction e was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for C20H16FN4OS (M+H)+: m/z =
3791, found 379.2.
N-(2-cyano-2'-fluoro-3'-methoxybiphenyl-3—yl)—4,5,6,7-tetrahydr0[1,3]thiazolo[5,4-
c]pyridine-2—carb0xamide
.0 o O ,C
F O
This compound was prepared using similar procedures as described for Example 2
with (2-fluoromethoxyphenyl)boronic acid (Combt-Blocks, Cat#:BB-2460) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by PLC (pH = 2,
acetonitrile/water+TFA) to give the d product as the TFA salt. LC-MS calculated for
C21H18FN4OZS (M+H)+: m/z = 409.1, found 409.2.
Example 6
N-[2-cyan0(2,3-dihydrobenzofuranyl)phenyl]-4,5,6,7-
tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide
l C”“
O D D up;
This compound was prepared using similar procedures as described for Example 2
with 2,3-dihydrobenzofuranylboronic acid (Ark Pharm, Cal#:AK14363 7) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C22H19N4028 (M+H)+: m/z = 403.1, found 403.2.
e 7
N-(2-cyanocyclohexenylphenyl)-4,5,6,7-tetrahydr0[1,3]thiazolo[5,4—c]pyridine-
2-carb0xamide
0 CN”
O a,”O
This compound was prepared using similar procedures as bed for e 2
with cycloheX-l-en-l-ylboronic acid pinacol ester (Aldrich, Cal#: 650277) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C20H21N4OS (M+H)+: m/z = 365.1, found 3652.
Example 8
N-(2-cyano-S-cyclohexylphenyl)—4,5,6,7-tetrahydr0[1,3]thiaz010[5,4-c]pyridine
amide
H ”QM
N \n/ks
A suspension of N-(2-cyanocyclohexenylphenyl)-4,5,6,7 -
tetrahydro[1,3]thiazolo[5,4-c]pyridinecarboxamide (4.0 mg, 0.01 mmol) from Example 7
and 10% Pd/C (5.0 mg) in ol (05 mL) was stirred under a hydrogen atmosphere (1
atm) at room temperature for 2 h. After the catalyst was filtered off, the filtrate was diluted
with methanol, and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for C20H23N4OS (M+H)+: m/z = 367 .2,
found 367.2.
Example 9
N-(2-cyan0-2',6'-difluor0biphenyl-3—yl)—4,5,6,7-tetrahydr0 [1,3]thiazolo [5,4-c] pyridine
carboxamide
INI OF H NCNH\,
F o “WO
A mixture of N-(3-bromocyanophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-
c]pyridinecarboxamide (8.0 mg, 0.022 mmol) from Example 2, step 2, 2,6-
difluorophenylboronic acid (6.2 mg, 0.026 mmol) (Aldrich, 70791),
dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine-(2'-aminobiphenyl
yl)(chlor0)palladium (1:1) (35 mg, 0.0044 mmol), and K3PO4 (12 mg, 0.055 mmol) in
tetrahydrofuran (0.4 mL) and water (005 mL) was purged with nitrogen. The reaction
mixture was stirred at room temperature for 2 h under Vigorous stirring. After being cooled to
room temperature, the mixture was diluted with methanol, and purified by prep-HPLC (pH =
2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
F2N4OS (M+H)+: m/z = 397.1, found 397.2.
Example 10
N-[2-cyan0(2,3—dihydr0-1,4-benzodioxinyl)phenyl]-4,5,6,7-tetrahydropyrazolo[1,5-
a] pyrazine-Z-carboxamide
This compound was ed using similar procedures as described for Example 1
with 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinecarboxylic acid
(AstaTeclz, Cal#: 74720) replacing 5-(tert-butoxycarbonyl)-4,5,6,7-
tetrahydro[1,3]thiazolo[5,4-c]pyridinecarboxylic acid in Step 2. The reaction mixture was
purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired t as the
TFA salt. LC-MS calculated for N503 (M+H)+: m/z = 4022, found 402.2.
Example 11
N-[2-cyan0(2,3—dihydro-1,4-benz0dioxinyl)phenyl]-5—(2-hydr0xyethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrazine—Z-carboxamide
A mixture ofN-[2-cyano(2,3-dihydro-1,4-benzodioxinyl)phenyl]-4,5,6,7-
tetrahydropyrazolo[l,5-a]pyrazinecarboxamide (5.0 mg, 0.01 mmol) from e 10, 2-
iodoethanol (6.4 mg, 0.04 mmol), and K2CO3 (8.6 mg, 0.06 mmol) in DMF (0.1 mL) was
stirred at room temperature for 3 h. The reaction mixture was diluted with water, and
extracted with ethyl acetate. The combined organic layers were washed with brine, dried over
NazSO4, d, and concentrated under reduced pressure. The residue was purified by prep-
HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS
calculated for C24H24N504 (M+H)+: m/z = 4462, found 446.3.
Example 12
N-[2-cyan0(2,3—dihydro-1,4-benz0dioxinyl)phenyl]methyl-4,5,6,7-tetrahydro-
1H-imidazo[4,5-c]pyridine-Z-carboxamide
Step 1: ulyl 1-methyl-1,4, 6, 7-z‘etrahydr0-5H-imida20[4,5-c]pyridinecarboxylaz‘e
A solution of l-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine (80 mg, 0.60
mmol) (Accela, Cal#:SY0324 76), di-tert-butyl dicarbonate (140 mg, 0.66 mmol) and
tnethylamine (0.10 mL, 0.72 mmol) in romethane (4.0 mL) was stirred at room
temperature for 1 h. The on was quenched with saturated aqueous NaHCO3 solution,
and extracted with ethyl acetate. The combined organic layers were washed with brine, dried
over , filtered, and concentrated under reduced pressure. The crude product was used
for next step without further purification. LCMS calculated for C12H20N302 (M+H)+: m/z =
2382, found 238.2.
Step 2: 5-tert—butyl 2-methyl 1-methyl-6, 7-dthydr0-1H—tmtdazo[4,5-c]pyrtdtne-2,5(4H)-
dtcarboxylate
oi/KN‘
n-Butyllithium in s (2.5 M, 0.29 mL, 0.72 mmol) was added to a cold (-78 °C)
solution of the crude t from Step 1 in tetrahydrofuran (3.0 mL). The reaction mixture
was stirred at -78 °C for 30 min prior to the addition of methyl formate (46 uL, 0.60
mmol). After being stirred at -78 °C for l h, the reaction mixture was allowed to warm up to
room temperature. The reaction was then quenched with saturated aqueous NaHCO3 solution,
and extracted with ethyl acetate, dried over NazSO4, filtered, and concentrated under reduced
pressure. The crude t was used for next step without further purification. LCMS
calculated for C14H22N3O4 (M+H)+: m/z = 2962, found 296.3.
Step 3: tert-butyl 2-({[2—cyan0(2,3-dthydr0-1,4-benzodt0xtn-6—
yUphenyljamtn0}carb0nyl)methyl-1, 4, 6, 7-tetrahydr0-5H—tmtdazo[4, 5-c]pyrtdtne
carboxylate
Potassium tert-butoxide (52 mg, 0.50 mmol) was added to a solution of the crude
product from Step 2, and 2-amino(2,3-dihydro-l,4-benzodioxinyl)benzonitrile (25 mg,
0.10 mmol) from Example 1, step 1 in tetrahydrofuran (0.5 mL). After being d at room
temperature for 3 h, the reaction mixture was quenched with water, and extracted with ethyl
e. The combined organic layers were washed with brine, dried over NazSO4, filtered,
and concentrated under d pressure. The crude product was used for next step without
further purification. LCMS calculated for C23H30N505 (M+H)+: m/z = 5162, found 516.2.
Step 4: N-[2-cyan0(2, 3-dthydr0-1, 4-benzodt0xtnyUphenyljmethyl-4, 5, 6, 7-
tetrahya’ro-IH-l'ml'a’azo[4, 5-c]pyrl'dmecarb0xaml'a’e
The crude product from Step 3 was dissolved in methanol (0.2 mL), and then treated
with 4.0 M hydrogen chloride in 1,4-dioxane (0.2 mL). After being stirred at 50 0C for 2 h,
the reaction was neutralized with saturated aqueous Na2CO3 solution, and extracted with
ethyl acetate. The ed organic layers were washed with brine, dried over NazSO4,
filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC
(pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS
calculated for C23H22N503 : m/z = 4162, found 416.3.
