WO2019060860A1

WO2019060860A1 - Heteroaryl compounds as cxcr4 inhibitors, composition and method using the same

Info

Publication number: WO2019060860A1
Application number: PCT/US2018/052503
Authority: WO
Inventors: Xiaohu Zhang; Jiyue ZHENG; Haikuo MA
Original assignee: Suzhou Yunxuan Yiyao Keji Youxian Gongsi
Priority date: 2017-09-25
Filing date: 2018-09-24
Publication date: 2019-03-28
Also published as: KR20200058443A; EP3687540A4; EP3687540A1

Abstract

The present disclosure provides heteroaryl compounds of Formula (I), processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of diseases and disorders, arising from or related to the CXCR4 pathway.

Description

HETEROARYL COMPOUNDS AS CXCR4 INHIBITORS, COMPOSITION AND METHOD USING THE SAME

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Chinese Patent Applications 201710875041.9, filed on September 25, 2017; 201810265417.9, filed on March 28, 2018; 201810710340.1, filed on July 2, 2018; and 201811034891.7, filed on September 5, 2018, 2018; all of which are hereby incorporated by reference.

FIELD OF INVENTION

[0002] The present invention generally relates to heteroaryl compounds and, more particularly, relates to novel heteroaryl compounds that are useful in the therapies targeting C-X-C chemokine receptor type 4 (CXCR4) inhibitors, and use of the CXCR4 inhibitors for therapeutic intervention in infectious diseases, inflammatory diseases, tumors, and cancers.

BACKGROUND OF THE INVENTION

[0003] C-X-C chemokine receptor type 4 (CXCR4) is a transmembrane protein that belongs to the G-protein-coupled receptors and it is involved in physiological processes in the hematopoietic and immune systems. Studies show that CXCR4 is expressed in tissues including lymphatic tissues, thymus, brain, spleen, stomach and small intestine. CXCR4 /transmits signals from its natural chemokine ligand, stromal cell-derived factor (SDF)-la, to intracellular biological pathways via G-proteins. The interaction between CXCR4 and SDF-la has been targeted in various therapeutic treatments for a number of diseases, including, for example, human immunodeficiency virus (HIV) infection, cancers, tumors, and inflammation and autoimmune disease such as rheumatoid arthritis and allergic asthma. The CXCR4 antagonist, Plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells. See Cho W.T.. et al., /. Med. Chem. 2011; 55: 977-94; Debnath B. et al., Theranostics 2013, 3 (1): 47-75.

SUMMARY OF THE INVENTION [0004] The present disclosure provides heteroaryl compounds as CXCR4 inhibitors, and compositions and applications thereof. These disclosed heteroaryl compounds, and compositions and applications thereof, may effectively inhibit necrosis, thereby finding application in treatments of necrotic pathway-related diseases and disorders, including, for example, inflammation, tumors, metabolic diseases and neurodegenerative diseases such as cerebral ischemia and stroke.

[0005] An aspect of the present disclosure provides a compound of formula I:

I

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein

Ar is 5-10 membered heteroaryl comprising one N and 1-3 additional heteroatoms independently selected from the group consisting of N, O, and S, and Ar is unsubstituted or substituted with 1-4 I½;

W is , each X is independently a bond, CR₃2R₃₃, O, NR₃4,

S, S(=0) or S(=0)₂; n is 0, 1, 2 or 3; o and p are different integers with values of 0 or 1; wherein when o is 0, p is 1, Bi is CRn, B2 is N, and Bi is bonded with Ar; wherein when o is 1, p is 0, Bi is N, B2 is CRn, and the carbon bearing R' 5 and R'₆ is bonded with Ar; or W is

, wherein the carbon bonded with R₅ and R₆ is connected the ring carbon bonded with Y;

Y is , wherein the carbon bonded with R₃ is bonded with the carbon bonded with R2;

each of Ri, R2, R₃, and R₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(d_₆ alkyl), -NHS(=0)₂(C₁_₆ alkyl), -S(=0)₂(C₁_₆ alkyl), d_₆ alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium; or R₄ together with the atoms it attached to forms a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

each of R5 and R₆ is independently selected from the group consisting of H, deuterium, -CN, Ci-6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_6 alkyl), -N(Ci_6 alkyl)2, -NHC(=0)(Ci_6 alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci_₃ alkoxy;

or R₅ and R₆ together forms

, and D₃ bonded with R₄ to form:

1) , wherein D₃ is N or CR'₄, and Di is NR'₄, O, S or C(R'₄)₂,

2) , wherein D₃ is N or CR'₄, O_t is NR'₄, O, S or C(R'₄)₂, D₂ is

NR'₄, or C(R'₄)₂, or

3) , wherein D₃ is N or CR'₄, Di is N or CR'₄, and D₂ is N or

CR'₄,

wherein each R'₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -N(Ci_₆ alkyl)₂, -S(=0)₂(Ci_6 alkyl), C₃_₆ cycloalkyl, Ci_-8 alkoxy, C₂_₆ alkenyl, and C₂_₆ alkynyl, wherein each of -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -S(=0)₂(C_1-6 alkyl), Ci-6 alkyl, C₃_₆ cycloalkyl, Ci_-8 alkoxy, C₂_₆ alkenyl, and C₂_₆ alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium;

R₇ is selected from the group consisting of H, deuterium, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-6

heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, amino, -OH, acyl, -CN, Ci_6 alkoxy, -NH(d_₆ alkyl), -N(d_₆ alkyl)₂, -C(=0)0(d_₆ alkyl), -C(=0)NH₂, -C(=0)NH(d_₆ alkyl), -C(=0)N(d_₆ alkyl)₂, -NHC(=0)0(d_₆ alkyl), -S(=0)₂(d_₆ alkyl), and C₃-₆ cycloalkyl;

each of Rg and R9 is independently selected from the group consisting of H, deuterium, -CN, Ci-6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, and C₁-3 alkoxy; or R₇ and Rg, and atoms attached thereto, form a ring;

or Rg and R9, together with atoms they attached to, form a ring;

each of R' 5, R'₆, R'₇, R's, R' 9, R' 10, R11, R32, and R33 is independently selected from the group consisting of H, deuterium, -CN, halide, Ci_6 alkyl, -C(=0)0(Ci_6 alkyl), C₃-6 cycloalkyl, Ci_6 alkoxy, and -OSi(Ci_6 alkyl)3, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_6 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, C₃-6 cycloalkyl, Ci_

6 alkyl, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), -NHC(=0)NH(Ci_₆ alkyl),

-NHC(=0)N(Ci_6 alkyl)₂, -NHS(=0)₂(Ci_6 alkyl), and Ci_6 alkoxy;

each of R19, R₂o, R₂i, R₂₂, R25, R₂₆, R₂₇, R₂8, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C₁-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₁-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_6 alkyl), -NHC(=0)0(Ci_6 alkyl), Ci_6 alkyl, and C1-3 alkoxy; or R21 and R2₃, together with atoms they attached to, form a ring; or R19 and R27, together with atoms they attached to, form a ring; or R21 and R27, together with atoms they attached to, form a ring; or R19 and R2₆, together with atoms they attached to, form a ring; or R21 and R2₆, together with atoms they attached to, form a ring;

R2₃ is selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a 5-7 membered heterocycle;

R24 is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, C₃-6 heterocycloalkyl comprising N or O, -C(=0)(Ci_6 alkyl), -C(=0)0(Ci_6 alkyl), and -C(=0)NH(Ci_6 alkyl), wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, amino, Ci_6 alkyl, C₃-6 cycloalkyl, C₃-6 heterocycloalkyl comprising N or O, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl),

-NHC(=0)0(Ci_6 alkyl), and C1-3 alkoxy; or R and R24, together with atoms they attached to, form a 5-7 membered heterocycle;

R₃1 is selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkynyl, C2-6 alkenyl, -S(Ci_6 alkyl), -NH(Ci_6 alkyl), -N(Ci_6 alkyl)₂, aryl, 5-7 membered heteroaryl comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, and 5-7 membered heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, aryl, heteroaryl, and heterocycle is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_6 alkoxy;

R34 is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, -C(=0)(Ci_8 alkyl), -S(=0)₂(C_1-8 alkyl), -C(=0)0(C_1-6 alkyl), and -C(=0)NH(Ci_₆ alkyl), wherein each of Ci_6 alkyl, Ci_-8 alkyl, and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci_₃ alkoxy;

R is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C_3- heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R and R₂₄, together with N atom they attached to, form a 5-7 membered heterocycle; or R and R₂i, together with N atom they attached to, form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C_3- heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R' and R₂i, together with atoms they attached to, form a 5-7 membered heterocycle.

[0006] In some embodiments of the present disclosure, the disclosed compound is according Formula la

la

Ar is unsubstituted or substituted with 1-4 groups of R₃1, and Ar is selected from the group consisting of:

each X is independently a bond, CR₃2R₃₃, O, or NR₃4;

each of R19, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, and C1-3 alkoxy; or R19 and R27, together with atoms they attached to, form a ring; or R21 and R27, together with atoms they attached to, form a ring;

each of R2₃ and R24 is independently selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a 5-7 membered heterocycle;

R₃1 is selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, C2-6 alkynyl, C2-6 alkenyl, -S(Ci_6 alkyl), -NH(Ci_6 alkyl), -N(Ci_6 alkyl)2, aryl, 5-7 membered heteroaryl comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, and 5-7 membered heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, aryl, heteroaryl, and heterocycle is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_6 alkoxy;

R is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, C₃-8 heterocycloalkyl comprising N or O, -C(=0)(Ci_6 alkyl), -C(=0)0(Ci_6 alkyl), and -C(=0)NH(Ci_6 alkyl) wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8

heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R and R24, together with N atom they attached to, form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C3-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R' and R21, together with N atom they attached to, form a 5-7 membered heterocycle.

[0007] In some embodiments of the present disclosure, the disclosed compound is according to Formula lb:

lb

Ar is unsubstituted or substituted with 1-4 groups of R31 , and Ar is selected from the group consisting of:

each X is independently a bond, CR₃2R₃₃, O, or NR₃4;

R is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R and R24, together with N atom they attached to, form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R' and R21, together with N atom they attached to, form a 5-7 membered heterocycle.

[0008] In some embodiments of the present disclosure, the disclosed compound is according to Formula Ic:

each of Zl, Z2 and Z3 is independently selected from the group consisting of O and

each of R41 and R42 is independently selected from the group consisting of H, deuterium, halide and C1-3 alkyl.

[0009] In some embodiments of the present disclosure, forthe disclosed compound:

each of R19, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, Ci_6 alkyl, and C1-3 alkoxy;

each of R2₃ and R24 is independently selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a 5-7 membered heterocycle; and each of R and R' is independently selected from the group consisting of H, Ci_6 alkyl, C_3- 6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-₆ cycloalkyl, Ci_₃ alkoxy, -S(=0)₂(C_1-6 alkyl), -C(=0)(C_1-6 alkyl), and C₃-₆ heterocycloalkyl comprising N or O.

[0010] In some embodiments of the present disclosure, the disclosed compound is selected from the group consisting of:



[0011] In some embodiments of the present disclosure, the disclosed compound is according to Formula II:

II

wherein

Wi is Di, Di-D₂, or Di=D₂, and Di is bonded with the pyridine ring;

each of Ri, R2, and R3 is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -N(Ci_₆ alkyl)₂, -S(=0)2(Ci_6 alkyl), C3-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium;

R₇ is selected from the group consisting of H, deuterium, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl, and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, amino, -OH, acyl, -CN, Ci_₆ alkoxy, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -C(=0)0(C_1-6 alkyl), -C(=0)NH₂, -C(=0)NH(Ci_6 alkyl), -C(=0)N(C_1-6 alkyl)₂, -NHC(=0)0(Ci_₆ alkyl), -S(=0)₂(Ci_6 alkyl), and C₃-₆ cycloalkyl;

R2₃ is selected from the group consisting of H, Ci_6 alkyl and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_6 alkyl), -N(C_1-6 alkyl)₂, and Ci_₃ alkoxy;

each of R19, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_6 alkyl), and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a ring; or R19 and R2₆, together with atoms they attached to, form a ring; or R21 and R2₆, together with atoms they attached to, form a ring;

each of R and R24 is independently selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, C₃-6 heterocycloalkyl comprising N or O, -C(=0)(Ci_6 alkyl),

-C(=0)0(Ci_6 alkyl), and -C(=0)NH(Ci_₆ alkyl), wherein each of Ci_₆ alkyl, C₃-₆ cycloalkyl, and C₃-6 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, C₃-6 cycloalkyl, C1-3 alkoxy, and C₃-6 heterocycloalkyl comprising N or O; or R and R24, together with N atom they attached to, form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, C₃-6 cycloalkyl, C1-3 alkoxy, -S(=0)₂(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), and C₃-6 heterocycloalkyl comprising N or O; or R' and R21, together with N atom they attached to, form a 5-7 membered heterocycle.

[0012] In some embodiments of the present disclosure, the disclosed compound is according to

Formula Ila:

Ila

each of Ri, R2, R₃, and R4₃ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -N(Ci_₆ alkyl)₂, -S(=0)2(Ci_6 alkyl), C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium.

[0013] In some embodiments of the present disclosure, the disclosed compound is according to

Formula lib:

lib or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein

each of Di, D2 and D3 is independently selected from the group consisting of N and CR'₄;

each of Ri, R2, R₃, and R'₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -N(Ci_₆ alkyl)₂, -S(=0)2(Ci_6 alkyl), C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium.

[0014] In some embodiments of the present disclosure, for the disclosed compound:

R2₃ is selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_6 alkyl), -N(C_1-6 alkyl)₂, and Ci_₃ alkoxy;

each of R19, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_6 alkyl), and C1-3 alkoxy; or R21 and R2₃, together with atoms they attached to, form a ring;

-C(=0)0(Ci_6 alkyl), and -C(=0)NH(Ci_₆ alkyl), wherein each of Ci_₆ alkyl and C₃-₆ cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, C₃-6 cycloalkyl, C1-3 alkoxy, and C₃-6 heterocycloalkyl comprising N or O; or R and R24, together with atoms they attached to, form a 5-7 membered heterocycle;

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci-3 alkoxy; or R' and R21, together with atoms they attached to, form a 5-7 membered heterocycle.

[0015] In some embodiments of the present disclosure, for the disclosed compound

selected from the group consisting of:



[0016] In some embodiments of the present disclosure, the disclosed compound is according to Formula III:

III

wherein

each of Ai, A₂, and A₃ is independently selected from the group consisting of N and CR44, wherein at least one of Ai, A₂, and A₃ is N;

each of Ri, R2, R3, and R₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), -NHS(=0)₂(Ci_₆ alkyl), Ci_₆ alkyl, C₃-₆ cycloalkyl, Ci_₈ alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C3-6 cycloalkyl, and Ci_ 8 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide and deuterium;

each of R5 and R₆ is independently selected from the group consisting of H, deuterium, -CN, Ci-6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_6 alkyl), -N(Ci_6 alkyf ,

-NHC(=0)(Ci_6 alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci_₃ alkoxy; or R₅ is O or CR^Rte, and R^ and R5, together with atoms they attached to, form a ring;

R₇ is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl comprising an O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl comprising an O;

each of Rg and R9 is independently selected from the group consisting of H, deuterium, -CN, Ci-6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, and C1-3 alkoxy; or R₇ and Rg, and atoms attached thereto, form a ring;

or Rg and R9, together with atoms they attached to, form a ring;

R44 is H, deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy,

-NH(d_₆ alkyl), -N(d_₆ alkyl)₂, -C(=0)NH(d_₆ alkyl), -C(=0)N(d_₆ alkyl)₂, -S(d_₆ alkyl), C2-6 alkenyl, C2-6 alkynyl, 4-7 membered heterocycle comprising 1-3 heteroatoms independently selected from the groups consisting of O, N and S, aryl, and 5-6 membered heteroaryl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, heterocycle, aryl and heteroaryl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH and C1-3 alkoxy;

each of R19, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl),

-NHC(=0)0(Ci_6 alkyl), and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a ring; or R19 and R2₆, together with atoms they attached to, form a ring; or R21 and R2₆, together with atoms they attached to, form a ring;

each of R and R24 is independently selected from the group consisting of H, Ci_6 alkyl,

C₃-6 cycloalkyl, C₃-6 heterocycloalkyl comprising N or O, -C(=0)(Ci_6 alkyl),

-C(=0)0(Ci_6 alkyl), and -C(=0)NH(Ci_₆ alkyl), wherein each of Ci_₆ alkyl, C₃-₆ cycloalkyl, and C₃-6 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, C₃-6 cycloalkyl, C1-3 alkoxy, and C₃-6 heterocycloalkyl comprising N or O; or R and R24, together with N atom they attached to, form a 5-7 membered heterocycle; or R and R21, together with N atom they attached to, form a 5-7 membered heterocycle;

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, C₃-6 cycloalkyl, C1-3 alkoxy, -S(=0)₂(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), and C₃-6 heterocycloalkyl comprising N or O; or R' and R21, together with N atom they attached to, form a 5-7 membered heterocycle; and

each of R45 and R_¾ is independently selected from the group consisting of H, deuterium, halide, C1-3 alkyl; or R45 and R4₆, together with the atoms they attached to, form a ring.

[0017] In some embodiments of the present disclosure, the disclosed compound is according to

Formula Ilia or Illb:

Ilia

Illb

wherein

each of Ei, E₂, and E3 is independently selected from the group consisting of O and

each of R45 and R_¾ is independently selected from the group consisting of H, deuterium, halide, C1-3 alkyl; or R45 and R4₆, together with the atoms they attached to, form a ring. [0018] In some embodiments of the present disclosure, the disclosed compound is according to formula Ilia and Illb, and each of Ei, E₂, and E₃ is independently selected from the group

consisting of CH2, O and ·'^' ; and at least one of Ei, E₂, and E₃ is

[0019] In some embodiments of the present disclosure, the disclosed compound is according to formula Ilia and Illb, and each of Ai and A2 is independently selected from the group consisting of N and CR44, wherein at least one of Ai and A2 is N;

[0020] In some embodiments of the present disclosure, -C(R5R₆)W2 is selected from the group consisting of:

[0021] In some embodiments of the present disclosure, for the disclosed compound is selected from the group consisting of:

[0022] In some embodiments of the present disclosure, of formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb or other compounds disclosed herein, U is unsubstituted or substituted with is unsubstituted or substituted with 1-3 groups selected from the group consisting of deuterium, halide, -OH, C1-3 alk l, and C1-3 alkox , and U is selected from the rou consistin of:

[0023] Another aspect of the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb or other compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0024] Another aspect of the present disclosure provides a combination composition comprising:

(a) a compound of formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb or other compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof; and

(b) one or more additional compounds selected from the group consisting of antitumor agents, anti-cancer agents, antibacterial agents, antiviral agents, central nervous system agents, and anti-diabetes agents.

[0025] Another aspect of the present disclosure provides a compound of formulas I, la, lb, Ic, II,

Ila, lib, III, Ilia, and Illb or other compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for treating diseases, mobilizing stem cells, and treating wounded or burned skin by antagonizing the CXCR4 pathway, wherein the diseases is selected from the group consisting of HIV infection, myocardial infarction, diseases associated with hematopoiesis, inflammation, allergic diseases, asthma, allergic pneumonia, interstitial lung disease, lupus erythematosus, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection, inflammatory bowel disease,

Crohn's disease, ulcerative colitis, scleroderma, psoriasis, dermatitis, retinitis pigmentosa, proliferative vitreoretinopathy, Best's vitelliform macular degeneration, eczema, urticaria, vasculitis, eosinophilic fasciitis, wet and dry age-related macular degeneration (ARMD), diabetic retinopathy, retinopathy of prematurity (ROP), diabetic macular edema, uveitis, retinal vein occlusion, cystic macular edema, glaucoma, vein branch occlusion, breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell carcinoma, thyroid cancer, sarcoma, osteosarcoma, desmofibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T cell lymphoma, chronic and non-progressive anemia, spontaneous or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, liver fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphoblastic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorders, encephaloma, astrocytoma, medulloblastoma, schwannoma, primary neuroectodermal tumor, and pituitary adenoma.

[0026] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure.

Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 depicts the 12G5 assay by compound A42.

[0028] FIG. 2 depicts the 12G5 assay by compound A43.

[0029] FIG. 3 depicts the 12G5 assay by compound A78.

[0030] FIG. 4 depicts the 12G5 assay by compound A83.

[0031] Before proceeding with the detailed description, it is to be appreciated that the following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses thereof. Hence, although the present disclosure is, for convenience of explanation, depicted and described as shown in certain illustrative embodiments, it will be appreciated that it can be implemented in various other types of embodiments and equivalents, and in various other systems and environments. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description. INCORPORATION BY REFERENCE [0032] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0033] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

DEFINITIONS

[0034] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon- carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.

[0035] As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" includes a plurality of such molecules, and the like.

[0036] The term "about" or "nearly" as used herein generally refers to within +/- 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the designated amount.

[0037] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon- carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.

[0038] The term "alkyl" as used herein generally refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-C₈ alkyl), from 1 to 6 carbon atoms (Ci-C₆ alkyl) and from 1 to 4 carbon atoms (Ci-C₄ alkyl), including, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, icri-butyl, pentyl, 2- pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. In some instances, a substituent of an alkyl group is specifically indicated. For example, "cyanoalkyl" refers to an alkyl group substituted with at least one cyano substituent.

[0039] The term "alkenyl" as used herein generally refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-C₈ alkenyl, C2-C₆ alkenyl and C2-C4 alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, including, for example, ethenyl, allyl or isopropenyl. The term "alkynyl" as used herein generally refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond.

Alkynyl groups include C2-C₈ alkynyl, C2-C₆ alkynyl and C2-C4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.

[0040] The term "cycloalkyl" as used herein generally refers to a group that comprises one or more saturated rings in which all ring members are carbon, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl. Cycloalkyl groups do not comprise an aromatic ring or a heterocyclic ring. For example, certain cycloalkyl groups are

C3-C7 cycloalkyl, in which the cycloalkyl group contains a single ring having from 3 to 7 ring members, all of which are carbon. The term "cycloalkenyl" as used herein generally refers to a group that comprises one or more unsaturated rings in which all ring members are carbon.

[0041] The term "alkoxy" as used herein generally refers to an alkyl group as described above attached via an oxygen bridge. Alkoxy groups include Ci-C₆ alkoxy and C1-C4 alkoxy groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, seobutoxy, i<?ri-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.

[0042] The term "alkylamino" as used herein generally refers to a secondary or tertiary amine that has the general structure -NH-R1 or -N(R1)(R2), wherein Rl and R2 are selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Such groups include, but are not limited to, for example, mono- and di-(Ci-C6 alkyl)amino groups, in which each Ci-C ₆ alkyl may be the same or different. It will be apparent that the definition of "alkyl" as used in the term "alkylamino" differs from the definition of "alkyl" used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups.

[0043] The term "alkylthio" as used herein generally refers to an alkyl-substituted thio group, wherein the term alkyl is as defined above.

[0044] The term "halogen" or "halide" as used herein generally refers to fluorine, chlorine, bromine, and iodine. The term "haloalkyl" as used herein generally refers to an alkyl group that is substituted with one or more independently chosen halogens (e.g., "Ci-C₆ haloalkyl" groups have from 1 to 6 carbon atoms and at least one halogen). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1,2,2,2- tetrafluoro-l-trifluoromethyl-ethyl.

[0045] The term "heteroaryl" as used herein generally refers to an aromatic group in which at least one aromatic ring comprises at least one heteroatom selected from N, O and S. Heteroaryls include, for example, 5-12 membered heteroaryls. Examples include, but are not limited to, imidazole, furan, furazan, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, tetrazole, thiazole and thiophene.

[0046] The term "heterocycloalkyl" as used herein generally refers to a ring structure containing

3-12 ring atoms, in which in which at least one ring atom is carbon and at least one ring atom is heteroatom selected from N, O, and S. Examples include, but are not limited to, aziridine, oxiran, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, and

tetrahydrothiophene.

[0047] The term "heterocyclic" or "heterocycle" as used herein generally refers to a ring structure containing 3-12 ring atoms, in which at least one ring atom is carbon and at least one ring atom is heteroatom selected from N, O, and S. A heterocyclic group may be aromatic or non-aromatic. Piperidine and oxetane are non-limiting examples of non-aromatic heterocycles. Thiazole and pyridine are non-limiting examples of aromatic heterocycles.

