KR102678977B1 - Heteroaryl compounds as CXCR4 inhibitors, compositions and methods of use thereof - Google Patents

Abstract

The present invention provides heteroaryl compounds of formula (I), methods for their preparation, pharmaceutical compositions comprising them, and their use in the treatment of diseases and disorders originating from or associated with the CXCR4 pathway.

Description

Heteroaryl compounds as CXCR4 inhibitors, compositions and methods of use thereof

related Cross-reference to applications

This application is related to Chinese patent application 201710875041.9 dated September 25, 2017, Chinese patent application 201810265417.9 dated March 28, 2018, Chinese patent application 201810710340.1 dated July 2, 2018, and Chinese patent application filed September 5, 2018 Priority for 201811034891.7 All of these documents are incorporated herein by reference.

Technical field of invention

The present invention relates to heteroaryl compounds in general, and more specifically to new heteroaryl compounds available for therapy targeting C-X-C chemokine receptor type 4 (CXCR4) inhibitors, and for therapeutic intervention in infectious diseases, inflammatory diseases, tumors and cancer. It relates to the use of CXCR4 inhibitors.

CXC chemokine receptor type 4 (CXCR4) is a transmembrane protein belonging to G-protein-coupled receptors and participates in physiological processes of hematopoiesis and immune system. In studies, CXCR4 was found to be expressed in tissues such as lymphoid tissue, thymus, brain, spleen, stomach and small intestine. CXCR4 transmits signals from the natural chemokine ligand matrix cell-derived factor (SDF)-1α to intracellular biological pathways via G-proteins. The interaction between CXCR4 and SDF-1α is implicated in a number of diseases, including, for example, human immunodeficiency virus (HIV) infection, cancer, tumors and inflammation, and autoimmune diseases such as rheumatoid arthritis and allergic asthma. It has been a target in various therapeutic treatments. The CXCR4 antagonist, Plerixafor, was approved by the FDA in 2008 for hematopoietic stem cell mobilization . Cho W.T. et al., J. Med . Chem . 2011; 55:977-94; See Debnath B. et al., Theranostics 2013, 3 (1): 47-75.

Disclosed herein are heteroaryl compounds and compositions and uses thereof as CXCR4 inhibitors. The Heteroaryl Compounds disclosed herein, and compositions and uses thereof, can effectively inhibit necrosis, and thus necroptosis pathway-related conditions, including, for example, inflammation, tumors, metabolic diseases, and neurodegenerative diseases such as cerebral ischemia, stroke, etc. It is used to treat diseases and disorders.

One aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,

Ar is a 5-10 membered heteroaryl containing one N atom and 1-3 additional heteroatoms independently selected from the group consisting of N, O and S, and Ar is unsubstituted or 1-4 R is replaced with ₃₁ ;

W is _{Here , each ​} n is 0, 1, 2 or 3; o and p are different integers of 0 or 1; If o is 0, p is 1, B ₁ is CR ₁₁ , B ₂ is N, and B ₁ is combined with Ar; If o is 1, p is 0, B ₁ is N, B ₂ is CR ₁₁ , and the carbon with R' ₅ and R' ₆ is bonded to Ar; or

W is Here, the carbon bonded to R ₅ and R ₆ is connected to the ring carbon bonded to Y;

Y is Here, the carbon bonded to R ₃ is bonded to the carbon bonded to R ₂ ; or Y is ego;

U is or ego;

Q is a bond or CR ₂₉ R ₃₀ ;

Each of R ₁ , R ₂ , R ₃ and R ₄ is independently H, deuterium, -CN, halide, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl), -NHS(=O) ₂ (C _1-6 alkyl), -S(=O ) ₂ (C _1-6 alkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl, each C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl are unsubstituted, or independently halide, -OH, methanesulfonyl and is substituted with 1-3 groups selected from the group consisting of deuterium; or

R ₄ together with the atom to which it is attached forms a carbocyclic, aryl, heterocyclic or heteroaryl ring;

Each of R ₅ and R ₆ is independently selected from the group consisting of H, deuterium, -CN, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted, or independently halide, deuterium, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl), and C _1-3 alkoxy; or

R ₅ and R ₆ together to form, and D ₃ combines with R ₄ ,

1) D ₃ is N or CR' ₄ and D ₁ is NR' ₄ , O, S or C(R' ₄ ) ₂ , ,

2) D ₃ is N or CR' ₄ , D ₁ is NR' ₄ , O, S or C(R' ₄ ) ₂ , and D ₂ is NR' ₄ or C(R' ₄ ) ₂ , , or

3) D ₃ is N or CR' ₄ , D ₁ is N or CR' ₄ , and D ₂ is N or CR' ₄ , forming,

Here, each R' ₄ is independently H, deuterium, -CN, halide, -OH, amino, C _1-6 alkyl, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -S(=O) ₂ (C _1-6 alkyl), C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl, respectively. -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -S(=O) ₂ (C _1-6 alkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl are unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, -OH, methanesulfonyl and deuterium. and;

R ₇ is selected from the group consisting of H, deuterium, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 heterocycloalkyl, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 Heterocycloalkyl is unsubstituted or independently halide, deuterium, amino, -OH, acyl, -CN, C _1-6 alkoxy, -NH(C _1-6 alkyl), -N(C _{1 -6} alkyl) ₂ , -C(=O)O(C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)NH(C _1-6 alkyl), -C(=O )N(C _1-6 alkyl) ₂ , -NHC(=O)O(C _1-6 alkyl), -S(=O) ₂ (C _1-6 alkyl) and C _3-6 cycloalkyl group consisting of is substituted with 1-3 groups selected from;

Each of R ₈ and R ₉ is independently selected from the group consisting of H, deuterium, -CN, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH and C _1-3 alkoxy; or R ₇ and R ₈ together with the atoms attached to them form a ring; or

R ₈ and R ₉ together with the atoms attached to them form a ring;

Each of R' ₅ , R' ₆ , R' ₇ , R' ₈ , R' ₉ , R' ₁₀ , R ₁₁ , R ₃₂ and R ₃₃ is independently selected from H, deuterium, -CN, halide, C _1-6 selected from the group consisting of alkyl, -C(=O)O(C _1-6 alkyl), C _3-6 cycloalkyl, C _1-6 alkoxy and -OSi(C _1-6 alkyl) ₃ , wherein each C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkoxy are unsubstituted or independently halide, deuterium, -OH, amino, C _3-6 cycloalkyl, C _1-6 alkyl, -NHC (=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl), -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)N( substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl) ₂ , -NHS(=O) ₂ (C _1-6 alkyl) and C _1-6 alkoxy;

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, Deuterium, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O( is substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl), C _1-6 alkyl and C _1-3 alkoxy; or R ₂₁₃ and R ₂₃ together with the atoms attached to them form a ring; or R ₁₉ and R ₂₇ together with the atoms attached to them form a ring; or R ₂₁ and R ₂₇ together with the atoms attached to them form a ring; or R ₁₉ and R ₂₆ together with the atoms attached to them form a ring; or R ₂₁ and R ₂₆ together with the atoms attached to them form a ring;

R ₂₃ is selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted or independently halide, deuterium , -OH, amino, C _1-6 alkyl, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC( =O) is substituted with 1-3 groups selected from the group consisting of O(C _1-6 alkyl) and C _1-3 alkoxy; or R ₂₂ and R ₂₃ together with the atoms to which they are attached form a 5-7 membered heterocycle;

R ₂₄ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl containing N or O, -C(=O)(C _1-6 alkyl), -C(= O)O(C _1-6 alkyl) and -C(=O)NH(C _1-6 alkyl), wherein each C _1-6 alkyl and C _3-6 cycloalkyl are non-substituted. or independently halide, deuterium, -OH, -CN, amino, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl containing N or O, -NH(C _{1- 6} alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl) and C _1-3 alkoxy. or substituted with 1-3 groups selected from the group consisting of; or R and R ₂₄ together with the atoms to which they are attached form a 5-7 membered heterocycle;

R ₃₁ is deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkynyl, C _2-6 alkenyl, -S (C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , aryl, 1-3 heteroatoms independently selected from the group consisting of O, N and S selected from the group consisting of a 5-7 membered heteroaryl containing and a 5-7 membered heterocycle containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each C _1-6 Alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl and heterocycle are unsubstituted or independently selected from deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C substituted with 1-3 groups selected from the group consisting of _3-6 cycloalkyl and C _1-6 alkoxy;

R ₃₄ is H, C _1-6 alkyl, C _3-6 cycloalkyl, -C(=O)(C _1-8 alkyl), -S(=O) ₂ (C _1-8 alkyl), -C( =O)O(C _1-6 alkyl) and -C(=O)NH(C _1-6 alkyl), wherein each of C _1-6 alkyl, C _1-8 alkyl and C _{3- 6} Cycloalkyl is unsubstituted or independently halide, deuterium, -OH, amino, C _1-6 alkyl, -NH(C _1-6 alkyl), -NH(C _1-6 alkyl), -N( A group 1 selected from the group consisting of C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl) and C _1-3 alkoxy -Substituted with 3;

R is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 cycloalkyl Alkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, -S( =O) 1-3 groups selected from the group consisting of ₂ (C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O substituted; or R and R ₂₄ together with the N atom to which they are attached form a 5-7 membered heterocycle; or R and R ₂₁ together with the N atom to which they are attached form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, -S A group 1-3 selected from the group consisting of (=O) ₂ (C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O replaced by a dog; or R' and R ₂₁ together with the atoms attached thereto form a 5-7 membered heterocycle.

In some embodiments of the invention, the compound herein is a compound according to Formula Ia, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

In the above equation,

Ar is unsubstituted or substituted with 1-4 R ₃₁ groups, and Ar is selected from the group consisting of: ;

Each X is independently a bond, CR ₃₂ R ₃₃ , O or NR ₃₄ ;

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, is substituted with 1-3 groups selected from the group consisting of deuterium, -OH, amino, C _1-6 alkyl and C _1-3 alkoxy; or R ₁₉ and R ₂₇ together with the atoms attached to them form a ring; or R ₂₁ and R ₂₇ together with the atoms attached to them form a ring;

Each R ₂₃ and R ₂₄ is independently selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each C _1-6 alkyl and C _3-6 cycloalkyl are unsubstituted or , or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, C _1-6 alkyl, and C _1-3 alkoxy; or R ₂₂ and R ₂₃ together with the atoms to which they are attached form a 5-7 membered heterocycle;

R ₃₁ is deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkynyl, C _2-6 alkenyl, -S (C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , aryl, 1-3 heteroatoms independently selected from the group consisting of O, N and S selected from the group consisting of a 5-7 membered heteroaryl containing and a 5-7 membered heterocycle containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each C _1-6 Alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl and heterocycle are unsubstituted or independently selected from deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C substituted with 1-3 groups selected from the group consisting of _3-6 cycloalkyl and C _1-6 alkoxy;

R is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-8 heterocycloalkyl containing N or O, -C(=O)(C _1-6 alkyl), -C(=O )O(C _1-6 alkyl) and -C(=O)NH(C _1-6 alkyl), wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 Heterocycloalkyl is unsubstituted, or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, -S(=O) ₂ (C is substituted with 1-3 groups selected from the group consisting of _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O; or R and R ₂₄ together with the N atom to which they are attached form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, -S A group 1-3 selected from the group consisting of (=O) ₂ (C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O replaced by a dog; or R' and R ₂₁ together with the N atom to which they are attached form a 5-7 membered heterocycle.

In some embodiments of the invention, the compound herein is a compound according to Formula Ib, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,

Ar is unsubstituted or substituted with 1-4 R ₃₁ groups, and Ar is selected from the group consisting of:

Each X is independently a bond, CR ₃₂ R ₃₃ , O or NR ₃₄ ;

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, is substituted with 1-3 groups selected from the group consisting of deuterium, -OH, amino, C _1-6 alkyl and C _1-3 alkoxy; or R ₁₉ and R ₂₇ together with the atoms attached to them form a ring; or R ₂₁ and R ₂₇ together with the atoms attached to them form a ring;

Each R ₂₃ and R ₂₄ is independently selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each C _1-6 alkyl and C _3-6 cycloalkyl are unsubstituted or , or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, C _1-6 alkyl, and C _1-3 alkoxy; or R ₂₂ and R ₂₃ together with the atoms to which they are attached form a 5-7 membered heterocycle;

R ₃₁ is deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkynyl, C _2-6 alkenyl, -S (C _1-6 alkyl), -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , aryl, 1-3 heteroatoms independently selected from the group consisting of O, N and S selected from the group consisting of a 5-7 membered heteroaryl containing and a 5-7 membered heterocycle containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein each C _1-6 Alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl and heterocycle are unsubstituted or independently selected from deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C substituted with 1-3 groups selected from the group consisting of _3-6 cycloalkyl and C _1-6 alkoxy;

R is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 cycloalkyl Alkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, -S( =O) 1-3 groups selected from the group consisting of ₂ (C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O substituted; or R and R ₂₄ together with the N atom to which they are attached form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy, -S A group 1-3 selected from the group consisting of (=O) ₂ (C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O replaced by a dog; or R' and R ₂₁ together with the N atom to which they are attached form a 5-7 membered heterocycle.

In some embodiments of the invention, the compound herein is a compound according to Formula Ic, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,

each Z1, Z2 and Z3 is independently selected from the group consisting of O and CR ₄₁ R ₄₂ ; and

Each R ₄₁ and R ₄₂ is independently selected from the group consisting of H, deuterium, halide, and C _1-3 alkyl.

In some embodiments of the invention, compounds defined as follows are disclosed:

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, substituted with 1-3 groups selected from the group consisting of deuterium, -OH, C _1-6 alkyl, and C _1-3 alkoxy;

Each R ₂₃ and R ₂₄ is independently selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each C _1-6 alkyl and C _3-6 cycloalkyl are unsubstituted or , or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH, amino, C _1-6 alkyl, and C _1-3 alkoxy; or R ₂₂ and R ₂₃ together with the atoms to which they are attached form a 5-7 membered heterocycle; and

Each R and R' is independently selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 Alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ From the group consisting of _-3 alkoxy, -S(=O) ₂ (C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O. It is substituted with 1-3 selected groups.

In some embodiments of the invention, the compounds herein are selected from the group consisting of:

In some embodiments of the invention, the compounds herein are compounds according to Formula II:

In the above equation,

W ₁ is D ₁ , D ₁ -D ₂ or D ₁ =D ₂ , and D ₁ is bonded to a pyridine ring;

Each of R ₁ , R ₂ and R ₃ is independently H, deuterium, -CN, halide, -OH, amino, C _1-6 alkyl, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -S(=O) ₂ (C _1-6 alkyl), C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl. However, each C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl is unsubstituted or independently halide, -OH, substituted with 1-3 groups selected from the group consisting of methanesulfonyl and deuterium;

R ₇ is selected from the group consisting of H, deuterium, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each C _1-6 alkyl and C _3-6 cycloalkyl are unsubstituted or independently halide. , deuterium, amino, -OH, acyl, -CN, C _1-6 alkoxy, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C(=O)O(C _{1 -6} alkyl), -C(=O)NH ₂ , -C(=O)NH(C _1-6 alkyl), -C(=O)N(C _1-6 alkyl) ₂ , -NHC(=O )O(C _1-6 alkyl), -S(=O) ₂ (C _1-6 alkyl) and C _3-6 cycloalkyl;

R ₂₃ is selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted or independently halide, deuterium , -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ and C _1-3 alkoxy;

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, Deuterium, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O( is substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl) and C _1-3 alkoxy; or R ₂₂ and R ₂₃ together with the atoms attached to them form a ring; or R ₁₉ and R ₂₆ together with the atoms attached to them form a ring; or R ₂₁ and R ₂₆ together with the atoms attached to them form a ring;

Each R and R ₂₄ are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl containing N or O, -C(=O)(C _1-6 alkyl ), -C(=O)O(C _1-6 alkyl) and -C(=O)NH(C _1-6 alkyl), wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-6 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _3-6 cycloalkyl, C _1-3 alkoxy and C ₃ containing N or O. _-6 is substituted with 1-3 groups selected from the group consisting of heterocycloalkyl; or R and R ₂₄ together with the N atom to which they are attached form a 5-7 membered heterocycle; and

R' is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _3-6 cycloalkyl, C _1-3 alkoxy, -S(=O) ₂ ( is substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O; or R' and R ₂₁ together with the N atom to which they are attached form a 5-7 membered heterocycle.

In some embodiments of the invention, the compound herein is a compound according to Formula IIa, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,

Ar is unsubstituted or substituted with 1-4 R ₃₁ groups, and Ar is selected from the group consisting of:

Each of R ₁ , R ₂ , R ₃ and R ₄₃ is independently H, deuterium, -CN, halide, -OH, amino, C _1-6 alkyl, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -S(=O) ₂ (C _1-6 alkyl), C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl selected from the group, wherein each C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl is unsubstituted or independently halide, -OH, methanesulfonyl, and deuterium.

In some embodiments of the invention, the compound herein is a compound according to Formula IIb, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,

each D ₁ , D ₂ and D ₃ is independently selected from the group consisting of N and CR′ ₄ ;

Ar is unsubstituted or substituted with 1-4 R ₃₁ groups, and Ar is selected from the group consisting of: ;

Each of R ₁ , R ₂ , R ₃ and R' ₄ is independently H, deuterium, -CN, halide, -OH, amino, C _1-6 alkyl, -NH(C _1-6 alkyl), -N( C _1-6 alkyl) ₂ , -S(=O) ₂ (C _1-6 alkyl), C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl. selected from the group consisting of, wherein each C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl is unsubstituted or independently halide. , -OH, methanesulfonyl, and deuterium.

In some embodiments of the invention, the compounds herein are defined as follows:

R ₂₃ is selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted or independently halide, deuterium , -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , and C _1-3 alkoxy;

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, Deuterium, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O( is substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl) and C _1-3 alkoxy; or R ₂₁ and R ₂₃ together with the atoms attached to them form a ring;

Each R and R ₂₄ are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl containing N or O, -C(=O)(C _1-6 alkyl ), -C(=O)O(C _1-6 alkyl) and -C(=O)NH(C _1-6 alkyl), wherein each of C _1-6 alkyl and C _3-6 Cycloalkyl is unsubstituted or independently of the group consisting of halide, deuterium, -OH, -CN, C _3-6 cycloalkyl, C _1-3 alkoxy and C _3-6 heterocycloalkyl containing N or O. or substituted with 1-3 groups selected from; or R and R ₂₄ together with the atoms to which they are attached form a 5-7 membered heterocycle;

R' is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently a group consisting of halide, deuterium, -OH, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy. or substituted with 1-3 groups selected from; or R' and R ₂₁ together with the atoms attached thereto form a 5-7 membered heterocycle.

In some embodiments of the invention, compounds selected from the group consisting of: .

In some embodiments of the invention, the compounds herein are compounds according to Formula III:

In the above equation,

each of A ₁ , A ₂ and A ₃ is independently selected from the group consisting of N and CR ₄₄ , and at least one of A ₁ , A ₂ and A ₃ is N;

W ₂ is or ego;

Each of R ₁ , R ₂ , R ₃ and R ₄ is independently H, deuterium, -CN, halide, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl), -NHS(=O) ₂ (C _1-6 alkyl), C _1-6 alkyl , C _3-6 cycloalkyl, C _1-8 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl, each of C _1-6 alkyl, C _3-6 cycloalkyl and C _{1 -8} alkoxy is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide and deuterium;

Each of R ₅ and R ₆ is independently selected from the group consisting of H, deuterium, -CN, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted, or independently halide, deuterium, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O(C _1-6 alkyl), and C _1-3 alkoxy; or R ₅ is O or CR ₄₅ R ₄₆ , and R ₄ and R ₅ together with the atoms attached to them form a ring;

R ₇ is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 heterocycloalkyl including O, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 heterocycloalkyl is unsubstituted or independently selected from the group consisting of halide, deuterium, C _3-6 cycloalkyl and C _3-6 heterocycloalkyl containing O. substituted;

Each of R ₈ and R ₉ is independently selected from the group consisting of H, deuterium, -CN, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted or substituted with 1-3 groups independently selected from the group consisting of halide, deuterium, -OH and C _1-3 alkoxy; or R ₇ and R ₈ together with the atoms attached to them form a ring; or

R ₈ and R ₉ together with the atoms attached to them form a ring;

R ₄₄ is H, deuterium, halide, -CN, -OH, amino, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C(=O)NH(C _1-6 alkyl), -C(=O)N(C _1-6 alkyl) ₂ , -S(C _1-6 alkyl), C _{2 -6} alkenyl, C _2-6 alkynyl, 4-7 membered heterocycle containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, aryl and 5-6 membered heteroaryl; , each C _1-6 alkyl, C _3-6 cycloalkyl, C _1-8 alkoxy, heterocycle, aryl and heteroaryl are unsubstituted, or independently halide, deuterium, -OH and C _1-3 alkoxy. is substituted with 1-3 groups selected from the group consisting of;

R ₂₃ is selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, wherein each of C _1-6 alkyl and C _3-6 cycloalkyl is unsubstituted or independently halide, deuterium , -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , and C _1-3 alkoxy;

Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ and R ₃₀ is independently H, deuterium, -CN, -OH, C _1-6 alkyl, selected from the group consisting of C _3-6 cycloalkyl and C _1-3 alkoxy, wherein each of C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy is unsubstituted or independently halide, Deuterium, -OH, amino, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=O)(C _1-6 alkyl), -NHC(=O)O( is substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl) and C _1-3 alkoxy; or R ₂₂ and R ₂₃ together with the atoms attached to them form a ring; or R ₁₉ and R ₂₆ together with the atoms attached to them form a ring; or R ₂₁ and R ₂₆ together with the atoms attached to them form a ring;

Each R and R ₂₄ are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl containing N or O, -C(=O)(C _1-6 alkyl ), -C(=O)O(C _1-6 alkyl) and -C(=O)NH(C _1-6 alkyl), wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-6 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _3-6 cycloalkyl, C _1-3 alkoxy and C ₃ containing N or O. _-6 is substituted with 1-3 groups selected from the group consisting of heterocycloalkyl; or R and R ₂₄ together with the N atom to which they are attached form a 5-7 membered heterocycle; or R and R ₂₁ together with the N atom to which they are attached form a 5-7 membered heterocycle;

R' is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl and C _3-8 heterocycloalkyl containing N or O, wherein each C _1-6 alkyl, C _3-6 Cycloalkyl and C _3-8 heterocycloalkyl are unsubstituted or independently halide, deuterium, -OH, -CN, C _3-6 cycloalkyl, C _1-3 alkoxy, -S(=O) ₂ ( is substituted with 1-3 groups selected from the group consisting of C _1-6 alkyl), -C(=O)(C _1-6 alkyl) and C _3-6 heterocycloalkyl containing N or O; or R' and R ₂₁ together with the N atom to which they are attached form a 5-7 membered heterocycle; and

Each R ₄₅ and R ₄₆ is independently selected from the group consisting of H, deuterium, halide, C _1-3 alkyl; Or R ₄₅ and R ₄₆ together with the atoms attached to them form a ring.

In some embodiments of the invention, the compounds herein are of formula IIIa or IIIb:

In the above equation,

each of E ₁ , E ₂ and E ₃ is independently selected from the group consisting of O and CR ₄₅ R ₄₆ ; and

Each R ₄₅ and R ₄₆ is independently selected from the group consisting of H, deuterium, halide, C _1-3 alkyl; or R ₄₅ and R ₄₆ together with the atoms attached thereto form a ring.

In some embodiments of the invention, the compounds herein are according to formulas IIIa and IIIb, wherein each of E ₁ , E ₂ and E ₃ is independently selected from CH ₂ , O and is selected from the group consisting of; One or more of E ₁ , E ₂ and E ₃ am.

In some embodiments of the invention, the compounds herein are compounds according to formulas IIIa and IIIb,

A ₃ is CR ₄₄ ;

each A ₁ and A ₂ is independently selected from the group consisting of N and CR ₄₄ , and at least one of A ₁ and A ₂ is N;

W ₂ is am.

In some embodiments of the invention, -C(R ₅ R ₆ )W ₂ is selected from the group consisting of:

In some embodiments of the invention, the compounds herein are selected from the group consisting of:

In some embodiments of the invention, in compounds of Formulas I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa and IIIb, or other compounds disclosed herein, U is unsubstituted, or is deuterium, halide. , -OH, C _1-3 alkyl and C _1-3 alkoxy, and U is selected from the group consisting of: .

Another aspect of the invention is a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa and IIIb or another compound disclosed herein, or a pharmaceutically acceptable salt, hydrate thereof. , solvates, stereoisomers or tautomers, and pharmaceutically acceptable carriers, diluents, adjuvants or excipients.

Another aspect of the present invention is

(a) Compounds of Formulas I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa and IIIb or other compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers or tautomers thereof. isomer; and

(b) one or more additional compounds selected from the group consisting of anti-neoplastic agents, anti-cancer agents, anti-bacterial agents, anti-viral agents, central nervous system agents, and anti-diabetic agents.

It provides a combination composition comprising.

Another aspect of the invention is Formula I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa for treating disease, mobilizing stem cells and treating damaged or burned skin by antagonizing the CXCR4 pathway. and IIIb or other compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers or tautomers thereof, and the diseases include HIV infection, myocardial infarction, hematopoiesis-related diseases, 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. Reaction, 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, cystoid macular edema, glaucoma, branch vein occlusion, breast cancer, Lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell cancer, thyroid cancer, sarcoma, osteosarcoma, dermatofibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, stomach cancer, myeloma, lymphoma, mantle cell lymphoma, skin 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 It is selected from the group consisting of leukemia, lymphoblastic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorder, brain tumor, astrocytoma, medulloblastoma, schwannoma, primitive neuroectodermal tumor and pituitary adenoma.

For those skilled in the art, additional aspects and advantages of the present disclosure will be readily apparent from the detailed description set forth below, which is merely intended to describe and explain exemplary embodiments of the present invention. As will be appreciated, the present disclosure is capable of various other embodiments and its several details may be modified in various obvious respects without departing from the scope of the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive.

Figure 1 shows the 12G5 analysis of compound A42.
Figure 2 shows the 12G5 analysis of compound A43.
Figure 3 shows the 12G5 analysis of compound A78.
Figure 4 shows the 12G5 analysis of compound A83.

Before describing the detailed description, it should be understood that the detailed description set forth below is illustrative in nature and is not intended to limit the invention or its application and use. Accordingly, although the present application is described and explained as shown in some example implementations for convenience of explanation, it will be understood that it can be implemented in various other types of implementations and equivalent forms, and in various other systems and environments. Additionally, there is no intention to be bound by any theory presented in the foregoing background description or the following detailed description.

reference by reference

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.

Although various embodiments of the invention have been described and illustrated herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Numerous modifications, changes and substitutions will occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the invention described herein may also be used.

Justice

Compounds are generally referred to herein by standard nomenclature. For compounds with asymmetric centers, it should be understood that all optical isomers and mixtures thereof (unless otherwise stated) are encompassed. Additionally, compounds with carbon-carbon double bonds can form Z-forms and E-forms, and unless otherwise stated, all isomeric forms of the compounds are included in the present invention. If a compound exists in various tautomeric forms, the referenced compounds are not limited to any one particular tautomeric form but are intended to encompass all tautomeric forms.

As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, “molecule” encompasses the plural of these molecules.

As used herein, the terms “about” or “approximately” generally mean +/- 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% of the stated amount. Or it means within 1%.

Compounds are generally referred to herein by standard nomenclature. For compounds with asymmetric centers, it is to be understood that all optical isomers and mixtures thereof (unless otherwise stated) are encompassed. Additionally, compounds with carbon-carbon double bonds can be formed in the Z-form and the E-form, and all isomeric forms of the compound are included in the present invention unless otherwise stated. If a compound exists in various tautomeric forms, a referenced compound is not limited to any one particular tautomeric form but is intended to encompass all tautomeric forms.

As used herein, the term “alkyl” refers to a linear or branched, saturated aliphatic hydrocarbon chain. Alkyl groups include groups with 1-8 carbon atoms (C ₁ -C ₈ alkyl), 1-6 carbon atoms (C ₁ -C ₆ alkyl) and 1-4 carbon atoms (C ₁ -C ₄ alkyl). Includes, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, tert -butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl, etc. In some instances, substituents on alkyl groups are specifically described. For example, “cyanoalkyl” refers to an alkyl group substituted with one or more cyano substituents.

At our headquarters, The term “alkenyl” refers to an alkene group of a linear or branched chain containing one or more unsaturated carbon-carbon double bonds. Alkenyl groups include C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkenyl and C ₂ -C ₄ alkenyl groups having 2-8, 2-6 or 2-4 carbon atoms respectively, for example , ethenyl, allyl, or isopropenyl. As used herein, the term “alkynyl” generally refers to a linear or branched chain alkyne group having one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C ₂ -C ₈ alkynyl, C ₂ -C ₆ alkynyl and C ₂ -C ₄ alkynyl groups having 2-8, 2-6 or 2-4 carbon atoms respectively.