Example 13
N-(2-cyano(2,3—dihydr0benzo [b] [1,4] yl)phenyl)(2-hydroxyethyl)—1-
methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-Z-carboxamide
EWfiQH
This compound was prepared using similar procedures as described for Example 11,
starting with N-[2-cyano(2,3-dihydro-1,4-benzodioxinyl)phenyl]methyl-4,5,6,7-
tetrahydro-1H-imidazo[4,5-c]pyridinecarboxamide from Example 12. The reaction
mixture was purified by PLC (pH = 2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for N504 (M+H)+: m/z = 4602, found
460.3.
Example 14
N-[2-cyan0(2,3—dihydr0-1,4-benzodioxinyl)phenyl]-5,6,7,8-
tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-Z-carboxamide
N /—\
E: O n ”1}”
This compound was prepared using similar procedures as described for Example 12
with 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (Ark Pharm, Cal#:AK-25630)
replacing 1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine in Step 1. The reaction
mixture was purified by PLC (pH = 2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for C21H19N603 (M+H)+: m/z = 4032, found
403.2.
Example 15
N-(2,3'-dicyan0-2'-fluorobiphenyl-3—yl)—4,5,6,7-tetrahydro[1,3]thiazolo[5,4—c]pyridine
carboxamide
This compound was prepared using similar procedures as described for Example 2
with (3-cyanofluorophenyl)boronic acid (Combi-Blocks, Cal#:BB-5008) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C21H15FNsOS (M+H)+: m/z = 4041; found 404.2.
Example 16
N-(2-cyano-3'-methoxybiphenyl-S-yl)—4,5,6,7-tetrahydr0thiazolo[5,4-c]pyridine
carboxamide
O CNH
\O O “1%;O
This compound was prepared using similar procedures as described for Example 2
with 3-methoxyphenylboronic acid ch, Cal#: 441686) replacing boronic acid in
Step 3. The reaction mixture was purified by PLC (pH = 2, acetonitrile/water+TFA) to
give the desired product as the TFA salt. LC-MS calculated for C21Hi9N4OzS : m/z =
391.1; found 391.2.
Example 17
N-(2-cyano-3'-fluoro-5'-methoxybiphenyl-S-yl)—4,5,6,7-tetrahydr0[1,3]thiazolo[5,4-
c] pyridine-Z-carboxamide
This compound was prepared using similar procedures as bed for Example 2
with (3-fluoromethoxyphenyl)boronic acid (Combt-Blocks, Cat#:BB-2775) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C21H18FN4OzS (M+H)+: m/z = 4091, found 409.2.
N-(2'-ch10ro-2—cyanobiphenyl-3—yl)—4,5,6,7-tetrahydr0 [1,3] thiazolo [5,4-c] pyridine
carboxamide
0 " H CH
0“ 8
CI 0
This compound was prepared using similar procedures as bed for Example 2
with (2-chlorophenyl)boronic acid (Aldrich, Cat#: 445215) replacing phenylboronic acid in
Step 3. The reaction mixture was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to
give the desired t as the TFA salt. LC-MS ated for C20H16ClN4OS : m/z
= 395.1, found 395.1.
Example 19
N-(2-cyan0-2'-fluoro-3'-methoxybiphenyl-3—yl)—5,6,7,8-tetrahydr0imidaz0[1,2—
a]pyrazinecarb0xamide
O H N’ NJ
\0 ON \
F O
This compound was prepared using similar procedures as described for Example 2
with ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinecarboxylate (AstaTeclz, Cat#: SC2741)
replacing 5-tert-butyl 2-ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)—dicarboxylate
in Step 1, and (2-fluoromethoxyphenyl)boronic acid (Combt-Blocks, Cat#: 38-2460)
ing phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH
= 2, acetonitrile/water+TFA) to give the d product as the TFA salt. LC-MS calculated
for C21H19FN502 (M+H)+: m/z = 3922, found 392.3.
Example 20
N- [3-(2,3-dihydr0-1,4-benzodioxinyl)—2-methylphenyl]-4,5,6,7-
tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide
Step 1: 3-(2, 3-dthydr0benzo[b][1, 4]a’t0xmyl)metlzylantlme
This compound was prepared using similar procedures as described for Example 1,
step 1, starting with 3-bromomethylaniline (460 mg, 2.5 mmol) (Combt-Blocks, Cat#:AN-
1321). The residue was purified by flash chromatography on a silica gel column g with
% ethyl acetate in hexanes to afford the desired product (502 mg, 83%). LCMS calculated
for C15H16N02 (M+H)+: m/z = 2421, found 242.2.
Step 2: tert-butyl 2-(3-(2, 3-dthydr0benzofl9][1, 4]a’toxmyl)metlzylplzenylcarbam0yl)-6, 7-
dthydrothtazol0[5, rta’me-5(4H)-carb0xylate
We” “‘3
This compound was ed using similar procedures as described for Example 2,
step I with 3-(2,3-dihydrobenzo[b][l,4]dioxinyl)methylaniline from Step 1 replacing 2-
aminobromobenzonitrile. The crude product was used for next step without further
purification. LCMS calculated for C27H30N3OsS (M+H)+: m/z = 5082, found 508.2.
Step 3: 2, 3-dtlzya’r0-1, 4-benzoa’t0xmyl)metlzylplzenyl]-4, 5, 6, 7-
tetralzya’rofl, 3]tlzta20l0[5, 4-c]pyrtdmecarb0xamtcle
This compound was prepared using similar procedures as bed for Example 2,
Step 2, starting with tert-butyl 2-(3-(2,3-dihydrobenzo[b] [1,4] yl)
methylphenylcarbamoyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate from Step 2.
The on mixture was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give
the desired product as the TFA salt. LC-MS calculated for C22H22N3O3S (M+H)+: m/z =
4081, found 408.2.
Example 21
N-(2'-flu0r0-3'-methoxy-2—methylbiphenylyl)-4,5,6,7-tetrahydr0 [1,3]thiazolo[5,4-
c] pyridine-Z-carboxamide
H [\f/CNH
\O O O Nm/LS
F O
This compound was prepared using similar procedures as described for Example 2
with 3-bromomethylaniline replacing obromobenzonitrile in Step 1, and (2-
fluoromethoxyphenyl)boronic acid replacing phenylboronic acid in Step 3. The on
mixture was d by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for C21H21FN3OzS (M+H)+: m/z = 398.1; found
398.2.
Example 22
N-(2'-flu0r0-3'-methoxy-2—methylbiphenylyl)methyl-4,5,6,7-tetrahydro-1H—
imidazo [4,5-c]pyridine-Z-carboxamide
\ 0 H Ni)
F o to
This compound was prepared using similar procedures as described for Example 12,
starting with 2'-fluoro-3'-methoxymethylbiphenylamine, prepared using r
procedures for the synthesis of 2-amino(2,3-dihydro-1,4-benzodioxinyl)benzonitrile in
Example 1, Step 1. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired t as the TFA salt. LC-MS calculated for
C22H24FN402 (M+H)+: m/z = 395.2; found 395.3.
Example 23
N- [2-methyl(1-methyl- 1H-indazolyl)phenyl] -4,5,6,7-tetrahydr0 [1,3] thiazolo [5,4-
c] pyridine-Z-carboxamide
o H C
\N. ON\n/‘\s N’ O
This compound was prepared using similar procedures as bed for e 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1, and (l-
methyl-1H-indazolyl)boronic acid (Combt-Blocks, cat#BB-9017) replacing phenylboronic
acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2,
itrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
NsOS (M+H)+: m/z = 4042, found 404.3.
N- [2'-flu0r0-3'-(hydr0xymethyl)—2-methylbiphenylyl]-4,5,6,7-
tetrahydr0[1,3]thiazolo [5,4-c] pyridine-Z-carboxamide
HO o C“kn/ks
F O o
This compound was ed using similar procedures as described for Example 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1, and [2-
fluoro(hydroxymethyl)phenyl]boronic acid (Combt-Blocks, Cat#: 88-65 79) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C21H21FN30zS (M+H)+: m/z = 3981, found 398.2.
Example 25
N- -indazolyl)methylphenyl] -4,5,6,7-tetrahydr0 [1,3] lo [5,4—c] pyridine-
2-carb0xamide
O N NH
N’ O Hm»?O
This nd was prepared using similar procedures as described for Example 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1, and
indazoleboronic acid hydrochloride (Aldrich, Cat#: 709379) replacing phenylboronic acid
in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA)
to give the desired product as the TFA salt. LC-MS calculated for C21H20N50$ (M+H)+: m/z
= 3901, found 390.2.
N-(2-methylbiphenylyl)-4,5,6,7-tetrahydr0 [1,3]thiazolo [5,4—c]pyridine—2—
carboxamide
0 up?“
This nd was prepared using similar procedures as described for Example 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1. The
reaction mixture was purified by PLC (pH = 2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for C20H20N3OS : m/z = 3501,
found 350.2.