[0048] The terms "substituent" and "substituted," as used herein, generally denote that a molecular moiety is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom. A straight chain substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a straight chain.

[0049] The term "pharmaceutically acceptable" as used herein generally refers to a form of the compound that is safe for administration to a subject. For example, a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound of formula I, which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.

[0050] Included in the compounds of formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb are the pharmaceutically acceptable salt forms of the free-base compounds. The term

"pharmaceutically-acceptable salts" as used herein generally refers to salts, commonly used to form alkali metal salts and to form addition salts of free acids or free bases, which have been approved by a regulatory agency. Salts are formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.

[0051] In some embodiments, the compound(s) of formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb is used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s), in one embodiment, is combined with one or more pharmaceutically acceptable excipients, including carriers, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.

[0052] The term "excipient" as used herein generally refers to any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration purposes.

[0053] The term "diluent" as used herein generally refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be present in the pharmaceutical composition within granules in the form of a single compound or in the form of a mixture of compounds. Non-limiting examples of diluent include lactose, starch,

pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0054] The term "adjuvant," as used herein generally refers to any substance or mixture of substances that increases the efficacy or potency of a compound disclosed herein on a target where the adjuvant is used together with the compound disclosed herein. However, when the adjuvant is used alone, no pharmacological effect is observed on the same target.

[0055] The terms "treat", "treating," "treatment," and "therapy" as used herein generally refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals. [0056] The phrase "effective amount" as used herein generally refers to quantifying the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. The effective amount, in one embodiment, is administered in a single dosage form or in multiple dosage forms.

[0057] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those of skill in the art.

[0058] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0059] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular hedgehog inhibitor employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0060] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0061] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. The mode of administration can have a large effect on dosage. Higher doses may be used for localized routes of delivery.

[0062] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Dosages for a given compound disclosed herein are readily determinable by those of skill in the art by a variety of means.

PHARMACEUTICAL COMPOSITIONS/FORMULATIONS

[0063] One embodiment provides a pharmaceutical composition comprising a compound of formula I, or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0064] In some embodiments, the compounds described herein are formulated into

pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), herein incorporated by reference for such disclosure. [0065] A pharmaceutical composition, as used herein, refers to a mixture of a compound of formula I with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0066] The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0067] All formulations for oral administration are in dosages suitable for such administration.

Examples of such dosage units are tablets or capsules. In some embodiments, these contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg. A suitable daily dose for a human or other mammal vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.

[0068] Conventional formulation techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

SYNTHETIC METHODS

[0069] Methods of the present invention may include the use of at least one compound of

Formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb, which inhibits necrosis in the regulation of repair and/or functional performance of a wide range of cells, tissues and organs, and have therapeutic and cosmetic applications ranging from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc. Accordingly, the methods and compositions of the present invention include the use of the subject inhibitors for all such uses as inhibitors of necrosis may be implicated. Moreover, the subject methods can be performed on cells which are provided in culture (in vitro), or on cells in a whole animal (in vivo).

[0070] The examples and preparations provided below illustrated and exemplify the compounds described herein and methods of preparing such compounds. In general, the compounds described herein may be prepared by processes known in the general chemical arts.

[0071] The compounds of the present invention can be prepared using various synthetic routes, including those described below, starting from commercially available materials. Starting materials of the invention, are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Functional groups may be removed according to known procedures in the art.

[0072] The protection of functional groups by protecting groups, the protecting groups themselves, and their removal reactions (commonly referred to as "deprotection") are described, for example, in standard reference works, such as J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E. Gross and J.

Meienhofer editors, Academic Press, London and New York (1981).

[0073] All synthetic procedures described herein can be carried out under known reaction conditions, advantageously under those described herein, either in the absence or in the presence (usually) of solvents or diluents.

[0074] The invention further encompasses "intermediate" compounds, including structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from carrying out steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all "intermediates" included in the invention. Further, structures produced by using starting materials in the form of a reactive derivative or salt, or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention.

[0075] New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In select embodiments, such starting materials are used and reaction conditions so selected as to obtain the desired compound(s).

[0076] Starting materials of the invention, are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Protecting groups, their introduction and removal are described above.

[0077] All reagents and solvents were obtained commercially unless stated otherwise. All commercial reagents and solvent were used without purification unless stated otherwise. When required, some reagents and solvents were purified by standard techniques. For example, tetrahydrofuran may be purified by distillation from sodium. All thin-layer chromatography (TLC, GF254) analyses and column purification (100-200 mesh) were performed on silica gel (Qingdao Haiyang Chemical Co. Ltd. or Yantai Chemical Co. Ltd.), using petroleum ether (b.p. 60-90 °C)/ethyl acetate (v/v) as eluent; and spots revealed by UV visualization at 254 nm and I₂ vapor or phosphomolybdic acid. All organic layers after extraction were dried over anhydrous Na₂S0₄ unless stated otherwise. All nuclear magnetic resonance spectra were recorded using a Bruck-400 spectrometer at 400 MHz using TMS as an internal standard. LC-MS was run using an Agilent 1100 system with LC-MSDTrap recorder, diode array detector (DAD) with detecting wavelength at 214 nm and 254 nm, and ESI source. The HPCL column is an Agela Durashell C18 3.5 μιη 4.6x50 mm column. Gradients were run using 0.1 NH₄HCC>3 aqueous solution and acetonitrile with gradient 5/95 to 95/5 in the run time indicated (for example, 5 min), flow rate at 1.8 mL/min.

[0078] The size and scale of the synthetic methods will vary depending on the desired amount of end product. It is understood that while specific reactants and amounts are provided in the Examples, one of skill in the art knows other alternative and equally feasible sets of reactants that will also yield the same compounds. Thus, where general oxidizers, reducers, solvents of various nature (aprotic, apolar, polar, etc.) are utilized, equivalents will be known in the art and are herein contemplated for use in the present methods.

[0079] Many of the steps below indicate various work-ups following termination of the reaction.

A work-up involves generally quenching of a reaction to terminate any remaining catalytic activity and starting reagents. This is generally followed by addition of an organic solvent and separation of the aqueous layer from the organic layer. The product is typically obtained from the organic layer and unused reactants and other spurious side products and unwanted chemicals are generally trapped in the aqueous layer and discarded. The work-up in standard organic synthetic procedures found throughout the literature is generally followed by drying the product by exposure to a drying agent, such as anhydrous Na₂S0₄, to remove any excess water or aqueous byproducts remaining partially dissolved in the organic layer and concentration of the remaining organic layer. Concentration of product dissolved in solvent may be achieved by any known means, such as evaporation under pressure, evaporation under increased temperature and pressure, and the like. Such concentrating may be achieved by use of standard laboratory equipment such as rotary-evaporator distillation, and the like. This is optionally followed by one or more purification steps which may include, but is not limited to, flash column

chromatography, filtration through various media and/or other preparative methods known in the art and/or crystallization/recrystallization. (See, for instance, Addison Ault, "Techniques and Experiments for Organic Chemistry," 6th Ed., University Science Books, Sausalito, Calif., 1998, Ann B. McGuire, Ed., pp. 45-59).

GENERAL SYNTHETIC ROUTES

[0080] The methods and examples provided below illustrated and exemplified the compounds described herein and methods of preparing such compounds. In general, the compounds described herein may be prepared by processes known in the general chemical arts. The following methods are embodiments for some general synthetic routes leading to compounds of Formulas I, la, lb, Ic, II, Ila, lib, III, Ilia, and Illb. Detailed reaction conditions for each Method can be found in the examples shown vide infra.

[0081] The compounds of the present invention can be prepared using various synthetic routes, including those described by methods A-N, BA-BS and AA-AT below, starting from

commercially available materials. Starting materials of the invention, are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processed described in the methods and examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Functional groups may be removed according to known procedures in the art.

[0082] Method A:

[0083] The (6-chloropyrimidin-4-yl)methanol could be converted to 4-chloro- 6chloromethyl)pyrimidinetreated with SOCI₂ (step a).

[0084] Method B:

step a i

[0085] Substituted 4-chloro-3-oxobutanoate could be reacted with amidine and carbonate to give the pyrimidine intermediate (step a). Conversion of the hydroxypyrimidine to the

chloropyrimidine may be achieved with POCl₃(step b).

[0086] Method C, D:

[0087] Substituted 4-chloro-3-oxobutanoate could also be reacted with amidine and DBU to give the pyrimidine intermediate (step a). Conversion of the hydroxypyrimidine to the chloropyrimidine may be achieved with POCl₃(step b).4-aminopyrimidine core may be synthesized via methyl amine substitution (step c) followed by condensation of

hydroxypyrimidine with 1-methylpiperazine (step d). [0088] Method E

s ep R.,

[0089] Pyrimidine-4-carbaldehyde core could be synthesized via cyclization to the pyrimidine core (step a) followed by condensation of hydroxypyrimidine with corresponded amine (step b), following hydrolysis (step c).

[0090] Method F, G, H

step e step d

[0091] The key intermediate 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2- (methylthio)pyrimidine may be formed via cyclization followed condensation 6- (dimethoxymethyl)-2-(methylthio)pyrimidin-4-ol with 1-methylpiperazine (step b) . Then 2- subsituted Pyrimidine-4-carbaldehyde core could be synthesized via oxidation of methyl sulfide to methylsulfonyl (step c), substitution with corresponding alcohol (step f) or amine (step d) followed by hydrolysis (step e, g) or can be formed by Suzuki coupling (step h) followed hydrolysis (step i).

[0092] Method I

step a step b ^F

[0093] The targeted compounds may be formed via cyclization (step a) followed condensation hydroxypyrimidine with 1-methylpiperazine (step b), following substitution with corresponding amine (step c).

[0094] Method J

[0095] 4-(4-methylpiperazin- l-yl)pyrimidine core can be achieved by condensation the amino acid with 2,2-dimethyl-l ,3-dioxane-4,6-dione followed decarboxylation (step a); following cyclization (step b) followed condensation hydroxypyrimidine with 1-methylpiperazine (step c) and at last de-Boc protective group (step c).

[0096] Method K

step a ^Wn ⁰ ^_\

[0097] The pyridine-2-one core could be formed vis treatment pyridine lithium reagent with N- Boc lactam (n = 0, 1, 2). [0098] Method L

[0099] The heteroaromatic core could be substituted with bromine treated with NBS and free radical initiator.

[00100] Method M

s ep a step b

s^teP ^c step d

[00101] The 2-methyl-5-nynaopyrimidine core may be achieved by cyclization (step a) followed condensation hydroxypyrimidine with corresponding amine (step b), following chlorination (step c) and substitution with corresponding amine (step d).

[00102] Method N

[00103] 5-bromo-2-(bromomethyl)imidazo[l,2-a]pyridine may be synthesized by 6- bromopyridin-2-amine cyclization with ethyl 3-bromo-2-oxopropanoate (step a), and then followed by reduction with NaBH₄ (step b) and bromination with PBr₃ (step c).

[00104] Method BA, BB M

[00105] The targeted core can be synthesized via the reductive amination(step a, b) with the ketone, or followed the reductive amination(step c) again with the aldehyde, then de- protective group treated with TFA (step d).

[00106] Method BC

[00107] The targeted core may be achieved by chlorination (step a) with TCCA and substitution with corresponding amine (step b).

[00108] Method BD

0 step a O

[00109] The 6,7-dihydroquinolin-8(5H)-one was treated with NaH and then added 1,2- dibromoethane to give 5',6'-dihydro-8'H-spiro[cyclopropane-l,7'-quinolin]-8'-one (step a).

[00110] Method BE

s ep a

[00111] The spiro[2.5]octan-6-one was reacted withprop-2-yn-l-amineat presence of NaAuCl₄ to give 7',8'-dihydro-5'H-spiro[cyclopropane-l,6'-quinoline (step a).

[00112] Method BF, BG

(1 ) CF3COOH

Method BG

(2) MsCI, TEA, DCM

step d NaOH

[00113] The intermediate l-(3-aminopyridin-2-yl)ethan-l-one may be formed by substitution with (4-methoxyphenyl)methanamine (step a) followed Grignard reaction using CHsMgCl (step b), then de-PMB group with TFA (step c). The targeted compounds can be obtained by acylation (step c) or mesylation (step d).

00114] Method BH BI

step e [00115] The 2-(pyrrolidin-2-yl)pyridine(S/R) can be formed by Grignard reaction with picolinonitrile and hydrolysis (step a), following the reductive animation with (4- methoxyphenyl)ethan-l-amine (R/S) (step b, d), then de-protective group treated with TFA (step c, e).

00116] Method BJ

step a step b

[00117] The racemic 2-(3-methylpyrrolidin-2-yl)pyridine may achieved by imidization catalysis by TsOH (step a) followed Michael addition reaction treatment with ethyl (E)-but-2- enoate (step b), following formation lactam with con. HCl (step c), then reduction using L1AIH₄ (step d).

[00118] Method BK

[00119] The Picolinaldehyde may be reacted with aminoacetonitrile to generate the Schiff base. Pyrrole ring could be made via a [3 + 2] cyclization. The cyano group could be knock out by a series of reductive reaction.

[00121] The substituted 8-nitroquinoline can be formed by cyclization treatment gly with 2-nitroaniline (step a), then substituted 8-nitroquinoline was reduced to the 8- aminoquinoline core with Pd/C(step b).

[00122] Method BM

[00123] The 8-aminoquinolinecore could be methylated using methyl iodide.

[00124] Method BN

step a

[00125] The quinoline containing core can be formed by cyclization treatment gly with 2-fluoroaniline (step a)and substitution with corresponding amine (step b).

[00126] Method BO

step a

[00127] The PMB protective group could be removed under the acid condition.

[00128] Method BP

[00129] 8-chloro-l,7-naphthyridine can be formed via cyclization (step a), then chlorination through Sandmeyer reaction (step b).

[00130] Method BQ

step a step b

[00131] 8-bromo-l,6-naphthyridine can be formed via cyclization (step a), then bromination with bromine.

[00132] Method BR

step a step b

[00133] 4-chloro-l,5-naphthyridine could be obtained via oxidation with mCPBA (step a) followed chlorination treatment with POCI₃ (step b).

[00134] Method BS

[00135] 2-(pyridin-2-yl)propan-2-amine could be formylated (step a) followed by alkylation and hydrolyzation (step b) to give the desired target.

00136] Method AA

step a step b

[00137] The finally targeted compounds can be obtained by substitution the chlorine of 4- chloro-6-(chloromethyl)pyrimidine with corresponding amines respectively (step a, b).

[00138] Method AB

step a step b

step c

[00139] The finally targeted compounds can be obtained by substitution the chlorine of 4- chloropyrimide core with N-Boc-piperazine (step a) followed de-Boc group treatment with acid (step b), following Michael addition reaction treatment with acrylonitrile (step c).

[00140] Method AC

step a

[00141] The finally targeted compounds may be formed by reduced animation using NaBH(OAc)₃ or NaBH₃CN (step a).

[00142] Method AD

step b

[00143] The finally targeted compounds may be formed by de-Boc group under acid condition (step a) followed reduced amination using NaBH(OAc)3 or NaB]¾CN (step b).

[00144] Method AE

[00145] The finally targeted compounds can be obtained by substitution the bromine of 4- (bromomethyl)-6-chloropyrimidine with corresponding amines firstly (step a), then substitution the chlorine of 6-chloropyrimidine with corresponding amines (step b).

[00146] Method AF

[00147] The heteroaromatic derivatives could be synthesized via the reductive amination (step a)followed by substitution with corresponding amine (step b).

00148] Method AG

[00149] The chlorine of the pyrimidine core was removed under Pd/C condition to give

N-methyl-N-(pyrimidin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine.

[00150] Method AH

ste a step b step c

step d

[00151] The (2-methylpyrimidin-5-yl)methanol containing targeted compounds could be synthesized from 2-methylpyrimidine-4,6-diol. The Vilsmeier-Haack reaction with DMF and POCI₃ (step a) followed by reduction aldehyde to alcohol with NaBH₄(step a); protection of the alcohol group with TBSCI (step b), and then heck reaction with trifluoroborate(step c). Oxidation of the double bind to aldehyde with ozone (step c);the reductive animation (step d)followed by displacement of the pyrimidine chlorine with corresponding amines (step e).

[00152] Method AI

[00153] The TBS protective group could be removed under the acid condition.

[00154] Method AJ

[00155] The methyl ester of quinoline core could be reduced to alcohol by NaBH₄ or LiAlH₄.

[00156] Method AK

Method AK

step b ^\ ^ step c ^

[00157] The finally targeted compounds can be obtained by substitution the bromine of 5- bromo-2-(bromomethyl)imidazo[l,2- ]pyridine with corresponding amines firstly (step a) followed by substitution the bromine of 5-bromoimidazo[l,2- ]pyridine core with 1- methylpiperazine(step b), following introduction of hydroxymethyl group at 3-position of imidazo[l,2-a]pyridine core under formaldehyde condition (step 3).

[00158] Method AL

s ep c

[00159] The finally targeted compound can be synthesized by fluorination of the commercially 6,7-dihydroquinolin-8(5H)-one using selectfluoro (step a), then the reduced amination of ketone with methyl amine (step b), following by alkylation with 4-chloro-6- (chloromethyl)-2-methylpyrimidine (step c), and finally substitution withl- methylpiperazine(step d).

[00160] Method AM

step a

[00161] The finally targeted compounds may be formed by reduced amination with corresponding aldehydes using NaBH(OAc)3 or NaB]¾CN (step a).

00162] Method AN

J. sstteepp aa I I

[00163] The finally targeted compounds may be formed by substitution with aryl halogen under base, high temperature condition (step a).

[00164] Method AO

step a

[00165] The finally targeted compounds may be formed by Buchwald coupling reaction with aryl halogen Pd₂(dba)₃, BINAP, Cs₂C0₃ condition (step a).

[00166] Method AP

[00167] The finally targeted compound may be formed by de-Boc group under the acid condition (step a) followed condensation using HATU (step b).

[00168] Method AQ

step a N N

[00169] The halogen of quinoline core could be converted to cyano group under the condition of Pd(PPh₃)₄, dppf, and zinc cyanide or Pd₂(dba)₃, dppf, and zinc cyanide.

[00170] Method AR

[00171] The halogen of quinoline core could be converted to methylsulfonyl group under the condition of sodium methanes ulfinate, L-Proline and cuprous iodide. [00172] Method AS

[00173] The finally targeted compounds could be synthesized from 8-fluoroquinoline. The nitrification with HNO₃ (step a) followed by displacement of the aryl fluorine with corresponding amines (step b). The nitro group can be reduced to the amino group with SnCl₂ (step c) and then mesylation with MsCl (step d).

00174] Method AT

The finally targeted compounds could be synthesized under the MsCl and TEA

[00176] Examples

[00177] General reaction progress was monitored by analytical thin layer chromatography performed on silica gel HSGF254 pre-coated plates. Organic solutions were dried over anhydrous Na₂S0₄, and the solvents were removed under reduced pressure. 1H NMR were obtained on 400 MHz (Varian) spectrometers. Chemical shifts were given in ppm using tetramethylsilane as internal standard. Mass spectra were obtained using an Agilent 1100 LC/MSD Trap SL version Mass Spectrometer. Final compounds were purified with silica gel 100-200 mesh for column chromatography.

[00178] Method A

-chloro-6-(chloromethyl)pyrimidine

[00180] Step a. 4-chloro-6-(chloromethyl)pyrimidine: To a solution of (6-

Chloropyrimidin-4-yl)methanol (280 mg, 1.9 mmol, see reference WO2016128529) in dichloromethane (10 mL) was added SOCI₂ (280 mg, 2.3 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched with saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine, dried over Na₂S0₄ and concentrated to give the desired product (180 mg, 58%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.95 (s, IH), 7.62 (s, IH), 4.62 (s, 2H).

[00181] Method B

[00183] Step a. 6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol: To a solution of ethyl 4- chloro-3- oxobutanoate (13 g, 79 mmol) and methyl carbamimidothioatesulphate (20 g, 72 mmol) in water (200 mL) was added sodium carbonate (11.5 g, 108 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched with 6M HC1 aqueous solution to pH acid and filtered. The filter cake was dried to give the desired product (11.1 g,

73%) as a white solid. ^!H NMR (400 MHz, CDC1₃) δ 12.91 (s, IH), 6.42 (s, IH), 4.36 (s, 2H),

2.59 (s, 3H).

[00184] Step b. 4-chloro-6-(chloromethyl)-2-(methylthio)pyrimidine: The solution of 6- (chloromethyl)-2- (methylthio)pyrimidin-4-ol (2.8 g, 14.7 mmol) in POCI₃ (10 mL) was heated to 100 °C, and stirred for 1 h. The reaction mixture was concentrated and added saturated NaHCC>3 aqueous solution (100 mL) and extracted with ethyl acetate (100 mL). The organic layers was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/3) to give the desired product (2.4 g, 80%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 7.23 (s, IH), 4.53 (s, 2H), 2.58 (s, 3H).

[00185] Method C

-chloro-6-(chloromethyl)-2-methylpyrimidine

[00187] Step a. 6-(chloromethyl)-2-methylpyrimidin-4-ol: To a solution of ethyl 4-chloro- 3- oxobutanoate (16.5 g, 100 mmol) and acetamidine hydrochloride (10 g, 106 mmol) in ethanol (150 mL) was slowly added DBU (30.4 g, 200 mmol) at 4 °C. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in dichloromethane (120 mL), then washed with brine (30 mL x 3). The organic layer was dried over Na₂S0₄ and concentrated to give the desired product (7.93 g, 50%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 13.01 (s, 1H), 6.53 (s, 1H), 4.37 (s, 2H), 2.50 (s, 3H).

[00188] Step b. 4-chloro-6-(chloromethyl)-2-methylpyrimidine: The solution of 6- (chloromethyl)-2- methylpyrimidin-4-ol (7.93 g, 50 mmol) in POCI₃ (20 mL) was heated to 110 °C, and stirred for 30 min. Then reaction mixture was concentrated and dissolved in ethyl acetate (20 mL), then added this solution into ice water (100 mL), extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over Na₂S0₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (4.0 g, 23%) as a yellow oil^H NMR (400 MHz, CDC13) δ 7.41 (s, 1H), 4.55 (s, 2H), 2.71 (s, 3H).

[00189] Method D

[00190] Preparation of N-methyl-l-(2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methanamine

[00191] Step c. 2-methyl-6-((methylamino)methyl)pyrimidin-4-ol: The solution of 6- (chloromethyl)-2- methylpyrimidin-4-ol (1.7 g, 11 mmol), methylamine solution (30 wt percent in absolute ethanol, 3 g), KI (183 mg, 1.1 mmol) and DIPEA (7.1 g, 55 mmol) in CH₃CN (50 mL) was added into a sealed tube, and heated to 60 °C. The reaction was stirred at this temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane /methanol = 10/1) to give the desired product (600 mg, 35%) as a yellow solid. H NMR (400 MHz, DMSO-cfe) δ 6.36 (s, 1H), 3.80 (s, 2H), 2.66 (s, 1H), 2.55 (s, 3H), 2.43 (s, 2H).

[00192] Step d. N-methyl-l-(2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methanamine: To a solution of 2-methyl-6-((methylamino)methyl)pyrimidin-4-ol (300 mg, 1.96 mmol), TEA (1.9 g, 19.6 mmol) and N-methylpiperazine (980 mg, 9.8 mmol) in CH₃CN (20 mL) was added PyBOP (1.1 g, 2.15 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane /methanol = 20/1) to give the desired product (300 mg, 65%) as a yellow solid. ^!H NMR (400 MHz, CDC1₃) δ 6.38 (s,lH), 3.67-3.63 (m, 6H), 2.47- 2.45 (m, 10H), 2.32 (s, 3H).

[00193] Method E aldehyde

[00195] Step a. 6-(dimethoxymethyl)-2-methylpyrimidin-4-ol: To a solution of methyl

4,4-dimethoxy-3-oxobutanoate (300 mg, 1.7 mmol) and acetamidine hydrochloride (320 mg, 3.4 mmol) in water (10 mL) was added K₂CO₃ (940 mg, 6.8 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched with AcOH to pH acid and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 50/1) to give the desired product (110 mg, 35%) as a white solid.

[00196] Step b. 4-(dimethoxymethyl)-2-methyl-6-(4-methylpiperazin-l-yl)pyrimidine: To a solution of 6-(dimethoxymethyl)-2-methylpyrimidin-4-ol (110 mg, 0.6 mmol), TEA (600 mg, 6 mmol) and N-methylpiperazine (90 mg, 0.9 mmol) in CH₃CN (10 mL) was added PyBOP (340 mg, 0.7 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction solution was evaporated to remove most of CH₃CN, added saturated NaHCC>3 aqueous solution (100 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol= 100/3) to give the desired product (140 mg, 88%) as a yellow oil.