As used herein, the term "cycloalkyl" generally refers to a group containing one or more saturated rings in which the ring elements are all carbon, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, adamantyl, etc. Cycloalkyl groups do not contain aromatic rings or heterocyclic rings. For example, some cycloalkyls are C ₃ -C ₇ cycloalkyl, where the cycloalkyl group has 3-7 ring members, all of which are carbon. As used herein, the term “cycloalkenyl” generally refers to a group where all ring members are carbon and contain one or more unsaturated rings.

At our headquarters, The term “alkoxy” generally refers to an oxygen bridge connected to an alkyl group as defined above. Alkoxy groups are C with 1-6 or 1-4 carbon atoms respectively._One-C₆ Alkoxy and C_One-C₄ Contains an alkoxy group. Representative alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

As used herein, the term "alkylamino" generally refers to a secondary or secondary group of the general structure -NH-R1 or -N(R1)(R2) wherein R1 and R2 are independently selected from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Refers to tertiary amines. Such groups include, but are not limited to, mono- and di-(C ₁ -C ₆ alkyl)amino groups, where each C ₁ -C ₆ alkyl may be the same or different from the other. The definition of "alkyl" in the term "alkylamino" will be understood to be different from the definition of "alkyl" used in all other alkyl-containing groups, including cycloalkyl and (cycloalkyl)alkyl groups.

As used herein, the term “alkylthio” generally refers to an alkyl-substituted thio group, where the term alkyl is defined as above.

As used herein, the term “halogen” or “halide” generally refers to fluorine, chlorine, bromine, and iodine. As used herein, the term “haloalkyl” refers to an alkyl group substituted by one or more independently selected from halogen (e.g., a “C ₁ -C ₆ haloalkyl” group has 1-6 carbon atoms and one or more halogens) ). 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.

As used herein, the term “heteroaryl” generally refers to an aromatic group in which one or more aromatic rings contain one or more heteroatoms selected from N, O and S. Heteroaryl includes, for example, 5-12 membered heteroaryl. Examples include, but are not limited to, imidazole, furan, furazan, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, tetrazole, thiazole and Contains thiophene.

At our headquarters, The term “heterocycloalkyl” generally refers to a ring structure containing 3-12 ring atoms, where at least one ring atom is carbon and at least one ring atom is a heteroatom selected from N, O and S. Examples include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thiethane, pyrrolidine, tetrahydrofuran, and tetrahydrothiophene.

At our headquarters, The term “heterocyclic” or “heterocycle” generally refers to a ring structure containing 3-12 ring atoms, where at least one ring atom is carbon and at least one ring atom is a heteroatom selected from N, O and S. Heterocyclic groups can 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.

At our headquarters, The terms “substituent” and “substituted” generally mean that a molecular moiety is covalently linked to an atom in the subject molecule. For example, a ring substituent can be a moiety such as a halogen, an alkyl group, a haloalkyl group, or any other group covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of the ring. The substituents of aromatic groups are usually covalently bonded to the ring carbon atom. A straight chain substituent may be a moiety such as a halogen, an alkyl group, a haloalkyl group, or any other group covalently bonded to a member atom of the straight chain (preferably a carbon or nitrogen atom).

As used herein, the term “pharmaceutically acceptable” generally refers to a form of a compound that is safe for administration to a subject. For example, the free base, salt form, or solvent of a compound of Formula I that has been cleared for use in mammals by oral ingestion or any other route of administration by a government agency or regulatory agency, such as the U.S. Food and Drug Administration (FDA). Cargo, hydrate, prodrug or derivative forms are pharmaceutically acceptable.

Compounds of formulas I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa and IIIb include pharmaceutically acceptable salts of the free-base compounds. As used herein, the term “pharmaceutically acceptable salt” generally refers to salts that are approved by regulatory agencies, which form alkali metal salts and which are commonly used to form addition salts of free acids or free bases. Salts are formed through ionic associations, charge-charge interactions, covalent bonds, complex formation, coordination, etc. As long as the salt is pharmaceutically acceptable, its nature is not critical.

In some embodiments, the compound(s) of Formulas I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa and IIIb are used to treat an individual by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s) are, in one embodiment, combined with one or more pharmaceutically acceptable excipients, such as carriers, diluents or adjuvants, to form suitable compositions as described in more detail herein.

As used herein, the term “excipient” generally refers to any pharmaceutically acceptable additive, carrier, adjuvant or other suitable ingredient other than the active pharmaceutical ingredient (API) that is typically included for purposes of formulation and/or administration. .

As used herein, the term “diluent” generally refers to a substance used as a filler to achieve the desired volume or weight of the composition. Diluents may be present in the pharmaceutical composition in granules in the form of a single compound or in the form of a mixture of compounds. Non-limiting examples of diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium. Contains phosphate, fructose, maltose, sorbitol or sucrose.

At our headquarters, The term “adjuvant” generally refers to any substance or mixture of substances that increases the efficacy or potency of a compound disclosed herein on a target when the adjuvant is used in conjunction with a compound disclosed herein. However, when the adjuvant is used alone, no pharmacological effect on the same target is observed.

As used herein, the terms “treat,” “treating,” “treatment,” and “therapy” generally include, but are not limited to, curative therapy, prophylactic therapy, and preventative therapy. therapy), etc.

As used herein, the expression “effective amount” refers quantitatively to that amount of each agent that achieves the objectives of improving the severity of the disorder and improving the frequency of attacks during the period of treatment of the agent itself, while avoiding the harmful side effects typically associated with alternative therapies. will be. In one embodiment, the effective amount is administered in a single dosage form or in multiple dosage forms.

Regardless of the route of administration chosen, the compounds of the invention and/or pharmaceutical compositions of the invention may be used in an appropriate hydrated form, in a pharmaceutically acceptable dosage form, or by other conventional methods known to those skilled in the art. It is formulated by

The actual dosage range of the active ingredient in the pharmaceutical composition of the present invention may vary in order to achieve an effective amount of the active ingredient to achieve the desired therapeutic response, composition and mode of administration in the individual patient without being detrimental to the patient. .

The dosage level selected will depend on the activity of the specific compound of the invention used, the mode of administration, the time of administration, the excretion rate of the specific compound being used, the duration of treatment, the specific hedgehog inhibitor used and other drugs used in combination, The decision will depend on a variety of factors, including the compound and/or substance, the age, sex, weight, condition of the patient being treated, overall health and previous medical history, and similar factors well known in the medical field.

A doctor or veterinarian skilled in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may begin the dosage of a compound of the invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. can be increased.

In general, the appropriate daily dose of the compound of the present invention will be the compound content that is the minimum dose effective to exert a therapeutic effect. Such effective amount will generally depend on the factors previously described. Generally, intravenous, intracerebroventricular and subcutaneous dosages of a compound of the present invention for a patient will range from about 0.0001 to about 100 mg/kg of body weight per day. The mode of administration can have a significant effect on dosage. Higher doses may be used for topical delivery routes.

If necessary, an effective daily dose of the active compound may be administered in 2, 3, 4, 5, 6 or more divided doses, optionally in unit dosage form, separated at appropriate intervals during the day. Those skilled in the art will readily appreciate that dosage levels may vary depending on the particular compound, the severity of symptoms, and the patient's susceptibility to side effects. The dosage of the compound disclosed herein can be easily determined by a person skilled in the art by various means.

Pharmaceutical composition/formulation

One embodiment provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In some embodiments, the compounds described herein are formulated in pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that allow the active compounds to be readily processed into pharmaceutically usable preparations. The appropriate formulation will depend on the route of administration chosen. Summaries of pharmaceutical compositions described herein see, e.g., 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, NY (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems , Seventh Ed., Lippincott Williams & Wilkins (1999), the disclosures of which are incorporated herein by reference.

As used herein, a pharmaceutical composition comprises a compound of Formula I and other chemical ingredients (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweetening agents, and sorbents. Refers to a mixture of dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combinations thereof. Pharmaceutical compositions facilitate the administration of compounds to an organism. In practicing the treatments or methods of use provided herein, a therapeutically effective amount of a compound described herein is administered in the form of a pharmaceutical composition to a mammal suffering from the disease, disorder or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary greatly depending on the severity of the disease, the age and relative health of the individual, the potency of the compound used, and other factors. The compounds can be used alone as a component of a mixture or in combination with one or more therapeutic agents.

The pharmaceutical formulations described herein can be administered to the subject by any suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. is administered to Pharmaceutical formulations described herein include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, Controlled release formulation, fast melt formulation, tablet, capsule, pill, delayed release formulation, extended release formulation, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Both formulations for oral administration are available in dosages suitable for such administration. Examples of such dosage units are tablets or capsules. In some embodiments, it comprises the active ingredient in an amount of about 1 to 2000 mg, advantageously about 1 to 500 mg, typically about 5 to 150 mg. The appropriate daily dosage for humans or other mammals varies greatly depending on the patient's condition and other factors, and can be determined again using routine methods and practices.

Common formulation techniques include, for example, (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. (fusion) includes one method or a combination of these methods. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g. wurster coating), tangential coating ( Includes tangential coating, top spraying, tableting, extruding, etc.

synthesis method

The method of the present invention inhibits necrosis in the recovery and/or regulation of functional performance of a wide range of cells, tissues and organs, regulation of formation and repair of nervous tissue, bone and cartilage, regulation of spermatogenesis, Formulas I, Ia, Ib, with therapeutic and cosmetic applications ranging from regulation of smooth muscle, regulation of lung, liver and other organs originating from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc. , Ic, II, IIa, IIb, III, IIIa and IIIb. Accordingly, the methods and compositions of the present invention include the use of inhibitors of interest for all such applications in which an inhibitor of necrosis may be relevant. Additionally, the method can be performed on cells provided in culture (in vitro) or on cells from the whole body of the animal (in vivo).

The examples and preparations presented below illustrate and illustrate the compounds described herein and methods of making such compounds. In general, the compounds described herein can be prepared by processes known in the art of general chemistry.

The compounds of the present invention can be prepared using various synthetic routes using commercially available materials as starting materials. The starting materials of the present invention are known, commercially available, or can be synthesized according to or similar methods known in the art. A number of starting materials can be prepared according to known processes, especially using the process described in the Examples. When synthesizing starting materials, in some cases, functional groups are protected using appropriate protecting groups, if necessary. Functional groups can be removed according to processes known in the art.

Protection of a functional group by a protecting group, the protecting group itself, and its removal reaction (commonly referred to as “deprotection”) is described, for example, in J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T.W. It is described in standard literature such as 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). .

All synthetic processes described herein can be carried out under known reaction conditions, advantageously under the conditions described herein, and in the absence or (generally) presence of solvents or diluents.

The present invention further includes “intermediate” compounds, including structures synthesized from the described synthetic processes, with or without isolation, prior to finally obtaining the desired compound. Structures prepared by performing steps from transient starting materials, structures prepared by branching off from the method(s) described in any step, and structures that form the starting materials under reaction conditions are all included as “intermediates” in the present invention. . Furthermore, structures prepared by using starting materials in the form of reactive derivatives or salts or structures prepared by compounds obtainable using the process according to the present invention, and structures prepared by processing the compounds of the present invention in situ are all of the present invention. included in the scope.

New starting materials and/or intermediate products as well as methods for their preparation are also the subject of the present invention. In selected embodiments, these starting materials are used and reaction conditions selected are used to obtain the desired compound(s).

The starting materials of the present invention are known, commercially available, or can be synthesized according to or similar methods known in the art. A number of starting materials can be prepared according to known processes, especially those described in the examples. When synthesizing starting materials, in some cases, functional groups are protected with appropriate protecting groups as necessary. Protecting groups, their introduction and removal are described above.

All reagents and solvents were commercially purchased unless otherwise noted. All commercially available reagents and solvents are used without purification unless otherwise noted. If necessary, some reagents and solvents were purified by standard techniques, for example tetrahydrofuran can be purified by distillation from sodium. All thin layer chromatography (TLC, GF254) analysis and column purification (100-200 mesh) were performed on silica gel (Qingdao Haiyang Chemical Co. Ltd. or Yantai Chemical Co. Ltd.) using petroleum ether (bp 60-90°C)/ This was performed using ethyl acetate (v/v) as eluent, and the spots were visualized by UV visualization at 254 nm and I ₂ vapor or phosphomolybdic acid. After extraction, all organic layers were dried over anhydrous Na ₂ SO ₄ unless otherwise stated. All nuclear magnetic resonance spectra were recorded at 400 MHz on a Bruck-400 spectrometer using TMS as an internal standard. LC-MS was performed on an Agilent 1100 system using an LC-MSDTrap recorder, diode array detector (DAD) with detection wavelengths of 214 nm and 254 nm, and an ESI source. The HPCL column was an Agela Durashell C18 3.5 μm 4.6x50 mm column. The concentration gradient was conducted using 0.1 NH ₄ HCO ₃ aqueous solution and acetonitrile at a gradient of 5/95 -> 95/5 for a specified operating time (e.g., 5 minutes), and the flow rate was 1.8 mL/min.

The size and scale of the synthetic method will vary depending on the desired amount of final product. Although specific reagents and amounts are presented in the Examples, those skilled in the art will recognize other alternative and equally feasible sets of reactants that can prepare the same compounds. Accordingly, where common oxidizing agents, reducing agents, solvents of various properties (non-protic, non-polar, polar, etc.) are used, equivalents will be known in the art and are contemplated for use in the present method.

A number of steps described below describe various work-ups after completion of the reaction. Work-up generally involves quenching the reaction and starting reagents to terminate any remaining catalytic activity. Thereafter, addition of an organic solvent and separation of the aqueous layer from the organic layer are generally performed. The products are typically obtained in the organic layer, and unused reactants and other spurious by-products and unwanted chemicals are generally collected in the aqueous layer and discarded. In standard organic synthesis processes found in the literature, the work-up typically involves drying the product by exposure to a desiccant such as anhydrous Na ₂ SO ₄ to remove any excess water or aqueous by-products remaining partially dissolved in the organic layer; Concentrate the remaining organic layer. Concentration of the product dissolved in the solvent can be achieved by any known means such as pressure evaporation, elevated temperature, and pressure evaporation. This concentration can be achieved using standard laboratory equipment such as rotary-evaporator distillation. Thereafter, one or more purification steps, which may optionally include, but are not limited to, flash column chromatography, filtration through various media and/or other preparative methods known in the art, and/or crystallization/recrystallization, etc. (e.g., 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 route

The methods and examples set forth below describe and illustrate the compounds described herein and methods of making such compounds. In general, the compounds described herein can be prepared by processes known in the art of general chemistry. The methods below are examples of some common synthetic routes leading to compounds of formulas I, Ia, Ib, Ic, II, IIa, IIb, III, IIIa and IIIb. Specific reaction conditions for each method can be found in the examples described below.

Compounds of the invention can be prepared starting from commercially available materials using a variety of synthetic routes, such as those described in Methods A-N, BA-BS and AA-AT below. The starting materials of the present invention are known, commercially available, or can be synthesized according to or similar methods known in the art. A number of starting materials can be prepared according to known processes, especially those described in the Methods and Examples. When synthesizing starting materials, in some cases, functional groups are protected with appropriate protecting groups, if necessary. The functional group can be removed according to processes known in the art.

Method A:

(6-chloropyrimidin-4-yl)methanol can be converted to 4-chloro-6chloromethyl)pyrimidine by treating it with SOCl ₂ (Step a).

Method B:

The pyrimidine intermediate can be prepared by reacting the substituted 4-chloro-3-oxobutanoate with amidine and carbonate (step a). The conversion of hydroxypyrimidine to chloropyrimidine can be achieved using POCl ₃ (step b).

Method C, D:

The substituted 4-chloro-3-oxobutanoate can also be reacted with amidine and DBU to prepare the pyrimidine intermediate (step a). The conversion of hydroxypyrimidine to chloropyrimidine can be achieved using POCl ₃ (step b). After methylamine substitution (step c), hydroxypyrimidine and 1-methylpiperazine can be condensed (step d) to synthesize the 4-aminopyrimidine core.

Method E

The pyrimidine-4-carbaldehyde core is synthesized through cyclization reaction to the pyrimidine core (step a) followed by condensation reaction of hydroxypyrimidine with the corresponding amine (step b) and hydrolysis (step c). You can.

Methods F, G, H

The main intermediate product 4-(dimethoxymethyl)-6-(4-methylpiperazin-1-yl)-2-(methylthio)pyrimidine is 6-(dimethoxymethyl)-2 after cyclization reaction. It can be prepared through condensation (step b) of -(methylthio)pyrimidin-4-ol and 1-methylpiperazine. The 2-substituted pyrimidine-4-carbaldehyde is then subjected to sequential oxidation of methyl sulfide to methylsulfonyl (step c) and substitution with the corresponding alcohol or amine (step d) (step f). reaction, and then hydrolysis (step e, g), or through Suzuki coupling (step h) and subsequent hydrolysis (step i) reaction.

Method I

The target compound can be synthesized through a cyclization reaction (step a) followed by a condensation reaction of hydroxypyrimidine and 1-methylpiperazine (step b), followed by a substitution reaction with the corresponding amine (step c). .

Method J

4-(4-methylpiperazin-1-yl)pyrimidine core is decarboxylated after condensation reaction of amino acid and 2,2-dimethyl-1,3-dioxane-4,6-dione (step a) ; This can be achieved through subsequent cyclization reaction (step b), condensation reaction of hydroxypyrimidine with 1-methylpiperazine (step c), and finally Boc deprotection reaction (step c).

Method K

The pyridine-2-one core can be prepared by treating pyridine lithium reagent with N-Boc lactam (n = 0, 1, 2).

Method L

The heteroaromatic core can be substituted with bromine by treatment with NBS and a free radical initiator.

Method M

The 2-methyl-5-cyanopyrimidine core is subjected, sequentially, to a cyclization reaction (step a), a condensation reaction of a hydroxypyrimidine with the corresponding amine (step b), chlorination (step c) and the corresponding amine. This can be achieved through a substitution reaction (step d).

Method N

5-Bromo-2-(bromomethyl)imidazo[1,2-a]pyridine is, sequentially, 6-bromopyridin-2-amine using ethyl 3-bromo-2-oxopropanoate. It can be synthesized through a cyclization reaction (step a), a reduction reaction using NaBH ₄ (step b), and a bromination reaction using PBr ₃ (step c).

Method BA, BB

The target core can be synthesized through reductive amination using a ketone (step a, b) or reductive amination using an aldehyde (step c), followed by a deprotection reaction using TFA (step d). .

Method B.C.

The target core can be achieved through chlorination with TCCA (step a) and substitution reaction with the corresponding amine (step b).

How BD

After reacting 6,7-dihydroquinolin-8(5H)-one with NaH, 1,2-dibromoethane was added to produce 5',6'-dihydro-8'H-spiro[cyclopropane-1 ,7'-quinoline]-8'-one (step a) was prepared.

How to be

Spiro[2.5]octan-6-one was reacted with prop-2-yn-1-amine in the presence of NaAuCl ₄ to produce 7',8'-dihydro- 5'H -spiro[cyclopropane-1,6. '-Quinoline was prepared (step a).

Method BF, BG

The intermediate product 1-(3-aminopyridin-2-yl)ethan-1-one is sequentially subjected to a substitution reaction with (4-methoxyphenyl)methanamine (step a), Grignard reaction using CH ₃ MgCl (step b), and PMB group removal reaction using TFA (step c). The target compound can be obtained by acylation (step c) or mesylation (step d).

Method BH, BI

2-(pyrrolidin-2-yl)pyridine (S/R) is, sequentially, Grignard reaction with picolinonitrile and hydrolysis (step a), (4-methoxyphenyl)ethane-1-amine It can be prepared through reductive amination using (R/S) (steps b, d), and protective group removal reaction using TFA (steps c, e).

How to BJ

Racemic 2-(3-methylpyrrolidin-2-yl)pyridine is, sequentially, catalyzed imidization by TsOH (step a), followed by Michael addition by treatment with ethyl (E)-but-2-enoate. Reaction (step b), con. It can be obtained through a lactam formation reaction with HCl (step c) and a reduction reaction using LiAlH ₄ (step d).

Method B.K.

Schiff base can be synthesized by reacting picolinaldehyde with aminoacetonitrile. The pyrrole ring can be formed through a [3 + 2] cyclization reaction. Cyano groups can be knocked out through a series of reduction reactions.

Method B.L.

Substituted 8-nitroquinoline can be synthesized through a cyclization reaction (step a) by treating glycerin with 2-nitroaniline, and then the substituted 8-nitroquinoline is reduced to an 8-aminoquinoline core using Pd/C. (step b).

Method B.M.

The 8-aminoquinoline core can be methylated using methyl iodide.

Method BN

The quinoline-containing core can be synthesized through a cyclization reaction by treating glycerin with 2-fluoroaniline (step a) and a substitution reaction with the corresponding amine (step b).

Method BO

The PMB protecting group can be removed under acidic conditions.

Method B.P.

8-Chloro-1,7-naphthyridine can be synthesized through cyclization (step a) followed by chlorination via Sandmeier reaction (step b).

Method BQ

8-Bromo-1,6-naphthyridine can be synthesized through a cyclization reaction (step a) and subsequent bromination reaction using bromine.

Method BR

4-Chloro-1,5-naphthyridine can be obtained through oxidation using mCPBA (step a) and subsequent chlorination reaction by treatment with POCl ₃ (step b).

Method B.S.

2-(Pyridin-2-yl)propan-2-amine can be obtained as the desired target compound through formylation (step a) followed by alkylation and hydrolysis (step b).

Method AA

The final target compound can be obtained by substituting the chlorine of 4-chloro-6-(chloromethyl)pyrimidine with the corresponding amine, respectively (steps a and b).

Method AB

The final target compound is obtained by substitution of the chlorine of the 4-chloropyrimide core with N -Boc-piperazine (step a), followed by removal of the Boc group by acid treatment (step b), and subsequent acrylonitrile treatment to form Michael. It can be obtained through addition reaction (step c).

Method AC

The final target compound can be synthesized by reductive amination (step a) using NaBH(OAc) ₃ or NaBH ₃ CN.

Method AD

The final target compound can be synthesized by Boc group removal reaction under acidic conditions (step a) followed by reductive amination using NaBH(OAc) ₃ or NaBH ₃ CN (step b).

Method AE

The final target compound is first a bromine substitution reaction of 4-(bromomethyl)-6-chloropyrimidine using the corresponding amine (step a) and then a subsequent substitution reaction of chlorine of 6-chloropyrimidine with the corresponding amine. It can be obtained through (step b).

Method AF

Heteroaromatic derivatives can be synthesized via reductive amination (step a) and substitution reaction with the corresponding amine (step b).

Method AG

Chlorine of the pyrimidine core was removed under Pd/C conditions to prepare N-methyl-N-(pyrimidin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine.

Method AH

(2-methylpyrimidin-5-yl)methanol containing the target compound can be synthesized from 2-methylpyrimidine-4,6-diol. Sequentially, the Vilsmeier-Haack reaction with DMF and POCl ₃ (step a), followed by reduction of the aldehyde to alcohol with NaBH ₄ (step a); Alcohol group protection with TBSCl (step b), and Heck reaction with trifluoroborate (step c). Oxidation of aldehyde double bonds by ozone treatment (step c); Reductive amination (step d), followed by substitution of the pyrimidine chlorine with the corresponding amine (step e).

Method AI

The TBS protecting group can be removed under acidic conditions.

Method A.J.

The methyl ester of the quinoline core can be reduced to alcohol by NaBH ₄ or LiAlH ₄ .

Method AK

The final target compound is first a substitution reaction of the bromine of 5-bromo-2-(bromomethyl)imidazo[1,2- a ]pyridine with the corresponding amine (step a), and then 5-bromoimidazo Substitution reaction of bromine of the [1,2- a ]pyridine core with 1-methylpiperazine (step b), followed by hydroxyl group at position 3 of the imidazo[1,2- a ]pyridine core under formaldehyde conditions. Through the introduction of a methyl group (step c), it can be obtained.

Method AL

The final target compound is fluorination of commercially available 6,7-dihydroquinolin-8(5 H )-one using selectfluoro (step a), and reductive amination of ketone using methylamine (step b). , alkylation using 4-chloro-6-(chloromethyl)-2-methylpyrimidine (step c), and finally substitution reaction with 1-methylpiperazine (step d).

Method AM

The final target compound can be synthesized through reductive amination (step a) with the corresponding aldehyde using NaBH(OAc) ₃ or NaBH ₃ CN.

Method AN

The final target compound can be synthesized through a substitution reaction (step a) with a base and an aryl halogen under high temperature conditions.

Method AO

The final target compound can be synthesized through a Buchwald coupling reaction (step a) under the conditions of aryl halogen Pd ₂ (dba) ₃ , BINAP, and Cs ₂ CO ₃ .

Method AP

The final target compound can be synthesized through a Boc-group removal reaction under acidic conditions (step a) and subsequent condensation reaction using HATU (step b).

Method AQ

The halogens of the quinoline core can be converted to cyano groups under the conditions of Pd(PPh ₃ ) ₄ , dppf and zinc cyanide or Pd ₂ (dba) ₃ , dppf and zinc cyanide.

Method AR

The halogen of the quinoline core can be converted to a methylsulfonyl group in the presence of sodium methanesulfinate, L-proline and CuI.

Method AS

The final target compound can be synthesized from 8-fluoroquinoline. Nitrification by HNO ₃ treatment (step a), followed by substitution reaction of the aryl fluorine with the corresponding amine (step b). The nitro group can be reduced to an amino group by treatment with SnCl ₂ (step c) followed by mesylation with MsCl (step d).

method AT

The final target compound can be synthesized under MsCl and TEA conditions.

Example

The progress of the general reaction was monitored by analytical thin layer chromatography performed on silica gel HSGF254 pre-coated plates. The organic solution was dried over anhydrous Na ₂ SO ₄ and the solvent was removed under reduced pressure. ¹ H NMR was obtained on a 400 MHz (Varian) spectrometer. Chemical shifts were reported in ppm using tetramethylsilane as internal material. Mass spectra were obtained using an Agilent 1100 LC/MSD Trap SL version mass spectrometer. The final compound was purified by column chromatography using silica gel 100-200 mesh.

Method A

Preparation of 4-chloro-6-(chloromethyl)pyrimidine

Step a. 4-Chloro-6-(chloromethyl)pyrimidine: SOCl ₂ (280 mg) in a solution of (6-chloropyrimidin-4-yl)methanol (280 mg, 1.9 mmol, see WO2016128529) in dichloromethane (10 mL) , 2.3 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NaHCO ₃ (50 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were rinsed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a yellow oil (180 mg, 58%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 7.62 (s, 1H), 4.62 (s, 2H).

Method B

Preparation of 4-chloro-6-(chloromethyl)-2-(methylthio)pyrimidine

Step a. 6-(Chloromethyl)-2-(methylthio)pyrimidin-4-ol: ethyl 4-chloro-3-oxobutanoate (13 g, 79 mmol) and methyl carbamimidothio in water (200 mL) To a solution of ate sulfate (20 g, 72 mmol), sodium carbonate (11.5 g, 108 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was quenched to acidic pH by adding 6M aqueous HCl solution and filtered. The filter cake was dried to yield the desired product (11.1 g, 73%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.91 (s, 1H), 6.42 (s, 1H), 4.36 (s, 2H), 2.59 (s, 3H).

step b. 4-Chloro-6-(chloromethyl)-2-(methylthio)pyrimidine: 6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol (2.8 g, in POCl ₃ (10 mL)) 14.7 mmol) The solution was heated to 100°C and stirred for 1 hour. The reaction mixture was concentrated, saturated aqueous NaHCO ₃ (100 mL) was added and then extracted with ethyl acetate (100 mL). The organic layer 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 (s, 1H), 4.53 (s, 2H), 2.58 (s, 3H).

Method C

Preparation of 4-chloro-6-(chloromethyl)-2-methylpyrimidine

Step a. 6-(Chloromethyl)-2-methylpyrimidin-4-ol: ethyl 4-chloro-3-oxobutanoate (16.5 g, 100 mmol) and acetamidine hydrochloride (10 g) in ethanol (150 mL) , 106 mmol) DBU (30.4 g, 200 mmol) was slowly added to the solution 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) and then rinsed with brine (30 mL x 3). The organic layer was dried over Na ₂ SO ₄ and then concentrated to give the desired product (7.93 g, 50%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.01 (s, 1H), 6.53 (s, 1H), 4.37 (s, 2H), 2.50 (s, 3H).

step b. 4-Chloro-6-(chloromethyl)-2-methylpyrimidine: A solution of 6-(chloromethyl)-2-methylpyrimidin-4-ol (7.93 g, 50 mmol) in POCl ₃ (20 mL) was added to 110 It was heated to ℃ and stirred for 30 minutes. Then, the reaction mixture was concentrated, dissolved in ethyl acetate (20 mL), and then this solution was poured into ice-water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over Na ₂ SO ₄ and then 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. ^1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 4.55 (s, 2H), 2.71 (s, 3H).