Example 27
—(2-hydroxyethyl)—N-(2-methylbiphenyl—3-yl)-4,5,6,7-tetrahydr0thiazolo[5,4-
c]pyridine-2—carb0xamide
0 H “M Nx
S OH
This compound was prepared using similar procedures as described for Example 11,
starting with N—(2-methylbiphenylyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine
carboxamide from Example 26. The reaction e was purified by prep-HPLC (pH = 2,
itrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C22H24N3OzS (M+H)+: m/z = 3942, found 394.2.
Example 28
2-(2-(2-methylbiphenyl-3—ylcarbamoyl)—6,7-dihydrothiazolo [5,4-c] pyridin-5(4H)-
yl)acetic acid
0 n NI§3WWH
O 0
Glyoxalic acid monohydrate (9.9 mg, 0.11 mmol) was added to a solution of N-(2-
methylbiphenylyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridinecarboxamide (17 mg,
0.05 mmol) from e 26, and N,N-diisopropylethylamine (19 uL, 0.11 mmol) in
dichloromethane (0.5 mL). After being stirred at room temperature for 15 min, sodium
triacetoxyborohydride (33 mg, 0.15 mmol) was added. The reaction mixture was stirred at
room temperature for 2 h. The solvent was removed under reduced pressure, and the residue
was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as
the TFA salt. LC-MS calculated for C22H22N3O3S (M+H)+: m/z = 408.1; found 408.2.
Example 29
N-[2-methyl(2-methyl-2H-indazolyl)phenyl]-4,5,6,7-tetrahydr0[1,3]thiazolo[5,4-
c] pyridine-Z-carboxamide
This compound was prepared using similar procedures as bed for Example 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1; and 2-
methyl-2H-indazolylboronic acid pinacol ester (Combi-Blocks, Cat#:PN-9131) replacing
phenylboronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH = 2;
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C22H22NsOS (M+H)+: m/z = 404.2; found 404.2.
Example 30
N-(2'-cyano-2—methylbiphenyl-3—yl)—4,5,6,7-tetrahydr0[1,3]thiazolo [5,4—c]pyridine-2—
carboxamide
| | O mpg/SSW
This compound was ed using similar procedures as bed for Example 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1; and 2-
cyanophenylboronic acid ch, Cat#: 521396) replacing boronic acid in Step 3. The
reaction mixture was d by prep-HPLC (pH = 2; acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS calculated for C21H19N4OS (M+H)+: m/z = 375.1;
found 375.2.
Example 31
N- [2'-(cyan0methyl)—2—methylbiphenyl-3—yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-
c] pyridine-Z-carboxamide
This compound was prepared using similar procedures as described for Example 2
with 3-bromomethylaniline replacing 2-aminobromobenzonitrile in Step 1, and 2-
(cyanomethyl)phenylboronic acid (Combt-Blocks, Cat#:BB-2136) replacing phenylboronic
acid in Step 3. The reaction e was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
N4OS (M+H)+: m/z = 3891, found 389.2.
Example 32
N-(2-chlor0-2'-fluoro-3'-meth0xybiphenylyl)-4,5,6,7-tetrahydro[1,3]thiazolo [5,4-
c]pyridine-2—carb0xamide
o 0' H C
F 0
Step 1: tert-butyl 2-(3-br0m0clzl0r0phenylcarbamoyl)-6, 7-dthydr0tlztazol0[5,4-c]pyrta’me-
(4H)-carb0xylate
BF\E,N\H/QS N’QNKo I
o
This compound was prepared using similar procedures as described for Example 2,
Step 1, ng with ochloroaniline (206 mg, 0.10 mmol) (AstaTeclz,
Cat#:CL9068) and 5-tert-butyl 2-ethyl 6,7-dihydro[l,3]thiazolo[5,4-c]pyridine-2,5(4H)-
dicarboxylate (312 mg, 0.10 mmol). The crude product was used for next step without r
purification. LCMS calculated for CistoBrClN3O3S (M+H)+: m/z = 4720, found 472.0.
Step 2: N-(3-br0m0-2—chl0r0plzenyl)-4, 5, 6, 7-tetralzydr0tlztazol0[5, 4-c]pyrta’me
carboxamta’e
HH/QNH
Br(jN
This compound was prepared using similar procedures as bed for Example 2,
Step 2, starting with tert-butyl 2-(3 -bromochlorophenylcarbamoyl)-6,7-
dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate from Step 1. The residue was purified by
flash chromatography on a silica gel column eluting with 5% methanol in dichloromethane to
afford the d product (238 mg, 64% over 2 steps). LCMS calculated for
C13H12BrClN3OS (M+H)+: m/z = 3720, found 372.0.
Step 3: N-(2-ch10r0-2’-flu0r0-3 ’-meth0xyblphenylyl)-4, 5, 6, 7-tetrahydr0[1, 3]thia2010[5, 4-
cjpyridine-Z-carboxamide
A mixture of N—(3-bromochlorophenyl)—4,5,6,7-tetrahydro[1,3]thiazolo[5,4-
c]pyridinecarboxamide (10.0 mg, 0.027 mmol), (2-fluoromethoxyphenyl)boronic acid
(5.02 mg, 0.030 mmol), K3PO4 (11 mg, 0.054 mmol) and
is(triphenylphosphine)palladium(0) (3.1 mg, 0.0027 mmol) in 1,4-dioxane (0.15
mL) and water (10 uL) was stirred at 100 °C for 1 h. After being cooled to room temperature,
the mixture was diluted with methanol, and purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS ated for
C20H18ClFN3OzS (M+H)+: m/z = 418.1, found 418.2.
Example 33
N-(2-ch10r0biphenyl—3-yl)-4,5,6,7-tetrahydr0[1,3]thiazolo[5,4—c]pyridine-Z-carboxamide
O
This compound was prepared using similar ures as described for e 32
with phenylboronic acid replacing (2-fluoromethoxyphenyl)boronic acid in Step 3. The
reaction mixture was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the
desired product as the TFA salt. LC-MS ated for C19H17C1N3OS (M+H)+: m/z = 3701,
found 370.2.
Example 34
N-[2-chlor0-3—(2,3-dihydr0-1,4-benzodioxin-G-yl)phenyl]-4,5,6,7-
tetrahydr0[1,3]thiazolo [5,4-c] pyridine-Z-carboxamide
[N39
This compound was ed using similar procedures as described for Example 32
with 2,3-dihydro-l,4-benzodioxinylboronic acid replacing ro
methoxyphenyl)boronic acid in Step 3. The reaction mixture was purified by prep-HPLC (pH
= 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated
for C21Hi9ClN3O3S (M+H)+: m/z = 428.1, found 428.2.
Example 35
N-(2-chloro(1—methyl-1H-indazolyl)phenyl)—4,5,6,7-tetrahydrothiazolo [5,4-
c]pyridine-2—carb0xamide
This nd was prepared using similar procedures as described for Example 32
with yl-lH-indazoleboronic acid (Combt-Blocks, cat#BB-9017) replacing (2-
fluoromethoxyphenyl)boronic acid in Step 3. The reaction mixture was purified by prep-
HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS
calculated for ClN508 (M+H)+: m/z = 424.1, found 424.2.
Example 36
N- [3-(2,3-dihydr0-1,4-benzodi0xinyl)flu0r0-2—methylphenyl]-4,5,6,7-
tetrahydr0[1,3]thiazolo [5,4-c] pyridine-Z-carboxamide
This compound was prepared using similar procedures as described for Example 20
with 3-bromofluoromethylaniline (Ark Pharm, Cat#:AK-82467) replacing 3-bromo
methylaniline in Step 1. The reaction mixture was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
FN3O3S (M+H)+: m/z = 426.1, found 426.2.
Example 37
2,3-dihydr0-1,4-benzodioxinyl)methylpyridin-4—yl]-4,5,6,7-
tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide
E H [\FCNH
o \ ”#8
N / O
This compound was prepared using similar procedures as described for e 20
with 2-chloromethylpyridinamine (AstaTeclz, Cat#: 25664) replacing 3-bromo
methylaniline in Step 1. The reaction mixture was d by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS ated for
C21H21N4O3S (M+H)+: m/z = 4091, found 409.2.
Example 38
N-[5-(2,3-dihydr0-1,4-benzodioxinyl)methylpyridin-3—yl]-4,5,6,7-
tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide
E H ”gm
0 \ Nfis
This compound was prepared using similar procedures as described for Example 20
with omethylpyridinamine (AstaTeclz, Cat#:36169) replacing 3-bromo
methylaniline in Step 1. The reaction e was purified by prep-HPLC (pH = 2,
acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for
C21H21N4O3S (M+H)+: m/z = 4091, found 409.2.