[00197] Step c. 2-methyl-6-(4-methylpiperazin-l-yl)pyrimidine-4-carbaldehyde: The mixture of 4-(dimethoxymethyl)-2-methyl-6-(4-methylpiperazin-l-yl)pyrimidine (140 mg, 0.5 mmol) and sulfuric acid (20 wt percent in water, 5 mL) was stirred at reflux overnight. Then the saturated NaHCC>3 aqueous solution was added to adjust pH to basic and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give the crude desired product (110 mg, 97%) as a yellow oil.

[00198] Method F

[00199] Preparation of 2-(dimethylamino)-6-(4-methylpiperazin-l-yl)pyrimidine-4- carbaldehyde

[00200] Step a. 6-(dimethoxymethyl)-2-(methyltliio)pyrimidin-4-ol: To a solution of methyl 4,4-dimethoxy-3-oxobutanoate (3 g, 17 mmol) and methyl carbamimidothioatesulphate (9.5 g, 34 mmol) in water (100 mL) was added K₂CO₃ (17.6 g, 76.5 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched with AcOH to adjust pH to acid and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column

chromatography (dichloromethane/methanol = 100/1) to give the desired product (3.4 g, 92%) as a white solid. H NMR (400 MHz, CDC1₃) δ 12.80 (s, 1H), 6.46 (s, 1H), 5.07 (s, 1H), 3.40 (s, 6H), 2.60 (s, 3H).

[00201] Step b. 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2- (methylthio)pyrimidine: To a solution of 6-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-ol (3.4 g, 16 mmol), TEA (16 g, 160 mmol) and N-methylpiperazine (2.4 g, 40 mmol) in CH₃CN (100 mL) was added PyBOP (9g, 17.6 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction solution was evaporated to remove most of CH₃CN, added saturated NaHCC>3 aqueous solution (200 mL) and extracted with dichloromethane (200 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol= 100/3) to give the desired product (2.8 g, 59%) as a yellow oil. ^!H NMR (400 MHz, CDC1₃) δ 6.45 (s, 1H), 5.07 (s, 1H), 3.70 (s, 4H), 3.40 (s, 6H), 2.51 (s, 3H), 2.47 (t, / = 5.0 Hz, 4H), 2.34 (s, 3H).

[00202] Step c. 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2- (methylsulfonyl)pyrimidine: To a solution of 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)- 2-(methylthio)pyrimidine (2.8 g, 9.4 mmol) in THF (90 mL) and water (4.5 mL) was added Oxone (7 g, 11 mmol). The reaction was stirred at room temperature for 4h. Then the reaction was added saturated NaHCC>3 aqueous solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated to give the desired product (2.4 g, 78%) as a yellow oil.

[00203] Step d. 4-(dimethoxymethyl)-N,N-dimethyl-6-(4-methylpiperazin-l-yl)pyrimidin- 2-amine: To a solution of 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2- (methylsulfonyl)pyrimidine (340 mg, 1 mmol) in THF (5 mL) in a sealed tube was added dimethylamine (5 mL). The reaction mixture was stirred at reflux overnight. Then the reaction solution was cooled to room temperature, added saturated NaHCC>3 aqueous solution (100 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 100/1/1 to 100/3/1) to give the desired product (260 mg, 88%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 6.06 (s, IH), 4.98 (s, IH), 3.62 (s, 4H), 3.39 (s, 6H), 3.11 (s, 6H), 2.42 (s, 4H), 2.30 (s, 3H).

[00204] Step e. 2-(dimethylamino)-6-(4-methylpiperazin-l-yl)pyrimidine-4-carbaldehyde: The mixture of 4-(dimethoxymethyl)-N,N-dimethyl-6-(4-methylpiperazin-l-yl)pyrimidin-2- amine (260 mg, 1.3 mmol) and sulfuric acid(20 wt percent in water, 5 mL) was stirred at reflux overnight. Then the saturated NaHCC>3 aqueous solution was added to adjust pH to basic and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give the crude desired product (210 mg, 65%) as a yellow solid. ^!H NMR (400 MHz, CDC1₃) δ 9.76 (s, IH), 6.39 (s, IH), 3.68 (s, 4H), 3.18 (s, 6H), 2.45 (s, 4H), 2.33 (s, 3H).

[00205] Method G

-ethoxy-6-(4-methylpiperazin-l-yl)pyrimidine-4-carbaldehyde

[00207] Step f. 4-(dimethoxymethyl)-2-ethoxy-6-(4-methylpiperazin-l-yl)pyrimidine: To a solution of 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2-(methylsulfonyl)pyrimidine (200 mg, 0.61 mmol) in ethanol (5 mL) was added sodium ethanolate (206 mg, 3 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction solution was cooled to room temperature, added saturated NaHCC>3 aqueous solution (100 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 100/1/1 to 100/3/1) to give the desired product (160 mg, 89%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 6.42 (s, IH), 5.04 (s, IH), 4.35 (q, / = 7.2 Hz, 2H), 3.68 (s, 4H), 3.40 (s, 6H), 2.45 (t, / = 5.0 Hz, 4H), 2.32 (s, 3H), 1.38 (t, 7 = 7.0 Hz, 3H).

[00208] Step g. 2-ethoxy-6-(4-methylpiperazin-l-yl)pyrimidine-4-carbaldehyde: The mixture of 4-(dimethoxymethyl)-2-ethoxy-6-(4-methylpiperazin-l-yl)pyrimidine (160 mg, 0.5 mmol) and sulfuric acid (20 wt percent in water, 5 mL) was stirred at reflux overnight. Then the reaction solution was cooled to room temperature, and the saturated NaHCC>3 aqueous solution was added to adjust pH to basic and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give the crude desired product (100 mg, 80%) as a yellow solid.

[00209] Method H

-(4-methylpiperazin-l-yl)-2-phenylpyrimidine-4-carbaldehyde

[00211] Step h. 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2-phenylpyrimidine: The mixture of 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2-(methylthio)pyrimidine (298 mg, 1 mmol), phenylboronic acid (244 mg, 2 mmol), copper(I) thiophene-2-carboxylate (497 mg, 2.6 mmol) and Pd(PPh₃)₄ (115 mg, 0.1 mmol) in THF (20 mL) was stirred at reflux overnight under N₂ atmosphere. Then the reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1.5) to give the desired product (240 mg, 73%) as a colorless oil. H NMR (400 MHz, CDC1₃) δ 8.41 (d, / = 3.6 Hz, 2H), 7.44-7.43 (m, 3H), 6.70 (s, 1H), 5.24 (s, 1H), 3.82-3.80 (m, 4H), 3.47 (s, 6H), 2.53- 2.52 (m, 4H), 2.37 (s, 3H).

[00212] Step i. 6-(4-methylpiperazin-l-yl)-2-phenylpyrimidine-4-carbaldehyde: The mixture of 4-(dimethoxymethyl)-6-(4-methylpiperazin-l-yl)-2-phenylpyrimidine (240 mg, 0.73 mmol) and sulfuric acid (20 wt percent in water, 10 mL) was stirred at reflux overnight. Then the reaction solution was cooled to room temperature, and washed with diethyl ether (10 mL). The water phase was added 6M NaOH aqueous solution to adjust pH to 10 and extracted with dichloromethane (30 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 100/2) to give the desired product (170 mg, 82%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 10.02 (s, 1H), 8.50-8.45 (m, 2H), 7.50-7.49 (m, 3H), 6.99 (s, 1H), 3.95-3.80 (m, 4H), 2.63-2.47 (m, 4H), 2.37 (s, 3H).

[00213] Method I

[00214] Preparation of l-(5-fluoro-2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)- N-methylmethanamine

[00215] Step a. ethyl 2,4-difluoro-3-oxobutanoate: To a solution of NaH (60 wt percent moistened with oil, 936 mg, 23.4 mmol) in diethyl ether (50 mL) was added dropwise ethyl 2- fluoroacetate (5 g, 47.2 mmol) at room temperature. The reaction was stirred at 40°C for 4h. The reaction mixture was cooled to 0°C and poured into 2M sulfuric acid aqueous solution (15 mL). The mixture was extracted with diethyl ether (50 mL x 3). The combined organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column

chromatography (petroleum ether/ethyl acetate = 10/1 to 2/1) to give the desired product (2 g, 25%) as a yellow oil.

[00216] Step b. 5-fluoro-6-(fluoromethyl)-2-methylpyrimidin-4-ol: To a solution of methyl 4,4-dimethoxy- 3-oxobutanoate (1.9 g, 11.4 mmol) and acetamidine hydrochloride (2.2 g, 22.8 mmol) in ethanol (40 mL) was added EtONa (2.3 g, 34.2 mmol). The reaction was stirred at reflux overnight. The mixture was cooled to room temperature. 6M HC1 aqueous solution (2 mL) was added and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to give the desired product (800 mg, 43%) as a yellow solid. H NMR (400 MHz, CDC13) δ 13.07 (br s, 1H), 5.35 (d, / = 46.8 Hz, 2H), 2.53 (s, 3H).

[00217] Step c. 5-fluoro-4-(fluoromethyl)-2-methyl-6-(4-methylpiperazin-l- yl)pyrimidine: To a solution of 5-fluoro-6-(fluoromethyl)-2-methylpyrimidin-4-ol (800 mg, 5 mmol), TEA (1.5 g, 15 mmol) and N-methylpiperazine (750 mg, 7.5 mmol) in C¾CN (10 mL) was added PyBOP (2.9 g, 5.5 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction solution was evaporated to remove most of C¾CN, added dichloromethane (100 mL) to dilute, washed with saturated NaCl aqueous solution (50 mL x 3). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (pure ethyl acetate) to give the desired product (1.0 g, 90%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 5.36 (d, J = 47.2 Hz, 2H), 3.87-3.73 (m, 4H), 2.57-2.50 (m, 4H), 2.49 (s, 3H), 2.33 (s, 3H).

[00218] Step d. l-(5-fluoro-2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)-N- methylmethanamine: The mixture of 5-fluoro-4-(fluoromethyl)-2-methyl-6-(4-methylpiperazin- l-yl)pyrimidine (1.0 g, 4.1 mmol) and 2M methyl amine (in methanol, 6 mL) in water (15 mL) and i-propanol (15 mL) in a sealed tube was stirred at reflux overnight. The reaction solution was evaporated to remove most of i-propanol, and extracted with dichloromethane (30 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 400/10/1 to 200/10/1) to give the desired product (800 mg, 76%) as a yellow oil. H NMR

(400 MHz, CDC1₃) δ 3.80-3.74 (m, 4H), 3.73 (s, 2H), 2.48 -2.46 (m, 4H), 2.44 (s, 6H), 2.31 (s, 3H).

[00219] Method J

[00220] Preparation of (5)-4-(4-methylpiperazin- l-yl)-2-(methylthio)-6-(pyrrolidin-2-

[00221] Step a. (5)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-l-carboxylate: To a mixture of Boc-L-Proline-OH (5 g, 23 mmol), 2,2-dimethyl-l,3-dioxane-4,6-dione (3.4 g, 23 mmol) and DMAP (5.7 g, 46 mmol) in dichloromethane (70 mL) was added DCC (4.8 g, 23 mmol) at 0 °C. The mixture was stirred at room temperature for 48 h before the reaction mixture was filtered. The filtrate was added 1M HC1 aqueous solution (100 mL) and the water phase was extracted with dichloromethane (200 mL). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give a yellow oil, about 7.5 g. This residue was diluted with EtOH (100 mL) and stirred at reflux for 2h. The resulting solution was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give the desired product (4.0 g, 60%) as a yellow oil^H NMR (400 MHz, CDC1₃) δ 4.41-4.23 (m, 1H), 4.23-4.13 (m, 2H), 3.59-3.39 (m, 4H), 2.25-2.05 (m, 2H), 1.91-1.83 (m, 2H), 1.46-1.40 (m, 9H), 1.31-1.23 (m, 3H).

[00222] Step b. (5)-tert-butyl 2-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)pyrrolidine-l- carboxylate: To a solution of (5)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-l- carboxylate (500 mg, 1.8 mmol) and methyl carbamimidothioatesulphate (1.0 g, 3.6 mmol) in water (25 mL) was added K₂CO₃ (1.1 g, 8.1 mmol). The reaction was stirred at room

temperature overnight. The reaction mixture was quenched with 1M HC1 aqueous solution to adjust pH to acid and extracted with dichloromethane (50 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to give the desired product (200 mg, 37%) as a colorless oil. H NMR (400 MHz, CDC1₃) δ 6.09-6.05 (m, 1H), 4.75-4.50 (m, 1H), 3.59- 3.39 (m, 2H), 2.55 (s, 3H), 2.28-2.14 (m, 1H), 2.00-1.80 (m, 3H), 1.51-1.32 (m, 9H).

[00223] Step c. (5)-4-(4-methylpiperazin-l-yl)-2-(methylthio)-6-(pyrrolidin-2- yl)pyrimidine: To a solution of (S)-tert-butyl 2-(6-hydroxy-2-(methylthio)pyrimidin-4- yl)pyrrolidine-l-carboxylate (200 mg, 0.64 mmol), TEA (650 mg, 6.4 mmol) and N- methylpiperazine (100 mg, 0.96 mmol) in CH₃CN (5 mL) was added PyBOP (510 mg, 0.96 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction solution was evaporated to remove most of CH₃CN, added dichloromethane (100 mL) to dilute, washed with saturated NaHCC>3 aqueous solution (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 100/1) to give the crude intermediate (150 mg) as a yellow oil. Then it was diluted with ethyl acetate (3 mL), added 3M HCl/ ethyl acetate (4 mL). The mixture was stirred at room temperature overnight. Then the reaction solution was evaporated, added saturated NaHC0₃ aqueous solution (50 mL), and extracted with dichloromethane (50 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated to give the desired product (100 mg, 53%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 6.29 (s, 1H), 3.98 (t, / = 7.4 Hz, 1H), 3.74-3.58 (m, 4H), 3.19-3.09 (m, 1H), 3.02-2.92 (m, 1H), 2.49 (s, 3H), 2.45 (t, / = 5.2 Hz, 4H), 2.33 (s, 3H), 2.23-2.10 (m, 1H), 1.82-1.76 (m, 2H), 1.76-1.63 (m, 1H).

[00224] Method K

-butyl 5-oxo-5-(pyridin-2-yl)pentylcarbamate

[00226] Step a. i<?ri-butyl 5-oxo-5-(pyridin-2-yl)pentylcarbamate: To a THF solution (30 mL) containing commercially available 2-bromopyridine (1.4 g, 9 mmol) and Ν,Ν,Ν'-Ν'- tetramethyl ethylene diamine (960 mg, 6.5 mmol), a hexane solution (3 mL, 7.5 mmol) of 2.5M n-butyl lithium was added dropwise at -78°C, and the resulting solution was stirred at the same temperature for 2h. To the reaction solution, tert-butyl 2-oxopiperidine-l-carboxylate (1 g, 5 mmol) was added at -78°C, and the resulting solution was stirred at the same temperature for 2h. To the reaction solution, water (10 mL) was added, and the solution was extracted with ethyl acetate (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (670 mg, 48%) as a yellow oil^H NMR (400 MHz, CDC1₃) δ 8.68 (d, / = 4.8 Hz, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.51-7.44 (m, 1H), 4.69 (s, 1H), 3.27-3.21 (m, 2H), 3.21-3.15 (m, 2H), 1.80-1.74 (m, 2H), 1.63-1.55 (m, 2H), 1.44 (s, 9H).

[00227] Method L

-(bromomethyl)-4-chloropyrimidine

[00229] Step a. 2-(bromomethyl)-4-chloropyrimidine: To a solution 4-chloro-2- methylpyrimidine (370 mg, 2.9 mmol), NBS (566 mg, 3.2 mmol) and AIBN (50 mg, 0.3 mmol) in CC1₄ (10 mL) was stirred at reflux overnight. Then the reaction solution was cooled to room temperature, added saturated NaHCC>3 aqueous solution (50 mL) and extracted with

dichloromethane (50 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to give the desired product (130 mg, 22%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.62 (d, / = 5.6 Hz, 1H), 7.27 (d, / = 5.6 Hz, 1H), 4.54 (s, 2H).

[00230] Method M

[00231] Preparation of i<?ri-butyl 4-(5-cyano-2-methyl-6-((methyl(l ,2,3,4- tetrahydronaphthalen- 1 - yl)amino)methyl)pyrimidin-4-yl)piperazine- 1 -carboxylate

[00232] Step a. 4-hydroxy-2,6-dimethylpyrimidine-5-carbonitrile: To a solution of methyl (Z)-ethyl 2-cyano-3-ethoxybut-2-enoate (5.0 g, 27 mmol) and acetamidine hydrochloride (3.9 g, 41 mmol) in ethanol (80 mL) was added K₂CO₃ (11.3 g, 82 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated, added 3M HCl aqueous solution to adjust pH to 5 and extracted with n-butanol (50 mL x 6). The combined organic layer was evaporated to give the desired product (3.5 g, 87%) as a yellow solid. ^!H NMR (400 MHz, DMSO-i¾) δ 13.30 (s, 1H), 2.39 (s, 3H), 2.35 (s, 3H).

[00233] Step b. feri-butyl 4-(5-cyano-2,6-dimethylpyrimidin-4-yl)piperazine-l- carboxylate: To a solution of 4-hydroxy-2,6-dimemylpyrimidine-5-carbonitrile (2.5 g, 16.8 mmol), TEA (5.1 g, 50.4 mmol) and i<?ri-butyl piperazine-l-carboxylate (4.7 g, 25.2 mmol) in CH₃CN (60 mL) was added PyBOP (9.6 g, 18.5 mmol). The reaction mixture was stirred at reflux overnight. Then the reaction solution was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 3/1) to give the desired product (4.3 g, 81%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 3.94 (s, 4H), 3.55 (s, 4H), 2.57 (s, 3H), 2.50 (s, 3H), 1.47 (s, 9H)

[00234] Step c. i<?ri-butyl 4-(6-(chloromethyl)-5-cyano-2-methylpyrimidin-4- yl)piperazine-l-carboxylate: A mixture of feri-butyl 4-(5-cyano-2,6-dimethylpyrimidin-4- yl)piperazine-l-carboxylate (10 g, 60 4.0 g, 12.6 mmol) in DCM (100 mL) was added TCCA (2.9 g, 12.6 mmol) at 0°C, and the resulting solution was stirred at the same temperature for lh, then stirred at room temperature for 6h. The reaction was quenched with the saturated Na₂S₂0₃ aqueous solution. The reaction mixture was filtered and the filtrate was extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with brine and dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column

chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to give the desired product (2.4 g,

54%) as a yellow solid. ^!H NMR (400 MHz, CDC1₃) δ 3.94 (s, 4H), 3.55 (s, 4H), 2.57 (s, 2.50 (s, 3H), 1.47 (s, 9H)

[00235] Step d. feri-butyl 4-(5-cyano-2-methyl-6-((methyl(l,2,3,4-tetrahydronaphthalen-

1- yl)amino)methyl)pyrimidin-4-yl)piperazine-l-carboxylate: A mixture of N-methyl-5, 6,7,8- tetrahydroquinolin-8-amine (421 mg, 2.6 mmol, see reference WO2006026703), feri-butyl 4-(6- (chloromethyl)-5-cyano-2-methylpyrimidin-4-yl)piperazine-l-carboxylate (1.0 g, 2.8 mmol), KI (45 mg, 0.3 mmol) and DIPEA (671 mg, 5.2 mmol) in CH₃CN (10 mL) was stirred at room temperature overnight. The reaction solution was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give the desired product (800 mg, 64%) as a yellow oil. ^!H NMR (400 MHz, CDC1₃) δ 8.44 (d, / = 3.6 Hz, 1H), 7.35 (d, / = 7.2 Hz, 1H), 7.04 (dd, 7 = 7.2, 4.8 Hz, 1H), 4.15-4.08 (m, 1H), 4.08-3.97 (m, 2H), 3.97-3.88 (m, 4H), 3.02-2.93 (m, 4H), 2.86-2.76 (m, 1H), 2.73-2.63 (m, 1H), 2.53 (s, 3H), 2.28 (s, 3H), 2.22-2.12 (m, 1H), 2.10-1.92 (m, 2H), 1.76 (s, 10H).

[00236] Method N

237] Preparation of 5-bromo-2-(bromometh l)imidazo[l,2- ]pyridine

step b step c [00238] Step a. ethyl 5-bromoimidazo[l,2-a]pyridine-2-carboxylate: The solution of methyl 6- bromopyridin-2-amine (1.7 g, 10 mmol) and ethyl 3-bromo-2-oxopropanoate (2.3 g , 12 mmol) in ethanol (80 mL) was stirred at reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was dried by oil pump to give the crude desired product (2.8 g) as a white solid. ^!H NMR (400 MHz, OMSO-d₆) δ 8.49 (s, 1H), 7.76 (d, / = 8.4 Hz, 1H), 7.53-7.50 (m, 1H), 7.47-7.43 (m, 1H), 4.36 (q, 7 = 7.2 Hz, 2H), 1.34 (q, J = 7.2 Hz, 3H).

[00239] Step b. (5-bromoimidazo[l,2- ]pyridin-2-yl)methanol: To the solution of ethyl 5- bromoimidazo[l,2- ]pyridine-2-carboxylate (1.5 g, 5.6 mmol) in ethanol (20 mL) was added NaBH₄ (1.0 g, 28 mmol), and stirred at reflux overnight. The reaction solution was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 40/1) to give the desired product (500 mg, 39 %) as a white solid. ^!H NMR (400 MHz, DMSO- d₆) δ 7.84 (s, 1H), 7.59 (d, / = 8.8 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.27-7.23 (m, 1H), 5.27 (br s, 1H), 4.64 (s, 2H).

[00240] Step c. 5-bromo-2-(bromomethyl)imidazo[l,2- ]pyridine: The solution of (5- bromoimidazo[l,2- ]pyridin-2-yl)methanol (400 mg, 1.76 mmol) in dichloromethane (50 mL) was added PBr₃ (475 mg, 1.73 mmol) at 0°C, and stirred at the same temperature for 4h. The saturated NaHCC>3 aqueous solution (10 mL) was added to adjust pH to 8. The water phase was extracted with dichloromethane (100 mL). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 40/1) to give the desired product (260 mg, 50 %) as a white solid. H NMR (400 MHz, CDC1₃) δ 7.85 (s, 1H), 7.59 (s, 1H), 7.14(s, 1H), 7.07 (s, 1H), 4.67 (s, 2H).

[00241] Method BA

[00242] Preparation of N-methyl-l-(3-methylpyridin-2-yl)ethanamine

[00243] Step a. N-methyl-l-(3-methylpyridin-2-yl)ethanamine: To a solution of l-(3- methylpyridin-2- yl)ethanone (500 mg, 3.7 mmol) in THF (10 mL) was added methylamine solution (30 wt percent in absolute ethanol, 14.8 mL) and Ti(OEt)₄ (1.7 g, 7.4 mmol). The reaction mixture was stirred for lOmin at room temperature, before NaB¾ (563 mg, 14.8 mmol) was added, this reaction mixture was stirred for 2h at room temperature. The saturated NaHCC>3 aqueous solution (100 mL) was added and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ ammonium hydroxide = 100/1/1) to give the desired product (300 mg, 54%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.44 (d, / = 4.8 Hz, 1H), 7.41 (d, / = 7.2 Hz, 1H), 7.09-7.02 (m, 1H), 3.95 (q, / = 6.4 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.31 (d, / = 6.4 Hz, 3H).