Method D

Preparation of N -methyl-1-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methanamine

step c. 2-Methyl-6-((methylamino)methyl)pyrimidin-4-ol: 6-(chloromethyl)-2-methylpyrimidin-4-ol (1.7 g, 11 mmol) in CH ₃ CN (50 mL) ), methylamine solution (30 wt%/anhydrous ethanol, 3 g), KI (183 mg, 1.1 mmol), and DIPEA (7.1 g, 55 mmol) solutions were placed in 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. ^1H NMR (400 MHz, DMSO _- d6 ) δ 6.36 (s, 1H), 3.80 (s, 2H), 2.66 (s, 1H), 2.55 (s, 3H), 2.43 (s, 2H).

step d. N -Methyl-1-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methanamine: ₂ -methyl-6-(( PyBOP (1.1 g, 2.15 mmol) in a solution of 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) was added. The reaction mixture was stirred at reflux overnight. The reaction mixture was then 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.38 (s, 1H), 3.67-3.63 (m, 6H), 2.47-2.45 (m, 10H), 2.32 (s, 3H).

Method E

Preparation of 2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde

Step a. 6-(Dimethoxymethyl)-2-methylpyrimidin-4-ol: Methyl 4,4-dimethoxy-3-oxobutanoate (300 mg, 1.7 mmol) and acetami in water (10 mL) To a solution of Dean hydrochloride (320 mg, 3.4 mmol) was added K ₂ CO ₃ (940 mg, 6.8 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched to acidic pH with AcOH and extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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.

step b. 4-(dimethoxymethyl)-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine: 6-(dimethoxymethyl)-2-methylpyrimidine in CH ₃ CN (10 mL) PyBOP (340 mg, 0.7 mmol) was added to a solution of midin-4-ol (110 mg, 0.6 mmol), TEA (600 mg, 6 mmol) and N -methylpiperazine (90 mg, 0.9 mmol). The reaction mixture was stirred at reflux overnight. Then, the reaction solution was evaporated to remove most of CH ₃ CN, and saturated aqueous NaHCO ₃ solution (100 mL) was added and extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , 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.

step c. 2-Methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde: 4-(dimethoxymethyl)-2-methyl-6-(4-methylpiperazine-1- 1) A mixture of pyrimidine (140 mg, 0.5 mmol) and sulfuric acid (20 wt%/water, 5 mL) was stirred at reflux overnight. Then, the pH was adjusted to basic by adding a saturated aqueous NaHCO ₃ solution and extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired crude product (110 mg, 97%) as a yellow oil.

Method F

Preparation of 2-(dimethylamino)-6-(4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde

Step a. 6-(Dimethoxymethyl)-2-(methylthio)pyrimidin-4-ol: Methyl 4,4-dimethoxy-3-oxobutanoate (3 g, 17 mmol) in water (100 mL) and K ₂ CO ₃ (17.6 g, 76.5 mmol) was added to a solution of methyl carbimidothioate sulfate (9.5 g, 34 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched by adjusting the pH to acidic with AcOH and extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 12.80 (s, 1H), 6.46 (s, 1H), 5.07 (s, 1H), 3.40 (s, 6H), 2.60 (s, 3H).

step b. 4-(dimethoxymethyl)-6-(4-methylpiperazin-1-yl)-2-(methylthio)pyrimidine: 6-(dimethoxymethyl)-2 in CH ₃ CN (100 mL) PyBOP (9 g, 17.6 mmol) was added to a solution of -(methylthio)pyrimidin-4-ol (3.4 g, 16 mmol), TEA (16 g, 160 mmol) and N -methylpiperazine (2.4 g, 40 mmol). Added. The reaction mixture was stirred at reflux overnight. Then, the reaction solution was evaporated to remove CH ₃ CN, saturated aqueous NaHCO ₃ solution (200 mL) was added, and then extracted with dichloromethane (200 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (s, 1H), 5.07 (s, 1H), 3.70 (s, 4H), 3.40 (s, 6H), 2.51 (s, 3H), 2.47 (t, J = 5.0 Hz, 4H), 2.34 (s, 3H).

step c. 4-(dimethoxymethyl)-6-(4-methylpiperazin-1-yl)-2-(methylsulfonyl)pyrimidine: 4-(dimethane in THF (90 mL) and water (4.5 mL) To a solution of toxymethyl)-6-(4-methylpiperazin-1-yl)-2-(methylthio)pyrimidine (2.8 g, 9.4 mmol) was added oxone (7 g, 11 mmol). The reaction was stirred at room temperature for 4 hours. Then, saturated NaHCO ₃ aqueous solution (200 mL) was added to the reaction, and then extracted with ethyl acetate (200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (2.4 g, 78%) as a yellow oil.

step d. 4-(dimethoxymethyl) -N ,N -dimethyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine: In a sealed test tube, 4-( in THF (5 mL) Dimethylamine (5 mL) was added to a solution of dimethoxymethyl)-6-(4-methylpiperazin-1-yl)-2-(methylsulfonyl)pyrimidine (340 mg, 1 mmol). The reaction mixture was stirred at reflux overnight. Then, the reaction solution was cooled to room temperature, saturated aqueous NaHCO ₃ solution (100 mL) was added, and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1 -> 100/3/1), and the desired product (260 mg, 88%) was obtained as a yellow oil. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.06 (s, 1H), 4.98 (s, 1H), 3.62 (s, 4H), 3.39 (s, 6H), 3.11 (s, 6H), 2.42 (s, 4H), 2.30 (s, 3H).

Step e. 2-(dimethylamino)-6-(4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde: 4-(dimethoxymethyl)-N,N-dimethyl-6-(4 A mixture of -methylpiperazin-1-yl)pyrimidin-2-amine (260 mg, 1.3 mmol) and sulfuric acid (20 wt%/water, 5 mL) was stirred at reflux overnight. Then, the pH was adjusted to basic by adding saturated aqueous NaHCO ₃ and extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired crude product (210 mg, 65%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 6.39 (s, 1H), 3.68 (s, 4H), 3.18 (s, 6H), 2.45 (s, 4H), 2.33 (s, 3H).

Method G

Preparation of 2-ethoxy-6-(4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde

Step f. 4-(dimethoxymethyl)-2-ethoxy-6-(4-methylpiperazin-1-yl)pyrimidine: 4-(dimethoxymethyl)-6-(4- in ethanol (5 mL) Sodium ethanolate (206 mg, 3 mmol) was added to a solution of methylpiperazin-1-yl)-2-(methylsulfonyl)pyrimidine (200 mg, 0.61 mmol). The reaction mixture was stirred at reflux overnight. Then, the reaction solution was cooled to room temperature, saturated aqueous NaHCO ₃ solution (100 mL) was added, and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1 -> 100/3/1), and the desired product (160 mg, 89%) was obtained as a yellow oil. Obtained. ^1H NMR (400 MHz, CDCl ₃ ) δ 6.42 (s, 1H), 5.04 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.68 (s, 4H), 3.40 (s, 6H) , 2.45 (t, J = 5.0 Hz, 4H), 2.32 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H).

step g. 2-Ethoxy-6-(4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde: 4-(dimethoxymethyl)-2-ethoxy-6-(4-methylpiperazine- 1-day) A mixture of pyrimidine (160 mg, 0.5 mmol) and sulfuric acid (20 wt%/water, 5 mL) was stirred at reflux overnight. Then, the reaction solution was cooled to room temperature, the pH was adjusted to basic by adding saturated aqueous NaHCO ₃ solution, and then extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired crude product (100 mg, 80%) as a yellow solid.

Method H

Preparation of 6-(4-methylpiperazin-1-yl)-2-phenylpyrimidine-4-carbaldehyde

Step h. 4-(dimethoxymethyl)-6-(4-methylpiperazin-1-yl)-2-phenylpyrimidine: 4-(dimethoxymethyl)-6-(4-methyl in THF (20 mL) Piperazin-1-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(PPh ₃ ) ₄ (115 mg, 0.1 mmol) were stirred at reflux under N ₂ atmosphere overnight. The reaction solution was then concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1.5) to obtain the desired product (240 mg, 73%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J = 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).

Step i. 6-(4-methylpiperazin-1-yl)-2-phenylpyrimidin-4-carbaldehyde: 4-(dimethoxymethyl)-6-(4-methylpiperazin-1-yl)-2 A mixture of -phenylpyrimidine (240 mg, 0.73 mmol) and sulfuric acid (20 wt%/water, 10 mL) was stirred at reflux overnight. Then, the reaction solution was cooled to room temperature and rinsed with diethyl ether (10 mL). 6M NaOH aqueous solution was added to the aqueous layer to adjust the pH to 10 and then extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Method I

Preparation of 1-(5-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-N-methylmethanamine

Step a. Ethyl 2,4-difluoro-3-oxobutanoate: Add ethyl 2-fluoroacetate (5 g, 47.2 mmol) was added dropwise at room temperature. The reaction was stirred at 40°C for 4 hours. The reaction mixture was cooled to 0°C and poured into 2M aqueous sulfuric acid solution (15 mL). The mixture was extracted with diethyl ether (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 -> 2/1) to give the desired product (2 g, 25%) as a yellow oil.

step b. 5-Fluoro-6-(fluoromethyl)-2-methylpyrimidin-4-ol: methyl 4,4-dimethoxy-3-oxobutanoate (1.9 g, 11.4 mmol) in ethanol (40 mL) ) and acetamidine hydrochloride (2.2 g, 22.8 mmol) were added to EtONa (2.3 g, 34.2 mmol). The reaction was stirred at reflux overnight. The mixture was cooled to room temperature. 6M HCl aqueous solution (2 mL) was added and then evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 -> 1/1) to give the desired product (800 mg, 43%) as a yellow solid. ^1H NMR (400 MHz, CDCl3) δ 13.07 (br s, 1H), 5.35 (d, J = 46.8 Hz, 2H), 2.53 (s, 3H).

step c. 5-Fluoro-4-(fluoromethyl)-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine: 5-fluoro-6-(fluoro) in CH ₃ CN (10 mL) PyBOP (2.9 g, 5.5 mmol) in a solution of romethyl)-2-methylpyrimidin-4-ol (800 mg, 5 mmol), TEA (1.5 g, 15 mmol) and N -methylpiperazine (750 mg, 7.5 mmol). mmol) was added. The reaction mixture was stirred at reflux overnight. The reaction solution was then evaporated to remove most of CH ₃ CN, diluted by adding dichloromethane (100 mL), and rinsed with saturated aqueous NaCl solution (50 mL x 3). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) 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).

step d. 1-(5-Fluoro-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)- N -methylmethanamine: In a sealed test tube, water (15 mL) and 5-Fluoro-4-(fluoromethyl)-2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine (1.0 g, 4.1 mmol) and 2M methyl in i-propanol (15 mL) Amine (dissolved in methanol, 6 mL) mixture was stirred at reflux overnight. The reaction solution was evaporated to remove most of the i-propanol and extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 400/10/1 -> 200/10/1), and the desired product (800 mg, 76%) was obtained as a yellow oil. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Method J

Preparation of ( S )-4-(4-methylpiperazin-1-yl)-2-(methylthio)-6-(pyrrolidin-2-yl)pyrimidine

Step a. ( S )-tert-Butyl 2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate: Boc-L-proline-OH (5 g) in dichloromethane (70 mL) , 23 mmol), DCC (4.8 g, 23 mmol) in a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (3.4 g, 23 mmol) and DMAP (5.7 g, 46 mmol) was added at 0°C. The mixture was stirred at room temperature for 48 hours and then the reaction mixture was filtered. 1M HCl aqueous solution (100 mL) was added to the filtrate, and then the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give a yellow oil, about 7.5 g. The residue was diluted with EtOH (100 mL) and stirred at reflux for 2 hours. 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. ¹ H NMR (400 MHz, CDCl ₃ ) 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).

step b. ( S )-tert-Butyl 2-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)pyrrolidine-1-carboxylate: ( S )-tert- in water (25 mL) K in a solution of butyl 2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (500 mg, 1.8 mmol) and methyl carbamidothioate sulfate (1.0 g, 3.6 mmol). ₂ CO ₃ (1.1 g, 8.1 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was quenched to acidic pH with 1M aqueous HCl solution and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) 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).

step c. ( S )-4-(4-methylpiperazin-1-yl)-2-(methylthio)-6-(pyrrolidin-2-yl)pyrimidine: ( S ) in CH ₃ CN (5 mL) -tert-Butyl 2-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)pyrrolidine-1-carboxylate (200 mg, 0.64 mmol), TEA (650 mg, 6.4 mmol) and N -methylpiperazine (100 mg, 0.96 mmol) were added to PyBOP (510 mg, 0.96 mmol). The reaction mixture was stirred at reflux overnight. The reaction solution was then evaporated to remove most of CH ₃ CN, diluted by adding dichloromethane (100 mL), and rinsed with saturated aqueous NaHCO ₃ solution (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1) to give the crude intermediate product (150 mg) as a yellow oil. It was then diluted with ethyl acetate (3 mL) and 3M HCl/ethyl acetate (4 mL) was added. The mixture was stirred at room temperature overnight. Then, the reaction solution was evaporated, saturated aqueous NaHCO ₃ solution (50 mL) was added, and then extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (100 mg, 53%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 6.29 (s, 1H), 3.98 (t, J = 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, J = 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).

Method K

Preparation of tert -butyl 5-oxo-5-(pyridin-2-yl)pentylcarbamate

Step a. tert -Butyl 5-oxo-5-(pyridin-2-yl)pentylcarbamate: commercially available 2-bromopyridine (1.4 g, 9 mmol) and N,N,N '-N' -tetramethyl ethylene To a THF solution (30 mL) of 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 incubated at the same temperature. It was stirred for 2 hours. To the reaction solution, tert-butyl 2-oxopiperidine-1-carboxylate (1 g, 5 mmol) was added at -78°C, and the obtained solution was stirred at the same temperature for 2 hours. 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 Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J = 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).

Method L

Preparation of 2-(bromomethyl)-4-chloropyrimidine

Step a. 2-(Bromomethyl)-4-chloropyrimidine: 4-chloro-2-methylpyrimidine (370 mg, 2.9 mmol), NBS (566 mg, 3.2 mmol) and AIBN (50 mg) in CCl ₄ (10 mL) mg, 0.3 mmol) solution was stirred at reflux overnight. Then, the reaction solution was cooled to room temperature, saturated aqueous NaHCO ₃ solution (50 mL) was added, and then extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (d, J = 5.6 Hz, 1H), 7.27 (d, J = 5.6 Hz, 1H), 4.54 (s, 2H).

Method M

tert -Butyl 4-(5-cyano-2-methyl-6-((methyl(1,2,3,4-tetrahydronaphthalen-1-yl)amino)methyl)pyrimidin-4-yl)piperazine -Preparation of 1-carboxylate

Step a. 4-Hydroxy-2,6-dimethylpyrimidine-5-carbonitrile: methyl (Z)-ethyl 2-cyano-3-ethoxybut-2-enoate (5.0 g, in ethanol (80 mL) 27 mmol) and acetamidine hydrochloride (3.9 g, 41 mmol) were added K ₂ CO ₃ (11.3 g, 82 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated, adjusted to pH 5 by adding 3M aqueous HCl solution, and then extracted with n-butanol (50 mL x 6). The combined organic layers were evaporated to give the desired product (3.5 g, 87%) as a yellow solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 13.30 (s, 1H), 2.39 (s, 3H), 2.35 (s, 3H).

step b. tert -Butyl 4-(5-cyano-2,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate: 4-hydroxy-2,6- in CH ₃ CN (60 mL) PyBOP (9.6 g) in a solution of dimethylpyrimidine-5-carbonitrile (2.5 g, 16.8 mmol), TEA (5.1 g, 50.4 mmol) and tert -butyl piperazine-1-carboxylate (4.7 g, 25.2 mmol). , 18.5 mmol) was added. 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 -> 3/1) to give the desired product (4.3 g, 81%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.94 (s, 4H), 3.55 (s, 4H), 2.57 (s, 3H), 2.50 (s, 3H), 1.47 (s, 9H).

step c. tert -Butyl 4-(6-(chloromethyl)-5-cyano-2-methylpyrimidin-4-yl)piperazine-1-carboxylate: tert -Butyl 4-(5) in DCM (100 mL) -Cyano-2,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate (10 g, 60 4.0 g, 12.6 mmol) was added to TCCA (2.9 g, 12.6 mmol) at 0°C. After addition, the obtained solution was stirred at the same temperature for 1 hour and then at room temperature for 6 hours. The reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ solution. The reaction mixture was filtered and the filtrate was extracted with dichloromethane (50 mL x 3). The combined organic layers were rinsed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 -> 5/1) to give the desired product (2.4 g, 54%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.94 (s, 4H), 3.55 (s, 4H), 2.57 (s, 3H), 2.50 (s, 3H), 1.47 (s, 9H)

step d. tert -Butyl 4-(5-cyano-2-methyl-6-((methyl(1,2,3,4-tetrahydronaphthalen-1-yl)amino)methyl)pyrimidin-4-yl)piperazine -1-Carboxylate: N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (421 mg, 2.6 mmol, see WO2006026703), tert -butyl 4- in CH ₃ CN (10 mL) (6-(chloromethyl)-5-cyano-2-methylpyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 2.8 mmol), KI (45 mg, 0.3 mmol) and DIPEA ( 671 mg, 5.2 mmol) the mixture 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 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).

Method N

Preparation of 5-bromo-2-(bromomethyl)imidazo[1,2- a ]pyridine

Step a. Ethyl 5-bromoimidazo[1,2- a ]pyridine-2-carboxylate: Methyl 6-bromopyridin-2-amine (1.7 g, 10 mmol) and ethyl 3-bro in ethanol (80 mL) A solution of parent-2-oxopropanoate (2.3 g, 12 mmol) was refluxed and stirred overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was dried by oil pump to give the desired crude product (2.8 g) as a white solid. ^1H NMR (400 MHz, DMSO -d6 ) δ 8.49 (s, _1H ), 7.76 (d, J = 8.4 Hz, 1H), 7.53-7.50 (m, 1H), 7.47-7.43 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.34 (q, J = 7.2 Hz, 3H).

step b. (5-Bromoimidazo[1,2- a ]pyridin-2-yl)methanol: Ethyl 5-bromoimidazo[1,2- a ]pyridine-2-carboxylate ( NaBH ₄ (1.0 g, 28 mmol) was added to the solution (1.5 g, 5.6 mmol), and the solution was refluxed and stirred overnight. The reaction solution was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 40/1) to obtain the desired product (500 mg, 39%) as a white solid. ^1H NMR (400 MHz, DMSO -d6 ) δ 7.84 (s, _1H ), 7.59 (d, J = 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).

step c. 5-Bromo-2-(bromomethyl)imidazo[1,2- a ]pyridine: (5-bromoimidazo[1,2- a ]pyridin-2-yl in dichloromethane (50 mL) ) PBr ₃ (475 mg, 1.73 mmol) was added to a solution of methanol (400 mg, 1.76 mmol) at 0°C, and stirred at the same temperature for 4 hours. Saturated NaHCO ₃ aqueous solution (10 mL) was added to adjust the pH to 8. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 40/1) to obtain the desired product (260 mg, 50%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.59 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 4.67 (s, 2H).

Method BA

Preparation of N -methyl-1-(3-methylpyridin-2-yl)ethanamine

Step a. N -Methyl-1-(3-methylpyridin-2-yl)ethanamine: Methylamine in a solution of 1-(3-methylpyridin-2-yl)ethanone (500 mg, 3.7 mmol) in THF (10 mL). solution (30 wt%/absolute ethanol, 14.8 mL) and Ti(OEt) ₄ (1.7 g, 7.4 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes, then NaBH ₄ (563 mg, 14.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO ₃ solution (100 mL) was added and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.09-7.02 (m, 1H), 3.95 (q, J = 6.4 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H).

Method BB

Preparation of ( S ) -N -methyl-1-(pyridin-2-yl)ethanamine

step b. ( S )-1-(4-methoxyphenyl) -N -(( S )-1-(pyridin-2-yl)ethyl)ethanamine and ( S )-1-(4-methoxyphenyl) -N -(( R )-1-(Pyridin-2-yl)ethyl)ethanamine: To a solution of 1-(pyridin-2-yl)ethanone (605 mg, 5 mmol) in dichloromethane (30 mL) was added NaBH( OAc) ₃ (2.12 mg, 10 mmol) and (S)-1-(4-methoxyphenyl)ethanamine (755 mg, 5 mmol) were added at 0°C. The prepared suspension was stirred overnight at room temperature. Saturated NaHCO ₃ aqueous solution (20 mL) was added to the reaction mixture and then extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ SO ₄ , 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)-1-(4-methoxyphenyl)-N-(( S)-1-(pyridin-2-yl)ethyl)ethanamine (1.0 g, 78%) was obtained as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.60 (d, J = 3.2 Hz, 1H), 7.66-7.54 (m, 1H), 7.20-7.12 (m, 3H), 7.06 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 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). Then, (S)-1-(4-methoxyphenyl)-N-((R)-1-(pyridin-2-yl)ethyl)ethanamine (70 mg, 6%) was obtained as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 7.61-7.50 (m, 1H), 7.26-7.11 (m, 4H), 6.81 (d, J = 7.2 Hz, 2H), 3.90- 3.80 (m, 1H), 3.80-3.70 (m, 4H), 1.42-1.30 (m, 6H).

step c. ( S )-1-(4-methoxyphenyl) -N -methyl- N -(( S )-1-(pyridin-2-yl)ethyl)ethanamine: ( S ) in dichloromethane (20 mL) -1-(4-methoxyphenyl) -N -(( S )-1-(pyridin-2-yl)ethyl)ethanamine (500 mg, 2 mmol) and formaldehyde (37 wt%/water, 1 mL ) NaBH(OAc) ₃ (636 mg, 3 mmol) was added to the solution. The prepared suspension was stirred overnight at room temperature. Saturated NaHCO ₃ aqueous solution (50 mL) was added to the reaction mixture and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 3.6 Hz, 1H), 7.74-7.58 (m, 1H), 7.49 (d, J = 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).

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

Method B.C.

Preparation of N -ethyl-5,6,7,8-tetrahydroquinolin-8-amine

Step a. 8-Chloro-5,6,7,8-tetrahydroquinoline: TCCA (21 g, 90 mmol) in a mixture of 5,6,7,8-tetrahydroquinoline (10 g, 60 mmol) in DCM (200 mL). was added and stirred under reflux overnight. The reaction mixture was filtered, and saturated aqueous NaHCO ₃ solution (50 mL) was added to the filtered solution. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 -> 5/1) to give the desired product (8.6 g, 86%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.6 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.6, 4.8 Hz, 1H), 5.43 (d, J = 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).

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

How BD

Preparation of 5' H -spiro[cyclopropane-1,7'-quinoline]-8'(6' H )-one

Step a. 5' H -spiro[cyclopropane-1,7'-quinoline]-8'(6'H)-one: 6 in a solution of NaH (60 wt%/oil, 420 mg, 10.5 mmol) in DMF (50 mL) ,7-dihydroquinolin-8( 5H )-one (441 mg, 3.0 mmol) and 1,2-dibromoethane (1.95g, 10.5 mmol)/DMF (5 mL) were continuously incubated at 0°C in N ₂ It was added dropwise under atmosphere. The reaction was stirred at 0°C for 1 hour. The reaction mixture was diluted with dichloromethane (40 mL) and rinsed with saturated brine solution (40 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.37 (s, 1H), 3.04 (d, J = 4.4 Hz, 2H), 2.03 (d, J = 4.8 Hz, 2H), 1.52 (s, 2H), 0.89 (s, 2H).

HOW TO BE

Preparation of 7',8'-dihydro-5' H -spiro[cyclopropane-1,6'-quinoline]

Step a. 7',8'-dihydro-5' H -spiro[cyclopropane-1,6'-quinoline]: in a solution of spiro[2.5]octan-6-one (667 mg, 6 mmol) in ethanol (25 mL). Prop-2-yn-1-amine (1.3 g, 24 mmol) and NaAuCl ₄ (60 mg, 0.15 mmol) were added sequentially. The reaction was stirred at 85°C for one day. The reaction mixture was concentrated, diluted with ethyl acetate (30 mL) and then rinsed with saturated aqueous NaHCO ₃ solution (15 mL) and saturated brine solution (15 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.37(s, 1H), 7.30(d, J = 7.2 Hz, 1H), 7.07-6.98 (m, 1H), 3.00(t, J = 6.4 Hz, 2H) , 2.64(s, 2H), 1.69(t, J = 6.0 Hz, 2H), 0.43(d, J = 10.0 Hz, 4H).

way bf

Preparation of N -(2-acetylpyridin-3-yl)acetamide

Step a. 3-(4-methoxybenzylamino)picolinonitrile: 3-fluoropicolinonitrile (10 g, 82 mmol), (4-methoxyphenyl)methanamine (16.8 g, 123 mmol) in DMF (50 mL) ) and Cs ₂ CO ₃ (40 g, 123 mmol) solutions were stirred at 70°C overnight. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL) and rinsed with saturated brine solution (20 mL x 3). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.28-7.18 (m, 3H), 7.00 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H) , 5.05 (s, 1H), 4.36 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H).

step b. 1-(3-(4-methoxybenzylamino)pyridin-2-yl)ethanone: In a solution of 3-(4-methoxybenzylamino)picolinonitrile (11 g, 46 mmol) in THF (200 mL) 3M CH ₃ MgCl/Et ₂ O solution (77 mL, 230 mmol) was added dropwise at 0°C and stirred for 30 minutes. The reaction mixture was quenched with a saturated aqueous solution of brine (50 mL) and then extracted with ethyl acetate (100 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) 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).

step c. N -(2-Acetylpyridin-3-yl)acetamide: solution of 1-(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, adjusted to pH 8 by adding saturated aqueous NaHCO ₃ solution, and then extracted with dichloromethane (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was dissolved in acetate acid (10 mL), Ac ₂ O (20 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated, adjusted to pH 8 by adding saturated NaHCO ₃ solution and extracted with dichloromethane (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (1 g, 97%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 11.54 (s, 1H), 9.10 (d, J = 8.8 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 7.48 (dd, J = 8.8 Hz) , 4.4 Hz, 1H), 2.80 (s, 3H), 2.26 (s, 3H).

Method BG

Preparation of N -(2-acetylpyridin-3-yl)methanesulfonamide

step d. N -(2-Acetylpyridin-3-yl)methanesulfonamide: 1-(3-(4-methoxybenzylamino)pyridin-2-yl)ethanone (1.3 g, 5.1 mmol) in TFA (7 mL) The solution was stirred at room temperature overnight. The reaction mixture was concentrated, adjusted to pH 8 by adding saturated NaHCO ₃ and extracted with dichloromethane (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was dissolved in dichloromethane (15 mL), TEA (1.5 g, 15.3 mmol) and MsCl (1.3 g, 11.2 mmol) were added, and stirred at room temperature for 1 hour. 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. The pH was adjusted to 8 by adding 1M HCl aqueous solution, and then extracted with dichloromethane (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (800 mg, 73%) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) 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).

Method BH

Preparation of ( S )-2-(pyrrolidin-2-yl)pyridine

Step a. 4-oxo-4-(pyridin-2-yl)butanal: in a solution of Mg powder (1.06 g, 44 mmol) and I ₂ (20 mg, 0.08 mmol) in THF (15 mL) A solution of 2-(2-bromoethyl)-1,3-dioxolane (7.16 g, 40 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. Then, this mixture was cooled to 0°C and added dropwise to THF (10 mL) containing picolinonitrile (2.08 g, 20 mmol) at 0°C. The reaction mixture was stirred at this temperature for 1.5 hours. The reaction was quenched by addition of water (10 mL) and the mixture was filtered. The filtrate was diluted with ethyl acetate (50 mL) and rinsed with saturated brine solution (30 mL x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the residue as a colorless oil (1.3 g). The residue was dissolved in acetone (15 mL), 3M aqueous HCl solution (10 mL) was added and stirred at room temperature overnight. The pH was adjusted to 9 by adding saturated NaHCO ₃ solution. Acetone was concentrated and the remaining aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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 slightly greenish oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.89 (s, 1H), 8.68 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.6 Hz) , 1H), 7.48 (t, J = 5.6 Hz, 1H), 3.57 (t, J = 8.0 Hz, 2H), 2.91 (t, J = 8.0 Hz, 2H).

step b. 2-(( S )-1-(( R )-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-yl)pyridine: 4-oxo-4-( in dichloromethane (20 mL) To a solution of pyridin-2-yl)butanal (490 mg, 3 mmol) was added NaBH(OAc) ₃ (1.9 g, 9 mmol) and AcOH (20 mg, 0.33 mmol) at -70°C. The prepared suspension was stirred at the same temperature for 30 minutes. The reaction was warmed to 0°C, and ( R )-1-(4-methoxyphenyl)ethanamine (500 mg, 3.3 mmol) was added. The prepared suspension was stirred overnight at room temperature. 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 4.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.79 (d, J = 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, J = 4.8 Hz, 3H).

step c. ( S )-2-(pyrrolidin-2-yl)pyridine: 2-(( S )-1-(( R )-1-(4-methoxyphenyl)ethyl)pyrroli in TFA (5 mL) A solution of din-2-yl)pyridine (400 mg, 1.48 mmol) was stirred at 50°C for 12 hours. The reaction mixture was concentrated and 1M aqueous HCl solution (15 mL) was added. This solution was rinsed with dichloromethane (5 mL x 3). Then, saturated NaHCO ₃ solution was added to adjust the pH to 9 and then extracted with dichloromethane (10 mL x 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (110 mg, 50%) as a colorless oil.