Example 39
N-(2-cyano-2'-flu0ro—3'-methoxybiphenyl-3—yl)—1-methyl-4,5,6,7-tetrahydro-1H-
imidazo [4,5-c]pyridine-Z-carboxamide
H NH
3 H W)
F oWO
This compound was ed using similar procedures as described for Example 12,
Step 3 t0 4, starting with -butyl 2-methyl l-methyl-6,7-dihydro-lH-imidazo[4,5-
c]pyridine-2,5(4H)-dicarboxylate from Example 12, Step 2 and 3-amino-2'-fluoro-3'—
methoxybiphenylcarbonitrile, prepared using similar procedures for the synthesis of 2-
amino(2,3-dihydro-l,4-benzodioxinyl)benzonitrile in Example 1, Step 1. The reaction
mixture was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired
product as the TFA salt. LC-MS calculated for C22H21FN502 (M+H)+: m/z = 4062, found
406.2.
N-(2-cyan0-2'-flu0r0-3'-meth0xybiphenyl-3—yl)—5—(2-hydr0xyethyl)methyl-4,5,6,7-
tetrahydro—lH—imidazo[4,5-c]pyridine-Z-carboxamide
\0 O O N 11/1"
F O
This compound was prepared using similar procedures as described for Example 11,
ng with N—(2-cyano-2'-fluoro-3'-methoxybiphenylyl)methyl-4,5,6,7-tetrahydro-
lH-imidazo[4,5-c]pyridinecarboxamide from Example 39. The on mixture was
purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the
TFA salt. LC-MS calculated for C24H25FN503 (M+H)+: m/z = 4502, found 4502.
Example 41
(2-{ [(2-cyan0-2'-fluoro-3'-meth0xybiphenylyl)amino] carbonyl}methyl- 1,4,6,7-
ydro—SH—imidazo [4,5-c] pyridin-S-yl)acetic acid
H N
F o WO
This compound was prepared using similar procedures as described for Example 28,
starting with N—(2-cyano-2'-fluoro-3'-methoxybiphenylyl)methyl-4,5,6,7-tetrahydro-
lH-imidazo[4,5-c]pyridinecarboxamide from Example 39. The reaction mixture was
d by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the
TFA salt. LC-MS calculated for C24H23FN504 (M+H)+: m/z = 4642, found 464.2.
Example 42
N-(2-cyan0(1-methyl-1H-indazolyl)phenyl)methyl-4,5,6,7-tetrahydr0-1H-
imidazo [4,5-c]pyridine-Z-carboxamide
N O NWKLN
This compound was prepared using similar procedures as described for Example 12,
Step 3 t0 4, starting with 5-tert-butyl 2-methyl yl-6,7-dihydro-1H-imidazo[4,5-
c]pyridine-2,5(4H)-dicarboxylate from e 12, Step 2 and o(1-methyl-1H-
indazolyl)benzonitrile, prepared using similar procedures for the synthesis of 2-amino
(2,3-dihydro-1,4-benzodioxinyl)benzonitrile in Example 1, Step 1. The reaction mixture
was purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as
the TFA salt. LC-MS calculated for C23H22N7O (M+H)+: m/z = 4122; found 412.2.
e A. PD-l/PD-Ll Homogeneous Time-Resolved Fluorescence (HTRF) binding
assay
The assays were ted in a standard black 384-well polystyrene plate with a final
volume of 20 uL. Inhibitors were first serially diluted in DMSO and then added to the plate
wells before the addition of other reaction components. The final concentration of DMSO in
the assay was 1%. The assays were carried out at 250 C in the PBS buffer (pH 7.4) with
0.05% Tween-20 and 0.1% BSA. Recombinant human PD-Ll protein (19-238) with a His-
tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant
human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from
AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay buffer
and 10 uL was added to the plate well. Plates were centrifuged and proteins were
preincubated with inhibitors for 40 minutes. The incubation was ed by the addition of
uL ofHTRF detection buffer supplemented with Europium cryptate-labeled anti-human
IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to ght®-
Allophycocyanin (APC, PerkinElmer-AD0059H). After centrifugation, the plate was
incubated at 250 C for 60 min. before reading on a PHERAstar FS plate reader
(665nm/620nm . Final concentrations in the assay were - 3 nM PD1, 10 nM PD-Ll, 1
nM europium uman IgG and 20 nM anti-His-Allophycocyanin.ICso determination was
performed by fitting the curve of percent control activity versus the log of the inhibitor
concentration using the GraphPad Prism 5.0 software.
Compounds of the present disclosure, as exemplified in Examples 1-42, showed IC50
values in the following ranges: + = IC50 S 100 nM; ++ = 100 nM < IC50 S 500 nM; +++ = 500
nM < IC50 S 10000 nM
Data ed for the Example compounds using the PD-l/PD-Ll homogenous time-
resolved fluorescence (HTRF) binding assay described in Example A is provided in Table 1.
Table 1
PD-l/PD-Ll HTRF
IC50 (nM)
[Qt—l +
00 ++
\D +
h—‘h—l l—‘O ++ ++
++ ++
NN l—‘O +
NNmN +++
N4; + +++
NO\ +
N00 +
N\D ++
b.) O ++
0303mm #UJNt—d + ++++ +
b.) m +
PD-1/PD-Ll HTRF
IC50 (nM)
Various modifications of the ion, in addition to those described herein, will be
apparent to those skilled in the art from the foregoing description. Such modifications are
also intended to fall within the scope of the appended claims. Each reference, including
Without limitation all patent, patent applications, and publications, cited in the t
application is incorporated herein by reference in its entirety.
Claims (36)
1. A compound of Formula (1): Y1 \GZ R9 N —"\ ”NV R5)“ \ Z 3 0 X1\ 2I’X X (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, n: (i) G1 is NR6 and G2 is CR7R7, or (ii) G1 is CRGR6 and G2 is NR7, X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, Z is O, S, N, NR4 or CR4, Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not aneously Cy is C640 aryl, C340 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to lO-membered heterocycloalkyl, each of which is optionally substituted with 1 to 5 independently selected R8 substituents, R1, R2 and R3 are each independently selected from H, C1-4 alkyl, C340 cycloalkyl, C3— 10 cycloalkyl-C1—4 alky1-, C640 aryl, C640 aryl-C1-4 a1ky1-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroary1)-C1—4 a1ky1-, (4-10 membered heterocycloalky1)-C1—4 , C2—4 alkenyl, C2.4 alkynyl, halo, CN, 0R1“, C1.4haloa1ky1, C1—4 haloalkoxy, NH2, -NHR10, -NR10R10, NHORlO, C(O)R1°, C(0)NR10R10, C(O)OR1°, OC(O)R1°, OC(O)NR1°R1°, NR1°C(O)R1°, NR1°C(O)OR1°, NR10C(O)NR10R1°, C(=NR1°)R10, C(=NR10)NR10R10, NR10C(=NR10)NR10R10, NR108(O)R10, NR1°S(O)2R1°, O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and R10R10, wherein each R10 is independently selected from H, C1—4 alkyl, C2—4 alkenyl, C2—4 alkynyl, C1—4 , C340 lkyl, C340 cycloalkyl-C1—4 alky1-, C640 aryl, C640 aryl-C1—4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroary1)-C1-4 alkyl-, and (4- 10 membered heterocycloalky1)-C1-4 alky1-, wherein the C14 alkyl, C2—4 alkenyl, C2—4 alkynyl, C1-4 alkoxy, C340 cycloalkyl, C340 cycloalkyl-C1-4 alkyl-, C640 aryl, C640 aryl-C1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroary1)-C1-4 alkyl-, and (4-10 ed heterocycloalkyl)-Ci.4 alkyl- of R1, R2, R3 and R10 are each ally substituted with l, 2 or 3 independently selected Rd substituents, R4, R5, R6, R7 and R8 are each independently selected from H, halo, C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci.6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, C(O)Ra, aRa, C(O)ORa, OC(O)R"‘, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa, NRaC(=NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered cycloalkyl, C640 aryl-Ci—4 alkyl- C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with l, 2, 3, 4 or 5 Rb substituents, or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered aryl ring or a fused C3.6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or ered heteroaryl ring and fused C3.6 cycloalkyl ring are each ally substituted with l, 2 or 3 independently selected Rb substituents, or two R5 tuents attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a C36 cycloalkyl ring or 4-, 5-, 6- or 7- membered heterocycloalkyl ring, wherein the C36 cycloalkyl ring and 4-, 5-, 6- or 7- ed heterocycloalkyl ring are each optionally substituted with l, 2 or 3 ndently selected Rb substituents, R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640 aryl, C340 lkyl, 5-14 ed aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-14 membered heteroaryl)-Ci—4 