[00244] Method BB

-N-methyl-l-(pyridin-2-yl)ethanamine

[00246] Step b. (5)- l-(4-methoxyphenyl)-N-((5)-l-(pyridin-2-yl)ethyl)ethanamine and (5)-l-(4- methoxyphenyl)-N-((R)-l-(pyridin-2-yl)ethyl)ethanamine: The solution of l-(pyridin- 2-yl)ethanone (605 mg, 5 mmol) in dichloromethane (30 mL) was added NaBH(OAc)3 (2.12 mg, 10 mmol) and (S)- l-(4-methoxyphenyl)ethanamine (755 mg, 5 mmol) at 0 °C. The resulting suspension was stirred at room temperature overnight. The reaction mixture was added saturated NaHC0₃ aqueous solution (20 mL) and extracted with dichloromethane (50 mL). The organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/acetone/ammonium hydroxide = 200/5/2) to give the desired product (S)-l-(4-methoxyphenyl)- N-((S)- l-(pyridin-2-yl)ethyl)ethanamine (1.0 g, 78%) as a yellow oil. ^!H NMR (400 MHz, CDC1₃) δ 8.60 (d, / = 3.2 Hz, 1H), 7.66-7.54 (m, 1H), 7.20- 7.12 (m, 3H), 7.06 (d, / = 7.6 Hz, 1H), 6.86(d, / = 8.0 Hz, 2H), 3.81 (s, 3H), 3.61-3.55 (m, 1H), 3.46-3.35 (m, 1H), 1.31-1.25 (m, 6H). And (S)- l-(4-methoxyphenyl)-N-((R)-l-(pyridin-2- yl)ethyl)ethanamine (70 mg, 6%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.54 (s, 1H), 7.61-7.50 (m, 1H), 7.26-7.11 (m, 4H), 6.81(d, / = 7.2 Hz, 2H), 3.90-3.80 (m, 1H), 3.80-3.70 (m, 4H), 1.42- 1.30 (m, 6H).

[00247] Step c. (5)- l-(4-methoxyphenyl)-N-methyl-N-((5)- l-(pyridin-2- yl)ethyl)ethanamine: The solution of (5)- l-(4-methoxyphenyl)-N-((5)- l-(pyridin-2- yl)ethyl)ethanamine (500 mg, 2 mmol) and formaldehyde (37 wt percent in water, 1 mL) in dichloromethane (20 mL) was added NaBH(OAc)₃ (636 mg, 3 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was added saturated NaHC0₃ aqueous solution (50 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1) to give the desired product (400 mg, 70%) as a yellow oil. ^!H NMR (400 MHz, CDC1₃) δ 8.56 (d, / = 3.6 Hz, 1H), 7.74-7.58 (m, 1H), 7.49 (d, / = 7.6 Hz, 1H), 7.33-7.27 (m, 2H), 7.20-7.10 (m, 1H), 6.88 d, J = 8.0 Hz, 2H), 3.99-3.93 (m, 1H), 3.87-3.72 (m, 4H), 2.02 (s, 3H), 1.39-1.25 (m, 6H).

[00248] Step d. (5)-N-methyl-l-(pyridin-2-yl)ethanamine: To a solution of (5)-l-(4- methoxyphenyl)-N- methyl-N-((5)-l-(pyridin-2-yl)ethyl)ethanamine (400 mg, 1.48 mmol) in dichloromethane (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and 1M HCl aqueous (15 mL) was added. The water phase was wash with ethyl acetate (10 mL x 3). Then 1M NaOH aqueous solution was added to adjust pH = 9, and extracted with dichloromethane (10 mL x 4). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give the desired product (90 mg, 45%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.56 (d, / = 4.0 Hz, 1H), 7.65 (t, / = 7.2 Hz, 1H), 7.28 (d, 7 = 8.0 Hz, 1H), 7.16 (t, 7 = 6.0 Hz, 1H), 3.81-3.70 (m, 1H), 2.31(s, 3H), 1.38 (d, / = 6.4 Hz, 3H).

[00249] Method BC

-ethyl-5,6,7,8-tetrahydroquinolin-8-amine

[00251] Step a. 8-chloro-5,6,7,8-tetrahydroquinoline: A mixture of 5,6,7,8- tetrahydroquinoline (10 g, 60 mmol) in DCM (200 mL) was added TCCA (21 g, 90 mmol) and stirred at reflux overnight. The reaction mixture was filtered and the filtrate was solution was added saturated NaHC0₃ aqueous solution (50 mL). The organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(petroleum ether/ethyl acetate = 10/1 to 5/1) to give the desired product (8.6 g, 86%) as a yellow oil H NMR (400 MHz, CDC1₃) δ 8.53 (d, / = 4.6 Hz, 1H), 7.49 (d, / = 7.8 Hz, 1H), 7.19 (dd, / = 7.6, 4.8 Hz, 1H), 5.43 (d, / = 3.4 Hz, 1H), 2.97-2.88 (m, 1H), 2.81-2.76 (m, 1H), 2.40-2.38 (m, 1H), 2.29-2.16 (m, 2H), 1.91- 1.89 (m, 1H).

[00252] Step b. N-ethyl-5,6,7,8-tetrahydroquinolin-8-amine: The solution of 8-chloro- 5,6,7,8- tetrahydroquinoline (500 mg, 3 mmol) in ethylamine/ethanol (10 mL) in a sealed tube was stirred at reflux overnight. Then the reaction solution was concentrated and added saturated NaHC0₃ aqueous solution (5 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was dried over Na2S0₄, filtered and evaporated to give the crude desired product (960 mg) as a brown oil^H NMR (400 MHz, CDC1₃) δ 8.42-8.35 (m, 1H), 7.37 (d, / = 7.6 Hz, 1H), 7.10- 7.02 (m, IH), 3.89-3.72 (m, IH), 2.86-2.71 (m, 4H), 2.20-2.12 (m, IH), 2.03-1.98 (m, IH), 1.79- 1.74 (m, 2H), 1.20 (t, / = 7.0 Hz, 3H).

[00253] Method BD

[00254] Preparation of 5'H-spiro[cyclopropane-l,7'-quinolin]-8'(6'H)-one

[00255] Step a. 5'H-spiro[cyclopropane-l,7'-quinolin]-8'(6'H)-one: To a solution of NaH (60 wt percent moistened with oil, 420 mg, 10.5 mmol) in DMF (50 mL) was added dropwise 6,7-dihydroquinolin-8(5H)-one (441 mg, 3.0 mmol) and 1,2-dibromoethane (1.95g, 10.5 mmol) in DMF (5 mL) in sequence at 0°C under N₂ atmosphere. The reaction was stirred at 0°C for lh. The reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated brine solution (40 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/3) to give the desired product (110 mg, 21%) as a white solid. H NMR (400 MHz, CDC1₃) δ 8.71 (s, IH), 7.66 (s, IH), 7.37 (s, IH), 3.04 (d, / = 4.4 Hz, 2H), 2.03 (d, / = 4.8 Hz, 2H), 1.52 (s, 2H), 0.89 (s, 2H).

[00256] Method BE

00257] Preparation of 7',8'-dihydro-5'H-spiro[cyclopropane-l,6'-quinoline]

[00258] Step a.7',8'-dihydro-5'H-spiro[cyclopropane-l,6'-quinoline]: To a solution of spiro[2.5]octan-6-one (667 mg, 6 mmol) in ethanol (25 mL) was added prop-2-yn-l-amine (1.3 g, 24 mmol) and NaAuCl₄ (60 mg, 0.15 mmol) in sequence. The reaction was stirred at 85 °C for 1 day. The reaction mixture was concentrated, diluted with ethyl acetate (30 mL) and washed with saturated NaHCC>3 aqueous solution (15 mL) and saturated brine solution (15 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 12/1) to give the desired product (118 mg, 12%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.37(s, IH), 7.30(d, / = 7.2 Hz, IH), 7.07-6.98 (m, IH), 3.00(t, / = 6.4 Hz, 2H), 2.64(s, 2H), 1.69(t, / = 6.0 Hz, 2H), 0.43(d, / = 10.0 Hz, 4H).

[00259] Method BF

[00260] Preparation of N-(2-acetylpyridin-3-yl)acetamide

[00261] Step a. 3-(4-methoxybenzylamino)picolinonitrile: The solution of 3- fluoropicolinonitrile (10 g, 82 mmol), (4-methoxyphenyl)methanamine (16.8 g, 123 mmol) and CS2CO₃ (40 g, 123 mmol) in DMF (50 mL) was stirred at 70°C overnight. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL) and washed with saturated brine solution (20 mL x 3). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to give the desired product (11 g, 56%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 7.98 (s, 1H), 7.28- 7.18 (m, 3H), 7.00 (d, / = 8.8 Hz, 1H), 6.90 (d, / = 8.0 Hz, 2H), 5.05 (s, 1H), 4.36 (d, / = 5.6 Hz, 2H), 3.81 (s, 3H).

[00262] Step b. l-(3-(4-methoxybenzylamino)pyridin-2-yl)ethanone: To a solution of 3-

(4- methoxybenzylamino)picolinonitrile (11 g, 46 mmol) in THF (200 mL) was added dropwise 3M CH₃MgCl/Et₂0 solution (77 mL, 230 mmol) at 0°C and stirred for 30min. The reaction mixture was quenched with saturated brine (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (4 g, 34%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 9.02 (s, 1H), 8.03-7.90 (m, 1H), 7.28-7.15 (m, 2H), 7.08-6.98 (m, 1H), 6.93-6.83 (m, 2H), 4.50-4.30 (m, 2H), 3.79 (s, 3H), 2.72 (s, 3H).

[00263] Step c. N-(2-acetylpyridin-3-yl)acetamide: The solution of l-(3-(4- methoxybenzylamino)pyridin- 2-yl)ethanone (1.5 g, 5.8 mmol) in TFA (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and added saturated NaHCC>₃ aqueous solution to adjust pH to 8, and extracted with dichloromethane (20 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was dissolved in acetate acid (10 mL), and added AC₂O (20 mL), stirred at room temperature overnight. The reaction mixture was concentrated and added saturated NaHCC>₃ to adjust pH to 8, and extracted with dichloromethane (20 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated to give the desired product (1 g, 97%) as a white solid. H NMR (400 MHz, CDCI₃) δ 11.54 (s, 1H), 9.10 (d, / = 8.8 Hz, 1H), 8.37 (d, / = 4.4 Hz, 1H), 7.48 (dd, / = 8.8 Hz, 4.4 Hz, 1H), 2.80 (s, 3H), 2.26 (s, 3H).

[00264] Method BG

[00265] Preparation of N-(2-acetylpyridin-3-yl)methanesulfonamide

[00266] Step d. N-(2-acetylpyridin-3-yl)methanesulfonamide: The solution of l-(3-(4- methoxybenzylamino)pyridin-2-yl)ethanone (1.3 g, 5.1 mmol) in TFA (7 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and added saturated NaHCC>3 to adjust pH to 8, and extracted with dichloromethane (20 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was dissolved in dichloromethane (15 mL), and added TEA (1.5 g, 15.3 mmol) and MsCI (1.3 g, 11.2 mmol), stirred at room temperature for lh. The reaction mixture was concentrated and the residue was dissolved in THF (10 mL). 1M NaOH aqueous solution (5 mL) was added and stirred at room temperature overnight. 1M HC1 aqueous solution was added to adjust pH to 8, and extracted with dichloromethane (20 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated to give the desired product (800 mg, 73%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 11.13 (s, 1H), 8.45-8.32 (m, 1H), 8.15-8.03 (m, 1H), 7.51-7.45 (m, 1H), 3.09 (s, 3H), 2.79 (s, 3H).

[00267] Method BH

[00269] Step a. 4-oxo-4-(pyridin-2-yl)butanal: To a solution of Mg powder (1.06 g, 44 mmol) and I2 (20 mg, 0.08 mmol) in THF (15 mL) was added drop wise the solution of 2-(2- bromoethyl)-l,3-dioxolane (7.16 g, 40 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature for 1.5h. Then this mixture was cooled to 0°C and added drop wise to a THF (10 mL) containing picolinonitrile (2.08 g, 20 mmol) at 0°C. The reaction mixture was stirred at this temperature for 1.5h. Water (10 mL) was added to quenched the reaction, and the mixture was filtered. The filtrate was diluted with ethyl acetate (50 mL), and washed with saturated brine solution (30 mL x 2). The organic layer was dried over Na₂S0₄, filtered and evaporated to get the residue as a colorless oil (1.3 g). This residue was dissolved in acetone (15 mL), and added 3M HCI aqueous solution (10 mL), then stirred at room temperature overnight. The saturated NaHC0₃ solution was added to adjust pH to 9. The acetone was concentrated and the residue water phase was extracted with dichloromethane (10 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give the desired product (800 mg, 82%) as a slight green oil. H NMR (400 MHz, CDC1₃) δ 9.89 (s, 1H), 8.68 (d, / = 4.0 Hz, 1H), 8.02 (d, / = 8.0 Hz, 1H), 7.83 (t, / = 7.6 Hz, 1H), 7.48 (t, / = 5.6 Hz, 1H), 3.57 (t, / = 8.0 Hz, 2H), 2.91 (t, 7 = 8.0 Hz, 2H).

[00270] Step b. 2-((5)-l-((R)-l-(4-methoxyphenyl)ethyl)pyrrolidin-2-yl)pyridine: The solution of 4-oxo-4-(pyridin-2-yl)butanal (490 mg, 3 mmol) in dichloromethane (20 mL) was added NaBH(OAc)₃ (1.9 g, 9 mmol) and AcOH (20 mg, 0.33 mmol) at -70°C. The resulting suspension was stirred at the same temperature for 30 min. The reaction was warmed to 0°C and added (R)- l-(4- methoxyphenyl)ethanamine (500 mg, 3.3 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/10) to give the desired product (410 mg, 48%) as a red solid. ^!H NMR (400 MHz, CDC1₃) δ 8.43 (s, 1H), 7.55 (s, 1H), 7.49 (d, / = 4.0 Hz, 1H), 7.16 (d, / = 8.0 Hz, 2H), 7.05 (s, 1H), 6.79 (d, / = 8.0 Hz, 2H), 3.98 (s, 1H), 3.80-3.71 (m, 4H), 3.11 (s, 1H), 2.63 (s, 1H), 2.24 (s, 1H), 1.99- 1.85 (m, 1H), 1.76 (s, 2H), 1.35 (d, / = 4.8 Hz, 3H).

[00271] Step c. (5)-2-(pyrrolidin-2-yl)pyridine: The solution of 2-((5)- l-((R)-l-(4- methoxyphenyl)ethyl)pyrrolidin-2-yl)pyridine (400 mg, 1.48 mmol) in TFA (5 mL) was stirred at 50°C for 12h. The reaction mixture was concentrated and 1M HC1 aqueous (15 mL) was added. This solution was wash with dichloromethane (5 mL x 3). Then saturated NaHC0₃ solution was added to adjust pH to 9, and extracted with dichloromethane (10 mL x 5). The combined organic layer was dried over Na2S0₄, filtered and evaporated to give the desired product (110 mg, 50%) as a colorless oil.

[00272] Method BI

-2-(pyrrolidin-2-yl)pyridine

[00274] Step d. 2-((R)-l-((5)-l-(4-methoxyphenyl)ethyl)pyrrolidin-2-yl)pyridine: The solution of 4-oxo-4-(pyridin-2-yl)butanal (326 mg, 2 mmol) in dichloromethane (15 mL) was added NaBH(OAc)₃ (1.27 g, 6 mmol) and HOAc (20 mg, 0.33 mmol) at -70°C. The resulting suspension was stirred at the same temperature for 30 min. The reaction was warmed to 0°C and added (5)-l-(4- methoxyphenyl)ethanamine (332 mg, 2.2 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/10) to give the desired product (400 mg, 71 %) as a red solid. ^!H NMR (400 MHz, CDC1₃) δ 8.42 (s, 1H), 7.58- 7.45 (m, 1H), 7.35 (d, / = 7.2 Hz, 1H), 7.15 (d, / = 7.6 Hz, 2H), 7.02 (s, 1H), 6.68 (d, / = 8.0 Hz, 2H), 3.91 (s, 1H), 3.74-3.71 (m, 4H), 3.09 (s, 1H), 3.62 (d, / = 7.2 Hz, 1H), 2.26-2.15 (m, 1H), 1.99- 1.89 (m, 1H), 1.76 (s, 2H), 1.34 (d, J = 4.8 Hz, 3H).

[00275] Step e. (R)-2-(pyrrolidin-2-yl)pyridine: The solution of 2-((R)-l-((5)-l-(4- methoxyphenyl)ethyl)pyrrolidin-2-yl)pyridine (400 mg, 1.48 mmol) in TFA (5 mL) was stirred at 50°C for 12h. The reaction mixture was concentrated and 1M HC1 aqueous (15 mL) was added. This solution was wash with dichloromethane (5 mL x 3). Then saturated NaHCC>3 solution was added to adjust pH to 9, and extracted with dichloromethane (10 mL x 5). The combined organic layer was dried over Na2S0₄, filtered and evaporated to give the desired product (100 mg, 45%) as a colorless oil.

[00276] Method BJ

-(3-methylpyrrolidin-2-yl)pyridine

[00278] Step a. N-(diphenylmethylene)-l-(pyridin-2-yl)methanamine: To the solution of pyridin-2- ylmethanamine (3.97g, 37 mmol) and benzophenone (6.69 g, 37 mmol) in toluene (50 mL) was added p-TsOH (10 mg, 0.058 mmol). The mixture was stirred at reflux overnight. The reaction solution was cooled to room temperature and washed with saturated NaHCC>3 solution (30 mL x 2). The organic layer was dried over Na2S0₄, filtered and evaporated to give the crude desired product (10 g) as a yellow oil.

[00279] Step b. ethyl 4-(diphenylmethyleneamino)-3-methyl-4-(pyridin-2-yl)butanoate: The solution of crude N-(diphenylmethylene)-l-(pyridin-2-yl)methanamine (1.5 g), NaOH solution (50 wt percent in water, 110 mg, 2.75 mmol) and BnEtsNCl (60 mg, 0.3 mmol) in acetonitrile (50 mL) was stirred at room temperature for 30 min. Then (£^")-ethyl but-2-enoate (630 mg, 5.5 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was extracted with dichloromethane (10 mL x 3). The combined organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/10) to give the crude desired product (1.3 g,) as a yellow oil.

[00280] Step c. 4-methyl-5-(pyridin-2-yl)pyrrolidin-2-one: The solution of crude ethyl 4- (diphenylmethyleneamino)-3-methyl-4-(pyridin-2-yl)butanoate (1.3 g) in acetonitrile (15 mL) was added drop wise concentrated HC1 aqueous (3 mL). The mixture was stirred at room temperature for 2h. The reaction solution was washed with dichloromethane (10 mL x 2). The water phase was diluted with acetonitrile (15 mL) and added dropwise ammonia water (5 mL). The mixture was stirred at room temperature for 5h. Then the reaction solution was extracted with dichloromethane (10 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol= 100/1) to give the desired product (360 mg, 62%) as a yellow oil. ^!H NMR (400 MHz, CDC1₃) δ 8.58 (s, IH), 7.73-7.70 (m, IH), 7.34-7.32 (m, IH), 7.25-7.22 (m, IH), 6.57 (s, IH), 4.40-4.39 (m, IH), 2.66-2.60 (m, IH), 2.51-2.46 (m, IH), 2.14-2.08 (m, IH), 1.27-1.26 (m, 3H).

[00281] Step d. 2-(3-methylpyrrolidin-2-yl)pyridine: The solution of 4-methyl-5-(pyridin- 2-yl)pyrrolidin- 2-one (200 mg, 1.1 mmol) in THF (5 mL) was added LiAlH₄ (174 mg, 4.5 mmol) in portions. The mixture was stirred at reflux overnight. Water (1 mL), NaOH solution (10 wt percent in water, 1 mL) and Water (1 mL) were added in sequence. The mixture was filtered and the filtrate was evaporated to give the desired product (89 mg, 50%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.54 (s, IH), 7.65-7.62 (m, IH), 7.28 (m, IH), 7.18-7.15 (m, IH), 3.67-3.60 (m, IH), 3.30-3.21 (m, IH), 3.10-3.02 (m, IH), 1.67 (s, IH), 1.60-1.53 (m, IH), 1.37- 1.33 (m, IH), 1.07 (d, / = 6.0 Hz, 3H).

[00282] Method BK

[00283] Preparation of ds-ethyl 2-(pyridin-2-yl)pyrrolidine-3-carboxylate

[00284] Step a. (£^')-2-(pyridin-2-ylmethyleneamino)acetonitrile: The solution of 2- aminoacetonitrile hydrochloride (5.09 g, 55 mmol) and TEA (9.09 g, 90 mmol) in ethanol (250 mL) was added stirred at room temperature for 30 min. Then picolinaldehyde (5.36 g, 50 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated and dissolved in Et20 (200 mL). The mixture was filtered and the filtrate was evaporated to give the crude desired product (4.8 g) as a yellow oil.

[00285] Step b. ds-ethyl 5-cyano-2-(pyridin-2-yl)pyrrolidine-3-carboxylate: To the solution of crude (£^')-2-(pyridin-2-ylmethyleneamino)acetonitrile (4.8 g, 33 mmol) in toluene (120 mL) was added AgOAc (550 mg, 3.3 mmol) and Cs₂C0₃ (2.15 g, 66 mmol) at 0°C, and stirred for 5 min. Then ethyl acrylate (3.31 g, 66 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was evaporated and the residue was purified by silica gel column chromatography (dichloromethane/methanol= 50/1) to give the crude desired product (2.0 g, 25%) as a yellow oil.

[00286] Step c. ds-ethyl 2-(pyridin-2-yl)pyrrolidine-3-carboxylate: To the solution of crude ds-ethyl 5-cyano-2-(pyridin-2-yl)pyrrolidine-3-carboxylate (245 mg, 1 mmol) in THF (5 mL) was added 1M BH₃/THF solution (2 mL, 2 mmol), and stirred for 20 min. Then cooled to 0°C, NaBH₄ (76 mg, 2 mmol) was added. The mixture was stirred at the same temperature for 3h before room temperature overnight. Water (1 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL x 2). The combined organic layer was evaporated and the residue was dissolved in ethanol (20 mL). Pd/C (10 wt percent, 0.2 g) was added to this solution, and stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol= 10/1) to give the desired product (88 mg, 40%) as a yellow oil.

[00287] Method BL

[00288] Preparation of 6-methylquinolin-8-amine

[00289] Step a. 6-methyl-8-nitroquinoline: The pure glycerol (5.0 g, 54 mmol) was heated to 150°C for 30 min. Then it was cooled to 110°C, and added 4-methyl-2-nitroaniline (3.0 g, 20 mmol) and Nal (60 mg, 0.40 mmol). The mixture was heated to 150°C again, and added concentrated sulfuric acid (4.51 g, 46 mmol). The resulting suspension was stirred at this temperature for lh. The reaction mixture was cooled to room temperature and added water (20 mL). This water phase was extracted with dichlorome thane (20 mL x 4). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (960 mg, 26%) as a yellow solid. H NMR (400 MHz, CDCI₃) δ 9.02-8.99 (m, 1H), 8.18-8.16 (m, 1H), 7.91-7.88 (m, 1H), 7.81-7.78 (m, 1H), 7.51 (s, 1H), 2.61 (s, 3H).

[00290] Step b. 6-methylquinolin-8-amine: To the solution of 6-methyl-8-nitroquinoline (350 mg, 1.86 mmol) in methanol (30 mL) was added Pd/C (10 wt percent, 0.2 g), and stirred at room temperature under N2 atmosphere overnight. The mixture was filtered and the filtrate was evaporated to give the crude desired product (250 mg, 85%) as a yellow oil. H NMR (400 MHz, CDCI₃) δ 8.69 (s, IH), 7.98 (s, IH), 7.33 (s, IH), 6.94 (s, IH), 6.79 (s, IH), 4.90 (s, 2H), 2.43 (s, 3H).

[00291] Method BM

-dimethylquinolin-8-amine hydroiodide

[00293] Step a. N,6-dimethylquinolin-8-amine hydroiodide: To the solution of 6- methylquinolin-8-amine (250 mg, 1.58 mmol) in ethanol (10 mL) in a sealed tube was added CH₃I (337 mg, 2.37 mmol), and stirred at reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with diethyl ether (10 mL) and the filer cake obtained was dried by oil pump to give the crude desired product hydroiodide (200 mg, 42%) as a red solid. H NMR (400 MHz, CDC1₃) δ 8.79 (s, IH), 8.58 (s, IH), 7.75 (s, IH), 7.08 (s, IH), 6.82 (s, IH), 3.08 (s, 3H), 2.57 (s, 3H).

[00294] Method BN

-difluoro-N-methylquinolin-8-amine

[00296] Step a. 5,6,8-trifluoroquinoline: To the solution of concentrated sulfuric acid (18 mL) diluted with water (6 mL), was added 2,4,5-trifluoroaniline (3.68 g, 25 mmol), glycerol (4.60 g, 50 mmol) and sodium 3-nitrobenzenesulfonate (6.75 g, 30 mmol) in sequence. The resulting suspension was stirred at 140°C overnight. The reaction mixture was cooled to room temperature and added saturated NaHCC>3 aqueous solution to adjust pH to 7, extracted with dichloromethane (200 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give the desired product (3.5 g, 76%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 8.99 (s, IH), 8.46- 8.44 (m, IH), 7.61-7.56 (m, IH), 7.38-7.31 (m, IH).