Method BI

Preparation of ( R )-2-(pyrrolidin-2-yl)pyridine

step d. 2-(( R )-1-(( S )-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-yl)pyridine: 4-oxo-4-( in dichloromethane (15 mL) To a solution of pyridin-2-yl)butanal (326 mg, 2 mmol) was added NaBH(OAc) ₃ (1.27 g, 6 mmol) and HOAc (20 mg, 0.33 mmol) at -70°C. The prepared suspension was stirred at the same temperature for 30 minutes. The reaction was warmed to 0°C, and ( S )-1-(4-methoxyphenyl)ethanamine (332 mg, 2.2 mmol) was added. The prepared suspension was stirred overnight at room temperature. 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.58-7.45 (m, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 2H) , 7.02 (s, 1H), 6.68 (d, J = 8.0 Hz, 2H), 3.91 (s, 1H), 3.74-3.71 (m, 4H), 3.09 (s, 1H), 3.62 (d, J = 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).

Step e. ( R )-2-(pyrrolidin-2-yl)pyridine: 2-(( R )-1-(( S )-1-(4-methoxyphenyl)ethyl)pyrroli in TFA (5 mL) A solution of din-2-yl)pyridine (400 mg, 1.48 mmol) was stirred at 50°C for 12 hours. The reaction mixture was concentrated and 1M aqueous HCl solution (15 mL) was added. This solution was rinsed with dichloromethane (5 mL x 3). Then, saturated NaHCO ₃ solution was added to adjust the pH to 9 and then extracted with dichloromethane (10 mL x 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (100 mg, 45%) as a colorless oil.

How to BJ

Preparation of 2-(3-methylpyrrolidin-2-yl)pyridine

Step a. N -(Diphenylmethylene)-1-(pyridin-2-yl)methanamine: Pyridin-2-ylmethanamine (3.97 g, 37 mmol) and benzophenone (6.69 g, 37 mmol) in toluene (50 mL) p-TsOH (10 mg, 0.058 mmol) was added to the solution. The mixture was stirred at reflux overnight. The reaction solution was cooled to room temperature and rinsed with saturated NaHCO ₃ solution (30 mL x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired crude product (10 g) as a yellow oil.

step b. Ethyl 4-(diphenylmethyleneamino)-3-methyl-4-(pyridin-2-yl)butanoate: crude product N- (diphenylmethylene)-1-(pyridine-2) in acetonitrile (50 mL) -1) A mixture of methanamine (1.5 g), NaOH solution (50 wt%/water, 110 mg, 2.75 mmol) and BnEt ₃ NCl (60 mg, 0.3 mmol) was stirred at room temperature for 30 minutes. Then, ( E )-ethylbut-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 layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/10) to give the desired crude product (1.3 g,) as a yellow oil.

step c. 4-Methyl-5-(pyridin-2-yl)pyrrolidin-2-one: crude ethyl 4-(diphenylmethyleneamino)-3-methyl-4-(pyridine-2) in acetonitrile (15 mL) -1) Concentrated HCl aqueous solution (3 mL) was added dropwise to the butanoate (1.3 g) solution. The mixture was stirred at room temperature for 2 hours. The reaction solution was rinsed with dichloromethane (10 mL x 2). The aqueous layer was diluted with acetonitrile (15 mL), and aqueous ammonia (5 mL) was added dropwise. The mixture was stirred at room temperature for 5 hours. Then, the reaction solution was extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 7.73-7.70 (m, 1H), 7.34-7.32 (m, 1H), 7.25-7.22 (m, 1H), 6.57 (s, 1H) ), 4.40-4.39 (m, 1H), 2.66-2.60 (m, 1H), 2.51-2.46 (m, 1H), 2.14-2.08 (m, 1H), 1.27-1.26 (m, 3H).

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

Method B.K.

Preparation of cis -ethyl 2-(pyridin-2-yl)pyrrolidine-3-carboxylate

Step a. ( E )-2-(Pyridin-2-ylmethyleneamino)acetonitrile: A solution of 2-aminoacetonitrile hydrochloride (5.09 g, 55 mmol) and TEA (9.09 g, 90 mmol) in ethanol (250 mL) was incubated at room temperature. It was stirred for 30 minutes. Then, picolinaldehyde (5.36 g, 50 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated and then dissolved in Et ₂ O (200 mL). The mixture was filtered and the filtrate was evaporated to give the desired crude product (4.8 g) as a yellow oil.

step b. cis -ethyl 5-cyano-2-(pyridin-2-yl)pyrrolidin-3-carboxylate: crude product ( E )-2-(pyridin-2-ylmethyleneamino) in toluene (120 mL) AgOAc (550 mg, 3.3 mmol) and Cs ₂ CO ₃ (2.15 g, 66 mmol) were added to a solution of acetonitrile (4.8 g, 33 mmol) at 0°C and stirred for 5 minutes. 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 desired crude product (2.0 g, 25%) as a yellow oil.

step c. cis -ethyl 2-(pyridin-2-yl)pyrrolidine-3-carboxylate: crude cis -ethyl 5-cyano-2-(pyridin-2-yl)pyrrolidine in THF (5 mL) 1M BH ₃ /THF solution (2 mL, 2 mmol) was added to the -3-carboxylate (245 mg, 1 mmol) solution, and stirred for 20 minutes. Then, it was cooled to 0°C and NaBH ₄ (76 mg, 2 mmol) was added. The mixture was stirred at the same temperature for 3 hours and then at room temperature overnight. The reaction was quenched by adding water (1 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were evaporated and the residue was dissolved in ethanol (20 mL). Pd/C (10 wt%, 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.

Method B.L.

Preparation of 6-methylquinolin-8-amine

Step a. 6-Methyl-8-nitroquinoline: Pure glycerol (5.0 g, 54 mmol) was heated to 150° C. for 30 min. Then it was cooled to 110°C and 4-methyl-2-nitroaniline (3.0 g, 20 mmol) and NaI (60 mg, 0.40 mmol) were added. The mixture was heated again to 150° C. and then concentrated sulfuric acid (4.51 g, 46 mmol) was added. The prepared suspension was stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature and water (20 mL) was added. The aqueous phase was extracted with dichloromethane (20 mL x 4). The combined organic layers were 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. ¹ H NMR (400 MHz, CDCl ₃ ) 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).

step b. 6-Methylquinolin-8-amine: To a solution of 6-methyl-8-nitroquinoline (350 mg, 1.86 mmol) in methanol (30 mL) was added Pd/C (10 wt%, 0.2 g) and N at room temperature. ₂ and stirred overnight under atmosphere. The mixture was filtered and the filtrate was evaporated to give the desired crude product (250 mg, 85%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.98 (s, 1H), 7.33 (s, 1H), 6.94 (s, 1H), 6.79 (s, 1H), 4.90 (s, 2H), 2.43 (s, 3H).

Method B.M.

Preparation of N ,6-dimethylquinolin-8-amine hydroiodide

Step a. N ,6-dimethylquinolin-8-amine hydroiodide: CH ₃ I (337 mg, 2.37 mmol) was added, and the mixture was refluxed and stirred overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with diethyl ether (10 mL) and the resulting filter cake was dried by oil pump to give the desired crude hydroiodide (200 mg, 42%) as a red solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 8.58 (s, 1H), 7.75 (s, 1H), 7.08 (s, 1H), 6.82 (s, 1H), 3.08 (s, 3H), 2.57 (s, 3H).

Method BN

Preparation of 5,6-difluoro- N -methylquinolin-8-amine

Step a. 5,6,8-trifluoroquinoline: 2,4,5-trifluoroaniline (3.68 g, 25 mmol), glycerol (4.60 g, 50 mmol) and sodium 3-nitrobenzenesulfonate (6.75 g, 30 mmol) were added successively. The prepared suspension was stirred at 140°C overnight. The reaction mixture was cooled to room temperature, adjusted to pH 7 by adding saturated aqueous NaHCO ₃ solution, and then extracted with dichloromethane (200 mL x 2). The combined organic layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.99 (s, 1H), 8.46-8.44 (m, 1H), 7.61-7.56 (m, 1H), 7.38-7.31 (m, 1H).

step b. 5,6-Difluoro- N -methylquinolin-8-amine: In a sealed test tube, 5,6,8-trifluoroquinoline (436 mg, 2.38 mmol) and K ₂ CO ₃ in DMSO (3 mL). (657 mg, 4.76 mmol) MeNH ₂ solution (30 wt% / ethanol, 3 mL) was added to the solution. The prepared 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) and 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.88 (d, J = 4.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.47-7.44 (m, 1H), 6.40-6.35 (m, 1H), 6.08 (s, 1H), 3.00 (s, 3H).

Method BO

Preparation of 7-fluoroquinolin-8-amine

Step a. 7-Fluoroquinolin-8-amine: 7-fluoro- N- (4-methoxybenzyl)quinolin-8-amine (480 mg, 1.7 mmol) and HBr solution (48 wt%/water, 15 mL) The mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, adjusted to pH 8 by adding saturated aqueous NaHCO ₃ solution, and then extracted with dichloromethane (30 mL x 2). The combined organic layers were 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] ⁺ .

Method B.P.

Preparation of 8-chloro-1,7-naphthyridine

Step a. 1,7-Naphthyridin-8-amine: pyridine-2,3-diamine (1.09 g, 10 mmol), glycerol (4.1 g, 33.6 mmol) in a solution of concentrated sulfuric acid (15 mL) diluted with water (15 mL). ) and sodium 3-nitrobenzenesulfonate (4.5 g, 20.1 mmol) were added successively. The prepared suspension was stirred at 125°C overnight. The reaction mixture was cooled to room temperature, adjusted to pH 8 by adding saturated aqueous NaOH solution, and then extracted with dichloromethane (100 mL x 2). The combined organic layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s,1H), 8.00-7.96 (m, 2H), 7.54 (d, J = 4.0 Hz, 1H), 6.93 (d, J = 5.6 Hz, 1H) , 5.92 (s, 2H).

step b. 8-Chloro-1,7-naphthyridine: To a solution of 1,7-naphthyridin-8-amine (290 mg, 2.0 mmol) in concentrated aqueous HCl (5 mL) was added NaNO ₂ (1.38 g, 20 mmol) and CuCl ( 238 mg, 33.6 mmol) was added continuously. The prepared suspension was stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH 8 by adding saturated aqueous NaHCO ₃ solution, and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were 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, CDCl ₃ ) δ 9.15 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.70 (dd , J = 8.0, 4.0 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H).

Method BQ

Preparation of 8-bromo-1,6-naphthyridine

Step a. 1,6-Naphthyridine: Pyridin-4-amine (3.76 g, 40.0 mmol), glycerol (12.52 g, 136 mmol) and sodium 3-nitrobenzene in a solution of concentrated sulfuric acid (30 mL) diluted with water (20 mL). Sulfonate (19.8 g, 88.0 mmol) was added sequentially. The prepared suspension was stirred at 130°C overnight. The reaction mixture was cooled to room temperature, adjusted to pH 10 by adding saturated aqueous NaOH solution, and then extracted with dichloromethane (200 mL x 2). The combined organic layers were 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s,1H), 9.12 (s,1H), 8.78 (d, J = 5.2 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 5.2 Hz, 1H), 7.62-7.48 (m, 1H).

step b. 8-Bromo-1,6-naphthyridine: To a solution of 1,6-naphthyridine (830 mg, 6.38 mmol) in HOAc (5 mL) was added dropwise dibromine (612 mg, 3.83 mmol). The prepared suspension was stirred at 80°C overnight. The reaction mixture was cooled to room temperature, adjusted to pH 8 by adding saturated aqueous NaHCO ₃ solution, and then extracted with dichloromethane (100 mL x 3). The combined organic layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.24 (d, J = 2.8 Hz, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 4.0 Hz, 1H).

Method BR

Preparation of 4-chloro-1,5-naphthyridine

Step a. 1,5-Naphthyridine 1-oxide: mCPBA (3.6 g, 20.9 mmol) was added to a solution of 1,5-naphthyridine (3.0 g, 23.1 mmol). The prepared suspension was stirred overnight at room temperature. 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.05 (d, J = 4.0 Hz, 1H), 9.04 (s, 1H), 8.56 (d, J = 6.0 Hz, 1H), 8.02 (d, J = 8.8 Hz) , 1H), 7.70-7.67 (m, 1H), 7.54 (dd, J = 8.4, 6.0 Hz, 1H).

step b. 4-Chloro-1,5-naphthyridine: A solution of 1,5-naphthyridine 1-oxide (3.0 g, 20.5 mmol) in POCl ₃ (30 mL) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated and diluted with dichloromethane (100 mL). Saturated NaHCO ₃ aqueous solution was added to this solution and the pH was adjusted to 8. Filtered and split the filtrate. The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.11 (dd, J = 4.4, 2.0 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.46 (dd, J = 8.4, 2.0 Hz, 1H) , 7.78 (d, J = 4.8 Hz, 1H), 7.74 (dd, J = 8.4, 4.0 Hz, 1H). MS (ESI/APCI) m/z 164.9 [M+H] ⁺ .

Method B.S.

Preparation of N -methyl-2-(pyridin-2-yl)propan-2-amine

Step a. N -(2-(pyridin-2-yl)propan-2-yl)formamide: in a solution of 2-(pyridin-2-yl)propan-2-amine (350 mg, 2.6 mmol) in toluene (10 mL) Formic acid (237 mg, 5.2 mmol) was added. The prepared suspension was refluxed and stirred for 6 hours. The reaction mixture was cooled to room temperature, saturated aqueous NaHCO ₃ solution (50 mL) was added and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1 -> 100/3/1), and the desired product (300 mg, 70%) was obtained as a slightly yellow color. The band was obtained as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 7.8 Hz, 1H), 7.24-7.17 (m, 1H), 1.75 (d, J = 28.0 Hz, 6H).

step b. N -methyl-2-(pyridin-2-yl)propan-2-amine: N -(2-(pyridin-2-yl)propan-2-yl)formamide (300 mg, 1.8) in THF (10 mL) mmol) NaH (60 wt%/oil, 222 mg, 5.4 mmol) was added to the solution. The prepared suspension was stirred at room temperature for 15 minutes. Then, CH ₃ I (390 mg, 2.7 mmol) was added, and the reaction mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature and a solution of NaOH (252 mg, 6.12 mmol) in methanol (5 mL) and water (1 mL) was added. 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 layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J = 4.4 Hz, 1H), 7.77-7.63 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 7.2, 4.8 Hz, 1H), 2.13 (s, 3H), 1.47 (s, 6H).

Example 1

N -methyl- N -((6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (A1) manufacturing

Method AA-Step a. N -((6-chloropyrimidin-4-yl)methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine: N -methyl-5 in CH ₃ CN (10 mL) ,6,7,8-tetrahydroquinolin-8-amine (160 mg, 1 mmol, see WO2006026703), 4-chloro-6-(chloromethyl)pyrimidine (170 mg, 1.05 mmol), KI (16 mg, 0.1 mmol) and DIPEA (320 mg, 2.5 mmol) were stirred at room temperature overnight. The reaction solution was evaporated to remove most of CH ₃ CN, then diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 -> 50/1) to give the desired product (200 mg, 69%) as a brown oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 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).

Method AA-Step b. N -methyl- N -((6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine: Ethanol (4 N -((6-chloropyrimidin-4-yl)methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (100 mg, 0.35 mmol) in mL), TEA (350 mg, 3.5 mmol) and N -methylpiperazine (40 mg, 0.38 mmol) were stirred at reflux overnight. The reaction mixture was concentrated, saturated aqueous NaHCO ₃ solution (50 mL) was added and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 2H), 7.33 (d, J = 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): calculated C ₂₀ H ₂₉ N ₆ [M+H] ⁺ 353.2448, found 353.2451.

Example 2

N -methyl- N -((6-(piperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (A7) and 3-( Preparation of 4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyrimidin-4-yl)piperazin-1-yl)propanenitrile (A8)

Method AB-Step a. tert-Butyl-4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyrimidin-4-yl)piperazine-1-carboxylate: Ethanol N -((6-chloropyrimidin-4-yl)methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (200 mg, 0.7 mmol) in (10 mL), TEA (700 mg, 7 mmol) and tert-butyl piperazine-1-carboxylate (140 mg, 0.77 mmol) was stirred at reflux overnight. Saturated NaHCO ₃ aqueous solution (50 mL) was added to the reaction mixture and then extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1 -> 25/1) to give the desired product (290 mg, 94%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.08 (dd, J = 7.6, 4.8 Hz, 1H) , 4.02 (t, J = 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] ⁺ .

Method AB-Step b. N -methyl- N -((6-(piperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine: Dichloromethane (5 mL ) in tert-butyl-4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyrimidin-4-yl)piperazine-1-carboxylate (270 mg, 0.6 mmol) 3M HCl/ethyl acetate (5 mL) was added dropwise to the solution. The mixture was stirred at room temperature for 12 hours. The pH was adjusted to pH = 9 by adding saturated aqueous NaHCO ₃ solution and then the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1 -> 25/1) to give the desired product (180 mg, 90%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49-8.48 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.06 (dd, J = 7.6, 4.8 Hz, 1H), 4.08-3.98 (m, 1H), 3.68-3.64 (m, 6H), 2.93 (t, J = 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] ⁺

Method AB-Step c. 3-(4-(6-((methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyrimidin-4-yl)piperazin-1-yl)propanenitrile: Methanol (2 mL ) mg, 0.13 mmol) TEA (15 mg, 0.13 mmol) and acrylonitrile (20 mg, 0.26 mmol) were added to the solution. The mixture was stirred at room temperature overnight. Saturated NaHCO ₃ aqueous solution (50 mL) was added to the reaction mixture and then extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1 -> 25/1) to give the desired product (40 mg, 78%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53-8.47 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.08 (dd, J = 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).

Example 3

N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine Preparation of (A9)

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 : N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (37 mg, 0.23 mmol, see WO2006026703), 2-methyl-6-( A mixture of 4-methylpiperazin-1-yl)pyrimidine-4-carbaldehyde (46 mg, 0.21 mmol) and AcOH (13 mg, 0.21 mmol) was stirred for 10 minutes. Afterwards, NaBH(OAc) ₃ (66 mg, 0.3 mmol) was added to the reaction solution. The prepared suspension was stirred overnight at room temperature. Saturated NaHCO ₃ aqueous solution (100 mL) was added to the reaction mixture and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/1 -> 50/1/1), and the desired product (30 mg, 39%) was obtained as a colorless oil. Obtained. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.07-7.03 (m, 2H), 4.04 (t, J = 7.4 Hz, 1H), 3.71 (t, J = 5.2 Hz, 4H), 3.60 (s, 2H), 2.86-2.75 (m, 1H), 2.73-2.65 (m, 1H), 2.46-2.43 (m, 7H) ), 2.39 (s, 3H), 2.33 (s, 3H), 2.15-2.07 (m, 1H), 2.04-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.74-1.71 (m, 1H) ).

Example 4

( S ) -N -((6-(( R )-2,4-dimethylpiperazin-1-yl)-2-methylpyrimidin-4-yl)methyl) -N -methyl-5,6, Preparation of 7,8-tetrahydroquinolin-8-amine (A63)

Method AD-Step a. ( S ) -N -Methyl- N -((2-methyl-6-(( R )-2-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8 -Tetrahydroquinolin-8-amine: ( R )-tert-butyl 3-methyl-4-(2-methyl-6-((methyl(( S )-5,6,7, To a solution of 8-tetrahydroquinolin-8-yl) amino) methyl) pyrimidin-4-yl) piperazine-1-carboxylate (50 mg, 0.11 mmol) was added 3M HCl/ethyl acetate (3 mL). Stirred overnight at room temperature. Saturated NaHCO ₃ aqueous solution (50 mL) was added to the reaction mixture and then extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (26 mg, 65%) as a colorless oil.

Method AD-Step b. ( S ) -N -((6-(( R )-2,4-dimethylpiperazin-1-yl)-2-methylpyrimidin-4-yl)methyl) -N -methyl-5,6, 7,8-Tetrahydroquinolin-8-amine: ( S ) -N -methyl- N -((2-methyl-6-(( R )-2-methyl) in 1,2-dichloroethane (4 mL) piperazin-1-yl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (26 mg, 0.07 mmol) and formaldehyde (37 wt% / water, 30 mg, 0.36 mmol) NaBH(OAc) ₃ (30 mg, 0.14 mmol) was added to the mixture. The prepared suspension was stirred overnight at room temperature. Saturated NaHCO ₃ aqueous solution (50 mL) was added to the reaction mixture and then extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.09-6.92 (m, 2H), 4.62 (s, 1H), 4.35-4.28 ( m, 1H), 4.09-3.98 (m, 1H), 3.74-3.49 (m, 2H), 3.23-3.08 (m, 1H), 2.91-2.83 (m, 1H), 2.82-2.75 (m, 1H), 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, 1H), 2.14-2.07 (m, 1H), 2.05-1.91 (m, 3H), 1.74-1.63 (m, 1H), 1.29-1.23 (m, 3H).

Example 5

N -methyl- N -((4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (A50) manufacturing

Method AE-Step a. N -((4-chloropyrimidin-2-yl)methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine: 2-(bromomethyl) in MeCN (10 mL) -4-Chloropyrimidine (94 mg, 0.58 mmol), N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (130 mg, 0.6 mmol, see WO2006026703), KI (10 mg, 0.06) mmol) and DIPEA (740 mg, 5.8 mmol) were stirred at room temperature for 4 hours. The reaction solution was evaporated to remove most of MeCN, saturated aqueous NaHCO ₃ solution (50 mL) was added, and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.62 (d, J = 4.8 Hz, 1H), 8.46 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.22 (d) , J = 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).

Method AE-Step b. N -methyl- N -((4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine: NMP (2 N -((4-chloropyrimidin-2-yl)methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (50 mg, 0.17 mmol) in mL), DIPEA (244 mg, 1.7 mmol) and 1-methylpiperazine (87 mg, 0.85 mmol) were stirred at 200°C for 2 hours under microwave irradiation. The reaction was diluted with ethyl acetate (50 mL) and then rinsed with brine (50 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.18 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.05-7.02 (m, 1H) , 6.32 (d, J = 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): calculated C ₂₀ H ₂₉ N ₆ [M+H] ⁺ 353.2448, found 353.2448.

Example 6

Preparation of N -methyl- N -((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (B6)

Method AF-Step a. N -((6-bromopyridin-2-yl)methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine: 6 in 1,2-dichloroethane (10 mL) -Bromopicolinaldehyde (162 mg, 0.68 mmol), N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (100 mg, 0.62 mmol, see WO2006026703), AcOH (48 mg, 0.62 mmol) ) The mixture was stirred for 15 minutes. Then, NaBH(OAc) ₃ (252 mg, 0.93 mmol) was added to the reaction solution. The prepared suspension was stirred overnight at room temperature. Saturated NaHCO ₃ aqueous solution (50 mL) was added to the reaction solution, and then extracted with dichloromethane (100 mL). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.2 Hz) , 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 5.8 Hz, 1H), 4.03 (t, J = 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) ).

Method AF-Step b. N -methyl- N -((6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine: NMP (2 mL ) 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) were stirred at 120°C overnight. The reaction was diluted with ethyl acetate (50 mL) and rinsed with brine (30 mL x 5). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1) to obtain the desired product (12 mg, 23%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J = 4.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.05 (d) , J = 4.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 4.03 (s, 1H), 3.64 (q, J = 15.0 Hz, 2H) ), 3.53 (s, 4H), 2.82-2.78 (m, 1H), 2.71-2.66 (m, 1H), 2.50 (t, J = 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): Calculated C ₂₁ H ₃₀ N ₅ [M+H] ⁺ 352.2496, actual value 352.2514.

Example 7

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

Method AG - Step a. N -methyl- N -(pyrimidin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-amine: N -((6-chloropyrimidin-4-yl) in 5 mL of methanol A mixture of methyl)- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine (70 mg, 0.24 mmol) and Pd/C (5 %, 15 mg) was incubated at 50°C in H ₂ (1 atm). ) and stirred 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.06 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 7.80 (d, J = 4.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.08-7.05 (m, 1H), 4.04-4.01 (m, 1H), 3.82-3.72 (m, 2H), 2.82-2.78 (m, 1H), 2.73-2.69 (m, 1H), 2.39 (s, 3H), 2.13 (s, 1H), 2.03 (s, 1H), 1.97-1.88 (m, 1H), 1.72 (s, 1H). MS (ESI/APCI) m/z 254.9 [M + H] ⁺ .

Example 8

( S )-(2-methyl-4-((methyl(1-(pyridin-2-yl)ethyl)amino)methyl)-6-(4-methylpiperazin-1-yl)pyrimidin-5-yl ) Preparation of methanol (A85)

Method AH-Step a. (4,6-dichloro-2-methylpyrimidin-5-yl)methanol: DMF (9.8 g, 134.8 mmol) was added dropwise to POCl ₃ (60.6 g, 396.5 mmol) at 0°C. The prepared suspension was stirred at the same temperature for 1 hour. Then, 2-methylpyrimidine-4,6-diol (10 g, 79.3 mmol) was added in portions, stirred at room temperature for 1 hour, and then stirred at 105°C overnight. The reaction solution was concentrated and diluted with cold ethyl acetate (100 mL). This solution was added dropwise to ice water and then filtered, and the filtrate was extracted with ethyl acetate (200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give a yellow oil (10 g). This oil was dissolved in THF (50 mL) and water (10 mL) and NaBH ₄ (4 g, 104.7 mmol) was added in portions at 0°C. The prepared suspension was stirred at the same temperature for 30 minutes. Water (50 mL) was added and extracted with ethyl acetate (50 mL). The organic layer was dried over Na ₂ SO ₄ , 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.91 (s, 2H), 2.69 (s, 3H).

Method AH-Step b. 5-(( tert -butyldimethylsilyloxy)methyl)-4,6-dichloro-2-methylpyrimidine: (4,6-dichloro-2-methylpyrimidine- in dichloromethane (20 mL) 5-day) TBSCl (1.7 g, 11.3 mmol) was added in portions to a solution of methanol (2 g, 10.3 mmol) and imidazole (770 mg, 11.3 mmol). The prepared suspension was stirred overnight at room temperature. Water (20 mL) was added and extracted with dichloromethane (20 mL). The combined organic layers were dried over Na ₂ SO ₄ , 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.85 (s, 2H), 2.68 (s, 3H), 0.91 (s, 9 H), 0.14 (s, 6H).

Method AH-Step c. 5-(( tert - butyldimethylsilyloxy)methyl)-6-chloro-2-methylpyrimidine-4-carbaldehyde: 5-( in 1,4-dioxane (20 mL) and water (4 mL) ( tert -butyldimethylsilyloxy)methyl)-4,6-dichloro-2-methylpyrimidine (1.5 g, 4.8 mmol), potassium vinyltrifluoroborate (655 mg, 4.88 mmol), Cs ₂ CO ₃ (2.4 g, 7.32 mmol) and Pd(PPh ₃ ) ₄ (566 mg, 0.49 mmol) solutions were stirred at reflux under N ₂ atmosphere overnight. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1) to give the crude oil (900 mg). Methanol (30 mL) and dichloromethane (7 mL) were added to the obtained oil to dissolve it. Then, O3 was added to this reaction solution at -65°C, stirred at this temperature for 4 hours, and then dimethyl sulfide was added to quench the reaction. The solvent was concentrated, water (20 mL) was added, and then extracted with dichloromethane (50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired crude product (610 mg) as a white solid.