alkyl-, (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, CN, N02, OR“, SR“, NH2, NHR“, NRHR“, NHOR“, C(O)R11, C(O)NR11R“, C(O)OR“, OC(O)R“, R11R11, NR11C(O)R11, NR11C(O)OR11,NR11C(O)NR11R11, C(=NR11)R11, C(=NR11)NR11R11, NR11C(=NR11)NR11R11, NR“C(=NOH)NR11R11, NCN)NR“R“, NR“S(O)R“, NR“S(O)2R11, NR“S(O)2NR11R“, S(O)R“, S(O)NR11R“, S(O)2R“, or S(O)2NR“R11, wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of R9 are each optionally substituted with 1, 2 or 3 Rb substituents, each R11 is ndently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 , (5-10 membered aryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of R11 are each optionally substituted with l, 2 or 3 Rb substituents, each Ra is ndently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-10 ed heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 , wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of , (5-10 Ra are each optionally substituted with l, 2 or 3 Rd substituents, each Rb substituent is independently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci— 6haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, CN, OH, NH2, N02, NHORC, ORG, SRC, C(O)RC, CRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, C(=NRC)NRCRC, NRCC(=NRC)NRCRC, NRCC(=NOH)NRCRC, NRCC(=NCN)NRCRC, NHRC, NRCRC, NRCC(O)RC, NRCC(O)ORC, NRCC(O)NRCRC, )RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC, S(O)NRCRC, S(O)2RC and RCRC, wherein the C16 alkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6- 10 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl-and (4- 10 ed cycloalkyl)-Ci-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents, each RC is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 , (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl- and (4-10 ed heterocycloalkyl)-Ci—4 alkyl- of , (5-10 RC are each optionally substituted with l, 2 or 3 Rf substituents independently selected from C1-6 alkyl, Ci.6 haloalkyl, Ci-6 haloalkoxy, C2-6 l, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl- C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, g, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg, S(O)NRgRg, g, )2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg, wherein the C1-6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered cycloalkyl)-Ci—4 alkyl- , (5-10 of Rf are each optionally substituted with l, 2 or 3 R11 substituents independently selected from C1—6 alkyl, Ci.6 haloalkyl, halo, CN, phenyl, C3.6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, C(O)R°, C(O)NR°R°, C(O)OR°, OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, )OR°, )NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°, )2NR°R°, and S(O)2NR°R°, wherein the C16 alkyl, Ci-6 haloalkyl, phenyl, C3—6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R11 is optionally substituted with l, 2 or 3 Rq substituents, each Rd is independently selected from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 i—4 alkyl- C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, CN, NH2, NHORe, ORG, SR6, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re, S(O)NReRe, e, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl, Ci—6 haloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 lkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of RC1 are each optionally substituted with 1-3 independently selected Rf tuents, each R6 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci—4 alkyl- and (4-10 membered heterocycloalkyl)—Ci—4 alkyl- of , (5-10 Re are each ally substituted with 1, 2 or 3 independently selected Rf substituents, each Rg is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 membered cycloalkyl, C640 i—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 , n the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 , (5-10 membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are each optionally substituted with 1-3 Rp substituents independently selected from C1—6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(=NRr)NRrRr, NRrC(=NRr)NRrRr, NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 , C340 cycloalkyl-Ci-4 , (5-10 membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci.4 alkyl- of Rp are each optionally substituted with 1, 2 or 3 Rq substituents, or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or bered heterocycloalkyl group optionally substituted with 1, 2 or 3 R11 substituents independently selected from C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7 membered cycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl- Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-6 membered heteroaryl)-Ci—4 alkyl-, (4-7 membered heterocycloalkyl)-Ci—4 alkyl-, Ci.6 haloalkoxy, C2—6 alkenyl, C2.6 alkynyl, halo, CN, 0R1, SR1, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, NOH)NRiRi, NRiC(=NCN)NRiRi, S(O)Ri, S(O)NRiRi, i, )2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7 ed cycloalkyl, C640 aryl, 5-6 membered heteroaryl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-6 ed heteroaryl)-Ci—4 alkyl-, (4-7 membered heterocycloalkyl)-Ci.4 alkyl- of R11 are each optionally substituted by l, 2, or 3 Rj substituents independently selected from C1—4 alkyl, C3.6 cycloalkyl, C640 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2—4 alkenyl, C2.4 alkynyl, halo, Ci.4 haloalkyl, Ci.4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(0)NRkRk, C(O)0Rk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, )ORk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, kRk, S(O)2Rk, NRkS(O)2Rk, )2NRkRk, and RkRk= wherein the C14 alkyl, C3-6 cycloalkyl, C640 aryl, 5- or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2—4 alkenyl, C2—4 alkynyl, Ci.4 haloalkyl, and Ci-4haloalkoxy of Rj are each optionally substituted with l, 2 or 3 Rq substituents, or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C36 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S, each Ri or Rk is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 ed heteroaryl)-Ci-4 alkyl-, and (4-10 membered cycloalkyl)-Ci-4 alkyl-, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl- and (4-10 membered cycloalkyl)-Ci—4 alkyl- of , (5-10 Ri or Rk are each optionally substituted with 1-3 independently selected Rp substituents, or any two RC substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh substituents, or any two Re substituents together with the en atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 ndently selected Rh substituents, or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh tuents, or any two Ri substituents er with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or ered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh tuents, or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group ally substituted with l, 2, or 3 independently selected Rh tuents, or any two R0 substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or ered heterocycloalkyl group optionally substituted with l, 2, or 3 ndently selected Rh substituents, or any two Rr substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh substituents, each R0 or Rr is independently ed from H, C1-6 alkyl, C1-6 kyl, C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, Ci—4 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein the C14 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C2—4 alkenyl, and C24 alkynyl of R0 or Rr are each optionally substituted with l, 2 or 3 Rq substituents, each Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-6 haloalkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered cycloalkyl, C3-6 cycloalkyl, NHR12 and NR12R12, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with halo, OH, CN, -COOH, NH2, Ci—4 alkoxy, Ci-4 haloalkyl, Ci.4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl and each R12 is independently C1-6 alkyl, m is a single bond or a double bond to maintain ring A being aromatic; and the subscript n is an integer of 1, 2, 3 or 4.
2. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) G1 is NR6 and G2 is CR7R7, or (ii) G1 is CRGR6 and G2 is NR7, X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, Z is O, S, N, NR4 or CR4, Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously Cy is C6-10 aryl, C3-10 lkyl, 5- to l4-membered heteroaryl, or 4- to bered heterocycloalkyl, each of which is optionally substituted with l to 5 independently ed R8 substituents, R1, R2 and R3 are each ndently selected from H, C14 alkyl, C3-6 cycloalkyl, C2—4 alkenyl, C2.4 l, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, Ci.4 haloalkoxy, NH2, -NH- C1-4 alkyl, -N(C1-4 alkyl)2, NHORlO, C(O)R1°, C(O)NR1°R1°, C(O)OR10, OC(O)R10, R10R10, NR10C(O)R10, NR10C(0)0R10, NR10C(0)NR10R10, C(=NR10)R10, C(=NR10)NR10R10, NR10C(=NR10)NR10R10, NR1°S(O)R1°, NR1°S(O)2R1°, NRIOS(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently selected from H and C14 alkyl optionally substituted with l or 2 groups independently selected from halo, OH, CN and C14 alkoxy, and wherein the C14 alkyl, C3-6 cycloalkyl, C2—4 alkenyl, C2—4 alkynyl and C14 alkoxy of R1, R2 and R3 are each optionally substituted with l or 2 substituents ndently selected from halo, OH, CN and C14 alkoxy, R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci—4 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, (5-14 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, CN, N02, ORa, SRa, NHORa, , C(O)NRaRa, C(O)ORa, OC(O)Ra, RaRa, NHRa, NRaRa, NRaC(O)Ra, )ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaC(=NOH)NRaRa, NRaC(=NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered aryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1—4 alkyl- C3—io cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 , and (4-10 membered heterocycloalkyl)-C1.4 alkyl- of R4, R5, R6, R7 and R8 are each optionally substituted with 1, 2, 3, 4 or 5 Rb substituents, or two adjacent R8 substituents on the Cy ring, taken er with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered aryl ring or a fused C3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or ered heteroaryl ring and fused C3-6 cycloalkyl ring are each optionally tuted with 1, 2 or 3 independently selected Rb substituents, or two R5 substituents attached to the same carbon atom, taken er with the carbon atom to which they are attached, form a C3-6 cycloalkyl ring or 4-, 5-, 6- or 7- membered heterocycloalkyl ring, wherein the C3-6 cycloalkyl ring and 4-, 5-, 6- or 7- membered heterocycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents, R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3—io cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1—4 alkyl-, C3-10 cycloalkyl-C1.4 alkyl-, (5-14 membered aryl)-C1—4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, N02, OR“, SR“, NH2, NHR“, NRHR“, NHOR“, C(O)R“, C(O)NR“R“, C(O)OR“, OC(O)R“, OC(O)NR“R11, NR11C(O)R11, O)OR11,NR11C(O)NR11R11, C(=NR11)R11, C(=NR11)NR11R11, NR11C(=NR11)NR11R11,NR11C(=N0H)NR11R11, NR11C(=NCN)NR11R11, NR“S(O)R11, NR“S(O)2R11, NR“S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, or S(O)2NR11R11, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-1o cycloalkyl, 5-14 membered aryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci—4 , C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered aryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R9 are each optionally substituted with 1, 2 or 3 Rb substituents, each R11 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of R11 are each ally substituted with l, 2 or 3 Rb substituents, each Ra is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 , and (4-10 membered heterocycloalkyl)-Ci-4 , wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of , (5-10 Ra are each optionally substituted with l, 2 or 3 Rd substituents, each Rb tuent is independently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci— 6haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 ed heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, CN, OH, NH2, N02, NHORC, ORG, SRC, C(O)RC, C(O)NRCRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, )NRCRC, NRCC(=NRC)NRCRC, NRCC(=NOH)NRCRC, NCN)NRCRC, NHRC, NRCRC, NRCC(O)RC, NRCC(O)ORC, NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC, S(O)NRCRC, S(O)2RC and S(O)2NRCRC, wherein the C16 alkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6- 10 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 , (5-10 membered heteroaryl)-Ci—4 alkyl-and (4- 10 ed heterocycloalkyl)-Ci-4 alkyl- of Rb are each further optionally substituted with 1-3 ndently selected Rd substituents, each RC is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 lkyl-Ci.4 alkyl-, (5-10 ed heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- ed heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- of , (5-10 RC are each optionally substituted with l, 2 or 3 Rf substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci-4 , (5-10 membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)0Rg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, )NRgRg, NRgC(=NRg)NRgRg, NRgC(=NOH)NRgRg, NRgC(=NCN)NRgRg, S(O)Rg, S(O)NRgRg, g, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg, wherein the C1-6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered aryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl- , (5-10 of Rf are each optionally substituted with l, 2 or 3 R11 substituents independently selected from C1—6 alkyl, Ci—6 haloalkyl, halo, CN, phenyl, C3—6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, NHOR", 0R0, SR0, C(O)R°, C(O)NR°R°, C(O)OR°, OC(O)R°, OC(O)NR°R°, NHRO, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, NR°C(O)OR°, C(=NR°)NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O)2R°, NR°S(O)2R°, NR°S(O)2NR°R°, and S(O)2NR°R°, wherein the C16 alkyl, Ci-6 haloalkyl, phenyl, C3—6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R11 is optionally substituted with l, 2 or 3 Rq substituents, each Rd is independently selected from C16 alkyl, Ci.6 haloalkyl, halo, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl- C340 cycloalkyl-Ci—4 alkyl-, (5-10 membered aryl)-Ci—4 alkyl-, (4-10 membered heterocycloalkyl)-Ci.4 alkyl-, CN, NH2, NHORe, ORG, SR6, C(O)Re, C(O)NReRe, e, e, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, n the C1-6 alkyl, Ci—6 haloalkyl, C640 aryl, 5-10 membered heteroaryl, C340 cycloalkyl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of RC1 are each optionally substituted with 1-3 independently selected Rf substituents, each R6 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 ed heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered aryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 , wherein the C16 alkyl, Ci—6 kyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 i—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl- and (4-10 ed heterocycloalkyl)-Ci—4 alkyl- of , (5-10 Re are each ally substituted with l, 2 or 3 ndently selected Rf substituents, each Rg is independently selected from H, C1—6 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 , wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl- and (4-10 membered heterocycloalkyl)-Ci-4 alkyl- of Rg are each optionally substituted with 1-3 Rp substituents independently selected from C16 alkyl, Ci—6 haloalkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered aryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci—4 alkyl- membered heteroaryl)-Ci-4 alkyl-, (4-10 membered heterocycloalkyl)—Ci.4 alkyl-, halo, , (5-10 CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)0Rr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(=NRr)NRrRr, NRrC(=NRr)NRrRr, NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C16 alkyl, Ci.6 haloalkyl, C2—6 l, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 ed heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci—4 alkyl- and (4-10 membered cycloalkyl)-Ci—4 alkyl- of Rp is optionally substituted with l, 2 or 3 Rq tuents, or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 R11 substituents independently selected from C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7 membered heterocycloalkyl, C640 aryl, 5-6 membered heteroaryl, C340 cycloalkyl-Ci-4 alkyl-, (5-6 membered heteroaryl)-Ci-4 , (4-7 membered heterocycloalkyl)-Ci—4 alkyl-, Ci.6 haloalkyl, C2—6 alkenyl, C2.6 alkynyl, halo, CN, 0R1, SR1, NHORi, C(O)Ri, iRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, NOH)NRiRi, NRiC(=NCN)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C16 alkyl, Ci.6 haloalkyl, C340 cycloalkyl, 4-7 membered cycloalkyl, C640 aryl, 5-6 membered heteroaryl, C340 cycloalkyl-Ci—4 alkyl-, (5-6 membered heteroaryl)-Ci—4 , (4-7 membered heterocycloalkyl)-Ci—4 alkyl- of R11 are each optionally substituted by l, 2, or 3 Rj substituents independently ed from C14 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, C2—4 alkenyl, C2.4 alkynyl, halo, Ci—4 haloalkyl, Ci.4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(0)NRkRk, C(O)0Rk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(0)NRkRk, NRkC(0)0Rk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(0)NRkRk, k, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk, or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S, or any two RC substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh substituents, or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with l, 2, or 3 independently selected Rh substituents, or any two Rg substituents together with the en atom to which they are attached form a 4-, 5-, 6-, or ered cycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh substituents, or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh substituents, or any two Rk tuents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh tuents, or any two R0 tuents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with l, 2, or 3 independently selected Rh substituents, or any two Rr substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with l, 2, or 3 independently selected Rh substituents, each R1, Rk, R0 or Rr is ndently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, Ci—4 haloalkyl, C2—4 alkenyl, and C24 alkynyl, wherein the C14 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, 4-6 membered heterocycloalkyl, 5 or ered heteroaryl, C2—4 alkenyl, and C24 l of R1, Rk, R0 or Rr are each optionally substituted with 1, 2 or 3 Rq substituents, each Rq is independently selected from OH, CN, -COOH, NH2, halo, C1-6 haloalkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, NHR12 and NR12R12, wherein the C1-6 alkyl, , C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with halo, OH, CN, -COOH, NH2, Ci—4 alkoxy, Ci-4 kyl, Ci.4 haloalkoxy, phenyl, C3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R12 is independently C1-6 alkyl, I is a single bond or a double bond to maintain ring A being aromatic, and the subscript n is an integer of 1, 2, 3 or 4.
3. The compound of claim 1, having Formula (11): R2 (II) or a pharmaceutically acceptable salt or a stereoisomer thereof.
4. The compound of claim 1, having Formula (111): R9 G Cy “\H/U (Ron R1 R3 R2 (111) or a pharmaceutically acceptable salt or a stereoisomer f.
5. The compound of claim 1, having Formula (IV): N/—G\2G1 11%;WR5)” (IV) or a pharmaceutically acceptable salt or a isomer thereof.
6. The compound of claim 1, having Formula (V): of}:fiif‘z or a pharmaceutically acceptable salt or a stereoisomer thereof.
7. The compound of claim 1, having Formula (VI): ::RHW/KA/ N’NFGCG (R5)n or a pharmaceutically able salt or a stereoisomer thereof.
8. The compound of claim 1, having Formula (VII): R9 N //<— (R5)n (VII) or a pharmaceutically acceptable salt or a stereoisomer thereof.
9. The nd of any one of claims 1-8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2 and R3 are each independently selected from H, C14 alkyl, C2-4 alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci-4 haloalkyl, or Ci.4 haloalkoxy.
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1 is H, R2 is H or halo, and R3 is H.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or a stereoisomer f, wherein Cy is phenyl, 5- or 6-membered heteroaryl, C3-6 cycloalkyl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected R8 substituents, or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered aryl ring or a fused C3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or ered heteroaryl ring each have 1-4 heteroatoms as ring s selected from N, O and S and n the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-6 cycloalkyl ring are each optionally substituted with l, 2 or 3 independently selected Rb substituents.