[00297] step b. 5,6-difluoro-N-methylquinolin-8-amine: To the solution of 5,6,8- trifluoroquinoline (436 mg, 2.38 mmol) and K₂CO₃ (657 mg, 4.76 mmol) in DMSO (3 mL) in a sealed tube, was added MeN¾ solution (30 wt percent in ethanol, 3 mL). The resulting suspension was stirred at 120°C for 2 days. The reaction mixture was cooled to room

temperature and filtered. The filtrate was diluted with ethyl acetate (50 mL) was added, extracted with water (15 mL). The organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give the desired product (200 mg, 43%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 8.88 (d, / = 4.4 Hz, 1H), 8.31 (d, / = 8.4 Hz, 1H), 7.47-7.44 (m, 1H), 6.40-6.35 (m, 1H), 6.08 (s, 1H), 3.00 (s, 3H).

[00298] Method BO

i -fluoroquinolin-8-amine

[00300] Step a. 7-fluoroquinolin-8-amine: The mixture of 7-fluoro-N-(4- methoxybenzyl)quinolin-8-amine (480 mg, 1.7 mmol) and HBr solution (48 wt percent in water, 15 mL) was stirred at 80°C overnight. The reaction mixture was cooled to room temperature and added saturated NaHCC>3 aqueous solution to adjust pH to 8, extracted with dichloromethane (30 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give the desired product (232 mg, 84%) as a yellow oil. MS (ESI/APCI) m z 163.0 [M + H]⁺.

[00301] Method BP

-chloro-l,7-naphthyridine

[00303] Step a. l,7-naphthyridin-8-amine: To the solution of concentrated sulfuric acid (15 mL) diluted with water (15 mL), was added pyridine-2, 3 -diamine (1.09 g, 10 mmol), glycerol (4.1g, 33.6 mmol) and sodium 3-nitrobenzenesulfonate (4.5 g, 20.1 mmol) in sequence. The resulting suspension was stirred at 125°C overnight. The reaction mixture was cooled to room temperature and added saturated NaOH aqueous solution to adjust pH to 8, extracted with dichloromethane (100 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol= 50/1) to give the desired product (295 mg, 20%) as a white solid H NMR (400 MHz, CDC1₃) δ 8.77 (s,lH), 8.00- 7.96 (m, 2H), 7.54 (d, / = 4.0 Hz, 1H), 6.93 (d, / = 5.6 Hz, 1H), 5.92 (s, 2H).

[00304] step b. 8-chloro-l,7-naphthyridine: To the solution of l,7-naphthyridin-8-amine (290 mg, 2.0 mmol) in concentrated HCl aqueous solution (5 mL), was added NaN0₂ (1.38 g, 20 mmol) and CuCl (238 mg, 33.6mmol) in sequence. The resulting suspension was stirred at room temperature for 3h. The reaction mixture was added saturated NaHC0₃ aqueous solution to adjust pH to 8, extracted with ethyl acetate (100 mL x 3). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1) to give the desired product (85 mg, 26%) as a pale solid. 1H NMR (400 MHz, CDC1₃) δ 9.15 (d, / = 2.4 Hz, 1H), 8.40 (d, / = 5.2 Hz, 1H), 8.22 (d, / = 8.4 Hz, 1H), 7.70 (dd, / = 8.0, 4.0 Hz, 1H), 7.63 (d, / = 5.2 Hz, 1H).

[00305] Method BQ

Preparation of 8-bromo-l,6-naphthyridine

[00307] Step a. 1,6-naphthyridine: To the solution of concentrated sulfuric acid (30 mL) diluted with water (20 mL), was added pyridin-4-amine (3.76 g, 40.0 mmol), glycerol (12.52 g, 136 mmol) and sodium 3-nitrobenzenesulfonate (19.8 g, 88.0 mmol) in sequence. The resulting suspension was stirred at 130°C overnight. The reaction mixture was cooled to room

temperature and added saturated NaOH aqueous solution to adjust pH to 10, extracted with dichloromethane (200 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give the desired product (900 mg, 69%) as a white solid. H NMR (400 MHz, CDC1₃) δ 9.30 (s,lH), 9.12 (s,lH), 8.78 (d, / = 5.2 Hz, 1H), 8.32 (d, / = 8.0 Hz, 1H), 7.94 (d, / = 5.2 Hz, 1H), 7.62-7.48 (m, 1H).

[00308] step b. 8-bromo-l,6-naphthyridine: To the solution of 1,6-naphthyridine (830 mg, 6.38 mmol) in HOAc (5 mL), was added dropwise dibromine (612 mg, 3.83 mmol). The resulting suspension was stirred at 80°C overnight. The reaction mixture was cooled to room temperature and added saturated NaHCC>3 aqueous solution to adjust pH to 8, extracted with dichloromethane (100 mL x 3). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give the desired product (700 mg, 68%) as a pale solid. ^!H NMR (400 MHz, CDC1₃) δ 9.24 (d, / = 2.8 Hz, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 8.34 (d, / = 8.0 Hz, 1H), 7.64 (dd, / = 8.0, 4.0 Hz, 1H).

[00309] Method BR

00310] Preparation of 4-chloro-l,5-naphthyridine

[00311] Step a. 1,5-naphthyridine 1-oxide: To the solution of 1,5-naphthyridine (3.0 g, 23.1 mmol), was added mCPBA (3.6 g, 20.9 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol= 50/1) to give the desired product (3.0 g, 89%) as an off-white solid. ^!H NMR (400 MHz, CDC1₃) δ 9.05 (d, / = 4.0 Hz, 1H), 9.04 (s, 1H), 8.56 (d, / = 6.0 Hz, 1H), 8.02 (d, / = 8.8 Hz, 1H), 7.70-7.67 (m, 1H), 7.54 (dd, / = 8.4, 6.0 Hz, 1H).

[00312] step b. 4-chloro-l,5-naphthyridine: The solution of 1,5-naphthyridine 1-oxide (3.0 g, 20.5 mmol) in POCI₃ (30 mL), was stirred at 100°C for 6h. The reaction mixture was concentrated and diluted with dichloromethane (100 mL). This solution was added saturated NaHCC>3 aqueous solution to adjust pH to 8. Filtered and the filtrate was partitioned. The water phase was extracted with ethyl acetate (100 mL). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the desired product (930 mg, 27%) as a pale solid. ^!H NMR (400 MHz, CDC1₃) δ 9.11 (dd, J = 4.4, 2.0 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.46 (dd, / = 8.4, 2.0 Hz, 1H), 7.78 (d, / = 4.8 Hz, 1H), 7.74 (dd, / = 8.4, 4.0 Hz, 1H). MS (ESI/APCI) m z 164.9 [M+H] ⁺.

[00313] Method BS

-methyl-2-(pyridin-2-yl)pro an-2-amine

[00315] Step a. N-(2-(pyridin-2-yl)propan-2-yl)formamide: To the solution of 2-(pyridin- 2-yl)propan-2-amine (350 mg, 2.6 mmol) in toluene(10 mL), was added formic acid (237 mg, 5.2 mmol). The resulting suspension was stirred at reflux for 6h. The reaction mixture was cooled to room temperature and added saturated NaHCC>3 aqueous solution (50 mL), the water phase was extracted with dichloromethane (50 mL). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 100/1/1 to 100/3/1) to give the desired product (300 mg, 70%) as a slight yellow oil H NMR (400 MHz, CDC1₃) δ 8.56-8.49 (m, 1H), 8.40-8.25 (m, 1H), 7.90 (s, 1H), 7.78-7.65(m, 1H), 7.40 (d, / = 7.8 Hz, 1H), 7.24-7.17 (m, 1H), 1.75 (d, 7 = 28.0 Hz, 6H).

[00316] Step b. N-methyl-2-(pyridin-2-yl)propan-2-amine: To the solution of N-(2- (pyridin-2-yl)propan-2-yl)formamide (300 mg, 1.8 mmol) in THF (10 mL), was added NaH (60 wt percent moistened with oil, 222 mg, 5.4 mmol). The resulting suspension was stirred at room temperature for 15 min. Then CH₃I (390 mg, 2.7 mmol) was added, the reaction mixture was stirred at reflux for 2h.The reaction mixture was cooled to room temperature and added the solution of NaOH (252 mg, 6.12 mmol) in methanol (5 mL) and water (1 mL). The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and extracted with dichloromethane (100 mL x 3). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (250 mg, 90%) as a yellow oil H NMR (400 MHz, CDC1₃) δ 8.59 (d, / = 4.4 Hz, 1H), 7.77-7.63 (m, 1H), 7.39 (d, / = 8.0 Hz, 1H), 7.13 (dd, / = 7.2, 4.8 Hz, 1H), 2.13 (s, 3H), 1.47 (s, 6H).

[00317] Example 1

[00318] Preparation of N-methyl-N-((6-(4-methylpiperazin- 1 -yl)pyrimidin-4-yl)methyl)- - tetrahydroquinolin-8-amine (Al)

step a step b

[00319] Method AA-Step a. N-((6-chloropyrimidin-4-yl)methyl)-N-methyl-5, 6,7,8- tetrahydroquinolin-8- amine: A mixture of N-methyl-5,6,7,8-tetrahydroquinolin-8-amine (160 mg, 1 mmol, see reference WO2006026703), 4-chloro-6-(chloromethyl)pyrimidine (170 mg, 1.05 mmol), KI (16 mg, 0.1 mmol) and DIPEA (320 mg, 2.5 mmol) in CH₃CN (10 mL) was stirred at room temperature overnight. The reaction solution was evaporated to remove most of CH₃CN, diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol= 100/1 to 50/1) to give the desired product (200 mg, 69%) as a brown oil. H NMR (400 MHz, CDC1₃) δ 8.83 (s, 1H), 8.50 (d, / = 8.0 Hz, 1H), 7.89 (s, 1H), 7.37 (d, / = 8.0 Hz, 1H), 7.08 (dd, / = 8.0, 4.0 Hz, 1H), 4.03-3.99 (m, 1H), 3.80 (s, 2H), 2.82-2.77 (m, 1H), 2.75-2.70 (m, 1H), 2.41 (s, 3H), 2.17- 2.14 (m, 1H), 2.06-2.04 (m, 1H), 1.92-1.89 (m, 1H), 1.72-1.71 (m, 1H).

[00320] Method AA-Step b. N-methyl-N-((6-(4-methylpiperazin- l-yl)pyrimidin-4- yl)methyl)-5,6,7,8- tetrahydroquinolin-8-amine: A mixture of N-((6-chloropyrimidin-4- yl)methyl)-N-methyl-5,6,7,8- tetrahydroquinolin-8-amine (100 mg, 0.35 mmol), TEA (350 mg, 3.5 mmol) and N-methylpiperazine (40 mg, 0.38 mmol) in ethanol (4 mL) was stirred at reflux overnight. The reaction mixture was concentrated and added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to give the desired product (98 mg, 80 %) as a colorless oil^H NMR (400 MHz, CDC1₃) δ 8.45 (s, 2H), 7.33 (d, / = 6.8 Hz, 1H), 7.20 (s, 1H), 7.03 (s, 4.8 Hz, 1H), 3.99 (s, 1H), 3.68 (s, 4H), 3.62 (s, 2H), 2.77 (s, 1H), 2.68-2.64 (m, 1H), 2.44 (s, 4H), 2.35 (s, 3H), 2.30 (s, 3H), 1.97 (s, 1H), 1.91-1.88 (m, 1H), 1.85 (s, 1H), 1.67 (s, 1H). HRMS (ESI): calcd for C2₀H29N₆ [M+H]⁺353.2448, found 353.2451.

[00321] Example 2

[00322] Preparation of N-methyl-N-((6-(piperazin-l-yl)pyrimidin-4-yl)methyl)-5,6,7,8- tetrahydroquinolin-8- amine (A7) and 3-(4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8-

[00323] Method AB-Step a. tert-butyl-4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8- yl)amino)methyl)pyrimidin-4-yl)piperazine-l-carboxylate: A mixture of N-((6-chloropyrimidin- 4- yl)methyl)-N-methyl-5,6,7,8-tetrahydroquinolin-8-amine (200 mg, 0.7 mmol), TEA (700 mg, 7 mmol) and tert-butyl piperazine-l-carboxylate (140 mg, 0.77 mmol) in ethanol (10 mL) was stirred at reflux overnight. The reaction mixture was added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (50 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 50/1 to 25/1) to give the desired product (290 mg, 94 %) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.50 (s, 2H), 7.37 (d, / = 7.6 Hz, 1H), 7.29 (s, 1H), 7.08 (dd, / = 7.6, 4.8 Hz, 1H), 4.02 (t, / = 7.6 Hz, 1H), 3.71 (s, 4H), 3.67 (s, 2H), 3.50 (s, 4H), 2.88-2.76 (m, 1H), 2.76-2.66 (m, 1H), 2.39 (s, 3H), 2.17-2.08 (m, 1H), 2.01 (s, 1H), 1.94-1.89 (m, 1H), 1.74-1.68 (m, 1H), 1.49 (s, 9H). MS (ESI/APCI) m z 438.8 [M + H]⁺.

[00324] Method AB-Step b. N-methyl-N-((6-(piperazin- l-yl)pyrimidin-4-yl)methyl)- 5,6,7,8- tetrahydroquinolin-8-amine: To a solution of tert-butyl-4-(6-((methyl(5,6,7,8- tetrahydroquinolin-8- yl)amino)methyl)pyrimidin-4-yl)piperazine-l-carboxylate (270 mg, 0.6 mmol) in dichloromethane (5 mL) was added dropwise 3M HC1/ ethyl acetate (5 mL). The mixture was stirred at room temperature for 12 h. Saturated aqueous NaHCC>3 solution was added to adjust pH = 9, and the mixture was then extracted with dichloromethane (20 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1 to 25/1) to give the desired product (180 mg, 90%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.49-8.48 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.06 (dd, / = 7.6, 4.8 Hz, 1H), 4.08-3.98 (m, 1H), 3.68-3.64 (m, 6H), 2.93 (t, / = 4.8 Hz, 4H), 2.86-2.76 (m, 1H), 2.72 (s, 1H), 2.40 (s, 3H), 2.11 (s, 1H), 2.01-1.97 (m, 1H), 2.00-1.88 (m, 1H), 1.76-1.67 (m, 2H). MS (ESI/APCI) m/z 338.9 [M + H]⁺

[00325] Method AB-Step c. 3-(4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8- yl)amino)methyl)pyrimidin-4- yl)piperazin-l-yl)propanenitrile: To a solution of N-methyl-N- ((6-(piperazin-l-yl)pyrimidin-4- yl)methyl)-5,6,7,8- tetrahydroquinolin-8-amine (50 mg, 0.13 mmol) in methanol (2 mL) was added TEA (15 mg, 0.13 mmol) and acrylonitrile (20 mg, 0.26 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (50 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1 to 25/1) to give the desired product (40 mg, 78 %) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.53-8.47 (m, 2H), 7.38 (d, / = 7.6 Hz, 1H), 7.25 (s, 1H), 7.08 (dd, / = 7.6, 4.8 Hz, 1H), 4.09-3.97 (m, 1H), 3.73 (s, 4H), 3.65 (s, 2H), 2.86-2.78 (m, 1H), 2.75-2.71 (m, 3H), 2.58-2.53 (m, 6H), 2.40 (s, 3H), 2.16-2.08 (s, 1H), 2.05-1.97 (m, 1H), 1.93-1.88 (m, 1H), 1.75-1.69 (m, 1H).

[00326] Example 3

[00327] Preparation of N-methyl-N-((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-

[00328] Method AC-Step a. N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 -yl)pyrimidin- 4-yl)methyl)- 5,6,7,8-tetrahydroquinolin-8-amine: A mixture of N-methyl-5, 6,7,8- tetrahydroquinolin-8-amine (37 mg, 0.23 mmol, see reference WO2006026703), 2-methyl-6-(4- methylpiperazin-l-yl)pyrimidine-4- carbaldehyde (46 mg, 0.21 mmol) and AcOH (13 mg, 0.21 mmol) in 1,2-dichloroethane (5 mL) was stirred for 10 min. NaBH(OAc)3 (66 mg, 0.3 mmol) was then added to the reaction solution. The resulting suspension was stirred at room

temperature overnight. The reaction mixture was added saturated NaHCC>3 aqueous solution (100 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1 to 50/1/1) to give the desired product (30 mg, 39 %) as a colorless oil. H NMR (400 MHz, CDC1₃) δ 8.49 (d, / = 4.6 Hz, 1H), 7.35 (d, / = 8.0 Hz, 1H), 7.07-7.03 (m, 2H), 4.04 (t, / = 7.4 Hz, 1H), 3.71 (t, / = 5.2 Hz, 4H), 3.60 (s, 2H), 2.86-2.75 (m, IH), 2.73-2.65 (m, IH), 2.46-2.43 (m, 7H), 2.39 (s, 3H), 2.33 (s, 3H), 2.15-2.07 (m, IH), 2.04-1.96 (m, IH), 1.95-1.87 (m, IH), 1.74-1.71 (m, IH).

[00329] Example 4

[00330] Preparation of (5)-N-((6-((R)-2,4-dimethylpiperazin- 1 -yl)-2-methylpyrimidin-4-

[00331] Method AD-Step a. (5)-N-methyl-N-((2-methyl-6-((R)-2-methylpiperazin- l- yl)pyrimidin-4- yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine: To a solution of (R)-tert-butyl 3- methyl-4-(2-methyl-6- ((methyl((5)-5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyrimidin-4- yl)piperazine-l-carboxylate (50 mg, 0.11 mmol) in ethyl acetate (2 mL) was added 3M HQ/ ethyl acetate (3 mL) and stirred at room temperature overnight. The reaction mixture was added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layer was dried over Na2S0₄, filtered and evaporated to give the desired product (26 mg, 65%) as a colorless oil.

[00332] Method AD-Step b. (5)-N-((6-((R)-2,4-dimethylpiperazin-l-yl)-2- methylpyrimidin-4-yl)methyl)- N-methyl-5,6,7,8-tetrahydroquinolin-8-amine: A mixture of (5)- N-methyl-N-((2-methyl-6-((R)-2- methylpiperazin-l-yl)pyrimidin-4-yl)methyl)-5, 6,7,8- tetrahydroquinolin-8-amine (26 mg, 0.07 mmol) and formaldehyde (37 wt percent in water, 30 mg, 0.36 mmol) in 1,2-dichloroethane (4 mL) was added NaBH(OAc)3 (30 mg, 0.14 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (10 mg, 38%) as a colorless oil^H NMR (400 MHz, CDC1₃) δ 8.48 (s, IH), 7.35 (d, J = 7.6 Hz, IH), 7.09-6.92 (m, 2H), 4.62 (s, IH), 4.35-4.28 (m, IH), 4.09-3.98 (m, IH), 3.74-3.49 (m, 2H), 3.23-3.08 (m, IH), 2.91-2.83 (m, IH), 2.82-2.75 (m, IH), 2.74-2.65 (m, 2H), 2.46 (s, 3H), 2.42-2.36 (m, 3H), 2.28 (s, 3H), 2.22-2.17 (m, IH), 2.14- 2.07 (m, IH), 2.05-1.91 (m, 3H), 1.74-1.63 (m, IH), 1.29- 1.23 (m, 3H).

[00333] Example 5

[00334] Preparation of N-methyl-N-((4-(4-methylpiperazin-l-yl)pyrimidin-2-yl)methyl)- 5,6,7,8- tetrahydroquinolin-8-amine (A50)

[00335] Method AE-Step a. N-((4-chloropyrimidin-2-yl)methyl)-N-methyl-5,6,7,8- tetrahydroquinolin-8- amine: The mixture of 2-(bromomethyl)-4-chloropyrimidine(94 mg, 0.58 mmol), N-methyl-5,6,7,8- tetrahydroquinolin-8-amine (130 mg, 0.6 mmol, see reference WO2006026703), KI (10 mg, 0.06 mmol) and DIPEA (740 mg, 5.8 mmol) in MeCN (10 mL) was stirred at room temperature for 4h. The reaction solution was evaporated to remove most of MeCN, added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (140 mg, 84%) as a yellow oil. H NMR (400 MHz, CDCI₃) δ 8.62 (d, / = 4.8 Hz, 1H), 8.46 (d, / = 2.8 Hz, 1H), 7.38 (d, / = 7.6 Hz, 1H), 7.22 (d, / = 4.8 Hz, 1H), 7.09-7.06 (m, 1H), 4.28-4.26 (m, 1H), 4.22 (s, 1H), 4.15-4.12 (m, 1H), 2.84-2.78 (m, 1H), 2.72-2.68 (m, 1H), 2.50 (s, 3H), 2.25-2.24 (m, 1H), 2.04-1.96 (m, 2H), 1.73-1.70 (m, 1H).

[00336] Method AE-Step b. N-methyl-N-((4-(4-methylpiperazin- l-yl)pyrimidin-2- yl)methyl)-5,6,7,8- tetrahydroquinolin-8-amine: The mixture of N-((4-chloropyrimidin-2- yl)methyl)-N-methyl-5, 6,7,8- tetrahydroquinolin-8-amine (50 mg, 0.17 mmol), DIPEA (244 mg, 1.7 mmol) and 1-methylpiperazine (87 mg, 0.85 mmol) in NMP (2 mL) was stirred at 200 °C under microwave for 2 h. The reaction was diluted with ethyl acetate (50 mL) and washed with brine (50 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (34 mg, 57%) as a yellow oil H NMR (400 MHz, CDCI₃) δ 8.46 (s, 1H), 8.18 (d, / = 6.0 Hz, 1H), 7.34 (d, / = 8.0 Hz, 1H), 7.05-7.02 (m, 1H), 6.32 (d, / = 6.4 Hz, 1H), 4.15-4.12 (m, 1H), 3.81 (s, 2H), 3.65 (s, 4H), 2.87-2.77 (m, 1H), 2.72-2.69 (m, 1H), 2.65-2.44 (m, 7H), 2.32 (s, 3H), 2.11-1.98 (m, 3H), 1.73-1.64 (m, 1H).

HRMS (ESI): calcd for C2₀H29N₆ [M+H]⁺353.2448, found 353.2448.

[00337] Example 6

[00338] Preparation of N-methyl-N-((6-(4-methylpiperazin-l-yl)pyridin-2-yl)methyl)- 5,6,7,8- tetrahydroquinolin-8-amine (B6)

[00339] Method AF-Step a. N-((6-bromopyridin-2-yl)methyl)-N-methyl-5,6,7,8- tetrahydroquinolin-8- amine: The mixture of 6-bromopicolinaldehyde (162 mg, 0.68 mmol), N- methyl-5,6,7,8- tetrahydroquinolin-8-amine (100 mg, 0.62 mmol, see reference

WO2006026703), AcOH (48 mg, 0.62 mmol) in 1,2-dichloroethane (10 mL) was stirred for 15 min. NaBH(OAc)3 (252 mg, 0.93 mmol) was then added to the reaction solution. The resulting suspension was stirred at room temperature overnight. The reaction solution was added saturated NaHCC>3 aqueous solution (50 mL) and extracted with dichloromethane (100 mL). The combined organic layers was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1) to give the desired product (180 mg, 87%) as a yellow oil H NMR (400 MHz, CDC1₃) δ 8.50 (s, 1H), 7.73 (d, / = 7.6 Hz, 1H), 7.50 (t, / = 7.6 Hz, 1H), 7.35 (d, / = 7.2 Hz, 1H), 7.29 (d, / = 7.6 Hz, 1H), 7.05 (t, / = 5.8 Hz, 1H), 4.03 (t, / = 7.0 Hz, 1H), 3.73 (s, 2H), 2.81-2.77 (m, 1H), 2.72-2.68 (m, 1H), 2.39 (s, 3H), 2.12 (s, 1H), 2.01(s, 1H), 1.95-1.87 (m, 1H), 1.71 (s, 1H).