Method AH-Step d. ( S )-(4-Chloro-2-methyl-6-((methyl(1-(pyridin-2-yl)ethyl)amino)methyl)pyrimidin-5-yl)methanol: dichloromethane (10 mL) ( S )-N-methyl-1-(pyridin-2-yl)ethanamine (544 mg, 4.0 mmol), 5-(( tert - butyldimethylsilyloxy)methyl)-6-chloro-2-methyl A mixture of pyrimidine-4-carbaldehyde (610 mg, 2.0 mmol) and AcOH (360 mg, 6.0 mmol) was stirred for 1 hour. NaBH(OAc) ₃ (1.3 g, 6.0 mmol) was added to the reaction solution. The prepared suspension was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture and then extracted with dichloromethane (10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 -> 50/1) to give the desired product (480 mg, 80%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 7.2 Hz, 3H).

Method AH-Step e. ( S )-(2-methyl-4-((methyl(1-(pyridin-2-yl)ethyl)amino)methyl)-6-(4-methylpiperazin-1-yl)pyrimidin-5-yl )Methanol: ( S )-(4-chloro-2-methyl-6-((methyl(1-(pyridin-2-yl)ethyl)amino)methyl)pyrimidin-5-yl) in ethanol (5 mL) A mixture of methanol (50 mg, 0.16 mmol), TEA (80 mg, 0.8 mmol) and 1-methylpiperazine (48 mg, 0.48 mmol) 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 -> 100/2/1), and the desired product (26 mg, 80%) was obtained as a colorless oil. Obtained. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.62-8.56 (m, 1H), 7.73-7.63 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23-7.15 (m, 1H), 4.45-4.35 (m, 2H), 3.92 (q, J = 6.8 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.79 (s, 4H), 3.68 (d, J = 13.2 Hz, 1H) ), 2.70 (s, 4H), 2.48 (s, 3H), 2.45 (s, 3H), 2.07 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H).

Example 9

(3 R ,5 R )-5-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-1-(( S )-5,6,7,8 Preparation of -tetrahydroquinolin-8-yl)pyrrolidin-3-ol (C16)

Method AI-Step a. (3 R ,5 R )-5-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-1-(( S )-5,6,7,8 -Tetrahydroquinolin-8-yl)pyrrolidin-3-ol: ( S )-8-(( 2R , 4R )-4-(tert-butyldimethylsilyloxy in 2M aqueous HCl solution (5 mL) )-2-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinoline ( 50 mg, 0.1 mmol) solution was stirred at room temperature for 2 hours. Saturated NaHCO ₃ aqueous solution (100 mL) was added to the reaction mixture and then extracted with dichloromethane (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (35 mg, 86%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.05-6.99 (m, 1H), 5.29 (s, 1H) , 4.28 (s, 1H), 4.03 (d, J = 10.0 Hz, 1H), 3.89 (s, 1H), 3.55-3.38 (m, 4H), 3.30 (d, J = 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, J = 13.6 Hz, 1H), 1.62-1.51 (m, 3H).

Example 10

Preparation of (8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinolin-6-yl)methanol (D55)

Method AJ-Step a. (8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinolin-6-yl)methanol: Methyl in THF (3 mL) 8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinoline-6-carboxylate (105 mg, 0.25 mmol) in solution LiAlH ₄ (19 mg, 0.5 mmol) was added at 0°C and stirred at room temperature for 20 minutes. The reaction was quenched by adding water and aqueous NaOH solution (15 wt%/water). 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 slightly yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.07 (d, J = 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).

Example 11

( S )-5-(4-methylpiperazin-1-yl)-2-((2-(3-methylpyridin-2-yl)pyrrolidin-1-yl)methyl)imidazo[1,2 - a ]pyridine (C38) and ( S )-(5-(4-methylpiperazin-1-yl)-2-((2-(3-methylpyridin-2-yl)pyrrolidin-1-yl ) Preparation of methyl) imidazo [1,2- a ] pyridin-3-yl) methanol (C39)

Method AK - Step a. ( S )-5-Bromo-2-((2-(3-methylpyridin-2-yl)pyrrolidin-1-yl)methyl)imidazo[1,2 -a ]pyridine: MeCN (15 mL ) 5-Bromo-2-(bromomethyl)imidazo[1,2- a ]pyridine (48 mg, 0.17mmol), ( S )-3-methyl-2-(pyrrolidin-2-yl) ) A mixture of pyridine (30 mg, 0.12 mmol), KI (3 mg, 0.017 mmol) and K ₂ CO ₃ (46 mg, 0.34 mmol) 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H),7.61 (s,1H), 7.48 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.03 -6.95 (m, 3H), 3.97-3.94 (m, 2H), 3.74 (s,1H), 3.43 (s, 1H), 2.55 (s, 1H), 2.37 (s, 3H), 2.21-1.95 (m , 4H).

Method AK-Step b. ( S )-5-(4-methylpiperazin-1-yl)-2-((2-(3-methylpyridin-2-yl)pyrrolidin-1-yl)methyl)imidazo[1,2 - a ]Pyridine: ( S )-5-bromo-2-((2-(3-methylpyridin-2-yl)pyrrolidin-1-yl)methyl) in 1-methylpiperazine (3 mL) The imidazo[1,2- a ]pyridine (40 mg, 0.11 mmol) mixture was stirred at 170°C for 1.5 hours under microwave irradiation. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 60/1) to obtain the desired product (20 mg, 48%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 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, J = 7.2 Hz, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.84 (t, J = 8.0 Hz, 1H), 3.67(d, J = 13.6 Hz, 1H), 3.39 (t, J = 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).

Method AK - Step c. ( S )-(5-(4-methylpiperazin-1-yl)-2-((2-(3-methylpyridin-2-yl)pyrrolidin-1-yl)methyl)imidazo[1, 2- a ]pyridin-3-yl)methanol: In a sealed test tube, ( S )-5-(4-methylpiperazin-1-yl)-2-((2-(3-methylpyridin-2-yl ) Pyrrolidin-1-yl) methyl) imidazo [1,2- a ] pyridine (46 mg, 0.12 mmol) and formaldehyde (37 wt% / water, 5 mL) mixture was stirred at 50°C for 2 days. . Saturated NaHCO ₃ aqueous solution (10 mL) was added to the reaction mixture and then extracted with dichloromethane (30 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to obtain the desired product (35 mg, 71%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 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, J = 6.8 Hz, 1H), 6.19 (brs, 1H), 5.27 (d, J = 14.0 Hz, 1H), 5.07 (d, J = 14.0 Hz, 1H), 4.05 (d, J = 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).

Example 12

7-Fluoro- N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5,6-dihydroquinoline-8- Preparation of amine (D1)

Method AL-Step a. 7,7-Difluoro-6,7-dihydroquinolin-8( 5H )-one: 6,7- in a solution of NaH (60 wt%/oil, 511 mg, 12.8 mmol) in THF (20 mL). A THF solution (5 mL) containing dihydroquinolin-8(5H)-one (588 mg, 4 mmol) was added dropwise at 0°C. The reaction was stirred at 0°C for 10 minutes, and then Selectfluor (3.0 g, 8.4 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water (20 mL). The aqueous layer was extracted with diethyl ether (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.57-7.45 (m, 1H), 3.26-3.08 (m, 2H), 2.76- 2.51 (m, 2H).

Method AL-Step b. 7,7-Difluoro- N -methyl-5,6,7,8-tetrahydroquinolin-8-amine: 7,7-difluoro-6 in 1,2-dichloroethane (2 mL), 7-dihydroquinolin-8( 5H )-one (18.3 mg, 0.1 mmol), MeNH ₂ solution (30 wt%/ethanol, 1 mL) and HOAc (5 mg, 0.083 mmol) in NaBH ₃ CN (13). mg, 0.2 mmol) was added. The prepared suspension was stirred overnight at room temperature. 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.19-7.15 (m, 1H), 3.89 (t, J = 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).

Method AL-Step c. 7-Fluoro- N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5,6-dihydroquinoline-8- Amine: 4-chloro-6-(chloromethyl)-2-methylpyrimidine (54 mg, 0.31 mmol), 7,7-difluoro- N -methyl-5,6, in CH ₃ CN (10 mL) A mixture of 7,8-tetrahydroquinolin-8-amine (55 mg, 0.28 mmol), KI (5 mg, 0.028 mmol) and DIPEA (90 mg, 0.7 mmol) was stirred at room temperature overnight. The reaction solution was evaporated to remove most of CH ₃ CN, then diluted with dichloromethane (15 mL) and rinsed with saturated brine solution (10 mL). The organic layer was dried over Na ₂ SO ₄ , 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 under reflux for 3 hours. 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 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] ⁺ .

Example 13

Preparation of N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinolin-8-amine (D2)

Method AM-Step a. N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinolin-8-amine: N -(( 2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinolin-8-amine (75 mg, 0.26 mmol) and formaldehyde (37 wt%/water, 42 mg) , 0.52 mmol) NaBH ₃ CN (25 mg, 0.4 mmol) was added to the mixture. The prepared suspension was stirred overnight at room temperature. The reaction was quenched by adding water (10 mL). The aqueous layer was extracted with diethyl ether (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.44-7.35 (m, 3H), 7.13 (d, J = 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, J = 4.8 Hz, 4H), 2.30 (s, 3H).

Example 14

Preparation of N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1,7-naphthyridin-8-amine (D21)

Method AN - Step a. N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1,7-naphthyridin-8-amine: DMSO (3 mL ) of 8-chloro-1,7-naphthyridine (56 mg, 0.34 mmol) and N- methyl-1-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl ) K ₂ CO ₃ (140 mg, 1.02 mmol) was added to a solution of methanamine (80 mg, 0.34 mmol). The prepared 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 8.10 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 7.6, 4.0 Hz, 1H), 6.96 (d, J = 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).

Example 15

Preparation of N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1,6-naphthyridin-8-amine (D22)

Method AO-Step a. N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1,6-naphthyridin-8-amine: Toluene (5 mL ), 8-bromo-1,6-naphthyridine (41 mg, 0.20 mmol), N- methyl-1-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4- 1) A mixture of methanamine (99 mg, 0.42 mmol), BINAP (13 mg, 0.02 mmol), Cs ₂ CO ₃ (152 mg, 0.46 mol) and Pd ₂ (dba) ₃ (9 mg, 0.01 mmol) at 100°C. It was stirred under N ₂ atmosphere 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 = 100/1/1) to give the desired product (20 mg, 28%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) 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).

Example 16

4-(((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)(quinolin-8-yl)amino)butanoic acid (D30) and 4-(( Preparation of (2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)(quinolin-8-yl)amino)butanamide (D31)

Method AP-Step a. 4-(((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)(quinolin-8-yl)amino)butanoic acid: concentrated aqueous HCl solution (6 mL) tert -butyl 4-(((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)(quinolin-8-yl)amino)butanoate (55 mg , 0.112 mmol) solution was stirred at 50°C overnight. The reaction mixture was evaporated to give the desired product hydrochloride (535 mg, 96%) as a yellow oil. ^1H NMR (400 MHz, D ₂ O) δ 9.14 (d, J = 8.4 Hz, 1H), 9.07 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.09- 8.06 (m, 1H), 8.02 (d, J = 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).

Method AP-Step b. 4-(((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)(quinolin-8-yl)amino)butanamide: 4 in DMF (3 mL) -(((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)(quinolin-8-yl)amino)butanoic acid (50 mg, 0.098 mmol), NH A mixture of ₄ Cl (27 mg, 0.51 mmol), HATU (47 mg, 0.122 mmol) and DIPEA (131 mg, 1.02 mmol) 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 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, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.50-2.48 (m, 4H), 2.34 (s, 3H), 2.26 (t, J = 7.2 Hz, 2H), 2.00-1.97 (m, 2H).

Example 17

Preparation of 8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinoline-7-carbonitrile (D50)

Method AQ-Step a. 8-(Methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinoline-7-carbonitrile: 7-bro in DMAc (8 mL) Parent- N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinolin-8-amine (210 mg, 0.48 mmol), ZnCN ₂ (112 mg, 0.95 mmol), dppf (53 mg, 0.1 mmol), Pd(PPh ₃ ) ₄ (110 mg, 0.1 mmol) and Pd ₂ (dba) ₃ (44 mg, 0.05 mmol) mixture at 150°C. The mixture was stirred under N ₂ atmosphere for 2 days. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol/ammonium hydroxide = 100/1/0.5) to obtain the crude product (80 mg). The crude product was further purified by Combi-Flash-C18 (MeCN/water, MeCN gradient 30% -> 60 vol% for 30 min) to give the desired product (13 mg, 7%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.91 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 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).

Example 18

N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(methylsulfonyl)quinolin-8-amine (D43) manufacture of

Method AR-Step a. N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-(methylsulfonyl)quinolin-8-amine: DMSO ( 5-Bromo- N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-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), K ₂ CO ₃ (28 mg, 0.2 mmol) and CuI (40 mg, 0.2 mmol) mixture. was stirred at 100°C for 2 days under N ₂ 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 obtain the crude product (50 mg). The crude product was further purified by Combi-Flash-C18 (MeCN/water, MeCN gradient 30% -> 70 vol% for 30 min) to obtain the desired product (15 mg, 10%) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.01 (dd, J = 8.8, 2.0 Hz, 1H), 8.75 (dd, J = 4.0, 2.0 Hz, 1H, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.8, 4.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 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] ⁺ .

Example 19

N -(8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinolin-5-yl)methanesulfonamide (D57) manufacturing

Method AS-Step a. 8-Fluoro-5-nitroquinoline: 8-Fluoroquinoline (3.76 g, 40.0 mmol) was added dropwise at 0°C to a solution of concentrated sulfuric acid (2 mL) diluted with concentrated nitric acid (1 mL). The prepared suspension was stirred at 0°C for 2 hours. The reaction mixture was poured into ice water and filtered. Saturated Na ₂ CO ₃ aqueous solution was added to the filter cake to adjust pH to 7 and then extracted with dichloromethane (20 mL x 2). The combined organic layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.16 (d, J = 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).

Method AS-Step b. N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-nitroquinolin-8-amine: in DMSO (3 mL) 8-Fluoro-5-nitroquinoline (80 mg, 0.42 mmol) and N -methyl-1-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methanamine (100 mg, 0.42 mmol) K ₂ CO ₃ (58 mg, 0.42 mmol) was added to the solution. The prepared 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 8.4 Hz, 1H), 8.69 (s, 1H), 8.48 (d, J = 9.2 Hz, 1H), 7.58-7.50 (m, 1H) , 6.92 (d, J = 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).

Method AS-Step c. N ⁸ -methyl- N ⁸ -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinoline-5,8-diamine: Ethanol (4 mL) N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-5-nitroquinolin-8-amine (80 mg, 0.2 mmol) ) SnCl ₂ (135 mg, 0.6 mmol) was added to the solution. The prepared suspension was stirred at 80°C for 3 hours. 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] ⁺ .

Method AS-Step d. N -(8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinolin-5-yl)methanesulfonamide: Pyridine (3 mL) N ⁸ -methyl- N ⁸ -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinoline-5,8-diamine (19 mg , 0.05 mmol), MsCl (10 mg, 0.09 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO ₃ aqueous solution was added to adjust the pH to 7 and then extracted with dichloromethane (20 mL x 2). The organic layer was evaporated. The residue was purified by preparative TLC (dichloromethane/methanol/ammonium hydroxide = 30/1/0.3) to give the desired product (12 mg, 53%) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (d, J = 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) . MS (ESI/APCI) m/z 455.9 [M+H] ⁺ .

Example 20

N -(8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinolin-6-yl)methanesulfonamide (D58) manufacturing

Method AT-Step a. N -(8-(methyl((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)amino)quinolin-6-yl)methanesulfonamide: dichloromethane (10 mL) N ⁸ -methyl- N ⁸ -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)quinoline-6,8-diamine ( MsCl (23 mg, 0.2 mmol) was added dropwise to a solution of crude product (100 mg, 0.1 mmol) and TEA (101 mg, 1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The pH was adjusted to 11 by adding 2M NaOH aqueous solution and then stirred for 1 hour. The mixture was split, and the aqueous layer was adjusted to pH 5 by adding 6M HCl aqueous solution. The pH was adjusted to 8 by adding saturated aqueous NaHCO ₃ solution and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.70 (d, J = 4.0 Hz, 1H), 8.01 (d, J = 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, J = 4.4 Hz, 2H), 3.63 (t, J = 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] ⁺ .

Example 21

( S )- N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1-(pyridin-2-yl)ethane- Preparation of 1-amine (A75)

Method AA-Step a. ( S ) -N -((6-Chloro-2-methylpyrimidin-4-yl)methyl) -N -methyl-1-(pyridin-2-yl)ethan-1-amine: CH ₃ CN (20 mL ) of ( S ) -N -methyl-1-(pyridin-2-yl)ethan-1-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) mixture was stirred at room temperature overnight. The reaction solution was evaporated to remove most of CH ₃ CN. Saturated NaHCO ₃ aqueous solution (20 mL) was added to the residue and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 4.4 Hz, 1H), 7.72-7.63 (m, 1H), 7.46 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H) , 7.17 (dd, J = 7.6, 4.8 Hz, 1H), 3.91 (q, J = 6.8 Hz, 1H), 3.72 (d, J = 16.4 Hz, 1H), 3.59 (d, J = 16.4 Hz, 1H) , 2.67(s, 3H), 2.28(s, 3H), 1.49 (d, J = 6.8 Hz, 3H).

Method AA-Step b. ( S )- N -methyl- N -((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methyl)-1-(pyridin-2-yl)ethane- 1-amine: ( S ) -N -((6-chloro-2-methylpyrimidin-4-yl)methyl) -N -methyl-1-(pyridin-2-yl)ethane- in ethanol (10 mL) A mixture of 1-amine (90 mg, 0.33 mmol), TEA (333 mg, 3.3 mmol) and N -methylpiperazine (163 mg, 1.6 mmol) 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 4.0 Hz, 1H), 7.69-7.58 (m, 1H), 7.41 (d, J = 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, J = 15.6 Hz, 1H), 3.44 (d, J = 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).

Example 22

( S ) -N -methyl- N -((5-(4-methylpiperazin-1-yl)imidazo[1,2- a ]pyridin-2-yl)methyl)-1-(pyridin-2- 1) ethane-1-amine (A95) and ( S )-(2-((methyl(1-(pyridin-2-yl)ethyl)amino)methyl)-5-(4-methylpiperazin-1-yl ) Preparation of imidazo [1,2- a ] pyridin-3-yl) methanol (A96)

Method AK - Step a. ( S ) -N -((5-bromoimidazo[1,2- a ]pyridin-2-yl)methyl) -N -methyl-1-(pyridin-2-yl)ethan-1-amine: MeCN 5-Bromo-2-(bromomethyl)imidazo[1,2- a ]pyridine (127 mg, 0.4 mmol), ( S ) -N -methyl-1-(pyridine-2-) in (10 mL) 1) A mixture of ethanamine (55 mg, 0.4 mmol), KI (7 mg, 0.04 mmol) and DIPEA (130 mg, 1 mmol) 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.74-7.67 (m, 1H), 7.62-7.52(m, 2H), 7.24- 7.18 (m, 1H), 7.13-7.01 (m, 2H), 4.17-4.05 (m, 1H), 4.04-3.96 (m, 1H), 3.96-3.87 (m, 1H), 2.44 (s, 3H), 1.64-1.59 (m, 3H).

Method AK-Step b. ( S ) -N -methyl- N -((5-(4-methylpiperazin-1-yl)imidazo[1,2- a ]pyridin-2-yl)methyl)-1-(pyridin-2- 1) ethane-1-amine: ( S ) -N -((5-bromoimidazo[1,2- a ]pyridin-2-yl)methyl) -N- in N -methylpiperazine (3 mL) The methyl-1-(pyridin-2-yl)ethan-1-amine (100 mg, 0.29 mmol) mixture was stirred at 190°C for 2 hours under microwave irradiation. 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, CDCl ₃ ) δ 8.56 (d, J = 4.0 Hz, 1H), 7.72-7.62 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H) , 7.31 (d, J = 8.8 Hz, 1H), 7.20-7.11 (m, 2H), 6.26 (d, J = 7.2 Hz, 1H), 3.97-3.81 (m, 2H), 3.72 (d, J = 14.0 Hz, 1H), 3.14 (s, 4H), 2.67 (s, 4H), 2.41 (s, 3H), 2.32 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H).

Method AK - Step c. ( S )-(2-((methyl(1-(pyridin-2-yl)ethyl)amino)methyl)-5-(4-methylpiperazin-1-yl)imidazo[1,2 -a ]pyridine -3-yl)methanol: In a sealed test tube, ( S ) -N -methyl- N -((5-(4-methylpiperazin-1-yl)imidazo[1,2 -a ]pyridine-2- A mixture of 1)methyl)-1-(pyridin-2-yl)ethan-1-amine (43 mg, 0.12 mmol) and formaldehyde (37 wt%/water, 10 mL) was stirred at 50°C for 3 days. Saturated NaHCO ₃ aqueous solution (10 mL) was added to the reaction mixture and then extracted with dichloromethane (20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to obtain the desired product (25 mg, 50%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.73-7.58 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H) , 7.20-7.12 (m, 1H), 7.12-7.04 (m, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.24-5.11 (m, 2H), 3.95-3.85 (m, 1H), 3.84 -3.73 (m, 2H), 3.73-3.62 (m,1H), 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, J = 6.4 Hz, 3H).

Table 1 lists selected compounds prepared according to the methods detailed above and mentioned in column 3 of the table.

Table 1. Selected compounds of the invention (A1-A100, B1-B8, C1-C39 and D1-D59)