12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Cy is phenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, dyl, 3,6-dihydro-2H-pyranyl, exyl, cyclohexenyl, 2,3-dihydro-l,4- benzodioxinyl, l,3-benzodioxinyl, 2-methylindazolyl or ylindazolyl, each of which is optionally substituted with l to 5 R8 substituents.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 koxy, CN, N02, and NH2.
14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R9 is halo, C1-6 alkyl, or CN.
15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R9 is CH3, CN or halo.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Z is S, CR4, NR4, or N and R4 is independently H or C1-6 alkyl.
17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Z is S, CH, NCH3 or N.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or a stereoisomer thereof, n Y1 is C or N and Y2 is C.
19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Y1 is C and Y2 is N.
20. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or a is ed from:
21. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or a isomer thereof, wherein (i) Y1 is N, Y2 is C and Z is N, (ii) Y1 is N, Y2 is C and Z is CR4, (iii) Y1 is C, Y2 is N and Z is N, (iv) Y1 is C, Y2 is N and Z is CR4, (V) Y1 is C, Y2 is C andZ is S, or (Vi) Y1 is C, Y2 is C andZ is O.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R5 is H.
23. The compound of any one of claims 1-22, or a ceutically acceptable salt or a isomer thereof, wherein G1 is NR6 and G2 is CR7R7.
24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein G1 is CRGR6 and G2 is NR7.
25. The compound of claims 23 or 24, or a pharmaceutically acceptable salt or a stereoisomer thereof, n R6 is H or C1-6 alkyl ally substituted with 1, 2 or 3 Rb substituents.
26. The compound of claims 23 or 24, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R7 is H or C1-6 alkyl optionally substituted with 1, 2 or 3 Rb substituents.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 koxy, CN, OH, NH2, ORG, C(O)RC, C(O)NRCRC, and C(O)ORC.
28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein each Rb tuent is independently selected from C1-6 alkyl, CN, OH, and C(O)ORC.
29. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) G1 is NR6 and G2 is CR7R7, or (ii) G1 is CRGR6 and G2 is NR7, X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, Z is O, S, N, NR4 or CR4, Y1 and Y2 are each ndently N or C, provided Y1 and Y2 are not simultaneously Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to l4-membered heteroaryl, or 4- to lO-membered heterocycloalkyl, each of which is optionally tuted with l to 5 independently selected R8 substituents, R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-6 cycloalkyl, C2—4 alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, Ci.4 haloalkoxy, NH2, -NH- C1—4 alkyl, -N(C1—4 alkyl)2, C(O)R10, C(O)NR1°R1°, C(O)OR10, OC(O)R1°, OC(O)NR10R10, NR1°C(O)R1°, NR1°C(O)OR1°, NR1°S(O)R10, NR1°S(O)2R1°, NRIOS(0)2NR10R10, S(O)R1°, S(O)NR1°R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is ndently selected from H and C14 alkyl optionally substituted with l or 2 groups independently selected from halo, OH, CN and C14 alkoxy, and wherein the C14 alkyl, C3-6 cycloalkyl, C2—4 l, C2—4 alkynyl and C14 alkoxy of R1, R2 and R3 are each optionally substituted with l or 2 tuents independently selected from halo, OH, CN and C14 alkoxy, R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)0Ra, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)R"‘, S(O)NR"‘R"‘, S(O)2R"‘, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R4, R5, R6, R7 and R8 are each optionally substituted with l, 2, 3, 4 or 5 Rb substituents, or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or ered heterocycloalkyl ring, a fused 5- or ered heteroaryl ring or a fused C3-6 cycloalkyl ring, wherein the fused 5-, 6- or ered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and n the fused phenyl ring, fused 5-, 6- or 7-membered cycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-6 cycloalkyl ring are each optionally substituted with l, 2 or 3 independently selected Rb substituents, R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, OR“, SR“,NH2,NHR11,NR11R11,NHOR11, C(O)R11, C(0)NR11R11, C(O)OR11, OC(O)R“, OC(O)NR“R“,NR“C(O)R11,NR11C(O)OR“,NR“C(O)NR“R11,NR“S(O)R11, NR“S(O)2R11, NR“S(O)2NR11R“, S(O)R“, S(O)NR11R“, S(O)2R“, or S(O)2NR“R11, wherein the C16 alkyl, C2—6 alkenyl, C2—6 alkynyl, Ci.6 haloalkyl, and C16 koxy of R9 are each optionally tuted with 1, 2 or 3 Rb substituents, each R11 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, and C26 alkynyl, each Ra is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, and C26 alkynyl, each Rb substituent is independently selected from halo, C16 alkyl, Ci.6 haloalkyl, Ci— 6haloalkoxy, CN, OH, NH2, N02, NHORC, ORG, SR9, C(O)RC, C(O)NRCRC, C(O)ORC, OC(O)RC, OC(O)NRCRC, NHRC, NRCRC, )RC, NRCC(O)ORC, NRCC(O)NRCRC, NRCS(O)RC, NRCS(O)2RC, NRCS(O)2NRCRC, S(O)RC, S(O)NRCRC, S(O)2RC and S(O)2NRCRC, wherein the C16 alkyl, Ci—6 haloalkyl, and C16 haloalkoxy of Rb are each r optionally substituted with 1-3 independently selected Rd substituents, each RC is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, and C26 alkynyl, wherein the C16 alkyl, Ci.6 kyl, C2—6 alkenyl, and C26 alkynyl of RC are each optionally substituted with 1, 2 or 3 Rf substituents independently selected from C16 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)0Rg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, )NRgRg, NRgC(O)ORg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg, each Rd is independently ed from C16 alkyl, Ci—6 kyl, halo, CN, NH2, ORG, SR6, C(O)Re, C(O)NReRe, C(O)ORe, e, ReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, each R6 is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 alkynyl, C640 aryl, C340 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C640 i—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-, each Rg is independently selected from H, C16 alkyl, Ci.6 haloalkyl, C2—6 alkenyl, C2—6 l, C640 aryl, C340 lkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C640 aryl-Ci—4 alkyl-, C340 cycloalkyl-Ci.4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci—4 alkyl-, I is a single bond or a double bond to maintain ring A being aromatic, and the subscript n is an integer of 1, 2, 3 or 4.
30. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) G1 is NR6 and G2 is CR7R7, or (ii) G1 is CRGR6 and G2 is NR7, X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, Z is S, N, NR4 or CR4, Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously Cy is C6-10 aryl, C3-10 cycloalkyl, 5- to l4-membered heteroaryl, or 4- to lO-membered heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected R8 substituents, R1, R2 and R3 are each independently selected from H, C14 alkyl, C3-6 cycloalkyl, C2—4 alkenyl, C2.4 alkynyl, halo, CN, OH, Ci-4 , Ci.4 haloalkyl, Ci.4 haloalkoxy, NH2, -NH- C1-4 alkyl, and -N(Ci-4 alkyl)2, R4, R5, R6, R7 and R8 are each independently selected from H, halo, C1-6 alkyl, C2-6 l, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, ORa, SRa, C(O)Ra, C(O)NRaRa, and C(O)ORa, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R4, R5, R6, R7 and R8 are each optionally substituted with l, 2, 3, 4 or 5 Rb substituents, or two nt R8 tuents on the Cy ring, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-6 cycloalkyl ring, wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or ered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-6 cycloalkyl ring are each optionally substituted with l, 2 or 3 ndently selected Rb substituents, R9 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 kyl, C1-6 haloalkoxy, CN, N02, or NH2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 haloalkoxy of R9 are each optionally tuted with l, 2 or 3 Rb substituents, each Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each Rb substituent is ndently selected from halo, C1-6 alkyl, C1-6 haloalkyl, Ci— shaloalkoxy, CN, OH, NH2, N02, ORG, SR6, C(O)RC, C(O)NRCRC, C(O)ORC, NHRC, NRCRC, and NRCC(O)RC, wherein the C1-6 alkyl, C1-6 haloalkyl, and C1-6 haloalkoxy of Rb are each further optionally tuted with 1-3 independently selected Rd substituents, each RC is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, NH2, ORG, SR6, C(O)Re, C(0)NReRe, C(0)0Re, NHRe, NReRe, and NReC(0)Re, each R6 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, I is a single bond or a double bond to maintain ring A being aromatic, and the subscript n is an integer of 1 or 2.
31. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) G1 is NR6 and G2 is CR7R7, or (ii) G1 is CRGR6 and G2 is NR7, X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, Z is S, N, NR4 or CR4, Y1 and Y2 are each independently N or C, provided Y1 and Y2 are not simultaneously Cy is phenyl, C3-10 cycloalkyl, 5- to l4-membered heteroaryl, or 4- to bered heterocycloalkyl, each of which is optionally substituted with l to 5 independently selected R8 substituents, R1, R2 and R3 are each independently selected from H, C14 alkyl, C2—4 alkenyl, C2—4 alkynyl, halo, CN, OH, Ci-4 alkoxy, Ci.4 haloalkyl, or Ci.4 haloalkoxy, R4, R5, R6, R7 and R8 are each independently ed from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 l, C1-6 haloalkyl, C1-6 haloalkoxy, CN, N02, ORa, and "‘, n the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of R4, R5, R6, R7 and R8 are each ally substituted with l or 2 Rb substituents, or two adjacent R8 substituents on the Cy ring, taken together with the atoms to which they are attached, form a fused 5-, 6- or 7-membered heterocycloalkyl ring, or a fused 5- or 6-membered heteroaryl ring, wherein the fused 5-, 6- or 7-membered cycloalkyl ring and fused 5- or ered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or ered heteroaryl ring are each optionally substituted with l or 2 independently selected Rb substituents, R9 is halo, C1-6 alkyl, or CN, each Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each Rb substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1— shaloalkoxy, CN, OH, NH2, ORG, C(O)RC, C(O)NRCRC, and C(O)ORC, each RC is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, I is a single bond or a double bond to maintain ring A being aromatic, and the subscript n is an integer of 1 or 2.
32. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound is selected from: yano(2,3-dihydro-l,4-benzodioxinyl)phenyl]-4,5,6,7- tetrahydro[1 azolo[5,4-c]pyridinecarboxamide, N—(2-cyanobiphenylyl)-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridine carboxamide, \l-[2-cyano(l-methyl-lH-indazolyl)phenyl]-4,5,6,7- tetrahydro[1 ,3]thiazolo[5,4-c]pyridinecarboxamide, \I-(2-cyano-2'-fluorobiphenylyl)-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridine carboxamide, \I-(2-cyano-2'-fluoro-3'-methoxybiphenylyl)-4,5,6,7-tetrahydro[l,3]thiazolo[5,4- c] pyridinecarboxamide, \l-[2-cyano(2,3-dihydro- l -benzofuranyl)phenyl]-4,5,6,7- tetrahydro[1 ,3]thiazolo[5,4-c]pyridinecarboxamide, N—(2-cyanocycloheX- l -en-l -ylphenyl)-4,5,6,7-tetrahydro[ l ,3]thiazolo[5,4- c] pyridinecarboxamide, yanocyclohexylphenyl)-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridine carboxamide, N—(2-cyan0-2',6'—difluor0biphenyly1)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4- c] pyridine-Z-carboxamide; N-[2-cyan0(2,3-dihydr0-1,4-benzodioxiny1)pheny1]-4,5,6,7- tetrahydropyrazolo[1,S-a]pyrazine-Z-carboxamide; N-[2-cyan0(2,3-dihydro-1,4-benzodioxiny1)pheny1](2-hydr0xyethy1)-4,5,6,7- tetrahydropyrazolo[1,S-a]pyrazine-Z-carboxamide; \I-[2-cyano(2,3-dihydro-1 ,4-benzodioxiny1)pheny1] -1 -methy1-4,5,6,7- tetrahydro-1H-imidazo[4,5-c] pyridine-Z-carboxamide; \I-(2-cyan0(2,3-dihydrobenzo[b] [1 ,4]dioxiny1)pheny1)—5-(2-hydr0xyethy1)—1 - methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyfidinecarb0xamide; \I-[2-cyan0(2,3-dihydr0-1,4-benzodioxiny1)pheny1]-5,6,7,8- tetrahydr0[1,2,4]tn'azolo[1,5-a]pyrazine-Z-carboxamide; \I-(2,3'-dicyan0-2'-flu0r0bipheny1y1)—4,5,6,7-tetrahydro[1,3]thiazolo[5,4- c]pyridinecarboxamide; \I-(2-cyano-3'-meth0xybiphenyl-3 ,5,6,7-tetrahydrothiazolo[5,4-c]pyfidine carboxamide; \I-(2-cyan0-3'-flu0ro-5'-methoxybipheny1y1)-4,5,6,7-tetrahydr0[1,3]thiazolo[5,4- c]pyridinecarboxamide; \I-(2'-chlor0cyanobipheny1y1)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyfidine carboxamide; cyano-2'-fluor0-3'-meth0xybipheny1y1)-5,6,7,8-tetrahydroimidazo[1,2- a] pyrazine-Z-carboxamide; N—[3-(2,3-dihydr0-1,4-benzodioxiny1)methy1pheny1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; N—(2'-fluor0-3'-methoxymethy1bipheny1—3-y1)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4- c] pyridine-Z-carboxamide; flu0r0-3'-methoxymethy1bipheny1—3-y1)methy1-4,5,6,7-tetrahydro-1H- imidazo[4,5-c]pyridine-Z-carboxamide; N—[2-methy1(1-methy1-1H-indazoly1)pheny1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; N-[2'-fluoro-3'-(hydroxymethy1)methy1biphenyly1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; N—[3-(1H-indazoly1)methy1pheny1]-4,5,6,7-tetrahydro[ 1 ,3]thiazolo[5,4- c] pyridine-Z-carboxamide; N—(2-methy1bipheny1y1)-4,5,6,7-tetrahydr0[1,3]thiazolo[5,4-c]py1idine carboxamide; 5-(2-hydr0xyethyl)-N-(2-methy1bipheny1y1)-4,5,6,7-tetrahydr0thiazolo[5,4- c] pyridine-Z-carboxamide; 2-(2-(2-methy1bipheny1y1carbamoy1)-6,7-dihydr0thiazolo[5,4-c]pyridin-5 (4H)- y1)acetic acid; N-[2-methy1(2-methy1-2H-indazoly1)pheny1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; N—(2'-cyanomethy1bipheny1y1)-4,5,6,7-tetrahydr0[1,3]thiazolo[5,4-c]pyfidine-Z- carboxamide; \I- [2'-(cyanomethy1)methy1bipheny1-3 -y1] -4,5 ,6,7-tetrahydro [1 ,3]thiazolo[5,4- c] pyridine-Z-carboxamide; \I-(2-chlor0-2'-flu0ro-3'-meth0xybipheny1y1)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4- c]pyridine-Z-carboxamide; chlorobiphenyly1)-4,5 etrahydr0[1,3]thiazolo[5 ,4-c] ne carboxamide; \I-[2-chlor0(2,3-dihydro-1,4-benzodioxiny1)pheny1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; \I-(2-chloro(1-methy1-1H-indazoly1)pheny1)—4,5,6,7-tetrahydrothiazolo[5,4- c] pyridine-Z-carboxamide; \I- [3 -(2,3 -dihydr0-1,4-benzodioxiny1)flu0r0methy1pheny1]-4,5 ,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; \I-[2-(2,3-dihydr0-1,4-benzodioxiny1)methy1pyridiny1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; \I-[S-(2,3-dihydr0-1,4-benzodioxiny1)methy1pyridiny1]-4,5,6,7- tetrahydr0[1,3]thiazolo[5,4-c]pyridine-Z-carboxamide; \I-(2-cyano-2'-flu0r0-3'-meth0xybipheny1y1)methy1-4,5,6,7-tetrahydr0-1H- imidazo[4,5-c]pyridine-Z-carboxamide; \I-(2-cyan0-2'-flu0ro-3'-meth0xybipheny1y1)(2-hydr0xyethy1)methy1-4,5,6,7- tetrahydro-1H-imidazo[4,5-c] pyridine-Z-carboxamide; (2- { [(2-cyan0-2'-flu0r0-3'-methoxybipheny1y1)amin0] carbonyl} methyl tetrahydro-SH-imidazo[4,5-c]pyridiny1)acetic acid; and N—(2-cyano(l-methyl-lH-indazolyl)phenyl)-l-methyl-4,5,6,7-tetrahydro-1H- imidazo[4,5-c]pyridinecarboxamide.
33. A pharmaceutical ition comprising a compound of any one of claims 1-32, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
34. A method of inhibiting PD-l/PD-Ll interaction, said method comprising administering to a patient a compound of any one of claims 1-32, or a pharmaceutically able salt or a stereoisomer thereof.
35. A method of treating a disease or disorder associated with inhibition of PD-l/PD-Ll interaction, said method comprising administering to a t in need thereof a therapeutically effective amount of a compound of any one of claims 1-32, or a pharmaceutically acceptable salt or a stereoisomer thereof.
36. A method of ing, stimulating and/or increasing the immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a nd of any one of claims 1-32, or a pharmaceutically acceptable salt or a stereoisomer thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/352,485 | 2016-06-20 | ||
| US62/396,353 | 2016-09-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ788114A true NZ788114A (en) | 2022-05-27 |
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