[00340] Method AF-Step b. N-methyl-N-((6-(4-methylpiperazin- l-yl)pyridin-2- yl)methyl)-5,6,7,8- tetrahydroquinolin-8-amine: The mixture of N-((6-bromopyridin-2- yl)methyl)-N-methyl-5,6,7,8- tetrahydroquinolin-8-amine (50 mg, 0.15 mmol), DIPEA (193 mg, 1.5 mmol) and 1-methylpiperazine (73 mg, 0.75 mmol) in NMP (2 mL) was stirred at 120 °C overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with brine (30 mL x 5). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1) to give the desired product (12 mg, 23%).¹H NMR (400 MHz, CDC1₃) δ 8.51 (d, / = 4.4 Hz, 1H), 7.43 (t, / = 7.8 Hz, 1H), 7.34 (d, / = 7.6 Hz, 1H), 7.05 (d, / = 4.8 Hz, 1H), 7.00 (d, / = 7.2 Hz, 1H), 6.46 (d, / = 8.4 Hz, 1H), 4.03 (s, 1H), 3.64 (q, / = 15.0 Hz, 2H), 3.53 (s, 4H), 2.82-2.78 (m, 1H), 2.71-2.66 (m, 1H), 2.50 (t, / = 4.4 Hz, 5H), 2.37 (s, 3H), 2.33 (s, 3H), 2.07 (s, 1H), 2.02-2.98 (m, 1H), 1.95-1.92 (m, 1H), 1.65 (s, 1H). HRMS (ESI): calcd for C₂iH₃oN₅ [M+H]⁺352.2496, found 352.2514.

[00341] Example 7

[00342] Preparation of N-methyl-N-(pyrimidin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8- amine (B2)

[00343] Method AG-Step a. N-methyl-N-(pyrimidin-4-ylmethyl)-5,6,7,8- tetrahydroquinolin-8-amine: A mixture of N-((6-chloropyrimidin-4-yl)methyl)-N-methyl- 5,6,7,8-tetrahydroquinolin-8-amine (70 mg, 0.24 mmol) and Pd/C (5 %, 15 mg) in 5 mL of methanol was stirred at 50 °C under ¾ (1 atm) overnight. The reaction solution was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol= 100/1) to give the desired product (50 mg, 82%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 9.06 (s, IH), 8.65 (d, / = 4.8 Hz, IH), 8.50 (s, IH), 7.80 (d, / = 4.4 Hz, IH), 7.37 (d, / = 7.2 Hz, IH), 7.08-7.05 (m, IH), 4.04-4.01 (m, IH), 3.82-3.72 (m, 2H), 2.82-2.78 (m, IH), 2.73-2.69 (m, IH), 2.39 (s, 3H), 2.13 (s, IH), 2.03 (s, IH), 1.97-1.88 (m, IH), 1.72 (s, IH). MS (ESI/APCI) m z 254.9 [M + H]⁺.

[00344] Example 8

[00345] Preparation of (5)-(2-methyl-4-((methyl(l-(pyridin-2-yl)ethyl)amino)methyl)-6- (4-methylpiperazin-l- yl)pyrimidin-5-yl)methanol (A85)

step a step b c

[00346] Method AH-Step a. (4,6-dichloro-2-methylpyrimidin-5-yl)methanol: To POCl₃ (60.6 g, 396.5 mmol) was added dropwise DMF (9.8 g, 134.8 mmol) at 0°C. The resulting suspension was stirred at the same temperature for lh. Then 2-methylpyrimidine-4,6-diol (10 g, 79.3 mmol) was added in portions and stirred at room temperature for lh, after that, stirred at 105 °C overnight. The reaction solution was concentrated and diluted with cold ethyl acetate (lOOmL). This solution was added dropwise into ice-water, filtered and the filtrate was extracted with ethyl acetate (200 mL). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give a yellow oil (10 g). This oil was dissolved in THF (50 mL) and water (10 mL), and NaBH₄ (4 g, 104.7 mmol) was added in portions at 0°C. The resulting suspension was stirred at the same temperature for 30min. Water (50 mL) was added, and extracted with ethyl acetate (50 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give the desired product (2 g, 20%) as a yellow solid. ^!H NMR (400 MHz, CDC1₃) δ 4.91 (s, 2H), 2.69 (s, 3H).

[00347] Method AH-Step b. 5-((feri-butyldimethylsilyloxy)methyl)-4,6-dichloro-2- methylpyrimidine: To the solution of (4,6-dichloro-2-methylpyrimidin-5-yl)methanol (2 g, 10.3 mmol) and imidazole (770 mg, 11.3 mmol) in dichloromethane (20mL) was added TBSC1 (1.7 g, 11.3 mmol) in portions. The resulting suspension was stirred at room temperature overnight. Water (20 mL) was added, and extracted with dichloromethane (20 mL). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1) to give the desired product (2.6 g, 84 %) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 4.85 (s, 2H), 2.68 (s, 3H), 0.91 (s, 9 H), 0.14 (s, 6H).

[00348] Method AH-Step c. 5-((½ri-butyldimethylsilyloxy)methyl)-6-chloro-2- methylpyrimidine-4- carbaldehyde: To the solution of 5-((½ri-butyldimethylsilyloxy)methyl)- 4,6-dichloro-2- methylpyrimidine (1.5 g, 4.8 mmol), potassium vinyltrifluoroborate (655 mg, 4.88 mmol), Cs₂C0₃ (2.4 g, 7.32 mmol) and Pd(PPh₃)₄ (566 mg, 0.49 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at reflux overnight under N₂ atmosphere. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1) to give a crude oil (900 mg). This resulting oil was added methanol (30 mL) and dichloromethane (7 mL) to dissolve. Then 03 was introduced into this reaction solution at -65 °C and stirred at this temperature for 4h before dimethyl sulfide was added to quench the reaction. The solvent was concentrated and added water (20 mL), extracted with dichloromethane (50 mL). The combined organic layer was dried over Na₂S0₄, filtered and evaporated to give the crude desired product (610 mg) as a white solid.

[00349] Method AH-Step d. (5)-(4-chloro-2-methyl-6-((methyl(l-(pyridin-2- yl)ethyl)amino)methyl)pyrimidin-5-yl)methanol: A mixture of (5)-N-methyl-l-(pyridin-2- yl)ethanamine (544 mg, 4.0 mmol), 5-((½ri-butyldimethylsilyloxy)methyl)-6-chloro-2- methylpyrimidine-4-carbaldehyde (610 mg, 2.0 mmol) and AcOH (360 mg, 6.0 mmol) in dichloromethane (10 mL) was stirred for lh. NaBH(OAc)₃ (1.3 g, 6.0 mmol) was then added to the reaction solution. The resulting suspension was stirred at room temperature overnight. The reaction mixture was added water (10 mL) and extracted with dichloromethane (10 mL). The combined organic layers was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 50/1) to give the desired product (480 mg, 80 %) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.66- 8.55 (m, 1H), 7.82-7.65 (m, 1H), 7.38-7.30 (m, 1H), 7.25-7.18 (m, 1H), 4.77 (s, 2H), 4.15-3.85 (m,3H), 2.66 (s, 3H), 2.19 (s, 3H), 1.56 (d, / = 7.2 Hz, 3H).

[00350] Method AH-Step e. (5)-(2-methyl-4-((methyl(l-(pyridin-2- yl)ethyl)amino)methyl)-6-(4- methylpiperazin-l-yl)pyrimidin-5-yl)methanol: The mixture of (5)-(4-chloro-2-methyl-6-((methyl(l- (pyridin-2-yl)ethyl)amino)methyl)pyrimidin-5- yl)methanol (50 mg, 0.16 mmol), TEA (80 mg, 0.8 mmol) and l-methylpiperazine (48 mg, 0.48 mmol) in ethanol (5 niL) was stirred at reflux overnight. The reaction solution was evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 100/1/1 to 100/2/1) to give the desired product (26 mg, 80%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.62-8.56 (m, 1H), 7.73- 7.63 (m, 1H), 7.31 (d, / = 8.0 Hz, 1H), 7.23-7.15 (m, 1H), 4.45-4.35 (m, 2H), 3.92 (q, / = 6.8 Ηζ,ΙΗ), 3.87 (d, / = 13.2 Hz, 1H), 3.79 (s, 4H), 3.68 (d, / = 13.2 Hz, 1H), 2.70 (s, 4H), 2.48 (s, 3H), 2.45 (s, 3H), 2.07 (s, 3H), 1.55 (d, / = 6.8 Hz, 3H).

[00351] Example 9

[00352] Preparation of (3R,5R)-5-(2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)-l- -5,6,7,8- tetrahydroquinolin-8-yl)pyrrolidin-3-ol (C16)

[00353] Method AI-Step a. (3R,5R)-5-(2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)-l-((5)-5,6,7,8- tetrahydroquinolin-8-yl)pyrrolidin-3-ol: The solution of (5)-8-((2R,4R)-4- (tert-butyldimethylsilyloxy)- 2-(2-methyl-6-(4-methylpiperazin- 1 -yl)pyrimidin-4-yl)pyrrolidin- l-yl)-5,6,7,8-tetrahydroquinoline (50 mg, 0.1 mmol) in 2M HCI aqueous solution (5 mL) was stirred at room temperature for 2h. The reaction mixture was added saturated NaHC0₃ aqueous solution (100 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated to give the desired product (35 mg, 86%) as a white solid. H NMR (400 MHz, CDC1₃) δ 8.38 (d, / = 4.8 Hz, 1H), 7.12 (d, / = 7.2 Hz, 1H), 7.05-6.99 (m, 1H), 5.29 (s, 1H), 4.28 (s, 1H), 4.03 (d, / = 10.0 Hz, 1H), 3.89 (s, 1H), 3.55-3.38 (m, 4H), 3.30 (d, / = 9.2 Hz, 1H), 2.92-2.83 (m, 1H), 2.63-2.53 (m, 1H), 2.53-2.45 (m, 1H), 2.44-2.37 (m, 7H), 2.33 (s, 3H), 2.14-2.05 (m, 2H), 1.77 (d, / = 13.6 Hz, 1H), 1.62-1.51 (m, 3H).

[00354] Example 10

[00355] Preparation of (8-(methyl((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)amino)quinolin-6-yl)methanol (D55)

[00356] Method AJ-Step a. (8-(methyl((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)amino)quinolin-6-yl)methanol: The solution of methyl 8-(methyl((2-methyl-6-(4- methylpiperazin- 1 -yl)pyrimidin-4-yl)methyl)amino)quinoline-6-carboxylate( 105 mg, 0.25 mmol) in THF (3 mL) was added L1AIH₄ (19 mg, 0.5 mmol) at 0°C, and stirred at room temperature for 20 min. Water and NaOH aqueous solution (15wt percent in water) was added to quench the reaction. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (60 mg, 61%) as a slight yellow oil. H NMR (400 MHz,

CDCI₃) δ 8.76 (s, 1H), 8.07 (d, / = 8.0 Hz, 1H), 7.45-7.30 (m, 2H), 7.17 (s, 1H), 6.79 (s, 1H), 4.81 (s, 2H), 4.66 (s, 2H), 3.63 (s, 4H), 3.03 (s, 3H), 2.54 (s, 3H), 2.50-2.43 (m, 4H), 2.32 (s, 3H).

[00357] Example 11

[00358] Preparation of (5)-5-(4-methylpiperazin- l-yl)-2-((2-(3-methylpyridin-2- yl)pyrrolidin-l- yl)methyl)imidazo[l,2- ]pyridine (C38) and (5)-(5-(4-methylpiperazin-l-yl)-2- -(3-methylpyridin-2- yl)pyrrolidin-l-yl)methyl)imidazo[l,2- ]pyridin-3-yl)methanol (C39)

[00359] Method AK-Step a. (5)-5-bromo-2-((2-(3-methylpyridin-2-yl)pyrrolidin-l- yl)methyl)imidazo[l,2- jpyridine: The mixture of 5-bromo-2-(bromomethyl)imidazo[l,2- ]pyridine(48 mg, 0.17mmol), (5)-3-methyl-2-(pyrrolidin-2-yl)pyridine (30 mg, 0.12 mmol), KI (3 mg, 0.017 mmol) and K₂C0₃ (46 mg, 0.34 mmol) in MeCN (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to give the desired product (40 mg, 78%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.48 (s, 1H),7.61 (s,lH), 7.48 (d, / = 8.8 Hz, 1H), 7.31 (d, / = 7.6 Hz, 1H), 7.03-6.95 (m, 3H), 3.97-3.94 (m, 2H), 3.74 (s,lH), 3.43 (s, 1H), 2.55 (s, 1H), 2.37 (s, 3H), 2.21-1.95 (m, 4H). [00360] Method AK-Step b. (5)-5-(4-methylpiperazin-l-yl)-2-((2-(3-methylpyridin-2- yl)pyrrolidin-l- yl)methyl)imidazo[l,2-a]pyridine: The mixture of (5)-5-bromo-2-((2-(3- methylpyridin-2-yl)pyrrolidin- l-yl)methyl)imidazo[l,2- jpyridine (40 mg, 0.11 mmol) in 1- methylpiperazine (3 mL) was stirred at 170°C under microwave for 1.5 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 60/1) to give the desired product (20 mg, 48%) as a colorless oil. ^!H NMR (400 MHz, CDC1₃) δ 8.49 (d, / = 3.6 Hz, 1H), 7.33 (s, 2H), 7.28 (s, 1H), 7.13-7.09 (m, 1H), 7.01-6.98 (m, 1H), 6.24 (d, / = 7.2 Hz, 1H), 3.96 (d, / = 13.6 Hz, 1H), 3.84 (t, / = 8.0 Hz, 1H), 3.67(d, / = 13.6 Hz, 1H), 3.39 (t, / = 8.0 Hz, 1H), 3.10 (s, 4H), 2.64 (s, 4H), 2.59-2.52 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H), 2.22-2.17 (m, 2H), 2.05-1.90 (m, 2H).

[00361] Method AK-Step c. (5)-(5-(4-methylpiperazin-l-yl)-2-((2-(3-methylpyridin-2- yl)pyrrolidin-l- yl)methyl)imidazo[l,2- ]pyridin-3-yl)methanol: The mixture of (5)-5-(4- methylpiperazin-l-yl)-2-((2- (3-methylpyridin-2-yl)pyrrolidin-l-yl)methyl)imidazo[l,2- jpyridine (46 mg, 0.12 mmol) and formaldehyde (37 wt percent in water, 5 mL) in a sealed tube was stirred at 50°C for 2 days. The reaction mixture was added saturated NaHCC>3 aqueous solution (10 mL) and extracted with dichloromethane (30 m). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to give the desired product (35 mg, 71%) as a colorless oil. H NMR (400 MHz, CDC1₃) δ 8.50 (d, / = 3.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.08-7.02 (m, 2H), 6.39 (d, / = 6.8 Hz, 1H), 6.19 (brs, 1H), 5.27 (d, / = 14.0 Hz, 1H), 5.07 (d, / = 14.0 Hz, 1H), 4.05 (d, / = 12.8 Hz, 1H), 3.86-3.84 (m, 1H), 3.50-3.47 (m, 2H), 3.26- 3.23 (m, 1H), 3.18-3.15 (m, 1H), 3.01-2.91 (m, 3H), 2.85-2.80 (m, 1H), 2.54-2.46 (m, 3H), 2.41(s, 3H), 2.38(s, 3H), 2.28-2.24 (m, 1H), 1.91-1.82(m, 3H).

[00362] Example 12

[00363] Preparation of 7-fluoro-N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1-

[00364] Method AL-Step a. 7,7-difluoro-6,7-dihydroquinolin-8(5H)-one: To a solution of NaH (60 wt percent moistened with oil, 511 mg, 12.8 mmol) in THF (20 mL) was added dropwise the THF solution (5 mL) containing 6,7-dihydroquinolin-8(5H)-one (588 mg, 4 mmol) at 0°C. The reaction was stirred at 0°C for 10 min followed by adding selectfluro (3.0 g, 8.4 mmol) in portions. The reaction mixture was stirred at room temperature for lh. Water (20 mL) was added to quench the reaction. The water phase was extracted with diethyl ether (20 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give the desired product (380 mg, 52%) as a white solid. H NMR (400 MHz, CDC1₃) δ 8.81 (s, 1H), 7.73 (d, / = 7.6 Hz, 1H), 7.57-7.45 (m, 1H), 3.26-3.08 (m, 2H), 2.76-2.51 (m, 2H).

[00365] Method AL-Step b.7,7-difluoro-N-methyl-5,6,7,8-tetrahydroquinolin-8-amine: The solution of 7,7-difluoro-6,7-dihydroquinolin-8(5H)-one (18.3 mg, 0.1 mmol), MeNH₂ solution (30 wt percent in ethanol, 1 mL) and HO Ac (5 mg, 0.083 mmol) in 1,2-dichloroethane (2 mL) was added NaBHsCN (13 mg, 0.2 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 150/1) to give the desired product (15 mg, 75%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.47 (d, / = 4.0 Hz, 1H), 7.46 (d, / = 7.6 Hz, 1H), 7.19-7.15 (m, 1H), 3.89 (t, / = 10.0 Hz, 1H), 3.01-2.91 (m, 2H), 2.72 (s, 3H), 2.61-2.41 (m, 1H), 2.30-2.17 (m, 1H).

[00366] Method AL-Step c. 7-fluoro-N-methyl-N-((2-methyl-6-(4-methylpiperazin-l- yl)pyrimidin-4- yl)methyl)-5,6-dihydroquinolin-8-amine: A mixture of 4-chloro-6- (chloromethyl)-2-methylpyrimidine (54 mg, 0.31 mmol), 7,7-difluoro-N-methyl-5,6,7,8- tetrahydroquinolin-8-amine (55 mg, 0.28 mmol), KI (5 mg, 0.028 mmol) and DIPEA (90 mg, 0.7 mmol) in C¾CN (10 mL) was stirred at room temperature overnight. The reaction solution was evaporated to remove most of C¾CN, diluted with dichloromethane (15 mL) and washed with saturated brine solution (10 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was dissolved in ethanol (10 mL). TEA (252 mg, 2.5 mmol) and N- methylpiperazine (125 mg, 1.25 mmol) were added and stirred at reflux for 3h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 50/1/1) to give the desired product (15 mg, 15%) as a colorless oil. H NMR (400 MHz, CDC1₃) δ 8.44 (d, / = 4.0 Hz, 1H), 7.40 (d, / = 7.2 Hz, 1H), 7.06-6.98 (m, 1H), 6.93 (s, 1H), 4.26 (s, 2H), 3.60 (s, 4H), 2.93 (s, 3H), 2.93-2.81 (m, 2H), 2.64-2.56 (m, 2H), 2.47 (s, 3H), 2.42 (s, 4H), 2.32 (s, 3H). MS (ESI/APCI) m z 382.9 [M+H]⁺.

[00367] Example 13 [00368] Preparation of N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 -yl)pyrimidin-4-

[00369] Method AM-Step a. N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 - yl)pyrimidin-4- yl)methyl)quinolin-8-amine: A mixture of N-((2-methyl-6-(4-methylpiperazin-l- yl)pyrimidin-4- yl)methyl)quinolin-8-amine (75 mg, 0.26 mmol) and formaldehyde (37 wt percent in water, 42 mg, 0.52 mmol) in methanol (3 mL) was added NaB¾CN (25 mg, 0.4 mmol). The resulting suspension was stirred at room temperature overnight. Water (10 mL) was added to quench the reaction. The water phase was extracted with diethyl ether (10 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (37 mg, 39%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.82 (d, / = 2.4 Hz, 1H), 8.11 (d, / = 8.4 Hz, 1H), 7.44-7.35 (m, 3H), 7.13 (d, / = 7.2 Hz, 1H), 6.68 (s, 1H), 4.69 (s, 2H), 3.57 (s, 4H), 3.06 (s, 3H), 2.51 (s, 3H), 2.39 (t, / = 4.8 Hz, 4H), 2.30 (s, 3H).

[00370] Example 14

[00371] Preparation of N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 -yl)pyrimidin-4-

[00372] Method AN-step a. N-methyl-N-((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin- 4-yl)methyl)- l,7-naphthyridin-8-amine: To the solution of 8-chloro-l,7-naphthyridine (56 mg, 0.34 mmol) and N- methyl- l-(2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)methanamine (80 mg, 0.34 mmol) in DMSO (3 mL), was added K₂C0₃ (140 mg, 1.02 mmol). The resulting suspension was stirred at 110°C overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 10/1/1) to give the desired product (17 mg, 11%) as a yellow oil. H NMR (400 MHz, CDCI₃) δ 8.66 (s, 1H), 8.10 (d, / = 5.2 Hz, 1H), 7.96 (d, / = 8.0 Hz, 1H), 7.43 (dd, / = 7.6, 4.0 Hz, 1H), 6.96 (d, / = 5.6 Hz, 1H), 6.46 (s, 1H), 5.26 (s, 2H), 3.57 (s, 4H), 3.36 (s, 3H), 2.52 (s, 3H), 2.45-2.34 (m, 4H), 2.29 (s, 3H).

[00373] Example 15

[00374] Preparation of N-methyl-N-((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)-l,6- naphthyridin-8-

step a

[00375] Method AO-step a. N-methyl-N-((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-

4-yl)methyl)- l,6-naphthyridin-8-amine: The mixture of 8-bromo-l,6-naphthyridine (41 mg, 0.20 mmol), N- methyl- l-(2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)methanamine (99 mg,0.42 mmol), ΒΙΝΑΡ (13 mg, 0.02 mmol), Cs₂C0₃(152 mg, 0.46 mol) and Pd₂(dba)₃ (9 mg, 0.01 mmol) in toluene (5 mL) was stirred at 100°C overnight under N₂ atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1) to give the desired product (20 mg, 28%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.96 (s, 1H), 8.81 (s, 1H), 8.37-8.13 (m, 2H), 7.50 (s, 1H), 6.62 (s, 1H), 4.84 (s, 2H), 3.60 (s, 4H), 3.13 (s, 3H), 2.51 (s, 3H), 2.42 (s, 4H), 2.31 (s, 3H).

[00376] Example 16

[00377] Preparation of 4-(((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)(quinolin-8- yl)amino)butanoic acid (D30) and 4-(((2-methyl-6-(4-methylpiperazin-l-

[00378] Method AP-Step a. 4-(((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)(quinolin-8- yl)amino)butanoic acid: The solution of feri-butyl 4-(((2-methyl-6-(4- methylpiperazin-l-yl)pyrimidin- 4-yl)methyl)(quinolin-8-yl)amino)butanoate (55 mg, 0.112 mmol) in concentrated HCl aqueous solution (6 mL) was stirred at 50°C overnight. The reaction mixture was evaporated to give the desired product hydrochloride (535 mg, 96%) as a yellow oil. H NMR (400 MHz, D₂0) δ 9.14 (d, / = 8.4 Hz, 1H), 9.07 (d, / = 5.6 Hz, 1H), 8.12 (d, / = 8.0 Hz, 1H), 8.09-8.06 (m, 1H), 8.02 (d, / = 7.6 Hz, 1H), 7.92-7.88 (m, 1H), 7.00 (s, 1H), 5.25 (s, 1H), 4.44 (s, 2H), 4.33 (s, 1H), 3.68-3.46 (m, 4H), 3.41-3.12 (m, 4H), 2.92 (s, 3H), 2.54 (s, 3H), 2.17 (t, J = 6.8 Hz, 2H), 1.61 (s, 2H).

[00379] Method AP-Step b. 4-(((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)(quinolin-8- yl)amino)butanamide: The mixture of 4-(((2-methyl-6-(4- methylpiperazin-l-yl)pyrimidin-4- yl)methyl)(quinolin-8-yl)amino)butanoic acid (50 mg, 0.098 mmol), NH₄C1 (27 mg, 0.51 mmol), HATU (47 mg, 0.122 mmol) and DIPEA (131 mg, 1.02 mmol) in DMF (3 mL) was stirred at 50°C overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 20/1/0.1) to give the desired product (25 mg, 58%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.82 (d, / = 4.4 Hz, 1H), 8.18 (d, / = 8.4 Hz, 1H), 7.45-7.42 (m, 3H), 7.30-7.29 (m, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 5.35 (s, 1H), 4.62 (s, 2H), 3.71 (s, 4H), 3.52 (t, / = 7.2 Hz, 2H), 2.58 (s, 3H), 2.50-2.48 (m, 4H), 2.34 (s, 3H), 2.26 (t, / = 7.2 Hz, 2H), 2.00-1.97 (m, 2H).