compound number structure method ¹ HNMR and MS A1 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 2H), 7.33 (d, J = 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): Calculated C ₂₀ H ₂₉ N ₆ [M+ H] ⁺ 353.2448, actual value 353.2451. A2 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 6.98 (s, 1H), 4.04-4.01 (m, 1H), 3.69 (s, 2H), 3.65 (s, 2H), 3.09 (s, 3H), 2.81-2.80 (m, 1H) ), 2.78-2.71 (m, 1H), 2.47 (t, J = 7.2 Hz, 2H), 2.38 (s, 3H), 2.27 (s, 6H), 2.10-2.09 (m, 1H), 2.03-2.01 ( m, 1H), 1.94-1.91 (m, 1H), 1.71-1.67 (m, 1H). MS (ESI/APCI) m/z 354.9 [M + H] ⁺ . A3 B, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 3.9 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.6, 4.8 Hz, 1H), 6.96 (s, 1H), 4.09-3.98 (m, 1H), 3.72 (s, 4H), 3.58 (s, 2H), 2.86-2.75 (m, 1H), 2.74-2.65 (m, 1H), 2.49 (s) , 3H), 2.47-2.43 (m, 4H), 2.39 (s, 3H), 2.33 (s, 3H), 2.10 (s, 1H), 2.03-2.00 (m, 1H), 1.91-1.87 (m, 1H) ), 1.65 (s, 1H). A4 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 4.2 Hz, 1H), 8.51 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 8.0 Hz) , 1H), 7.19-7.13 (m, 1H), 6.78 (s, 1H), 3.90 (q, J = 6.8 Hz, 1H), 3.69 (s, 4H), 3.61 (d, J = 15.6 Hz, 1H) , 3.46 (d, J = 15.6 Hz, 1H), 2.54-2.45 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H). A5 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 4.02 (s, 1H) , 3.71-3.65 (m, 8H), 2.81-2.78 (m, 1H), 2.71-2.67 (m, 2H), 2.57 (s, 6H), 2.39 (s, 3H), 2.11 (s, 1H), 2.00 (s, 1H), 1.97-1.88 (m, 1H), 1.70-1.68 (m, 1H). HRMS (ESI): calculated C21H31N6O [M+H] ⁺ 383.2554, found 383.2555. A6 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50-8.47 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.07 (dd, J = 7.6, 4.8 Hz, 1H), 4.03 (t, J = 7.4 Hz, 1H), 3.73 (s, 4H), 3.64 (s, 2H), 3.55 (t, J = 5.4 Hz, 2H), 3.38 (s, 3H), 2.85- 2.77 (m, 1H), 2.72-2.68 (m, 1H), 2.62 (t, J = 5.4 Hz, 2H), 2.56 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H), 2.17-2.07 (m, 1H), 2.07-1.98 (m, 1H), 1.99-1.88 (m, 1H), 1.76-1.67 (m, 1H). A7 A, AB ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 4.05-4.04 (m, 1H), 3.80-3.70 (m, 6H), 3.02-2.98 (m, 4H), 2.81-2.79 (m, 1H), 2.72-2.68 (m, 1H), 2.58 (s, 1H), 2.41 (s, 3H), 2.13 (s, 1H), 2.01 (m, 1H), 1.95-1.89 (m, 1H), 1.71-1.69 (m, 1H). MS (ESI/APCI) m/z 338.9 [M + H] ⁺ . A8 A, AB ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53-8.47 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.08 (dd, J = 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). A9 E, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.07-7.03 (m, 2H), 4.04 (t, J = 7.4 Hz, 1H), 3.71 (t, J = 5.2 Hz, 4H), 3.60 (s, 2H), 2.86-2.75 (m, 1H), 2.73-2.65 (m, 1H), 2.46-2.43 (m, 7H) ), 2.39 (s, 3H), 2.33 (s, 3H), 2.15-2.07 (m, 1H), 2.04-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.74-1.71 (m, 1H) ). A10 E, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 6.87 (s, 1H), 4.03 (t, J = 7.4 Hz, 1H), 3.88 (s, 3H), 3.70 (d, J = 5.0 Hz, 4H), 3.58 (s, 2H), 2.84-2.78 (m, 1H), 2.74-2.65 (m, 1H), 2.44 (t, J = 5.6Hz, 4H), 2.37 (s, 3H), 2.32 (s, 3H), 2.15-2.06 (m, 1H), 2.05-1.96 (m, 1H), 1.97-1.87 (m, 1H), 1.72-1.66 (m, 1H). A11 E, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 7.02 (s, 1H), 4.04 (s, 1H), 3.67 (t, J = 5.0 Hz, 4H), 3.61 (s, 2H), 2.85-2.75 (m, 1H), 2.73-2.65 (m, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.40 (s, 3H), 2.32 (s, 3H), 2.15-1.94 (m, 4H),.1.74-1.64 (m, 1H), 1.04-1.00 (m) , 2H), 0.91-0.86 (m, 2H). A12 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 7.6, 4.8 Hz, 1H), 6.49 (s, 1H), 4.06 (s, 1H), 3.65 (s, 4H), 3.55-.49 (m, 2H), 3.11 (s, 6H), 2.83-2.76 (m, 1H), 2.74-2.64 ( m, 1H), 2.46-2.40 (m, 4H), 2.38 (s, 3H), 2.32 (s, 3H), 2.12-2.07 (m, 1H), 2.03-1.97 (m, 1H), 1.95-1.91 ( m, 1H), 1.72-1.64 (m, 1H). A13 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 4.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.04 (dd, J = 7.6, 4.8 Hz, 1H), 6.48 (s, 1H), 4.07 (t, J = 7.4 Hz, 1H), 3.65 (t, J = 5.2 Hz, 4H), 3.58-3.48 (m, 6H), 2.84-2.76 (m, 1H), 2.71- 2.68 (m, 1H), 2.43 (t, J = 5.2 Hz, 4H), 2.35 (s, 3H), 2.31 (s, 3H), 2.13-2.08 (m, 1H), 2.03-1.98 (m, 1H) , 1.96-1.87 (m, 5H), 1.70-1.64 (m, 1H). A14 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 6.57 (s, 1H), 4.05 (t, J = 7.2 Hz, 1H), 3.72 (s, 8H), 3.64 (d, J = 5.0 Hz, 4H), 3.52 (d, J = 4.8 Hz, 2H), 2.84 -2.76 (m, 1H), 2.72-2.64 (m, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H), 2.32 (s, 3H), 2.14-2.06 (m, 1H) ), 2.04-1.98 (m, 1H), 1.98-1.88 (m, 1H), 1.73-1.63 (m, 1H). A15 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.34 (s, 1H), 7.05 (s, 1H), 6.52 (s, 1H), 4.04 (s, 1H) , 3.83 (t, J = 4.6 Hz, 2H), 3.69-3.63 (m, 6H), 3.50 (d, J = 8.0 Hz, 2H), 3.15 (s, 3H), 2.85-2.75 (m, 1H), 2.72-2.64 (s, 1H), 2.45-2.41 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.12-2.05 (m, 1H), 2.04-1.97 (m, 1H), 1.94-1.86 (m, 2H), 1.73-1.63 (m, 1H). A16 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.59 (s, 1H), 4.65 (s, 2H) , 4.04 (s, 1H), 3.65 (s, 4H), 3.50 (s, 2H), 2.84-2.75 (m, 1H), 2.75-2.64 (m, 1H), 2.45-2.40 (m, 4H), 2.37 (s, 3H), 2.32 (s, 3H), 2.13-2.06 (m, 1H), 2.04-1.98 (m, 1H), 1.96-1.87 (m, 1H), 1.72-1.64 (m, 1H). A17 H, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 8.37-8.32 (m, 2H), 742 -7.40 (m, 3H), 7.37 (d, J = 7.2 Hz, 1H), 7.19 ( s, 1H), 7.07 (s, 1H), 4.17-4.02 (m, 1H), 3.84-3.82 (m, 4H), 3.74 (s, 2H), 2.90-2.77 (m, 1H), 2.75-2.65 ( m, 1H), 2.52-2.50 (m, 4H), 2.45 (s, 3H), 2.36 (s, 3H), 2.16-2.14 (m, 1H), 2.02-1.87 (m, 2H), 1.73-1.71 ( m, 1H). A18 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 6.51 (s, 1H), 4.79 (s, 1H), 4.12-.02 (m, 1H), 3.67 (t, J = 5.0 Hz, 4H), 3.50 (d, J = 5.2 Hz, 2H), 2.92 (d) , J = 4.8 Hz, 3H), 2.84-2.75 (m, 1H), 2.75-2.64 (m, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.13-1.04 (m, 1H), 2.03-1.97 (m, 1H), 1.93-1.87 (m, 1H), 1.74-1.63 (m, 1H). A19 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 6.0 Hz, 1H), 6.49 (s , 1H), 4.77 (s, 1H), 4.05 (t, J = 7.6 Hz, 1H), 3.66 (d, J = 5.0 Hz, 4H), 3.49 (d, J = 4.4 Hz, 2H), 3.38 (t , J = 7.0 Hz, 2H), 2.83-2.75 (m, 1H), 2.72-2.64 (m, 1H), 2.43 (d, J = 5.2 Hz, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 2.13-2.05 (m, 1H), 2.03-1.98 (m, 1H), 1.96-1.85 (m, 1H), 1.72-1.64 (s, 1H), 1.18 (t, J = 7.2 Hz, 3H) . A20 F, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.08-7.02 (m, 1H), 6.48 (s, 1H) , 4.60 (s, 1H), 4.09-4.02 (m, 2H), 3.65 (d, J = 5.2 Hz, 4H), 3.47 (d, J = 7.8 Hz, 2H), 2.84-2.75 (m, 1H), 2.71-2.63 (m, 1H), 2.43 (t, J = 5.0 Hz, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.13-2.05 (s, 1H), 2.03-1.95 (m, 1H), 1.92-1.86 (m, 1H), 1.68-1.62 (m, 1H), 1.18 (d, J = 6.4 Hz, 6H). A21 H, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 2.8 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.06 (s, 2H), 4.10 - 4.09 (m, 1H), 3.92 (s, 3H), 3.77- 3.75 (m, 4H), 3.66 (s, 2H), 2.84-2.76 (m, 1H), 2.72-2.66 (m, 1H), 2.49-2.47 (m, 4H), 2.41 (s, 3H), 2.34 (s, 3H), 2.13-2.10 (m, 1H), 2.01-1.93 (m, 2H), 1.92-1.90 (m, 1H). A22 A, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.05 (s, 2H), 4.04 - 4.01 (m, 1H), 3.84 (s, 1H), 3.69 (s, 1H), 3.64 (s, 3H), 2.81-2.77 (m, 1H), 2.71-2.67 (m, 3H), 2.55 (s, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 2.09 (s, 1H), 1.99 (s, 1H), 1.94-1.89 (m, 4H), 1.72 (s, 1H).MS (ESI /APCI) m/z 366.9 [M + H] ⁺ . A23 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 4.02 (t, J = 6.8 Hz, 1H), 3.72 (s, 4H), 3.64 (s, 2H), 2.81-2.78 (m, 1H), 2.71-2.67 (m, 1H), 2.50 (s, 4H), 2.46-2.42 (m) , 2H), 2.40 (s, 3H), 2.10 (s, 1H), 2.00 (s, 1H), 1.94-1.88 (m, 1H), 1.71 (s, 1H), 1.12 (t, J = 6.8 Hz, 3H). MS (ESI/APCI) m/z 366.9 [M + H] ⁺ . A24 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49-8.47 (m, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 4.02 (s, 1H), 3.70 (s, 4H), 3.64 (s, 2H), 2.81-2.78 (m, 1H), 2.72 (s, 2H), 2.57 (s, 4H), 2.39 (s, 3H), 2.10 (s) , 1H), 2.00 (s, 1H), 1.94-1.89 (m, 1H), 1.67 (s, 1H), 1.07 (d, J = 6.0 Hz, 6H). MS (ESI/APCI) m/z 380.9 [M + H] ⁺ . A25 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50-8.47 (m, 2H), 7.36 (d, J = 6.8 Hz, 1H), 7.23 (s, 1H), 7.06 (s, 1H), 4.53 (s, 2H), 4.02 (s, 1H), 3.72-3.71 (m, 1H), 3.63 (s, 2H), 2.90-2.84 (m, 3H), 2.71-2.67 (m, 1H), 2.38 (s, 4H) , 2.29 (s, 6H), 2.10 (s, 1H), 2.01 (s, 1H), 1.91 (s, 3H), 1.43 (t, J = 11.0 Hz, 2H). MS (ESI/APCI) m/z 380.9 [M + H] ⁺ A26 A, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.42 (s, 1H), 7.35 (s, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 4.03 (s, 1H), 3.71 (s, 4H), 3.57 (s, 2H), 3.41 (s, 2H), 2.78 (s, 1H), 2.71-2.68 (m, 1H), 2.58 (s, 2H), 2.46 (s) , 4H), 2.38 (s, 3H), 2.11 (s, 1H), 2.00 (m, 1H), 1.95-1.89 (m, 1H), 1.68 (s, 1H). HRMS (ESI): calculated C ₂₁ H ₃₁ N ₆ [M+H] ⁺ 383.2554, found 383.2553. A27 E, A.C. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.09-7.02 (m, 1H), 3.99-3.94 (m, 1H), 3.76-3.66 (m, 2H), 3.45-3.30 (m, 4H), 2.88-2.77 (m, 1H), 2.72-2.65 (m, 1H), 2.53-2.47 (m, 7H), 2.33 ( s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 2.06-2.00 (m, 2H), 1.96-1.88 (s, 1H), 1.75-1.64 (m, 1H). A28 E, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 6.9 Hz, 2H), 4.04 (t , J = 7.4 Hz, 1H), 3.72 (d, J = 5.2 Hz, 4H), 3.61 (s, 2H), 2.85-2.76 (m, 1H), 2.71 (dd, J = 7.8, 4.0 Hz, 3H) , 2.46 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H), 2.34 (s, 3H), 2.10 (s, 1H), 1.99 (d, J = 4.8 Hz, 1H), 1.97-1.90 ( m, 1H), 1.75-1.63 (m, 1H), 1.28 (t, J = 7.6 Hz, 3H). A29 E, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.07-7.00 (m, 2H), 4.04 (t, J = 7.6 Hz, 1H), 3.72 (d, J = 5.2 Hz, 4H), 3.61 (s, 2H), 2.94 (p, J = 6.8 Hz, 1H), 2.82 (dd, J = 15.8, 4.6 Hz, 1H) , 2.69 (d, J = 16.4 Hz, 1H), 2.47 (t, J = 4.6 Hz, 4H), 2.40 (s, 3H), 2.34 (s, 3H), 2.14 (dd, J = 14.2, 7.8 Hz, 1H), 2.01 (d, J = 7.2 Hz, 1H), 1.93 (q, J = 12.0 Hz, 1H), 1.72-1.65 (m, 1H), 1.25 (dd, J = 6.4, 3.2 Hz, 6H). A30 G, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.13-7.00 (m, 1H), 6.87 (s, 1H) , 4.31 (q, J = 7.2 Hz, 2H), 4.08-3.96 (m, 1H), 3.69 (s, 4H), 3.57 (s, 2H), 2.88-2.76 (m, 1H), 2.74-2.65 (m) , 1H), 2.49-2.42 (m, 4H), 2.39 (s, 3H), 2.32 (s, 3H), 2.14-2.06 (m, 1H), 2.05-1.98 (m, 1H), 1.98-1.87 (m , 1H), 1.37 (t, J = 7.2 Hz, 3H). A31 G, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.08-7.02 (m, 1H), 6.86 (s, 1H) , 5.25-5.12 (m, 1H), 4.10-3.99 (m, 1H), 3.75-3.64 (m, 4H), 3.56 (s, 2H), 2.85-2.76 (m, 1H), 2.74-2.65 (m, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H), 2.32 (s, 3H), 2.13-2.06 (m, 1H), 2.05-1.98 (m, 1H), 1.98-1.87 (m, 1H), 1.69-1.64 (m, 1H), 1.33 (d, J = 6.0 Hz, 6H). A32 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.10-6.98 (m, 1H), 6.85 (s, 1H) , 4.18-4.03 (m, 2H), 3.74-3.63 (m, 4H), 2.86-2.74 (m, 1H), 2.72-2.61 (m, 1H), 2.50 (s, 3H), 2.46 (t, J = 4.6 Hz, 4H), 2.33 (s,3H), 2.15 (s, 3H), 1.98 (m, 4H), 1.68-1.60 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H). A33 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53-8.46 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.28-7.26 (m, 1H), 7.06-7.00 (m, 1H), 4.02-3.91 (m, 1H), 3.88-3.78 (m, 1H), 3.71 (s, 4H), 2.83-2.72 (m, 1H), 2.70-2.58 (m, 1H), 2.49 (s, 3H), 2.44-2.36 (m, 4H), 2.30 (s,3H), 2.21 (s, 3H), 2.08-1.98 (m, 1H), 1.90-1.78 (m, 2H), 1.66-1.54 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H). A34 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.09-7.00 (m, 1H), 6.83 (s, 1H) , 4.16-4.00 (m, 2H), 3.74-3.63 (m, 4H), 2.87-2.75 (m, 1H), 2.72-2.63 (m, 1H), 2.50 (s, 3H), 2.46 (t, J = 4.8 Hz, 4H), 2.34 (s,3H), 2.14 (s, 3H), 2.05-1.90 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H). A35 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.08-7.01 (m, 1H) , 4.02-3.92 (m, 1H), 3.90-3.80 (m, 1H), 3.72 (s, 4H), 2.83-2.73 (m, 1H), 2.72-2.63 (m, 1H), 2.50 (s, 3H) , 2.47-2.37 (m, 4H), 2.31 (s,3H), 2.22 (s, 3H), 2.15-1.85 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). A36 K, BA, B, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.58 (d, J = 4.8 Hz, 1H), 7.70-7.61 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.46 (s, 1H), 4.59 (s, 1H), 3.75-3.65 (m, 5H), 3.58 (d, J = 15.6 Hz, 1H), 3.33 (d, J = 15.6 Hz, 1H), 3.13-3.00 (m, 2H), 2.54-2.43 (m, 7H), 2.34 (s, 3H), 2.23 (s, 3H), 2.04-1.90 (m, 2H), 1.53-1.45 (m, 2H), 1.42 (s) , 9H), 1.33-1.27 (m, 1H), 1.22-1.12 (m, 1H). A37 K, BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.58 (d, J = 4.8 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.20-7.13 (m, 1H), 6.59 (s, 1H), 4.80 (s, 1H), 3.74 (t, J = 7.2 Hz, 1H), 3.71-3.61 (m, 5H), 3.34 (d, J = 15.6 Hz, 1H), 3.18-3.08 (m, 2H), 2.52-2.44 (m, 7H), 2.34 (s, 3H), 2.22 (s, 3H), 2.07-1.96 (m, 2H), 1.59-1.51 (m, 1H), 1.42 (s, 10H). A38 K, BA, C, AA, AD ^1H NMR (400 MHz, DMSO -d ₆ ) δ 11.99 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.29 (t, J = 7.8 Hz, 1H), 8.19 (s, 3H) , 7.99 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 6.4 Hz, 1H), 7.64 (s, 1H), 5.06-4.50 (m, 3H), 4.25 (d, J = 14.8 Hz, 1H), 4.11 (d, J = 14.4 Hz, 1H), 3.81-3.45 (m, 4H), 3.25-3.11 (m, 2H), 2.79 (s, 5H), 2.61 (s, 3H), 2.46 (s) , 3H), 2.38-2.21 (m, 2H), 1.58-1.44 (m, 1H), 1.41-1.29 (m, 1H). A39 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 4.03 (s, 1H) , 3.92-3.84 (m, 1H), 3.66 (s, 3H), 3.44 (s, 1H), 3.26 (s, 1H), 2.83-2.78 (m, 2H), 2.71-2.67 (m, 1H), 2.40 (s, 3H), 2.31 (s, 6H), 2.23 (s, 1H), 2.10 (s, 1H), 2.01 (s, 1H), 1.93-1.88 (m, 2H), 1.69 (s, 1H). MS (ESI/APCI) m/z 366.9 [M + H] ⁺ . A40 BD, BA, E, AC ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J = 4.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.11-7.08 (m, 1H), 6.46 (s, 1H) , 3.79-3.46(m, 6H), 2.99(s, 2H), 2.61-2.60(m, 1H), 2.47-2.33(m, 14H), 1.11-1.09(m, 1H), 0.92-0.89(m, 1H), 0.64-0.62(m, 1H), 0.23-0.21(m, 2H). A41 BD, BA, C, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J = 4.4 Hz, 1H), 7.43 (d, J = 4.0 Hz, 1H), 7.15-7.04 (m, 1H), 6.63 (s, 1H) , 3.88-3.58(m, 6H), 3.01(s, 1H), 2.95-2.80(m, 1H), 2.48-2.35(m, 14H), 1.15-1.10(t, J = 4.0,1Hz), 0.94- 0.88(t, J = 4.0,1 Hz), 0.66(t, J = 4.0 Hz, 1H), 0.23(t, J = 4.8 Hz, 2H). A42 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.09-7.01 (m, 2H), 4.04 (t, J = 7.6 Hz, 1H), 3.71 (s, 4H), 3.60 (s, 2H), 2.88-2.75 (m, 1H), 2.74-2.65 (m, 1H), 2.48-2.44 (m, 7H), 2.39 (s) , 3H), 2.33 (s, 3H), 2.16-2.06 (m, 1H), 2.04-1.98(m, 1H), 1.95-1.84 (m, 1H), 1.77-1.68 (m, 1H). A43 BB, C, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54-8.46 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.10-7.02 (m, 2H), 4.10-4.00 (m, 1H), 3.72 (s, 4H), 3.60 (s, 2H), 2.87-2.76 (m, 1H), 2.75-2.64 (m, 1H), 2.53-2.42 (m, 9H), 2.40 (s, 3H), 2.16- 2.07 (m, 1H), 2.05-1.98 (m, 1H), 1.96-1.89 (m, 1H), 1.76-1.66 (m, 1H), 1.12 (t, J = 7.4 Hz, 3H). A44 BD, BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.36(s, 1H), 7.36(d, J = 6.8 Hz), 7.05(s, 1H), 6.75(s, 1H), 3.66(s, 4H), 3.60 (s, 2H), 3.47(s, 1H), 3.15-3.07(m, 1H), 2.90-2.86(m, 1H), 2.8-2.70(m, 2H), 2.48(s, 4H), 2.42(s , 3H), 2.35(s, 3H), 2.10-2.04(m, 1H), 1.28-1.20(m, 1H), 1.01(t, J = 6.8 Hz, 3H), 0.89-0.82(m, 1H), 0.51-0.46(m, 1H), 0.42-0.38(m, 1H), 0.27-0.23(m, 1H). A45 BD, BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.36(s, 1H), 7.42(d, J = 8.0 Hz, 1H), 7.11(d, J = 4.8 Hz, 1H), 6.61(s, 1H), 3.86 -3.56(m, 6H), 3.00(s, 2H), 2.86-2.83(m, 1H), 2.50-2.36(m, 12H), 1.15-1.11 (m, 4H), 0.93-0.88(m, 1H) , 0.68-0.60(m, 1H), 0.28-0.19(m, 1H). A46 B.E., B.C., C., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.51(s, 1H), 7.30(d, J = 7.2 Hz, 1H), 7.07-7.01(m, 2H), 4.17-4.13(m, 1H), 3.71( s, 4H), 3.60(d, J = 5.2 Hz, 2H), 3.23(d, J = 16.8 Hz, 1H), 2.47(s, 7H), 2.42 (s, 3H), 2.34(s, 3H), 2.26-2.17(m, 1H), 2.01(d, J = 16.0 Hz, 1H), 1.52-1.45(m, 1H), 0.57-0.48(m, 2H), 0.37-0.30(m, 2H). A47 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.07-7.03 (m, 2H), 4.08-4.01 (m, 1H), 3.70-3.63 (m, 4H), 3.61 (s, 2H), 2.83-2.74 (m, 1H), 2.73-2.69 (m, 1H), 2.68-2.63 (m, 4H), 2.47 (s, 3H), 2.40 (s, 3H), 2.16-2.07 (m, 1H), 2.05-1.96 (m, 1H), 1.95-1.86 (m, 1H), 1.69-1.66 (m, 1H), 1.65-1.59 ( m, 1H), 0.51-0.43 (m, 4H). A48 E, BB, AC ^1H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J = 3.6 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.08-7.04 (m, 1H) , 4.06-3.96 (m, 1H), 3.84-3.72 (m, 4H), 3.72-3.60 (m, 2H), 2.87-2.75 (m, 1H), 2.74-2.61 (m, 1H), 2.53-2.42 ( m, 4H), 2.42 (s, 3H), 2.34 (s,3H), 2.16-2.08 (m, 1H), 2.07-1.96 (m, 1H), 1.96-1.86 (m, 1H), 1.76-1.64 ( m, 1H). A49 BB, C, AA 1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.10-7.01 (m, 2H), 4.713-4.60 (m, 4H) ), 4.10-3.95 (m, 1H), 3.74 (s, 4H), 3.61 (s, 2H), 3.55-3.46 (m, 1H), 2.86-2.75 (m, 1H), 2.713-2.673 (m, 1H) ), 2.47 (s, 3H), 2.38 (s, 7H), 2.20-2.07 (m, 1H), 2.06-1.96 (m, 1H), 1.93-1.88 (m, 1H), 1.78-1.65 (m, 1H) ). A50 L,A.E. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.18 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.05-7.02 (m, 1H) , 6.32 (d, J = 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). A51 I, B.C. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.06-7.02 (m, 1H), 4.11-4.00 (m, 1H), 3.81-3.73 (m, 4H), 3.73-3.69 (m, 2H), 3.68-3.60 (m, 1H), 2.89-2.75 (m, 1H), 2.75-2.62 (m, 1H), 2.50- 2.45 (m, 4H), 2.46-2.42 (m, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.07-2.01 (m, 2H), 1.76-1.680 (m, 1H). A52 C, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 4.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 7.6, 4.8 Hz, 1H), 6.65 (s, 1H), 3.90 (q, J = 6.6 Hz, 1H), 3.69 (t, J = 5.0 Hz, 4H), 3.57 (d, J = 15.6 Hz, 1H) , 3.44 (d, J = 15.6 Hz, 1H), 2.48 (d, J = 5.0 Hz, 7H), 2.35 (s, 3H), 2.28 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H) . A53 BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.40 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6, 4.8 Hz, 1H), 6.44 (s, 1H), 4.12 (q, J = 6.8 Hz, 1H), 3.62 (t, J = 5.0 Hz, 4H), 3.53 (s, 2H), 2.48-2.40 (m, 10H), 2.33 (s, 3H), 2.26 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H). A54 BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J = 4.8 Hz, 1H), 7.24 (s, 1H), 6.97 (d, J = 4.8 Hz, 1H), 6.65 (s, 1H), 3.90 -3.83 (m, 1H), 3.75-3.64 (m, 4H), 3.57 (d, J = 15.6 Hz, 1H), 3.43 (d, J = 15.6 Hz, 1H), 2.50-2.45 (m, 7H), 2.36-2.32 (m, 6H), 2.29 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H). A55 BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 3.87 (d, J = 6.9 Hz, 1H), 3.69-3.67 (m, 4H), 3.56 (d, J = 15.6 Hz, 1H), 3.42 (d, J = 15.6 Hz, 1H), 2.50-2.46 (m, 7H), 2.35 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). A56 BA, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ7.56-7.48 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H) ), 3.83 (q, J = 6.6 Hz, 1H), 3.69 (s, 4H), 3.57 (d, J = 15.6 Hz, 1H), 3.42 (d, J = 15.6 Hz, 1H), 2.53 (s, 3H) ), 2.47 (d, J = 6.4 Hz, 7H), 2.34 (s, 3H), 2.28 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H). A57 C, B.C., A.A. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.38-7.29 (m, , 1H), 7.21 (s, 1H), 7.03 (s, 1H), 4.13 (s, 1H), 3.73 (s, 4H), 3.64-3.45 (m, 2H), 2.90-2.60(m, 4H), 2.55-2.40 (m, 7H), 2.34 (s, 3H), 2.20-2.06 (m, 1H), 2.06 -1.90 (m, 1H), 1.90-1.78 (m, 1H), 1.78-1.70 (m, 1H), 1.10-0.98 (m, 3H). A58 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.22 (s, 1H), 7.04-6.99 (m, 1H), 4.18-4.05 ( m, 1H), 3.72 (s, 4H), 3.64-3.48 (m, 2H), 2.90-2.65 (m, 4H), 2.53-2.39(m, 7H), 2.34 (s, 3H), 2.20-2.03 ( s, 1H), 2.05-1.90 (m, 1H), 1.90-1.73 (m, 1H), 1.75-1.68 (m, 1H), 1.10-0.94 (m, 3H). A59 C, B.C., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.02 (s, 1H), 4.30-4.18 (m, 1H), 3.80-3.55 ( m, 6H), 2.85-2.52 (m, 4H), 2.52-2.40 (m, 7H), 2.35 (s, 3H), 2.20-2.10 (m, 1H), 2.02-1.90 (m, 1H), 1.88- 1.76 (m, 2H), 0.90-0.78 (m, 1H), 0.45-0.30 (m, 2H), 0.12-0.03 (m, 2H). A60 A, E, AC ^1H NMR (400 MHz, CDCl ₃ ) δ 8.54-8.46 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.12-7.03 (m, 1H), 4.03 ( t, J = 7.2 Hz, 1H), 3.74 (s, 4H), 3.65 (s, 2H), 2.88-2.76 (m, 1H), 2.74-2.66 (m, 1H), 2.59 (s, 4H), 2.39 (s, 3H), 2.30 (d, J = 6.4 Hz, 2H), 2.17-2.08 (m, 1H), 2.06-1.98 (m, 1H), 1.98-1.87 (m, 1H), 1.76-1.741 (m) , 1H), 0.94-0.84 (m, 1H), 0.60-0.50 (m, 2H), 0.17-0.06 (m, 2H). MS (ESI/APCI) m/z 392.9 [M + H] ⁺ . A61 E, BB, AC ^1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.07-7.01 (m, 1H), 4.02-3.92 (m, 1H), 3.80-3.69 (m, 2H), 3.39-3.25 (m, 4H), 2.88-2.76 (m, 1H), 2.73-2.65 (m, 1H), 2.51 (s, 7H), 2.33 (s, 3H), 2.23 (s, 3H), 2.08-1.98 (m, 3H), 1.74-1.63 (m, 1H). A62 C, B.S., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.65-7.55 (m, 1H), 7.13-7.08 (m, 1H), 6.70 (s, 1H), 3.71 (t, J = 5.0 Hz, 4H), 3.40 (s, 2H), 2.51 (t, J = 5.0 Hz, 4H), 2.45 (s, 3H), 2.36 ( s, 3H), 2.27 (s, 3H), 1.48 (s, 6H). A63 BB, C, AA，AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.09-6.92 (m, 2H), 4.62 (s, 1H), 4.35-4.28 ( m, 1H), 4.09-3.98 (m, 1H), 3.74-3.49 (m, 2H), 3.23-3.08 (m, 1H), 2.91-2.83 (m, 1H), 2.82-2.75 (m, 1H), 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, 1H), 2.14-2.07 (m, 1H), 2.05-1.91 (m, 3H), 1.74-1.63 (m, 1H), 1.29-1.23 (m, 3H). A64 BB, C, AA，AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.51-8.44 (m, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.09-7.02 (m, 1H), 7.02-6.89 (m, 1H), 4.61 (s, 1H), 4.31 (d, J = 13.2 Hz, 1H), 4.05 (q, J = 7.8 Hz, 1H), 3.63 (d, J = 8.0 Hz, 1H), 3.56 (s, 1H), 3.21 -3.10 (m, 1H), 2.89-2.83 (m, 1H), 2.81-2.74 (m, 1H), 2.74-2.67 (m, 2H), 2.46 (s, 3H), 2.37 (d, J = 6.0 Hz, 3H), 2.23 (s, 3H), 2.21-2.15 (m, 1H), 2.15-2.05 (m, 1H), 2.04-1.95 (m, 2H), 1.95-1.92 (m, 1H), 1.74- 1.63 (m, 1H), 1.30-1.25 (m, 2H), 1.18 (d, J = 6.8 Hz, 1H). A65 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52-8.47 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.09-7.00 (m, 2H), 4.35 (s, 1H), 4.25 ( s, 1H), 4.04 (t, J = 7.6 Hz, 1H), 3.68-3.55 (m, 2H), 3.14- 3.03 (m, 1H), 2.88-2.82 (m, 1H), 2.82-2.76 (m, 1H), 2.74-2.63 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 2.29-2.18 (m, 1H), 2.14-2.06 (m, 2H) , 2.04-1.97 (m, 1H), 1.93-1.87 (m, 1H), 1.73-1.64 (m, 1H), 1.17-1.09 (m, 3H). A66 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 4.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.09-7.01 (m, 2H), 4.35 (s, 1H) , 4.25 (s, 1H), 4.05 (t, J = 7.6 Hz, 1H), 3.68-3.55 (m, 2H), 3.14-3.02 (m, 1H), 2.89-2.82 (m, 1H), 2.80-2.74 (m, 1H), 2.74-2.63 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 2.28-2.19 (m, 1H), 2.14-2.06 (m , 2H), 2.04-1.98 (m, 1H), 1.97-1.87 (m, 1H), 1.73-1.64 (m, 1H), 1.16-1.10 (m, 3H). A67 BB, C, AA，AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.06 (s, 2H), 4.32 (s, 2H), 4.05 (t, J = 7.6 Hz, 1H), 3.63 (s, 2H), 2.85-2.76 (m, 1H), 2.75-2.62 (m, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 2.29 (s, 3H) ), 2.24-2.16 (m, 2H), 2.13-2.07 (m, 1H), 2.05-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.71-1.65 (m, 1H), 1.18 (t , J = 6.0 Hz, 6H). A68 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.55-8.48 (m, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.14-7.02 (m, 2H), 4.75-4.35 (m, 2H), 4.11-3.97 (m, 1H), 3.61 (s, 2H), 3.15-3.08 (m, 2H), 3.05-2.96 (m, 1H), 2.86-2.76 (m, 1H), 2.74-2.57 (m, 2H) ), 2.46 (s, 3H), 2.38 (s, 3H), 2.23-1.83 (m, 9H), 1.74-1.63 (m, 2H), 1.55-1.42 (m, 1H). A69 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.11-7.03 (m, 2H), 4.68-4.37 (m, 2H), 4.09- 3.99 (m, 1H), 3.68-3.55 (m, 2H), 3.17-3.07 (m, 2H), 3.06-2.97 (m, 1H), 2.84-2.74 (m, 1H), 2.71-2.60 (m, 2H) ), 2.47 (s, 3H), 2.38 (s, 3H), 2.28-2.06 (m, 3H), 2.04-1.82 (m, 6H), 1.71-1.59 (m, 1H), 1.54-1.43 (m, 1H) ). A70 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.12-7.02 (m, 1H), 6.73 (s, 1H), 5.50 (s, 1H), 4.13-3.95 (m, 1H), 3.72 (s, 4H), 3.59 (s, 2H), 3.44 (s, 2H), 2.88-2.76 (m, 1H), 2.75-2.63 (m, 1H) , 2.50-2.40 (m, 9H), 2.38 (s, 3H), 2.18-2.08 (m, 1H), 2.06-1.96 (m, 1H), 1.96-1.88 (m, 2H), 1.76-1.73 (m, 2H). A71 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53-8.48 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.10-7.02 (m, 1H), 6.75 (s, 1H), 5.52 ( s, 1H), 4.08-4.02 (m, 1H), 3.72 (s, 4H), 3.56 (s, 2H), 3.42 (s, 2H), 2.84-2.77 (m, 1H), 2.74-2.65 (m, 1H), 2.62-2.56 (m, 2H), 2.46 (s, 7H), 2.38 (s, 3H), 2.15-2.08 (m, 1H), 2.06-1.98 (m, 1H), 1.96-1.85 (m, 1H), 1.80-1.75 (m, 1H). A72 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.51-8.47 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.11-7.02 (m, 2H), 4.58 (d, J = 12.0 Hz, 2H), 4.03 (t, J = 7.2 Hz, 1H), 3.72 (s, 4H), 3.61 (s, 2H), 2.88-2.76 (m, 3H), 2.74-2.65 (m, 1H), 2.56 (s) , 4H), 2.46 (s, 4H), 2.38 (s, 3H), 2.15-1.96 (m, 2H), 1.95-1.85 (m, 3H), 1.76-1.65 (m, 1H), 1.55-1.42 (m) , 2H). A73 C, BB, AA，AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52-8.45 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.115-7.04 (m, 2H), 4.63 (s, 1H), 4.29 ( s, 1H), 4.08-3.83 (m, 3H), 3.62-3.58 (m, 2H), 3.48-3.36 (m, 1H), 3.06 (d, J = 11.6 Hz, 1H), 2.90 (d, J = 10.8 Hz, 1H), 2.85-2.75 (m, 1H), 2.74-2.63 (m, 1H), 2.45 (d, J = 5.2 Hz, 3H), 2.38 (d, J = 14.0Hz, 3H), 2.30 ( s, 3H), 2.17-2.07 (m, 2H), 2.06-1.97 (m, 2H), 1.96-1.88 (m, 1H), 1.75-1.63 (m, 1H). A74 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.10-7.02 (m, 2H), 4.59 (d, J = 13.2 Hz, 2H), 4.04 (t, J = 7.2 Hz, 1H), 3.60 (s, 2H), 2.90-2.75 (m, 3H), 2.71-2.55 (m, 5H), 2.54-2.43 (m, 7H) ), 2.39 (s, 3H), 2.29 (s,3H), 2.17-1.84 (m, 7H), 1.56-1.40 (m, 2H). A75 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 4.0 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.15 (t , J = 6.4 Hz, 1H), 6.64(s, 1H), 3.92-3.80 (m, 1H), 3.68 (s, 4H), 3.59-3.42 (m, 2H), 2.55-2.40 (m, 7H), 2.34 (s, 3H), 2.27(s, 3H), 1.47(d, J = 6.4 Hz, 3H). A76 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 4.0 Hz, 1H), 7.70-7.56 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.21-7.11 (m, 1H), 6.64(s, 1H), 3.92-3.80 (m, 1H), 3.68 (s, 4H), 3.59-3.42 (m, 2H), 2.55-2.40 (m, 7H), 2.34 (s, 3H) , 2.27(s, 3H), 1.47(d, J = 6.4 Hz, 3H). A77 M, A.D. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 8.0, 4.8 Hz, 1H), 4.15 -4.08 (m, 1H), 4.08-3.93 (m, 6H), 2.87-2.75 (m, 1H), 2.75-2.62 (m, 1H), 2.55-2.45 (m, 7H), 2.33 (s, 3H) , 2.23 (s, 3H), 2.08-1.90 (m, 3H), 1.77-1.64 (m, 1H). A78 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, J = 4.8 Hz, 1H), 7.67-7.57 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.18-7.08 (m, 1H), 6.65 (s, 1H), 4.63-4.50 (m, 1H), 4.46-4.30 (m, 1H), 3.89 (q, J = 6.8 Hz, 1H), 3.56 (d, J = 15.6 Hz, 1H) ), 3.43 (d, J = 15.6 Hz, 1H), 3.17-3.07 (m, 2H), 3.07-2.95 (m, 1H), 2.69-2.58 (m, 1H), 2.45 (s, 3H), 2.26 ( s, 3H), 2.23-2.11 (m, 2H), 2.00-1.71 (m, 4H), 1.54-1.39 (m, 4H). A79 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 4.8 Hz, 1H), 7.67-7.57 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.18-7.10 (m, 1H), 6.70 (s, 1H), 4.63-4.50 (m, 1H), 4.46-4.30 (m, 1H), 3.91 (q, J = 6.8 Hz, 1H), 3.58 (d, J = 15.6 Hz, 1H) ), 3.45 (d, J = 15.6 Hz, 1H), 3.19-3.10 (m, 2H), 3.09-2.98 (m, 1H), 2.73-2.61 (m, 1H), 2.47 (s, 3H), 2.28 ( s, 3H), 2.26-2.13 (m, 2H), 2.03-1.76 (m, 4H), 1.57-1.42 (m, 4H). A80 BB, C, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.8 Hz, 1H), 7.68-7.54 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.16-7.06 (m, 1H), 6.72 (s, 1H), 4.08 (q, J = 6.8 Hz, 1H), 3.73-3.60 (m, 5H), 3.54 (d, J = 16.8 Hz, 1H), 2.75-2.63 (m, 1H) ), 2.60-2.51 (m, 1H), 2.49-2.40 (m, 7H), 2.33 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 6.8 Hz, 3H) . A81 E, BB, AC ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 7.68-7.62 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.18-7.14 (m, 1H), 6.69 ( s, 1H), 4.55 (s, 2H), 3.95-3.83 (m, 2H), 3.77-3.65 (m, 4H), 3.60 (d, J = 16.0 Hz, 1H), 3.47 (d, J = 16.0 Hz) , 1H), 2.55-2.42 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H). MS (ESI/APCI) m/z 356.9 [M+H] ⁺ . A82 E, BB, AC ^1H NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 7.61-7.57 (m, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.11-7.06 (m, 1H), 6.64 ( s, 1H), 4.58-4.42 (m, 3H), 4.41-4.26 (m, 1H), 3.98-3.72 (m, 2H), 3.55 (d, J = 15.6 Hz, 1H), 3.41 (d, J = 15.6 Hz, 1H), 3.08-2.95 (m, 3H), 2.71-2.56 (m, 1H), 2.24 (s, 3H), 2.21-2.09 (m, 2H), 1.98-1.72 (m, 4H), 1.51 -1.47 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H). MS (ESI/APCI) m/z 382.9 [M+H] ⁺ . A83 F, BB, AC ^1H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.68-7.58 (m, 1H), 7.47-7.37 (m, 1H), 7.18-7.09 (m, 1H), 6.22 (s, 1H) ), 4.66 (s, 2H), 3.95-3.76 (m, 1H), 3.61 (s, 4H), 3.44 (d, J = 15.2 Hz, 1H), 3.29 (d, J = 15.2 Hz, 1H), 2.45 (s, 4H), 2.33 (s, 3H), 2.26 (s, 3H), 1.46 (d, J = 6.8 Hz, 1H).
A84 C, BB, AA, AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 7.80-7.60 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.25-7.05 (m, 2H), 4.66- 4.27 (m, 2H), 4.10-3.88 (m, 3H), 3.87-3.60 (m, 3H), 3.41 (s, 1H), 3.15-3.00 (m, 1H), 2.94 (d, J = 10.8 Hz, 1H) , 2.49 (d, J = 6.0 Hz, 3H), 2.40 (s, 3H), 2.35-2.30 (m, 4H) , 2.20-2.10 (m, 1H), 1.60-1.50 (m, 3H). A85 B.B., A.H. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.62-8.56 (m, 1H), 7.73-7.63 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23-7.15 (m, 1H), 4.45-4.35 (m, 2H), 3.92 (q, J = 6.8 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.79 (s, 4H), 3.68 (d, J = 13.2 Hz, 1H) ), 2.70 (s, 4H), 2.48 (s, 3H), 2.45 (s, 3H), 2.07 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H). A86 B.B., A.H. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J = 4.8 Hz, 1H), 7.73-7.63 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.22-7.15 (m, 1H), 6.81 (br s, 1H), 4.48-4.32 (m, 3H), 4.28 (d, J = 12.0 Hz, 1H), 4.00-3.83 (m, 2H), 3.61 (d, J = 13.2 Hz, 1H), 3.20-3.05 (m, 3H), 2.79 (t, J = 11.4 Hz, 1H), 2.47 (s, 3H), 2.40-2.30 (m, 1H), 2.24-2.16 (m, 1 H), 2.15-2.10 (m, 1H), 2.08 (s, 3H), 1.92-1.83 (m, 2H), 1.80-1.74 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H). A87 B.B., A.H. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.60 (d, J = 4.8 Hz, 1H), 7.71-7.65 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.22-7.15 (m, 1H), 6.80 (br s, 1H), 4.43-4.35 (m, 3H), 4.28 (d, J = 12.8 Hz, 1H), 3.93 (q, J = 6.8 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 3.70 (d, J = 13.2 Hz, 1H), 3.25-3.05 (m, 3H), 2.79 (t, J = 11.4 Hz, 1H), 2.47 (s, 3H), 2.40-2.30 ( m, 1H), 2.24-2.16 (m, 1 H), 2.15-2.10 (m, 1H), 2.08 (s, 3H), 1.93-1.83 (m, 2H), 1.80-1.72 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H). A88 B.B., A.H. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.60 (d, J = 5.2 Hz, 1H), 7.72-7.63 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.22-7.16 (m, 1H), 4.48-4.35 (m, 2H), 4.21-4.13 (m, 1H), 4.12-4.04 (m, 1H), 3.93 (q, J = 6.8 Hz, 1H), 3.86 (d, J = 12.8 Hz) , 1H), 3.63 (d, J = 13.2 Hz, 1H), 3.28-3.16 (m, 1H), 2.91-2.84 (m, 1H), 2.84-2.77 (m, 1H), 2.48 (s, 3H), 2.41-2.35 (m, 1 H), 2.33 (s, 3H), 2.27-2.21 (m, 1H), 2.08 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H). A89 B.B., A.H. ^1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.74-7.64 (m, 1H), 7.38-7.30 (m, 1H), 7.22-7.14 (m, 1H), 6.75 (br s, 1H) ), 4.40 (s, 2H), 4.16 (d, J = 13.2 Hz, 1H), 4.08 (d, J = 13.2 Hz, 1H), 3.97-3.85 (m, 1H), 3.80 (d, J = 13.2 Hz) , 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.20 (t, J = 12.8 Hz, 1H), 2.92-2.83 (m, 1H), 2.82-2.75 (m, 1H), 2.48 (s, 3H), 2.42-2.36 (m, 1 H), 2.33 (s, 3H), 2.23 (s, 1H), 2.08 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 5.6 Hz, 3H). A90 D, B.C. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.08 (s, 2H), 6.88 (s, 1H), 4.39 (s, 1H), 4.17 (s, 1H), 4.06 (s, 1H), 3.81-3.60 (m, 6H), 2.55-2.40 (m, 7H), 2.38 (s, 3H), 2.33(s, 3H), 2.26 (s, 1H), 2.13 (s, 1H). A91 C, BB, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.09 (s, 2H), 6.89 (s, 1H), 4.44-4.37 (m, 1H), 4.17 (t, J = 8.4 Hz, 1H), 4.06 (t, J = 6.4 Hz, 1H), 3.75-3.63 (m, 6H), 2.47 (s, 7H), 2.39 (s, 3H), 2.33 (s, 3H), 2.30-2.21 (m , 1H), 2.18-2.10 (m, 1H).

A92 C, BB, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 2.4 Hz, 1H), 7.12 (s, 2H), 6.59 (s, 1H), 4.50--4.46 (m, 1H), 3.79 (s) , 3H), 3.66 (s, 4H), 3.58-3.47 (m, 2H), 2.46 (s, 7H), 2.32 (s, 3H), 2.26 (s, 3H), 1.47-1.45 (m, 3H). A93 C, BF, BB, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 11.18 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 4.8 Hz, 1H), 7.24-7.12 (m, 1H) , 6.19 (s, 1H), 4.13-4.00 (m, 1H), 3.82-3.72 (m, 1H), 3.73-3.60 (m, 5H), 2.54-2.42 (m, 7H), 2.38-2.26 (m, 6H), 2.13 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H). MS (ESI/APCI) m/z 398.1 [M+H] ⁺ .

A94 C, BG, BB, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.18-7.13 (m, 1H)，6.39 (s, 1H) , 4.12-3.98 (m, 1H), 3.74-3.61 (m, 4H), 3.52(s, 2H), 2.98(s, 3H), 2.50-2.37 (m, 7H), 2.28(s, 3H), 2.16 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H). A95 N, BB, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 4.0 Hz, 1H), 7.72-7.62 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H) , 7.31 (d, J = 8.8 Hz, 1H), 7.20-7.11 (m, 2H), 6.26 (d, J = 7.2 Hz, 1H), 3.97-3.81 (m, 2H), 3.72 (d, J = 14.0 Hz, 1H), 3.14 (s, 4H), 2.67 (s, 4H), 2.41 (s, 3H), 2.32 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H).
A96 N, BB, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.73-7.58 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H) , 7.20-7.12 (m, 1H), 7.12-7.04 m, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.24-5.11 (m, 2H), 3.95-3.85 (m, 1H), 3.84- 3.73 (m, 2H), 3.73-3.62 (m,1H), 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, J = 6.4 Hz, 3H). A97 N, BB, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 2.8Hz, 1H), 7.68-7.63 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H) , 7.31 (d, J = 8.8 Hz, 1H), 7.21-7.08 (m, 2H), 6.29 (d, J = 6.8 Hz, 1H), 4.00-3.82 (m, 2H), 3.80-3.68 (m, 1H) ), 3.59-3.49 (m, 1H), 3.45-3.37(m, 1H), 3.22-3.11 (m, 2H), 3.00-2.89 (m, 1H), 2.70-2.48 (m, 2H), 2.40-2.25 (m, 5H), 1.93-1.75 (m, 3H), 1.58-1.40 (m, 4H). A98 N, BB, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 4.0 Hz, 1H), 7.73-7.61 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H) , 7.31 (d, J = 8.8 Hz, 1H), 7.18-7.06 (m, 2H), 6.28 (d, J = 6.8 Hz, 1H) 3.93-3.81 (m, 3H), 3.72 (d, J = 14.0 Hz) , 1H), 3.58-3.48 (m, 1H), 3.47-3.38 (m, 1H), 3.22-3.11 (m, 2H), 3.00-2.87 (m, 1H), 2.66-2.59 (m, 1H), 2.56 -2.51 (m, 1H), 2.36-2.26 (m, 5H), 1.93-1.76 (m, 3H), 1.57-1.44 (m, 4H). A99 N, BB, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.80-7.60 (m, 1H), 7.48-7.36 (m, 1H), 7.35-7.28 (m, 1H), 7.20-7.16 (m) , 1H), 7.15-7.06 (m, 1H), 6.45-6.30(m, 1H), 6.00 (brs, 1H), 5.36-5.00 (m, 2H), 4.00-3.70 (m, 3H), 3.55-3.35 (m, 2H), 3.20-3.07 (m, 2H), 2.97-2.80 (m, 1H), 2.70-2.50 (m, 2H), 2.34-2.21 (m, 2H), 2.15 (d, J = 3.6 Hz , 3H), 1.95-1.70 (m, 3H), 1.56-1.40 (m, 4H). A100 N, BB, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 7.69 (d, J = 6.4 Hz, 1H), 7.42 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 8.8 Hz) , 1H), 7.21-7.14 (m, 1H), 7.14-7.06 (m, 1H), 6.46 (d, J = 6.4 Hz, 1H), 5.30-5.07 (m, 2H), 3.99-3.72 (m, 3H) ), 3.53 (d, J = 9.6 Hz, 1H), 3.44 (d, J = 10.8 Hz, 1H), 3.25-3.09 (s, 2H), 3.00-2.83 (m, 1H), 2.71-2.53 (m, 2H), 2.47-2.26 (m, 2H), 2.17 (s, 3H), 2.03-1.84 (m, 3H), 1.60-1.45 (m, 4H). B1 A, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J = 4.6 Hz, 1H), 8.22 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.04 (dd, J = 7.6, 4.8 Hz, 1H), 5.80 (s, 1H), 4.00-3.82 (m, 1H), 3.66-3.56 (m, 4H), 3.31-3.23 (m, 1H), 3.11 (s, 3H), 2.83-2.70 (m, 2H), 2.48 (t, J = 5.2 Hz, 4H), 2.33 (s, 3H), 2.03-1.91 (m, 1H), 1.91-1.85 (m, 2H), 1.76-1.70 (m, 2H) ). B2 A, AA, AG ^1H NMR (400 MHz, CDCl ₃ ) δ 9.06 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 7.80 (d, J = 4.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.08-7.05 (m, 1H), 4.04-4.01 (m, 1H), 3.82-3.72 (m, 2H), 2.82-2.78 (m, 1H), 2.73-2.69 (m, 1H), 2.39 (s, 3H), 2.13 (s, 1H), 2.03 (s, 1H), 1.97-1.88 (m, 1H), 1.72 (s, 1H). MS (ESI/APCI) m/z 254.9 [M + H] ⁺ . B3 A, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 2H), 7.36 (s, 1H), 7.06 (s, 2H), 4.04 (s, 1H), 3.67 (s, 2H), 3.12 (s, 6H), 2.81 (s, 1H), 2.71-2.67 (m, 1H), 2.40 (s, 3H), 2.16-2.12 (m, 1H), 2.04-2.01 (m, 1H), 1.94-1.92 (m, 1H), 1.69 (s, 1H). B4 L,A.E. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (dd , J = 7.6, 4.8 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 4.06-3.98 (m, 1H), 3.82 (t, J = 5.0 Hz, 4H), 3.59 (q, J = 13.8 Hz, 2H), 2.87-2.77 (m, 1H), 2.74-2.66 (m, 1H), 2.45 (t, J = 5.2 Hz, 4H), 2.38 (s, 3H), 2.33 (s, 3H), 2.14-1.99 (m, 2H), 1.98-1.89 (m, 1H), 1.73-1.66 (m, 1H). B5 AF ¹ H NMR (400 MHz, CDCl ₃ ) ㉧ 8.51 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.06 (dd , J = 7.2, 4.8 Hz, 1H), 6.86 (s, 1H), 6.67 (d, J = 4.8 Hz, 1H), 3.99-3.96 (m, 1H), 3.67-3.64 (m, 1H), 3.56 ( s, 4H), 3.52-3.48 (m, 1H), 2.84-2.78 (m, 1H), 2.71-2.67 (m, 1H), 2.51 (t, J = 4.6 Hz, 4H), 2.34 (s, 3H) , 2.31 (s, 3H), 2.04-2.02 (m, 2H), 1.96-1.90 (m, 1H), 1.73-1.69 (m, 1H). B6 AF ^1H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J = 4.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.05 (d) , J = 4.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 4.03 (s, 1H), 3.64 (q, J = 15.0 Hz, 2H) ), 3.53 (s, 4H), 2.82-2.78 (m, 1H), 2.71-2.66 (m, 1H), 2.50 (t, J = 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). B7 WO2009121063 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.14 -7.04 (m, 1H), 6.30 (s, 1H), 4.08-3.96 (m, 1H), 3.75-3.59 (m, 2H), 3.49-3.32 (m, 3H), 3.24 (d, J = 12.8 Hz , 1H), 3.13 (s, 6H), 2.86-2.68 (m, 2H), 2.19 (s, 3H), 2.14-2.08 (m, 1H), 2.06-1.99 (m, 1H), 1.90-1.79 (m , 1H), 1.77-1.66 (m, 1H), 1.37 (s, 9H). B8 WO2009121063 ^1H NMR (400 MHz, CDCl ₃ ) δ 13.27 (s, 1H), 9.35 (s, 1H), 8.59 (s, 1H), 8.40 (s, 3H), 8.12 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.44 (s, 1H), 4.91 (s, 1H), 4.61 (d, J = 14.0 Hz, 1H), 4.31 (d, J = 13.2 Hz, 2H), 3.86-3.72 ( m, 3H), 3.21 (s, 6H), 3.10 (s, 2H), 2.86-2.77 (m, 2H), 2.69 (s, 3H), 2.42 (s, 1H), 2.09-1.99 (m, 2H) . C1 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J = 4.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.07-6.95 (m, 2H), 4.05-3.93 (m, 2H), 3.74-3.61 (m, 4H), 3.01-2.90 (m, 1H), 2.82-2.72 (m, 2H), 2.72-2.64 (m, 1H),2.48 (s, 3H), 2.44 (t, J = 5.0 Hz, 4H), 2.32 (s, 3H), 2.30-2.24 (m, 1H), 2.12-2.01 (m, 1H), 2.00-1.90 (m, 2H), 1.83-1.69 (m, 4H).
C2 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J = 4.4 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.04-6.96 (m, 1H), 6.57 (s, 1H) , 4.65-4.53 (m, 1H), 4.06-3.98 (m, 1H), 3.72-3.58 (m, 4H), 2.98-2.89 (m, 1H), 2.84-2.73 (m, 1H), 2.69-2.58 ( m, 2H), 2.51-2.44 (m, 7H), 2.34 (s, 3H), 2.33-2.26 (m, 1H), 2.00-1.90 (m, 3H), 1.66-1.55 (m, 1H).
C3 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J = 4.4 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.04-6.97 (m, 1H), 6.57 (s, 1H) , 4.57 (s, 1H), 4.01 (s, 1H), 3.67 (s, 4H), 2.98-2.90 (m, 1H), 2.85-2.74 (m, 1H), 2.69-2.58 (m, 2H), 2.51 -2.45 (m, 7H), 2.35 (s, 3H), 2.33-2.23 (m, 2H), 1.95 (s, 3H), 1.72 (s, 3H).
C4 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J = 4.4 Hz, 1H), 7.31-7.27 (m, 1H), 7.06-6.96 (m, 2H), 3.98 (s, 2H), 3.68 ( s, 4H), 2.96 (s, 1H), 2.83-2.73 (m, 2H), 2.72-2.63 (m, 1H), 2.49 (s, 3H), 2.47-2.42 (m, 4H), 2.32 (s, 5H), 2.11-2.01 (s, 1H), 2.01-1.90 (m, 2H), 1.82-1.74 (m, 3H).
C5 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J = 4.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.11 (s, 1H), 7.02-6.92 (m, 1H), 4.06- 3.92 (m, 2H), 3.67 (s, 4H), 3.03-2.89 (m, 1H), 2.81-2.62 (m, 3H), 2.45 (s, 7H), 2.32 (s, 3H), 2.30-2.23 ( m, 1H), 2.10-2.01 (m, 3H), 2.00-1.87 (m, 3H), 1.71-1.60 (m, 1H).
C6 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53-8.47 (m, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.05-6.95 (m, 2H), 4.08-3.97 (m, 1H), 3.69 (s, 4H), 3.58 (d, J = 10.4 Hz, 1H), 2.77-2.65 (m, 1H), 2.64-2.56 (m, 1H), 2.49 (s, 3H), 2.43 (s, 4H) , 2.38-2.34 (m, 1H), 2.30 (s, 3H), 1.97-1.85 (m, 4H), 1.83-1.56 (m, 4H), 1.55-1.45 (m, 2H), 1.40-1.28 (m, 1H).
C7 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 4.4 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.01-6.91 (m, 1H), 6.55 (s, 1H) , 4.54 (d, J = 10.8 Hz, 1H), 3.91 (t, J = 8.6 Hz, 1H), 3.63 (s, 4H), 2.75-2.60 (m, 2H), 2.57-2.53 (m, 1H), 2.51 (s, 3H), 2.48-2.44 (m, 4H), 2.34 (s, 3H), 2.20-2.02 (m, 2H), 1.93-1.84 (m, 2H), 1.82-1.67 (m, 2H), 1.67-1.44 (m, 4H), 1.38-1.28 (m, 1H). C8 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.14-7.08 (m, 1H) , 4.08-4.00 (m, 1H), 3.88-3.61 (m, 5H), 2.76-2.70 (m, 1H), 2.68-2.62 (m, 1H), 2.57-2.53 (m, 1H), 2.52-2.47 ( m, 7H), 2.35 (s, 3H), 2.08-1.92 (m, 4H), 1.84-1.75 (m, 2H), 1.70-1.62 (m, 2H), 1.62-1.50 (m, 2H), 1.33- 1.26 (m, 1H). C9 J, B.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.98-6.91 (m, 1H), 6.55 (s, 1H) , 4.53 (d, J = 10.8 Hz, 1H), 3.91 (t, J = 8.4 Hz, 1H), 3.63 (s, 4H), 2.75-2.67 (m, 1H), 2.67-2.59 (m, 1H), 2.55 (s, 1H), 2.51 (s, 3H), 2.46 (d, J = 4.6 Hz, 4H), 2.34 (s, 3H), 2.13-2.05 (m, 1H), 1.95-1.85 (m, 4H) , 1.80-1.68 (m, 2H), 1.68-1.59 (m, 1H), 1.60-1.50 (m, 2H), 1.53-1.40 (m, 1H). C10 E, A.C. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 4.4 Hz, 1H), 7.67-7.55 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.16-7.07 (m, 1H), 6.45 (s, 1H), 3.70 (s, 4H), 3.50-3.42 (m,2H), 3.09-3.02 (m, 2H), 2.50-2.45 (m, 7H), 2.45 (s, 3H) , 2.36 (s, 2H), 1.90-1.25 (m, 5H).
C11 E, A.C.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.0 Hz, 1H), 7.67-7.57 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.17-7.06 (m, 1H), 6.32 (s, 1H), 3.73-3.64 (m, 6H), 3.36-3.31 (m, 2H), 2.47-1.95 (m, 15H).

C12 C, A.A.

^1H NMR (400 MHz, CDCl ₃ )δ 8.52 (d, J = 4.0 Hz, 1H), 7.65-7.54 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.16-7.05 (m, 1H), 6.45 (s, 1H), 3.72-3.68 (m, 2H), 3.63(s, 4H), 3.40-3.31 (m, 2H), 2.46-2.40 (m, 8H), 2.34-2.29 (m, 4H), 2.05-1.95 (m, 1H), 1.93-1.90 (m, 2H).
C13 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 4.8 Hz, 1H), 7.26 (s, 1H), 6.90-6.81 (m, 1H), 5.84 (s, 1H), 4.66 (t, J = 8.6 Hz, 1H), 3.58 (s, 1H), 3.48-3.42 (m, 1H), 3.41-3.28 (m, 4H), 3.13 (q, J = 8.2 Hz, 1H), 2.89-2.72 (m , 2H), 2.52-2.43 (m, 1H), 2.40 (s, 3H), 2.39-2.33 (m, 4H), 2.34-2.30 (m, 4H), 2.13-2.05 (m, 1H), 1.92-1.83 (m, 1H), 1.75-1.65 (m, 2H).
C14 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J = 4.4 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.13-7.07 (m, 1H), 6.81 (s, 1H) ,4.25 (t, J = 8.2 Hz, 1H), 3.69 (s, 4H), 3.66-3.58 (m, 2H), 3.27 (t, J = 8.0 Hz, 1H), 2.88-2.75 (m, 1H), 2.75 -2.62 (m, 1H), 2.50 (s, 3H), 2.49-2.43 (m, 4H), 2.42-2.36 (m, 1H), 2.34 (s, 3H), 2.04-1.89 (m, 2H), 1.78-1.71 (m, 1H), 1.66-1.56 (m, 1H), 1.53-1.42 (m, 1H). C15 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 4.8 Hz, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 7.00-6.93 (m, 1H), 4.36 (s, 1H), 4.05 (s, 1H), 3.94-3.88 (m, 1H), 3.66 (s, 4H), 3.07-3.01 (m, 1H), 2.99-2.93 (m, 1H), 2.79-2.63 (m, 2H), 2.61-2.51 (m, 1H), 2.45-2.42 (m, 7H), 2.32 (s, 3H), 2.12-2.06 (m, 1H), 1.93-1.88 (m, 2H), 1.81-1.75 ( m, 1H), 1.71-1.62 (m, 1H), 0.79 (s, 9H), 0.01 (s, 6H). C16 J, BA, A.I. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.05-6.99 (m, 1H), 5.29 (s, 1H) , 4.28 (s, 1H), 4.03 (d, J = 10.0 Hz, 1H), 3.89 (s, 1H), 3.55-3.38 (m, 4H), 3.30 (d, J = 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, J = 13.6 Hz, 1H), 1.62-1.51 (m, 3H). C17 J, AI, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 7.6, 4.8 Hz, 1H), 6.74 (s, 1H), 4.31 (s, 1H), 4.22 (dd, J = 11.6, 5.2 Hz, 1H), 4.04 (t, J = 8.4 Hz, 1H), 3.86 (dd, J = 11.2, 4.0 Hz, 1H), 3.68 (s, 4H), 3.43 (d, J = 11.2 Hz, 1H), 2.71-2.63 (m, 2H), 2.48 (t, J = 5.2 Hz, 4H), 2.44 (s, 3H), 2.35 (s, 3H), 2.02-1.98 (m, 1H), 1.89-1.83 (m, 2H), 1.72-1.63 (m, 2H), 1.54-1.45 (m, 1H). C18 C, A.A.
^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 7.63-7.59 (m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 6.4 Hz, 1H) , 6.64 (s, 1H), 3.70 (s, 4H), 3.56-3.48 (m, 2H), 3.14-3.07 (m, 2H), 2.51 (s, 4H), 2.45 (s, 3H), 2.36 (s) , 3H), 2.21 (s, 1H), 2.06 (s, 4H), 1.86 (t, J = 16.0 Hz, 2H)
C19 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.07-6.99 (m, 1H), 4.26 (t, J = 8.4 Hz, 1H), 4.05-3.95 (m, 1H), 3.70 (s, 4H), 3.41-3.23 (m, 1H), 3.23-3.06 (m, 1H), 2.83-2.62 (m, 4H) , 2.49-2.43 (m, 7H), 2.33 (s, 3H), 2.30-2.18 (m, 1H), 1.91-1.78 (m, 2H), 1.75-1.58 (m, 1H).
C20 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.06-6.99 (m, 1H) , 4.17 (t, J = 8.0 Hz, 1H), 4.03-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.70 (s, 4H), 3.27 (s, 3H), 3.25-3.16 (m , 1H), 2.85-2.71 (m, 1H), 2.71-2.61 (m, 2H), 2.48 (s, 3H), 2.46-2.41 (m, 4H), 2.41-2.34 (m, 1H), 2.32 (s) , 3H), 2.20-2.06 (m, 1H), 1.97-1.90 (m, 2H), 1.86-1.77 (m, 1H), 1.72-1.59 (m, 1H). C21 J, B.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J = 4.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.17 (s, 1H), 7.03-6.97 (m, 1H), 4.07- 3.96 (m, 1H), 3.97-3.85 (m, 2H), 3.73-3.65 (m, 4H), 3.21 (s, 3H), 3.09-2.96 (m, 1H), 2.938-2.82 (m, 1H), 2.80-2.57 (m, 4H), 2.46-2.43 (m, 7H), 2.35-2.28 (m, 4H), 2.14-2.02 (m, 1H), 1.87-1.78 (m, 1H), 1.70-1.60 (m , 1H).
C22 J, B.A. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.58-8.42 (m, 1H), 7.68-7.40 (m, 1H), 7.36-7.25 (m, 1H), 7.18-6.98 (m, 1H), 6.82-6.45 (m, 1H), 3.95-3.85 (m, 1H), 3.83-3.74 (m, 1H), 3.70 (s, 2H), 3.60 (s, 2H), 3.15-3.03 (m, 1H), 2.78-2.2 (m, 1H), 2.51-2.48 (m, 4H), 2.44 (s, 3H), 2.38-2.30 (m, 3H), 2.28-2.15 (m, 1H), 1.87-1.73 (m, 2H), 1.68 -1.57 (m, 1H), 1.45-1.30 (m, 3H). C23 C, BH, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 7.61-7.57 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.17-7.05 (m, 1H), 6.45 ( s, 1H), 3.71-3.67 (m, 2H), 3.63 (s, 4H), 3.39-3.32 (m, 2H), 2.46-2.43 (m, 8H), 2.40-2.31 (m, 4H), 2.01- 1.95 (m, 1H), 1.97-1.86 (m, 2H).
C24 C, B.I., A.A.
^1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J = 4.0 Hz, 1H), 7.65-7.54 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.15-7.08 (m, 1H), 6.45 (s, 1H), 3.72-3.68 (m, 2H), 3.63 (s, 4H), 3.40-3.31 (m, 2H), 2.46-2.40 (m, 8H), 2.40-2.31 (m, 4H), 2.05-1.95 (m, 1H), 1.91-1.83 (m, 2H).
C25 C, BH, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.01 (s, 1H), 6.39 (s, 1H), 3.92-3.78 (m, 1H), 3.71-3.48 (m, 5H), 3.41-3.29 (m, 2H), 2.43(s, 8H), 2.33(d, J = 7.6 Hz, 6H), 2.25-1.83 (m, 4H).
C26 C, BH, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.26 (s, 1H), 6.93 (s, 1H), 6.42 (s, 1H), 3.74-3.54 (m, 6H), 3.41- 3.27 (m, 2H), 2.57-2.38 (m, 8H), 2.38-2.32 (s, 3H), 2.31-2.25 (m, 4H), 2.00-1.90 (m, 1H), 1.90-1.86 (m, 2H) ).