[00380] Example 17

[00381] Preparation of 8-(methyl((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- )

'^ step a

[00382] Method AQ-Step a. 8-(methyl((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4- yl)methyl)amino)quinoline-7-carbonitrile: The mixture of 7-bromo-N-methyl-N-((2-methyl-6- (4- methylpiperazin-l-yl)pyrimidin-4-yl)methyl)quinolin-8-amine (210 mg, 0.48 mmol), ZnCN₂ (112 mg, 0.95 mmol), dppf (53 mg, 0.1 mmol), Pd(PPh₃)₄(H0 mg, 0.1 mmol) and Pd₂(dba)₃ (44 mg, 0.05 mmol) in DMAc (8 mL) was stirred at 150°C for 2 days under N₂ atmosphere. The reaction mixture was concentrated. The residue was purified by silica gel column

chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/0.5) to give the a crude product (80 mg). The crude product was further purified by Combi-Flash-C18

(MeCN/water, MeCN gradient 30% to 60% volume percent through 30 min) to give the desired product (13 mg, 7%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.91 (d, / = 2.4 Hz, 1H), 8.14 (d, / = 8.0 Hz, 1H), 7.58-7.46 (m, 3H), 7.06 (s, 1H), 4.91 (s, 2H), 3.75 (s, 4H), 3.31 (s, 3H), 2.49 (s, 7H), 2.34 (s, 3H).

[00383] Example 18 [00384] Preparation of N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 -yl)pyrimidin-4- ne (D43)

[00385] Method AR-Step a. N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 -yl)pyrimidin- 4- yl)methyl)-5-(methylsulfonyl)quinolin-8-amine: The mixture of 5-bromo-N-methyl-N-((2- methyl-6-(4- methylpiperazin-l-yl)pyrimidin-4-yl)methyl)quinolin-8-amine (150 mg, 0.34 mmol), sodium methanesulfinate (70 mg, 0.68 mmol), L-Proline (47 mg, 0.41 mmol), K₂COs(28 mg, 0.2 mmol) and Cul (40 mg, 0.2 mmol) in DMSO (2 mL) was stirred at 100°C for 2 days under N₂ atmosphere. The reaction mixture was cooled to room temperature and diluted with dichloromethane (20 mL). The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 20/1/0.1) to give the a crude product (50 mg). The crude product was further purified by Combi-Flash-C18 (MeCN/water, MeCN gradient 30% to 70% volume percent through 30 min) to give the desired product (15 mg, 10%) as a yellow oil. ^!H NMR (400 MHz, CDC1₃) δ 9.01 (dd, J = 8.8, 2.0 Hz, IH), 8.75 (dd, J = 4.0, 2.0 Hz, IH, IH), 8.21 (d, J = 8.4 Hz, IH), 7.52 (dd, 7 = 8.8, 4.0 Hz, IH), 7.01 (d, J = 8.4 Hz, IH), 6.55 (s, IH), 4.97 (s, 2H), 3.68-3.55 (m, 4H), 3.20 (s, 3H), 3.14 (s, 3H), 2.52 (s, 3H), 2.46- 2.38 (m, 4H), 2.31 (s, 3H). MS (ESI/APCI) m z 441.2 [M+H]⁺.

[00386] Example 19

[00387] Preparation of N-(8-(methyl((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-

[00388] Method AS-Step a. 8-fluoro-5-nitroquinoline: To the solution of concentrated sulfuric acid (2 mL) diluted with concentrated nitric acid (1 mL), was added dropwise 8- fluoroquinoline (3.76 g, 40.0 mmol) at 0°C. The resulting suspension was stirred at 0°C for 2h. The reaction mixture was poured into ice-water and filtered. The filter cake was added saturated Na2CC>3 aqueous solution to adjust pH to 7 and extracted with dichloromethane (20 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1) to give the desired product (330 mg, 61%) as a white solid. H NMR (400 MHz, CDC1₃) δ 9.16 (d, / = 8.4 Hz, 1H), 9.12 (s, 1H), 8.56-8.42 (m, 1H), 7.78-7.74(m, 1H), 7.53-7.48(m, 1H).

[00389] Method AS-step b. N-methyl-N-((2-methyl-6-(4-methylpiperazin- l-yl)pyrimidin- 4-yl)methyl)-5- nitroquinolin-8-amine: To the solution of 8-fluoro-5-nitroquinoline (80 mg, 0.42 mmol) and N-methyl-l-(2-methyl-6-(4-methylpiperazin-l-yl)pyrirmdin-4-yl)methanamine (100 mg, 0.42 mmol) in DMSO (3 mL), was added K₂C0₃ (58 mg, 0.42 mmol). The resulting suspension was stirred at 110°C overnight. The reaction mixture was cooled to room

temperature and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 50/1/0.5) to give the desired product (80 mg, 47%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 9.32 (d, / = 8.4 Hz, 1H), 8.69 (s, 1H), 8.48 (d, / = 9.2 Hz, 1H), 7.58-7.50 (m, 1H), 6.92 (d, / = 8.8 Hz, 1H), 6.54 (s, 1H), 5.07 (s, 2H), 3.70-3.60 (s, 4H), 3.27 (s, 3H), 2.61 (s, 3H), 2.55 (s, 7H).

[00390] Method AS-step c. N⁸-methyl-N⁸-((2-methyl-6-(4-methylpiperazin- 1- yl)pyrimidin-4- yl)methyl)quinoline-5,8-diamine: To the solution of N-methyl-N-((2-methyl-6- (4-methylpiperazin-l- yl)pyrimidin-4-yl)methyl)-5- nitroquinolin-8-amine (80 mg, 0.2 mmol) in ethanol (4 mL), was added SnCi₂ (135 mg, 0.6 mmol). The resulting suspension was stirred at 80°C for 3h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol/ammonium hydroxide = 50/1/0.5) to give the desired product (19 mg, 25%) as a yellow solid. MS (ESI/APCI) m z 377.8 [M+H]⁺.

[00391] Method AS-Step d. N-(8-(methyl((2-methyl-6-(4-methylpiperazin-l- yl)pyrimidin-4- yl)methyl)amino)quinolin-5-yl)methanesulfonamide: To the solution of N⁸- methyl-N⁸-((2-methyl-6-(4- methylpiperazin-l-yl)pyrimidin-4- yl)methyl)quinoline-5,8-diamine (19 mg, 0.05 mmol) in Pyridine (3 mL) was added dropwise MsCl (10 mg, 0.09 mmol) at 0°C. The reaction mixture was stirred at room temperature for lh. The saturated NaHC0₃ aqueous solution was added to adjust pH to 7, and extracted with dichloromethane (20 mL x 2). The organic layer was evaporated. The residue was purified by preparation TLC

(dichloromethane/methanol/ammonium hydroxide = 30/1/0.3) to give the desired product (12 mg, 53%) as a yellow solid. H NMR (400 MHz, CDC1₃) δ 8.76 (s, 1H), 8.61 (d, / = 8.0 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (d, / = 8.0 Hz, 1H), 6.87 (s, 1H), 4.69 (s, 2H), 3.78 (s, 4H), 3.05 (s, 3H), 3.01 (s, 3H), 2.61 (s, 7H), 2.43 (s, 3H) S (ESI/APCI) m/z 455.9 [M+H]⁺. [00392] Example 20

[00393] Preparation of N-(8-(methyl((2-methyl-6-(4-methylpiperazin- l-yl)pyrimidin-4- lfonamide(D58)

[00394] Method AT-Step a. N-(8-(methyl((2-methyl-6-(4-methylpiperazin- 1 - yl)pyrimidin-4-yl)methyl)amino)quinolin-6-yl)methanesulfonamide: To the solution of N⁸- methyl-N⁸-((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)methyl)quinoline-6,8-diamine (crude 100 mg, 0.1 mmol) and TEA (101 mg, 1 mmol) in dichloromethane (10 mL) was added dropwise MsCl (23 mg, 0.2 mmol) at 0°C. The reaction mixture was stirred at room temperature for lh. The 2M NaOH aqueous solution was added to adjust pH to 11 and stirred for lh.The mixture was partitioned and the water phase was added 6MHC1 aqueous solution to adjust pH to 5. The saturated NaHCC>3 aqueous solution was added to adjust pH to 8 and extracted with ethyl acetate (30 mL x 3). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide =

20/1/0.05) to give the desired product (10 mg, 22%) as a brown oil. H NMR (400 MHz, CDC1₃) δ 8.70 (d, / = 4.0 Hz, 1H), 8.01 (d, / = 8.4 Hz, 1H), 7.38-7.30 (m, 1H), 7.27 (s, 1H), 6.91 (s, 1H), 6.67 (s, 1H), 4.68 (s, 2H), 3.77 (t, / = 4.4 Hz, 2H), 3.63 (t, / = 4.4 Hz, 2H), 3.07 (s, 3H), 3.04 (s, 3H), 2.48 (s, 3H), 2.44-2.34 (m, 4H), 2.29 (s, 3H). MS (ESI/APCI) m z 455.7 [M+H]⁺.

[00395] Example 21

[00396] Preparation of (5)-N-methyl-N-((2-methyl-6-(4-methylpiperazin-l-yl)pyrimidin- -yl)methyl)-l-(pyridin-2-yl)ethan-l-amine (A75)

[00397] Method AA-Step a.(5)-N-((6-chloro-2-methylpyrimidin-4-yl)methyl)-N-methyl- l-(pyridin-2-yl)ethan-l-amine: A mixture of (5)-N-methyl-l-(pyridin-2-yl)ethan-l-amine (150 mg, 1.1 mmol), 4-chloro-6-(chloromethyl)pyrimidine (195 mg, 1.1 mmol), KI (16 mg, 0.1 mmol) and DIPEA (426 mg, 3.3 mmol) in C¾CN (20 mL) was stirred at room temperature overnight. The reaction solution was evaporated to remove most of CH₃CN. The residue was added saturated NaHCC>3 aqueous solution (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was dried over Na₂S04, filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 200/1/0.5) to give the desired product (280 mg, 92%) as a yellow oil. H NMR (400 MHz, CDCI₃) δ 8.57 (d, / = 4.4 Hz, 1H), 7.72-7.63 (m, 1H), 7.46 (s, 1H), 7.42 (d, / = 7.6 Hz, 1H), 7.17 (dd, / = 7.6, 4.8 Hz, 1H), 3.91 (q, / = 6.8 Hz, 1H), 3.72 (d, / = 16.4 Hz, 1H), 3.59 (d, / = 16.4 Hz, 1H), 2.67(s, 3H), 2.28(s, 3H), 1.49 (d, / = 6.8 Hz, 3H).

[00398] Method AA-Step b. (5)-N-methyl-N-((2-methyl-6-(4-methylpiperazin- 1 - yl)pyrimidin-4-yl)methyl)- l-(pyridin-2-yl)ethan-l-amine: A mixture of (5)-N-((6-chloro-2- methylpyrimidin-4-yl)methyl)-N-methyl-l-(pyridin-2-yl)ethan-l -amine (90 mg, 0.33 mmol), TEA (333 mg, 3.3mmol) and N-methylpiperazine (163 mg, 1.6 mmol) in ethanol (10 mL) was stirred at reflux overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/2/1) to give the desired product (70 mg, 63 %) as a colorless oil^H NMR (400 MHz, CDC1₃) δ 8.56 (d, / = 4.0 Hz, 1H), 7.69-7.58 (m, 1H), 7.41 (d, / = 7.6 Hz, 1H), 7.18-7.11 (m, 1H), 6.64(s, 1H), 3.92-3.80 (m, 1H), 3.68 (s, 4H), 3.57 (d, / = 15.6 Hz, 1H), 3.44 (d, / = 15.6 Hz, 1H), 2.55-2.40 (m, 7H), 2.34 (s, 3H), 2.27(s, 3H), 1.47(d, J = 6.4 Hz, 3H).

[00399] Example 22

[00400] Preparation of (5)-N-methyl-N-((5-(4-methylpiperazin-l-yl)imidazo[l,2- ]pyridin-2-yl)methyl)- l-(pyridin-2-yl)ethan-l -amine (A95) and (5)-(2-((methyl(l-(pyridin-2-

[00401] Method AK-Step a. (5)-N-((5-bromoimidazo[l,2- ]pyridin-2-yl)methyl)-N- methyl- l-(pyridin-2-yl)ethan- l-amine: The mixture of 5-bromo-2-(bromomethyl)imidazo[l,2- jpyridine (127 mg, 0.4 mmol), (5)-N-methyl-l-(pyridin-2-yl)ethanamine (55 mg , 0.4 mmol), KI (7 mg, 0.04 mmol) and DIPEA (130 mg, 1 mmol) in MeCN (10 mL) was stirred at room temperature overnight. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1) to give the desired product (100 mg, 72%) as a yellow oil. H NMR (400 MHz, CDC1₃) δ 8.59 (d, / = 4.0 Ηζ, ΙΗ), 7.92 (s, IH), 7.74-7.67 (m, IH), 7.62-7.52(m, 2H), 7.24-7.18 (m, IH), 7.13-7.01 (m, 2H), 4.17-4.05 (m, IH), 4.04-3.96 (m, IH), 3.96-3.87 (m, IH), 2.44 (s, 3H), 1.64- 1.59 (m, 3H

[00402] Method AK-Step b. (5)-N-methyl-N-((5 -(4-methylpiperazin- l-yl)imidazo[l, 2- ]pyridin-2-yl)methyl)- l-(pyridin-2-yl)ethan-l -amine: The mixture of (5)-N-((5- bromoimidazo[ 1 ,2- ]pyridin-2-yl)methyl)-N- methyl- 1 -(pyridin-2-yl)ethan- 1-amine (100 mg , 0.29 mmol) in N-methylpiperazine (3 mL) was stirred at 190°C under microwave for 2 h. The reaction mixture was concentrated. The residue was purified by silica gel column

chromatography (dichloromethane/methanol = 50/1) to give the desired product (60 mg, 57%) as a yellow oil. 1H NMR (400 MHz, CDC1₃) δ 8.56 (d, J = 4.0 Hz, IH), 7.72-7.62 (m, IH), 7.54 (d, / = 7.6 Hz, IH), 7.46 (s, IH), 7.31 (d, / = 8.8 Hz, IH), 7.20-7.11 (m, 2H), 6.26 (d, / = 7.2 Hz, IH), 3.97-3.81 (m, 2H), 3.72 (d, / = 14.0 Hz, IH), 3.14 (s, 4H), 2.67 (s, 4H), 2.41 (s, 3H), 2.32 (s, 3H), 1.50 (d, / = 6.4 Hz, 3H).

[00403] Method AK-Step c. (5)-(2-((methyl(l-(pyridin-2-yl)ethyl)amino)methyl)-5-(4- methylpiperazin-l-yl)imidazo[l,2- ]pyridin-3-yl)methanol: The mixture of (5)-N-methyl-N-((5- (4-methylpiperazin- 1 -yl)imidazo [ 1 ,2-a]pyridin-2-yl)methyl)- 1 -(pyridin-2-yl)ethan- 1-amine (43 mg, 0.12 mmol) and formaldehyde (37 wt percent in water, 10 mL) in a sealed tube was stirred at 50°C for 3 days. The reaction mixture was added saturated NaHCC>3 aqueous solution (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over Na2S0₄, filtered and evaporated. The residue was purified by silica gel column chromatography

(dichloromethane/methanol = 50/1) to give the desired product (25 mg , 50%) as a colorless oil. H NMR (400 MHz, CDC1₃) δ 8.57 (s, IH), 7.73-7.58 (m, IH), 7.40 (d, / = 7.6 Hz, IH), 7.29 (d, / = 8.8 Hz, IH), 7.20-7.12 (m, IH), 7.12-7.04 (m, IH), 6.40 (d, / = 7.2 Hz, IH), 5.24-5.11 (m, 2H), 3.95-3.85 (m, IH), 3.84-3.73 (m, 2H), 3.73-3.62 (m, lH), 3.42-3.29 (m, 2H), 3.00-2.86 (m, 4H), 2.50-2.42 (m, 2H), 2.39 (s, 3H), 2.13 (s, 3H), 1.52 (d, / = 6.4 Hz, 3H).

[00404] Table 1 shows a selection of the compounds prepared according to the methods discussed above in details and indicated in the third column of the table.

[00405] Table 1. Selected compounds (A1-A100, B 1-B8, C1-C39 and D1-D59) of the present invention

I l l Ή NMR (400 MHz, CDC1₃) δ 8.49 (d, / = 4.0 Hz, IH),

8.47 (s, IH), 7.35 (d, / = 7.6 Hz, IH), 7.05 (dd, / = 7.6, 1 ^¾_j 4.8 Hz, IH), 6.98 (s, IH), 4.04-4.01 (m, IH), 3.69 (s,

A2 2H), 3.65 (s, 2H), 3.09 (s, 3H), 2.81-2.80 (m, IH), 2.78-

A, AA

2.71 (m, IH), 2.47 (t, / = 7.2 Hz, 2H), 2.38 (s, 3H), 2.27 (s, 6H), 2.10-2.09 (m, IH), 2.03-2.01 (m, IH), 1.94-1.91 (m, IH), 1.71-1.67 (m, 1H).MS (ESI/APCI) m/z 354.9 [M + H]⁺.

Ή NMR (400 MHz, CDC1₃) δ 8.49 (d, / = 3.9 Hz, IH), 7.36 (d, J = 7.6 Hz, IH), 7.06 (dd, J = 7.6, 4.8 Hz, IH), 1

A3 6.96 (s, IH), 4.09-3.98 (m, IH), 3.72 (s, 4H), 3.58 (s,

B, AA

2H), 2.86-2.75 (m, IH), 2.74-2.65 (m, IH), 2.49 (s, 3H), 2.47-2.43 (m, 4H), 2.39 (s, 3H), 2.33 (s, 3H), 2.10 (s, IH), 2.03-2.00 (m, IH), 1.91-1.87 (m, IH), 1.65 (s, IH).

Ή NMR (400 MHz, CDC1₃) δ 8.57 (d, / = 4.2 Hz, IH), 8.51 (s, IH), 7.65 (t, / = 7.2 Hz, IH), 7.43 (d, / = 8.0 Hz,

A4 IH), 7.19-7.13 (m, IH), 6.78 (s, IH), 3.90 (q, / = 6.8 Hz,

A, AA

IH), 3.69 (s, 4H), 3.61 (d, / = 15.6 Hz, IH), 3.46 (d, / = 15.6 Hz, IH), 2.54-2.45 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H), 1.48 (d, / = 6.8 Hz, 3H).

Ή NMR (400 MHz, CDC1₃) δ 8.48 (s, 2H), 7.37 (d, J = 7.2 Hz, IH), 7.26 (s, IH), 7.07 (s, IH), 4.02 (s, IH), 1 3.71-3.65 (m, 8H), 2.81-2.78 (m, IH), 2.71-2.67 (m, 2H),

A5 A, AA 2.57 (s, 6H), 2.39 (s, 3H), 2.11 (s, IH), 2.00 (s, IH),

1.97-1.88 (m, IH), 1.70-1.68 (m, IH). HRMS (ESI): calcd for C21H31N60 [M+H]⁺383.2554, found 383.2555.

Ή NMR (400 MHz, CDC1₃) δ 8.50-8.47 (m, 2H), 7.37 (d, J = 7.8 Hz, IH), 7.20 (s, IH), 7.07 (dd, J = 7.6, 4.8 1 ' Hz, IH), 4.03 (t, / = 7.4 Hz, IH), 3.73 (s, 4H), 3.64 (s,

A6 A, AA 2H), 3.55 (t, / = 5.4 Hz, 2H), 3.38 (s, 3H), 2.85-2.77 (m,

IH), 2.72-2.68 (m, IH), 2.62 (t, / = 5.4 Hz, 2H), 2.56 (t, / = 5.0 Hz, 4H), 2.39 (s, 3H), 2.17-2.07 (m, IH), 2.07- 1.98 (m, IH), 1.99-1.88 (m, IH), 1.76-1.67 (m, IH).

Ή NMR (400 MHz, CDC1₃) δ 8.49 (s, 2H), 7.38 (d, / = 7.2 Hz, IH), 7.21 (s, IH), 7.08 (s, IH), 4.05-4.04 (m,

A7 IH), 3.80-3.70 (m, 6H), 3.02-2.98 (m, 4H), 2.81-2.79 (m,

A, AB

IH), 2.72-2.68 (m, IH), 2.58 (s, IH), 2.41 (s, 3H), 2.13 (s, IH), 2.01 (m, IH), 1.95-1.89 (m, IH), 1.71-1.69 (m, IH). MS (ESI/APCI) m/z 338.9 [M + H]⁺.

Ή NMR (400 MHz, CDC1₃) δ 8.53-8.47 (m, 2H), 7.38 1 (d, / = 7.6 Hz, IH), 7.25 (s, IH), 7.08 (dd, / = 7.6, 4.8

A8 Hz, IH), 4.09-3.97 (m, IH), 3.73 (s, 4H), 3.65 (s, 2H),

A, AB

2.86-2.78 (m, IH), 2.75-2.71 (m, 3H), 2.58-2.53 (m, 6H), 2.40 (s, 3H), 2.16-2.08 (s, IH), 2.05-1.97 (m, IH), 1.93- 1.88 (m, IH), 1.75-1.69 (m, IH).

Ή NMR (400 MHz, CDC1₃) δ 8.49 (d, / = 4.6 Hz, IH), 7.35 (d, / = 8.0 Hz, IH), 7.07-7.03 (m, 2H), 4.04 (t, / = 1

A9 7.4 Hz, IH), 3.71 (t, / = 5.2 Hz, 4H), 3.60 (s, 2H), 2.86-

E, AC

2.75 (m, IH), 2.73-2.65 (m, IH), 2.46-2.43 (m, 7H), 2.39 (s, 3H), 2.33 (s, 3H), 2.15-2.07 (m, IH), 2.04-1.96 (m, IH), 1.95-1.87 (m, IH), 1.74-1.71 (m, IH).

Ή NMR (400 MHz, CDC1₃) δ 8.48 (d, / = 4.4 Hz, IH), 1 7.35 (d, / = 7.6 Hz, IH), 7.05 (dd, / = 7.6, 4.8 Hz, IH),

A10 E, AC 6.87 (s, IH), 4.03 (t, / = 7.4 Hz, IH), 3.88 (s, 3H), 3.70

(d, / = 5.0 Hz, 4H), 3.58 (s, 2H), 2.84-2.78 (m, IH), 2.74-2.65 (m, IH), 2.44 (t, / = 5.6Hz, 4H), 2.37 (s, 3H),

Ή NMR (400 MHz, CDC1₃) δ 8.45 (d, / = 3.2 Hz, IH),

7.35 (d, / = 7.2 Ηζ, ΙΗ), 7.01 (t, / = 6.0 Hz, IH), 6.30 (s,

C36 C, BH, IH), 3.83-3.87 (m, 3H), 3.63-3.66 (m ,3H), 3.35 (d, / =

AA 14.2 Hz, 2H), 2.62 (s, 2H), 2.53 (s 2H), 2.41 (s, 3H), 2.36

(d, / = 2.8 Hz, 6H), 2.17-2.19 (m, 1Η), 1.96-2.06 (m, 6H)

Ή NMR (400 MHz, CDC1₃) δ 8.46 (s, IH), 7.45-7.30

C, BH, (m, IH), 7.09-6.95 (m, IH), 6.39 (s, IH), 4.40 (s, 2H),

C37 3.84 (s, IH), 3.72-3.58 (m, IH), 3.47-3.28 (m, 2H), 2.77

AA

(s, 2H), 2.55-2.40 (m, 5H), 2.40-2.33 (s, 3H), 2.29 (s, 6H), 2.08-1.95 (m, 2H), 1.95-1.80 (m, 4H), 1.40 (s, 2H).

Ή NMR (400 MHz, CDC1₃) δ 8.49 (d, / = 3.6 Hz, IH), 7.33 (s, 2H), 7.28 (s, IH), 7.13-7.09 (m, IH), 7.01-6.98

N— ' N, BH, (m, IH), 6.24 (d, / = 7.2 Hz, IH), 3.96 (d, / = 13.6 Hz,

C38 IH), 3.84

AK (t, / = 8.0 Hz, IH), 3.67(d,/ = 13.6 Hz, IH),

3.39 (t, / = 8.0 Hz, IH), 3.10 (s, 4H), 2.64 (s, 4H), 2.59- 2.52 (m, IH), 2.42 (s, 3H), 2.38 (s, 3H), 2.22-2.17 (m, 2H), 2.05-1.90 (m, 2H).

Ή NMR (400 MHz, CDC1₃) δ 8.50 (d, / = 3.6 Hz, IH), 7.40 (d, J = 7.2 Ηζ,ΙΗ), 7.29(d, J = 8.8 Hz, IH), 7.02- 7.08 (m, 2H), 6.39 (d, / = 6.8 Hz, IH), 6.19 (d, / = 14.4

Wo N, BH, Hz, IH), 5.27 (d, / = 14.0 Hz , 1H), 5.07 (d, / = 14.0 Hz,

C39 IH), 4.05

AK (d, / = 12.8 Hz, IH), 3.85 (d, / = 8.0 Hz, IH),

3.49 (d, / =12.8 Hz, 2H), 3.24 (d, J = 10.8 Hz, IH), 3.16 (t, J = 7.8 Hz, IH), 2.91-3.01 (m, 3H), 2.83 (t, J = 11.0 Hz, IH), 2.46-2.51 (m, 3H), 2.41(s, 3H), 2.38(s, 3H), 2.24(s, IH), 1.84-1.91 (m, 3H).

Ή NMR (400 MHz, CDC1₃) δ 8.44 (d, / = 4.0 Hz, IH), 7.40 (d, J = 7.2 Hz, IH), 7.06-6.98 (m, IH), 6.93 (s, IH),

Dl C, AL 4.26 (s, 2H), 3.60 (s, 4H), 2.93 (s, 3H), 2.93-2.81 (m,

2H), 2.64-2.56 (m, 2H), 2.47 (s, 3H), 2.42 (s, 4H), 2.32 (s, 3H). MS (ESI/APCI) m/z 382.9 [M+H]⁺.

Ή NMR (400 MHz, CDC1₃) δ 8.82 (d, / = 2.4 Hz, IH), 8.11 (d, / = 8.4 Hz, IH), 7.44-7.35 (m, 3H), 7.13 (d, / =

D2 C, AA,

7.2 Hz, IH), 6.68 (s, IH), 4.69 (s, 2H), 3.57 (s, 4H), 3.06 AM

(s, 3H), 2.51 (s, 3H), 2.39 (t, / = 4.8 Hz, 4H), 2.30 (s, 3H).

Ή NMR (400 MHz, CDC1₃) δ 8.82 (d, / = 2.4 Hz, IH),

C, BM, 8.10 (d, / = 8.0 Hz, IH), 7.42-7.32 (m, 3H), 7.11 (d, / =

D3 7.2 Hz, IH), 6.44 (s, IH), 4.72 (s, 2H), 4.10 -3.22 (m,

AA

4H), 3.08 (s, 3H), 2.50-2.42(m, 7H), 2.30 (s, 3H), 1.82 (s, 2H).

Ή NMR (400 MHz, CDC1₃) δ 8.82 (s, IH), 8.12 (d, / = 7.6 Hz, IH), 7.42-7.36 (m, 3H), 7.14 (d, / = 6.0 Hz, IH),

D4 C, BM,

6.67 (s, IH), 4.71 (s, 2H), 4.14-4.03 (m, 2H), 3.06 (s, AA

4H), 2.82-2.78 (m, IH), 2.65-2.62 (m, IH), 2.52 (s, 3H), 2.03-2.17(m, IH), 1.08 (d, / = 4.4 Hz, 3H).

⁰ Ή NMR (400 MHz, CDC1₃) δ 9.00 (d, J = 3.2 Hz, IH),

6 8.23 (dd, / = 8.4, 1.6 Hz, IH), 8.18 (d, / = 8.8 Hz, IH),

D51 C, BN, 7.84 (d, / = 8.8 Hz, IH), 7.52 (dd, / = 8.8, 4.4 Hz, IH),

AA, AR 7.16 (s, IH), 5.15 (brs, IH), 4.21 (brs, IH), 3.86-3.70 (m,

4H), 3.36 (s, 3H), 3.07 (s, 3H), 2.57-2.42 (m, 7H), 2.35 (s, 3H). MS (ESI/APCI) m/z 441.2 [M+H]⁺.

Ή NMR (400 MHz, CDC1₃) δ 8.70 (s, IH), 8.03 (d, J = 7.6 Hz, IH), 7.40-8.32 (m, IH), 6.94 (d, / = 7.6 Hz, IH), 6.84 (d, / = 11.2 Hz, IH), 6.65 (s, IH), 4.79 (s, 2H),

D52 C, BN,

4.10-3.95 (m, 2H), 3.80-3.76 (m, IH), 3.52 (d, / = 10.8 AA

Hz, IH), 3.32 (t, / = 10.8 Hz, IH), 3.13-2.95 (m, 4H), 2.81 (d, / = 10.4 Hz, IH), 2.51 (s, 3H), 2.38-2.20 (m, 5H).

Ή NMR (400 MHz, CDC1₃) δ 8.70 (s, IH), 8.03 (d, J = 8.0 Hz, IH), 7.36 (dd, / = 7.2, 3.6 Hz, IH), 6.95 (d, / =

D53 C, BN, 8.0 Hz, IH), 6.96-6.70 (m, 2H), 4.78 (s, 2H), 4.56 (s,

AA, AD IH), 4.10-3.88 (m, 3H), 3.42 (t, / = 10.4 Hz, IH), 3.10- 3.00 (m, 4H), 2.86 (d, / = 10.4 Hz, IH), 2.51 (s, 3H), 2.35-2.24 (m, 4H), 2.09 (t, / = 9.2 Hz, IH).

Op Ή NMR (400 MHz, CDC1₃) δ 8.82 (s, IH), 8.12 (d, J =

8.0 Hz, IH), 7.45-7.36 (m, 3H), 7.12 (d, J = 7.2 Hz, IH),

D54 E, AC,

6.70 (s, IH), 4.75 (s, 2H), 4.56 (s, 2H), 3.86 (br s, IH), AM

3.68-3.51 (m, 4H), 3.05 (s, 3H), 2.47-2.35 (m, 4H), 2.30 (s, 3H). MS (ESI/APCI) m z378.9 [M+H]⁺.

Ή NMR (400 MHz, CDC1₃) δ 8.76 (s, IH), 8.07 (d, J =

D55 D, BN, 8.0 Hz, IH), 7.45-7.30 (m, 2H), 7.17 (s, IH), 6.79 (s,

AO, AJ IH), 4.81 (s, 2H), 4.66 (s, 2H), 3.63 (s, 4H), 3.03 (s, 3H),

2.54 (s, 3H), 2.50-2.43 (m, 4H), 2.32 (s, 3H).

Ή NMR (400 MHz, CDC1₃) δ 8.90 (s, IH), 8.14 (d, J = 8.0 Hz, IH), 7.63 (d, J = 8.0 Hz, IH), 7.50 (d, J = 8.0 Hz,

D56 D, BN,

IH), 7.37-7.30 (m, IH), 6.36 (s, IH), 5.30 (s, IH), 4.70- AN, AJ

^N II 4.20 (m, 3H), 3.69 (s, 4H), 2.96 (s, 3H), 2.53 (s, 3H),

2.48 (s, 4H), 2.34 (s, 3H).

Ή NMR (400 MHz, CDC1₃) δ 8.76 (s, IH), 8.61 (d, J = 8.0 Hz, IH), 7.51-7.46 (m, 2H), 7.00 (d, / = 8.0 Hz, IH),

D57 D, AS 6.87 (s, IH), 4.69 (s, 2H), 3.78 (s, 4H), 3.05 (s, 3H), 3.01

(s, 3H), 2.61 (s, 7H), 2.43 (s, 3H).MS (ESI/APCI) m/z 455.9 [M+H]⁺.

BIOLOGICAL ACTIVITIES

[00406] Example 22: HPB-ALL CXCR4 competitive binding assay

[00407] HPB-ALL cells were maintained in RPMI-1640 (Gibico) supplemented with 10% FBS (Hyclone). APC-conjugated anti-human CXCR4 was from Sungene. ECso was first determined for 12G5 binding to CXCR4. Then the compounds for testing were added into 96- well plates serially diluted at a ratio of 1:3. Cells were washed once with ice-cold assay buffer (DPBS+2% HI-FBS) and then re-suspended in the same buffer at a final concentration of 1 x 10⁶/mL. Cell suspension was then added into the wells and with the addition of APC-conjugated anti-human CXCR4 clone 12G5 at its ECso determined. The mix of cell, compounds and APC- conjugated anti-human CXCR4 were incubated at 4 °C for 3 h before addition of 100 of 4% PFA. Cells were then washed once and resuspended in assay buffer and examined by FACS. The percent (%) effect at each concentration of compound was calculated and relative to the amount of calcium produced in the positive and negative control wells contained within each assay plate. The concentrations and % effect values for tested compounds were plotted and the concentration of compound required for 50% effect (IC₅₀) was determined. Tables 2 summarize results of the CXCR4 competitive binding assay for selected compounds disclosed in the present disclosure. Table 3 summarizes results of the CXCR4 competitive binding assay for control compounds. FIGs. 1-2 depict the IC₅₀ curves of compounds A42 and A43. [00408] Table 2. Results of selected compounds of the present invention tested by thel2G5 binding assay

C17 9000 C18 429 C19 1709

C20 9000 C21 82 C22 9000

C23 144 C24 9000 C25 68

C26 206 C27 279 C28 2283

C29 1200 C30 9000 C31 9000

C32 9000 Dl 18 D2 65

D4 55 D14 57 D20 675

D25 151 D28 338 D30 3822

D36 1171

[00409] Table 3. Results of selected control compounds tested by thel2G5 binding assay

[00410] Example 23: FLIPR Tetra calcium mobilization assay

[00411] The FLIPR Tetra calcium mobilization assay was performed by HD Bioscience. Briefly, The Molecular Devices, Fluorescent Imaging Plate Reader (FLIPR) Tetra was used in this assay. Excitation was achieved through unique placement of LED' s within the instrument and emission captured by a CCD camera (EMCCD camera for FI and ICCD camera for luminescence). The homogeneous FLIPR Calcium 4 assay kit from Molecular Devices was used as the fluorescence reagent. Compounds were solubilized in 100% dimethyl sulfoxide (DMSO) to a concentration of 30 mM. A 10-point, 4-fold, intermediate dilution series was created in 100% DMSO with a top concentration of 4 mM and a bottom concentration of 0.01 μΜ. A near assay ready, direct dilution plate (ddNARP) was prepared from this compound dilution plate by transferring 1 μΐ_^ of each dilution of compound in 100% DMSO to a Greiner#781201 plate. In addition, each ddNARP plate also contained positive and negative control wells to define the upper and lower limits for the assay signal. The final assay concentration range of compound was 10 μΜ to 0.035 nM in 0.5% DMSO. Human CD⁴⁺ T-Cells were isolated from human whole blood and subsequently activated and expanded using a CD3/CD28 expansion kit (Life Technologies). The cells were frozen in ThermoFisher-formulated Recovery Cell Culture Freezing Medium containing 10% Dimethyl sulfoxide (DMSO) and 10% Fetal Bovine Serum (FBS) (ThermoFisher Catalog No. 10100147). When used, cells were resuspended using room temperature IX HBSS/20mM HEPES/0.005% P-104 assay buffer, adjusted the volume of the suspension to achieve a cell concentration of 2.5 x 10⁶ cells/mL.2X Calcium 4 dye (20 μΕΛ εΙΙ) were added and the mixture were centrifuged briefly (~10s) and stopped when it reached 1000 rpm. The plates were allowed to equilibrate before compounds and CXCL12 were added to the plates. The raw data were analyzed using Abase. The percent (%) effect at each concentration of compound was calculated by Abase and was based on and relative to the amount of calcium produced in the positive and negative control wells contained within each assay plate. The concentrations and % effect values for tested compounds were plotted by Abase and the concentration of compound required for 50% effect (IC₅₀) was determined with a four-parameter logistic dose response equation. Table 4 summarizes the results of selected compounds in the calcium mobilization assay. FIGs. 3 and 4 summarize the results of Compounds A78 and A83 in the calcium mobilization assay.

[00412] Table 4. Results of selected compounds of the present invention tested by the calcium mobilization assay

D2 0.24 D3 0.63 D4 0.14

D5 2.1 D6 2.4 D7 0.75

D8 1.4 D9 0.59 D10 2.9

Dll 1700 D12 0.61 D13 2.9

D14 0.3 D15 0.4 D16 2.7

D17 74 D18 0.79 D19 0.4

D20 3.1 D21 1581 D22 965

D23 20000 D24 12400 D25 016

D26 2.3 D27 1.7 D28 0.21

D29 12.7 D30 9.3 D31 1.25

D32 0.53 D33 0.51 D34 0.83

D35 1.2 D36 3.6 D37 0.95

D38 0.18 D39 0.088 D40 2850

D41 6.3 D42 96 D43 3380

D44 104 D45 3.0 D46 53

D47 13 D48 928 D49 4.5

D50 14 D51 2087 D52 4.5

D53 6.7 D54 7.2 D55 39

D56 5.5 D57 2880 D58 55

D59 450

Claims

What is claimed is:

1. A compound of Formula I:

I

Ar is 5-10 membered heteroaryl comprising one N and 1-3 additional heteroatoms independently selected from the group consisting of N, O, and S, and Ar is unsubstituted or substituted with 1-4 I½ ;

W is , each X is independently a bond, CR₃2R₃₃, O, NR₃4,

S, S(=0) or S(=0)₂; n is 0, 1, 2 or 3; o and p are different integers with values of 0 or 1; wherein when o is 0, p is 1, Bi is CRn, B2 is N, and Bi is bonded with Ar; wherein when o is 1, p is 0, Bi is N, B2 is CRn, and the carbon bearing R'5 and R'₆ is bonded with Ar;

or W is

, wherein the carbon bonded with R5 and R₆ is connected the ring carbon bonded with Y;

each of Ri, R2, R₃, and R₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(d_₆ alkyl), -NHS(=0)₂(C₁_₆ alkyl), -S(=0)₂(C₁_₆ alkyl), d_₆ alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium;

or R₄ together with the atoms it attached to forms a carbocyclic, aryl, heterocyclic, or heteroaryl ring;

each of R5 and R₆ is independently selected from the group consisting of H, deuterium, -CN, Ci-6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_6 alkyl), -N(Ci_6 alkyl)₂, -NHC(=0)(Ci_6 alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci_₃ alkoxy;

or R₅ and R₆ together forms

, and D3 bonded with R₄ to form:

1) , wherein D₃ is N or CR'₄, and Di is NR'₄, O, S or C(R'₄)₂

2) , wherein D₃ is N or CR'₄, Di is NR'₄, O, S or C(R'₄)₂, D₂ is

NR'₄, or C(R'₄)₂, or

D₃^

D

3) , wherein D₃ is N or CR'₄, Di is N or CR'₄, and D₂ is N or

CR'₄,

wherein each R'₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -N(Ci_₆ alkyl)₂, -S(=0)₂(Ci_6 alkyl), C₃-6 cycloalkyl, Ci_-8 alkoxy, C₂_₆ alkenyl, and C₂_₆ alkynyl, wherein each of -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -S(=0)₂(C_1-6 alkyl), Ci-6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C₂_₆ alkenyl, and C₂_₆ alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium;

each of Rg and R9 is independently selected from the group consisting of H, deuterium, -CN, Ci-6 alkyl, and C3-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, and C1-3 alkoxy; or R₇ and Rg, and atoms attached thereto, form a ring;

or Rg and R9, together with atoms they attached to, form a ring;

each of R' 5, R'₆, R'₇, R' s, R' 9, R' 10, R11, R32, and R33 is independently selected from the group consisting of H, deuterium, -CN, halide, Ci_6 alkyl, -C(=0)0(Ci_6 alkyl), C₃-6 cycloalkyl, Ci_6 alkoxy, and -OSi(Ci_6 alkyl)3, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_6 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, C₃-6 cycloalkyl, Ci_ 6 alkyl, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), -NHC(=0)NH(Ci_₆ alkyl), -NHC(=0)N(Ci_6 alkyl)₂, -NHS(=0)₂(Ci_6 alkyl), and Ci_6 alkoxy;

each of R19, R₂o, R₂i, R₂₂, R25, R₂₆, R₂₇, R₂8, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_6 alkyl), -NHC(=0)0(Ci_6 alkyl), Ci_6 alkyl, and C1-3 alkoxy; or R₂i and R₂3, together with atoms they attached to, form a ring; or R19 and R₂₇, together with atoms they attached to, form a ring; or R₂i and R₂₇, together with atoms they attached to, form a ring; or R19 and R₂₆, together with atoms they attached to, form a ring; or R₂i and R₂₆, together with atoms they attached to, form a ring; R2₃ is selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a 5-7 membered heterocycle;

R₃4 is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl,

alkyl), -S(=0)₂(C_1-8 alkyl), -C(=0)0(C_1-6 alkyl), and -C(=0)NH(Ci_₆ alkyl), wherein each of Ci_6 alkyl, Ci_-8 alkyl, and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci_₃ alkoxy;

R is selected from the group consisting of H, Ci_6 alkyl, C3-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_₆ alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R and R24, together with N atom they attached to, form a 5-7 membered heterocycle; or R and R21, together with N atom they attached to, form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_₆ alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R' and R21, together with atoms they attached to, form a 5-7 membered heterocycle.

2. The compound of claim 1 according to Formula la:

la or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein

each X is independently a bond, CR₃2R₃₃, O, or NR₃4;

each of R2₃ and R24 is independently selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a 5-7 membered heterocycle; R31 is selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, C2-6 alkynyl, C2-6 alkenyl, -S(Ci_6 alkyl), -NH(Ci_6 alkyl), -N(Ci_6 alkyl)2, aryl, 5-7 membered heteroaryl comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, and 5-7 membered heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, aryl, heteroaryl, and heterocycle is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_6 alkoxy;

3. The compound of claim 1 according to Formula lb:

lb

each X is independently a bond, CR₃2R₃₃, O, or NR₃4;

R₃1 is selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, C2-6 alkynyl, C2-6 alkenyl, -S(Ci_6 alkyl), -NH(Ci_6 alkyl), -N(Ci_6 alkyl)₂, aryl, 5-7 membered heteroaryl comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, and 5-7 membered heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_6 alkoxy, aryl, heteroaryl, and heterocycle is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_6 alkoxy;

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_3 alkoxy, -S(=0)₂(Ci_-6 alkyl), -C(=0)(Ci_₆ alkyl), and C₃_₆ heterocycloalkyl comprising N or O; or R' and R21, together with N atom they attached to, form a membered heterocycle.

4. The compound of claim 2 according to Formula Ic:

Ic

5. The compound of claim 1 according to Formula II:

II wherein

Wi is Di, Di-D₂, or Di=D₂, and Di is bonded with the pyridine ring;

each of Ri, R2, and R₃ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, Ci_₆ alkyl, -NH(Ci_₆ alkyl), -N(Ci_₆ alkyl)₂, -S(=0)2(Ci_6 alkyl), C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, C2-6 alkenyl, and C2-6 alkynyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl, and deuterium;

each of R19, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_6 alkyl), and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a ring; or R19 and R2₆, together with atoms they attached to, form a ring; or R21 and R2₆, together with atoms they attached to, form a ring; each of R and R24 is independently selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, C₃-6 heterocycloalkyl comprising N or O, -C(=0)(Ci_6 alkyl),

6. The compound of claim 5 according to Formula Ila:

Ila

7. The compound of claim 5 according to Formula lib:

8. The compound of claim 1 according to Formula III:

Ill

wherein

each of Ai, A₂, and A3 is independently selected from the group consisting of N and CR44, wherein at least one of Ai, A₂, and A3 is N;

each of Ri, R2, R3, and R₄ is independently selected from the group consisting of H, deuterium, -CN, halide, -OH, amino, -NH(Ci_₆ alkyl), -N(C_1-6 alkyl)₂, -NHC(=0)(Ci_₆ alkyl), -NHC(=0)0(Ci_₆ alkyl), -NHS(=0)₂(Ci_₆ alkyl), Ci_₆ alkyl, C₃-₆ cycloalkyl, Ci_₈ alkoxy, C2-6 alkenyl, and C2-6 alkynyl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and Ci_ 8 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide and deuterium;

-NHC(=0)(Ci_6 alkyl), -NHC(=0)0(Ci_₆ alkyl), and Ci_₃ alkoxy; or R₅ is O or CR^Rte, and R^ and R5, together with atoms they attached to, form a ring; R₇ is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl comprising an O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, C₃-6 cycloalkyl, and C₃-6 heterocycloalkyl comprising an O;

or Rg and R9, together with atoms they attached to, form a ring;

R44 is H, deuterium, halide, -CN, -OH, amino, Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, -NH(d_₆ alkyl), -N(d_₆ alkyl)₂, -C(=0)NH(d_₆ alkyl), -C(=0)N(d_₆ alkyl)₂, -S(d_₆ alkyl), C2-6 alkenyl, C2-6 alkynyl, 4-7 membered heterocycle comprising 1-3 heteroatoms independently selected from the groups consisting of O, N and S, aryl, and 5-6 membered heteroaryl, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, Ci_-8 alkoxy, heterocycle, aryl and heteroaryl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH and C1-3 alkoxy;

R2₃ is selected from the group consisting of H, Ci_6 alkyl and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, -NH(Ci_6 alkyl), -N(C_1-6 alkyl)₂, and Ci_3 alkoxy;

R' is selected from the group consisting of H, Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, C₃-6 cycloalkyl, C1-3 alkoxy, -S(=0)2(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), and C₃-6 heterocycloalkyl comprising N or O; or R' and R21, together with N atom they attached to, form a 5-7 membered heterocycle; and

9. The compound of claim 8 according to Formula Ilia or Illb:

Ilia

Illb

wherein

10. The compound of claim 9, wherein each of Ei, E₂, and E3 is independently selected from the

group consisting of CH2, O and

; and at least one of Ei, E₂, and E₃ is

11. The compound of claim 8, wherein each of Ai and A2 is independently selected from the group consisting of N and CR44, wherein at least one of Ai and A2 is N;

12. The compound as in any one of claims 1, 2, 3, and 4, wherein

each of Rig, R20, R21, R22, R25, R26, R27, R28, R29, and R30 is independently selected from the group consisting of H, deuterium, -CN, -OH, Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C1-3 alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, Ci_6 alkyl, and C1-3 alkoxy;

each of R2₃ and R24 is independently selected from the group consisting of H, Ci_6 alkyl, and C₃-6 cycloalkyl, wherein each of Ci_6 alkyl and C₃-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, Ci_6 alkyl, and C1-3 alkoxy; or R22 and R2₃, together with atoms they attached to, form a 5-7 membered heterocycle; and

each of R and R' is independently selected from the group consisting of H, Ci_6 alkyl, C_3- 6 cycloalkyl, and C₃-8 heterocycloalkyl comprising N or O, wherein each of Ci_6 alkyl, C₃-6 cycloalkyl, and C₃-8 heterocycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, -CN, Ci_6 alkyl, C₃-₆ cycloalkyl, Ci_₃ alkoxy, -S(=0)₂(C_1-6 alkyl), -C(=0)(C_1-6 alkyl), and C₃-₆ heterocycloalkyl comprising N or O.

13. The compound as in any one of claims 1, 2, 3, and 4, wherein the compound is selected from the group consisting of:

162

14. The compound as in any one of claims 1, 5, 6, and 7, wherein

15. The compound as in any one of claims 1, 5, 6, and 7, wherein the compound is selected from the group consisting of:

PCT/US2018/052503

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16. The compound as in any one of claims 1, 8, 9, 10, and 11, wherein -C(R5R₆)W2 is selected from the group consisting of:

17. The compound as in any one of claims 1, 8, 9, 10, and 11, wherein the compound is selected from the group consisting of:

18. The compound of any one of claims 1-11, wherein U is unsubstituted or substituted with is unsubstituted or substituted with 1-3 groups selected from the group consisting of deuterium, halide, -OH, C1-3 alkyl, and C1-3 alkoxy, and U is selected from the group consisting of:

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

20. A combination composition comprising:

(a) a compound of any one of claims 1-11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof; and

21. A compound of any one of claims 1-11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for treating diseases, mobilizing stem cells, and treating wounded or burned skin by antagonizing the CXCR4 pathway, wherein the diseases is selected from the group consisting of HIV infection, myocardial infarction, diseases associated with hematopoiesis, inflammation, allergic diseases, asthma, allergic pneumonia, interstitial lung disease, lupus erythematosus, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, scleroderma, psoriasis, dermatitis, retinitis pigmentosa, proliferative vitreoretinopathy, Best's vitelliform macular degeneration, eczema, urticaria, vasculitis, eosinophilic fasciitis, wet and dry age-related macular degeneration (ARMD), diabetic retinopathy, retinopathy of prematurity (ROP), diabetic macular edema, uveitis, retinal vein occlusion, cystic macular edema, glaucoma, vein branch occlusion, breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell carcinoma, thyroid cancer, sarcoma, osteosarcoma, desmofibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T cell lymphoma, chronic and non-progressive anemia, spontaneous or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, liver fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphoblastic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorders, encephaloma, astrocytoma, medulloblastoma, schwannoma, primary neuroectodermal tumor, and pituitary adenoma.