C27 C, BH, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.46 (s, 1H), 3.71 -3.54 (m, 6H), 3.37-3.25 (m, 2H), 2.54-2.38 (m, 8H), 2.34 (s, 3H), 2.29 (s, 4H), 2.07-1.94 (m, 1H), 1.89 -1.78 (m, 2H).
C28 C, BH, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.44 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.48 (s, 1H) ), 3.74-3.55 (m, 6 H), 3.38-3.15 (m, 2H), 2.52 (s, 3H), 2.49-2.30 (m, 8H), 2.30-2.26 (m, 4H), 1.99-1.75 ( m, 3H).
C29 C, BJ, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, J = 3.6 Hz, 1H), 7.62-7.58 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.14-7.11 (m, 1H), 6.44 (s, 1H), 3.65-3.61 (m, 5H), 3.35-3.31 (m, 2H), 3.22 (d, J = 7.6 Hz, 1H), 2.47-2.43 (m, 8H), 2.35 (s, 3H), 2.27-2.21 (m, 2H), 1.52 (s, 1H), 1.05 (d, J = 8.0 Hz, 3H).
C30 C, BK, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.4 Hz, 1H), 7.62-7.58 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.15-7.12 (m, 1H), 6.51 (s, 1H), 4.18 (d, J = 9.6 Hz, 1H), 3.75-3.66 (m, 5H), 3.56-3.38 (m, 4H), 2.54-2.48 (m, 5H), 2.45 (s, 3H), 2.37 (s, 3H), 2.11-2.07 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H). MS (ESI/APCI) m/z 424.8 [M+H] ⁺ .
C31 C, BK, AA, AJ ¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (d, J = 4.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.57-7.55 (m, 1H), 7.26-7.23 (m, 1H) , 6.58 (s, 1H), 3.94-3.92 (m, 1H), 3.71-3.58 (m, 6H), 3.44-3.41 (m, 1H), 3.35-3.33 (m, 1H), 3.04 (d, J = 7.2 Hz, 1H), 2.71-2.65 (m, 1H), 2.50-2.48 (m, 6H), 2.35 (s, 3H), 2.33 (s, 3H), 2.13-2.06 (m, 1H), 1.88-1.78 (m, 1H).MS (ESI/APCI) m/z 382.9 [M+H] ⁺ .
C32 C, BK, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 4.8 Hz, 1H), 7.65-7.58 (m, 1H), 7.46-7.31 (m, 1H), 7.19-7.14 (m, 1H), 6.33-6.22 (m, 1H), 4.59-4.29 (m, 2H), 3.92-3.40 (m, 9H), 3.04-2.84 (m, 1H), 2.49-2.30 (m, 11H), 0.91-0.80 (m) , 3H). MS (ESI/APCI) m/z 450.1 [M+H] ⁺ .
C33 BH, I
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.35 (s, 1H), 7.00 (s, 1H), 4.03-3.65 (m, 6H), 3.62-3.43 (m, 1H), 3.41-3.24 (m, 1H), 2.67-2.45 (m, 5H), 2.39 (s, 6H), 2.33(s, 3H), 2.26-2.12 (m, 1H), 2.09-1.96 (m, 1H), 1.95-1.77 (m, 2H).
C34 M, BH, AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.35 (d, J = 6.4 Hz, 1H), 7.01 (s, 1H), 4.11-3.93 (m, 1H), 3.92 (s, 4H), 3.87-3.78 (m, 1H), 3.71-3.58 (m, 1H), 3.48-3.34 (m, 1H), 2.64-2.55 (m, 1H), 2.49 (s, 4H), 2.45 (s, 3H), 2.41(s, 3H), 2.33 (s, 3H), 2.26-2.14 (m, 1H), 2.14-2.01 (m, 1H), 2.01-1.93 (m, 1H), 1.91-1.81 (m, 1H). C35 C, BH, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.03-6.98 (m, 1H), 6.33 (s, 1H) , 5.42 (s, 1H), 3.86 (s, 1H), 3.73 (s, 4H), 3.66-3.57 (m, 1H), 3.44-3.19 (m, 4H), 2.56 (t, J = 6.0 Hz, 2H) ), 2.47 (s, 4H), 2.43 (s, 3H), 2.40-2.30 (m, 4H), 2.25-2.12 (m, 1H), 2.12-1.95 (m, 2H), 1.95-1.83 (m, 1H) ). C36 C, BH, AA ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 3.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.01 (t, J = 6.0 Hz, 1H), 6.30 (s) , 1H), 3.83-3.87 (m, 3H), 3.63-3.66 (m ,3H), 3.35 (d, J = 14.2 Hz, 2H), 2.62 (s, 2H), 2.53 (s 2H), 2.41 (s) , 3H), 2.36 (d, J = 2.8 Hz, 6H), 2.17-2.19 (m, 1H),1.96-2.06 (m, 6H).
C37 C, BH, AA
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7.45-7.30 (m, 1H), 7.09-6.95 (m, 1H), 6.39 (s, 1H), 4.40 (s, 2H), 3.84 (s, 1H), 3.72-3.58 (m, 1H), 3.47-3.28 (m, 2H), 2.77 (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).
C38 N, BH, AK ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 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, J = 7.2 Hz, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.84 (t, J = 8.0 Hz, 1H), 3.67 (d, J = 13.6 Hz, 1H), 3.39 (t, J = 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). C39 N, BH, AK ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (d, J = 3.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.02-7.08 (m, 2H), 6.39 (d, J = 6.8 Hz, 1H), 6.19 (d, J = 14.4 Hz, 1H), 5.27 (d, J = 14.0 Hz, 1H), 5.07 (d, J = 14.0 Hz) , 1H), 4.05 (d, J = 12.8 Hz, 1H), 3.85 (d, J = 8.0 Hz, 1H), 3.49 (d, J = 12.8 Hz, 2H), 3.24 (d, J = 10.8 Hz, 1H) ), 3.16 (t, J = 7.8 Hz, 1H), 2.91-3.01 (m, 3H), 2.83 (t, J = 11.0 Hz, 1H), 2.46-2.51 (m, 3H), 2.41(s, 3H) , 2.38(s, 3H), 2.24(s, 1H), 1.84-1.91 (m, 3H). D1 C, A.L. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 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] ⁺ .
D2 C, A. A., A. M. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.44-7.35 (m, 3H), 7.13 (d, J = 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, J = 4.8 Hz, 4H), 2.30 (s, 3H).
D3 C, B.M., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.42-7.32 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.44 (s, 1H), 4.72 (s, 2H), 4.10 -3.22 (m, 4H), 3.08 (s, 3H), 2.50-2.42(m, 7H), 2.30 (s, 3H) ), 1.82 (s, 2H).
D4 C, B.M., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.42-7.36 (m, 3H), 7.14 (d, J = 6.0 Hz, 1H) , 6.67 (s, 1H), 4.71 (s, 2H), 4.14-4.03 (m, 2H), 3.06 (s, 4H), 2.82-2.78 (m, 1H), 2.65-2.62 (m, 1H), 2.52 (s, 3H), 2.03-2.17(m, 1H), 1.08 (d, J = 4.4 Hz, 3H). D5 C, B.M., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.42-7.36 (m, 3H), 7.13 (d, J = 6.8 Hz, 1H), 6.68 (s, 1H), 4.69 (s, 2H), 3.63 (t, J = 5.2 Hz, 2H), 3.56 (s, 4H), 3.06 (s, 3H), 2.75-2.45 ( m, 10H).
D6 C, B.M., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.50-7.30 (m, 3H), 7.13-7.11 (m, 1H), 6.68 ( s, 1H), 4.71 (s, 2H), 4.37( s, 2H), 3.07 (s, 3H), 2.76 ( s, 2H), 2.52 (s, 4H), 2.34 (s, 6H), 1.86 (s , 2H), 1.49-1.30 (m, 2H).
D7 C, B.M., A.A. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.44-7.29 (m, 3H), 7.12 (d, J = 6.8 Hz, 1H) , 6.32 (s, 1H), 4.74 (s, 2H), 4.20-3.10 (m, 4H), 3.08 (s, 3H), 2.69 (s, 1H), 2.52 (s, 3H), 2.26 (s, 6H) ), 2.20-2.12 (m, 1H), 1.80 (s, 1H).
D8 C, B.M., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.12 (d, J = 8 Hz, 1H), 7.41-7.32 (m, 3H), 7.12 (d, J = 6.8 Hz, 1H) , 6.65 (s, 1H), 4.69 (s, 2H), 3.50 (m, 4H), 3.06 (s, 3H), 2.59 (s, 4H), 2.51 (s, 3H), 1.59 (s, 1H), 0.46-0.43 (m, 4H).
D9 C, B.M., A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.41-7.35 (m, 3H), 7.12 (d, J = 7.2 Hz, 1H) , 6.65 (s, 1H), 4.71 (s, 2H), 3.57 (s, 4H), 3.07 (s, 3H), 2.76 (d, J = 7.6 Hz, 2H), 2.39 (s, 4H), 2.29 ( s, 3H), 1.30 (t, J = 7.6 Hz, 3H).
D10 C, B.M., A.A. ^1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.16 (s, 1H), 7.42 (s, 3H), 7.18 (s, 1H), 6.72 (s, 1H), 4.65 (s, 2H) ), 3.61 (s, 4H), 3.07 (s, 3H), 2.42 (s, 4H), 2.31 (s, 3H), 2.04 (s, 1H), 1.10 (s, 2H), 1.00 (s, 2H) .
D11 F, AC, AM
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.11 (s, 1H), 7.38 (s, 3H), 7.13 (s, 1H), 5.92 (s, 1H), 4.69 (s, 2H), 3.75-3.27 (m, 4H), 3.08 (s, 9H), 2.44 (s, 4H), 2.33 (s, 3H).
D12 B, BM, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.43-7.33 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H) , 6.47 (s, 1H), 4.71 (s, 2H), 3.56 (s, 4H), 3.06 (s, 3H), 2.44 (s, 3H), 2.42-2.35 (m, 4H), 2.30 (s, 3H) ).
D13 G, AC, AM ^1H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.40-7.37 (m, 3H), 7.12 (d, J = 5.6 Hz, 1H) , 6.39(s, 1H), 4.71 (s, 2H), 3.85 (s, 3H), 3.55 (s, 4H), 3.08 (s, 3H), 2.37 (s, 4H), 2.29 (s, 3H).
D14 C, BL, BM, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.92-8.90 (m, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.58-7.55 (m, 1H), 7.44-7.41 (m, 1H), 7.38-7.34 (m, 1H), 7.22 (s, 1H), 4.62 (s, 2H), 3.76-3.73 (m, 4H), 3.10 (s, 3H), 2.65 (s, 3H), 2.56-2.51 ( m, 7H), 2.39 (s, 3H).
D15 C, BL, BM, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J = 4.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.15 (s, 1H) , 6.96 (s, 1H), 6.69 (s, 1H), 4.68 (s, 2H), 3.58-3.55 (m, 4H), 3.04 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H) ), 2.41-2.38 (m, 4H), 2.30 (s, 3H). MS (ESI/APCI) m/z 377.0 [M+H] ⁺ .
D16 C, BN, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.83 (d, J = 4.8 Hz, 1H), 8.29-8.25 (m, 1H), 7.41-7.38 (m, 1H), 7.25-7.21 (m, 1H), 7.075-7.03 (m, 1H), 6.75 (s, 1H), 4.60 (s, 2H), 3.59-3.58 (m, 4H), 3.01 (s, 3H), 2.57 (s, 3H), 2.51 (s, 3H), 2.41-2.39 (m, 4H), 2.30 (s, 3H). D17 C, BN, BO, AA, AM ^1H NMR (400 MHz, CDCl ₃ ) δ 8.80 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.42-7.39 (m, 1H), 7.23-7.13 (m, 2H), 6.69 (s, 1H), 4.70 (s, 2H), 3.96-3.94 (m, 4H), 3.73-3.69 (m, 4H), 3.63-3.61 (m, 6H), 2.53 (s, 3H) .
D18 C, BN, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.37-7.34 (m, 1H), 6.95-6.92 (m, 1H), 6.85- 6.82 (m, 1H), 6.64 (s, 1H), 4.80 (s, 2H), 3.59 (s, 4H), 3.05 (s, 3H), 2.51 (s, 3H), 2.41 (s, 4H), 2.31 (s, 3H).
D19 C, BN, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.90 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 7.47-7.44 (m, 1H), 7.10-7.05 (m, 2H), 6.72 ( s, 1H), 4.58 (s, 2H), 3.60 (s, 4H), 3.02 (s, 3H), 2.51 (s, 3H), 2.42-2.40 (m, 4H), 2.31 (s, 3H). MS (ESI/APCI) m/z 381.0 [M+H] ⁺ .
D20 C, BN, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.39-8.35 (m, 1H), 7.44 (s, 1H), 6.92 (s, 1H), 6.70 (s, 1H), 4.67 ( s, 2H), 3.63 (s, 4H), 3.01 (s, 3H), 2.53-2.45 (m, 7H), 2.30 (s, 3H). MS (ESI/APCI) m/z 399.2 [M+H] ⁺ .
D21 D, B.P., A.N. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 8.10 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 7.6, 4.0 Hz, 1H), 6.96 (d, J = 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). D22 D, BQ, AO ^1H NMR (400 MHz, CDCl3) 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).
D23 D, BR, AN ^1H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.54-7.52 (m, 1H) , 6.75 (d, J = 5.6 Hz, 1H), 6.40 (s, 1H), 5.24 (s, 2H), 3.58 (s, 4H), 3.26 (s, 3H), 2.53 (s, 3H), 2.41 ( s, 4H), 2.31 (s, 3H). MS (ESI/APCI) m/z 364.2 [M+H] ⁺ . D24 D, A.N. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.64 (s, 2H), 8.09 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 6.20 (s, 1H), 5.49 (s, 2H) , 3.55 (s, 7H), 2.51 (s, 3H), 2.39 (s, 4H), 2.28 (s, 3H).
D25 C, A. A., A. M. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.38 (s, 3H), 7.14 (s, 1H), 6.58 (s, 1H), 4.62 (s, 2H), 3.65 (q, J = 6.8 Hz, 2H), 3.46 (s, 4H), 2.50 (s, 3H), 2.31 (s, 4H), 2.26 (s, 3H), 1.12 (t, J = 6.8 Hz, 3H).
D26 C, AO, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.80 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.47-7.44k (m, 2H), 7.41-7.36 (m, 2H), 6.21 (s, 1H), 5.16 (s, 2H), 3.44 (s, 4H), 2.81 (s, 1H), 2.46 (s, 3H), 2.35 (s, 4H), 2.29 (s, 3H), 0.80 ( d, J = 5.6 Hz, 2H), 0.68 (s, 2H).
D27 C, AO, AA
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.11 (s, 1H), 7.37 (s, 3H), 7.11 (s, 1H), 6.57 (s, 1H), 4.62 (s, 3H), 3.57 (s, 2H), 3.47 (s, 4H), 3.05 (s, 2H), 2.49 (s, 3H), 2.33 (s, 3H), 2.29 (s, 4H), 1.63 (s, 2H) ), 1.40 (s, 11H).
D28 C, AO, AA, AD
^1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.37 (s, 3H), 7.12 (s, 1H), 6.58 (s, 1H) , 4.62 (s, 2H), 3.57 (t, J = 7.2 Hz, 2H), 3.47 (s, 4H), 2.63 (t, J = 6.4 Hz, 2H), 2.49 (s, 3H), 2.33 (s, 4H), 2.26 (s, 3H), 1.68-1.60 (m, 4H), , 1.42- 1.40 (m, 2H).
D29 C, AO, AA
^1H NMR (400 MHz, CDCl ₃ ) δ 8.84-8.82 (m, 1H), 8.11-8.09 (m, 1H), 7.38-7.35 (m, 3H), 7.19-7.17 (m, 1H), 6.75 (s) , 1H), 4.64 (s, 2H), 3.58-3.53 (m, 6H), 2.50 (s, 3H),2.38-2.35 (m, 4H), 2.29 (s, 3H), 2.18 (t, J = 7.6 Hz, 2H), 1.90-1.83 (m, 2H), 1.34 (s, 9H).
D30 C, AO, AA, AP ^1H NMR (400 MHz, D ₂ O) δ 9.14 (d, J = 8.4 Hz, 1H), 9.07 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.09- 8.06 (m, 1H), 8.02 (d, J = 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).
D31 C, AO, AA, AP ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 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, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.50-2.48 (m, 4H), 2.34 (s, 3H), 2.26 (t, J = 7.2 Hz, 2H), 2.00-1.97 (m, 2H).
D32 C, BL, AA, AM ^1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.36-7.33 (m, 1H), 7.20 (s, 1H) , 7.07 (s, 1H), 6.91 (s, 1H), 4.64 (s, 2H), 3.74-3.55 (m, 6H), 2.57 (s, 3H), 2.53-2.45 (m, 7H), 2.34 (s) , 3H), 1.11 (t, J = 7.2 Hz, 3H).
D33 E, A.C., A.M. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.43-7.30 (m, 3H), 7.11 (d, J = 4.4 Hz, 1H) , 4.85 (s, 2H), 3.24 (s, 4H), 3.05 (s, 3H), 2.53 (s, 3H), 2.47 (s, 4H), 2.31 (s, 3H), 1.86 (s, 3H).
D34 I, B.M. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.90 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.38 (s, 3H), 7.03 (s, 1H), 4.95 (s, 2H) , 3.60 (s, 4H), 3.07 (s, 3H), 2.40 (s,7H), 2.29 (s, 3H).
D35 B, BM, AA ^1H NMR (400 MHz, CDCl ₃ ) δ 8.83 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.41-7.33 (m, 3H), 7.11 (d, J = 6.8 Hz, 1H), 5.10 (s, 2H), 3.53 (s, 4H), 3.16 (s, 3H), 2.49 (s, 4H), 2.45 (s, 3H), 2.32 (s, 3H).
D36 M, B.M., A.D. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.46-7.30 (m, 3H), 7.09 (s, 1H), 5.10 (s, 2H), 3.87 (s, 4H), 3.17 (s, 3H), 2.46 (s, 7H), 2.31 (s, 3H).
D37 A.H., A.M.
^1H NMR (400 MHz, CDCl ₃ ) δ 8.87 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.62-7.31 (m, 4H), 4.51 (s, 2H) , 4.46 (s, 2H), 4.38-3.96 (m, 4H), 3.36-3.11 (m, 4H), 2.83 (s, 3H), 2.79 (s, 3H), 2.59 (s, 3H). MS (ESI/APCI) m/z 392.8 [M+H] ⁺ .
D38 N, BM, AK
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.99 (s, 1H), 8.19 (d, J
= 8.0 Hz, 1H), 7.48-7.44 (m, 3H), 7.36 (d, J = 8.8 Hz, 1H), 7.20-7.15 (m, 2H), 7.09 (s, 1H), 6.28 (d, J = 7.2 Hz, 1H), 5.07 (s, 2H), 3.14 (s, 3H), 3.03 (s, 4H), 2.56 (s, 4H), 2.42 (s, 3H).
D39 N, BM, AK
^1H NMR (400 MHz, CDCl ₃ ) δ 8.93 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.50 (s, 2H), 7.44-7.38 (m, 2H), 7.32 (s, 1H), 7.15-7.12 (m, 1H), 6.45 (d, J = 7.2 Hz, 1H), 5.81 (s, 1H), 5.21 (s, 2H), 4.75 (s, 2H), 3.44 (d, J = 11.2 Hz, 2H），2.99-2.91 (m, 7H), 2.53-2.49 (m, 2H), 2.41 (s, 3H).
D40 D, B.N. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.47 (dd , J = 8.8, 4.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.61 (s, 1H), 4.84 (s, 2H), 3.59 (s, 4H), 3.13 (s, 3H) , 2.52 (s, 3H), 2.46-2.37 (m, 4H), 2.30 (s, 3H). D41 C, BN, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.81-8.79 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.48-7.45 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 4.66 (s, 2H), 3.58-3.55 (s, 4H), 3.05 (s, 3H), 2.50 (s, 3H) ), 2.40-2.38 (s, 4H), 2.29 (s, 3H). D42 C, BN, AA, AQ ^1H NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J = 3.2 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.50 (dd , J = 8.4, 4.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H), 4.99 (s, 2H), 3.61-3.52 (m, 4H), 3.19 (s, 3H), 2.50 (s, 3H), 2.43-2.37 (m, 4H), 2.29 (s, 3H). MS (ESI/APCI) m/z 388.2 [M+H] ⁺ . D43 C, BN, AA, AR ^1H NMR (400 MHz, CDCl ₃ ) δ 9.01 (dd, J = 8.8, 2.0 Hz, 1H), 8.75 (dd, J = 4.0, 2.0 Hz, 1H, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.8, 4.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 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] ⁺ . D44 D, B.N.
^1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.44 (dd, J = 7.6 Hz, J = 3.6 Hz , 1H), 7.20 (s, 1H), 6.60 (s, 1H), 4.84 (s, 2H), 3.58 (s, 4H), 3.09 (s, 3H), 2.50 (s, 3H), 2.44-2.38 ( m, 4H), 2.30 (s, 3H).
D45 C, BN, A.A.
^1H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.39-7.36 (m, 1H), 7.16 (s, 1H), 6.72 (s, 1H), 4.78 (s, 2H), 3.66 (s, 4H), 3.03 (s, 3H), 2.54 (s, 3H), 2.49 (s, 4H), 2.35 (s, 3H) ).
D46 C, BN, AA, AQ ^1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (dd, J = 4.4, 2.0 Hz, 1H), 8.13 (dd, J = 8.4, 2.0 Hz, 1H), 7.70 (s, 1H), 7.46 (dd, J = 8.4, 4.4 Hz, 1H), 7.14 (s, 1H), 6.63 (s, 1H), 4.80 (s, 2H), 3.67-3.54 (m, 4H), 3.08 (s, 3H), 2.51 (s) , 3H), 2.46-2.40 (m, 4H), 2.31 (s, 3H).
D47 C, BN, AA, AR ^1H NMR (400 MHz, CDCl ₃ ) δ 8.87 (d, J = 4.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.52-7.43 (m, 2H) , 6.65 (s, 1H), 4.86 (s, 2H), 3.67-3.58 (m, 4H), 3.12 (s, 6H), 2.51 (s, 3H), 2.47-2.42 (m, 4H), 2.32 (s) , 3H). MS (ESI/APCI) m/z 441.1 [M+H] ⁺ .
D48 D, B.N. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.98 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.76 (s, 2H), 7.49 (dd, J = 8.4, 4.0 Hz, 1H) , 7.15 (s, 1H), 4.64 (s, 2H), 3.81 (s, 4H), 3.03 (s, 3H), 2.61-2.58 (m, 4H), 2.52 (s, 3H), 2.40 (s, 3H) ). D49 C, BN, A.A.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.89 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41(s, 2H), 4.68 (s, 2H), 3.74(s, 4H), 3.05 (s, 3H), 2.49 (s, 7H), 2.35 (s, 3H). MS (ESI/APCI) m/z 441.1 [M+H] ⁺ .
D50 C, BN, AA, AQ
^1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 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).
D51 C, BN, AA, AR ^1H NMR (400 MHz, CDCl ₃ ) δ 9.00 (d, J = 3.2 Hz, 1H), 8.23 (dd, J = 8.4, 1.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 8.8, 4.4 Hz, 1H), 7.16 (s, 1H), 5.15 (brs, 1H), 4.21 (brs, 1H), 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] ⁺ .
D52 C, BN, A.A. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.40-8.32 (m, 1H), 6.94 (d, J = 7.6 Hz, 1H) , 6.84 (d, J = 11.2 Hz, 1H), 6.65 (s, 1H), 4.79 (s, 2H), 4.10-3.95 (m, 2H), 3.80-3.76 (m, 1H), 3.52 (d, J = 10.8 Hz, 1H), 3.32 (t, J = 10.8 Hz, 1H), 3.13-2.95 (m, 4H), 2.81 (d, J = 10.4 Hz, 1H), 2.51 (s, 3H), 2.38-2.20 (m, 5H).
D53 C, BN, AA, AD ^1H NMR (400 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 7.2, 3.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.96-6.70 (m, 2H), 4.78 (s, 2H), 4.56 (s, 1H), 4.10-3.88 (m, 3H), 3.42 (t, J = 10.4 Hz, 1H), 3.10-3.00 (m, 4H), 2.86 (d, J = 10.4 Hz, 1H), 2.51 (s, 3H), 2.35-2.24 (m, 4H), 2.09 (t, J = 9.2 Hz, 1H).
D54 E, A.C., A.M.
^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.45-7.36 (m, 3H), 7.12 (d, J = 7.2 Hz, 1H) , 6.70 (s, 1H), 4.75 (s, 2H), 4.56 (s, 2H), 3.86 (br s, 1H), 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] ⁺ .
D55 D, BN, AO, AJ
^1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.07 (d, J = 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).

D56 D, BN, AN, AJ

^1H NMR (400 MHz, CDCl ₃ ) δ 8.90 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz) , 1H), 7.37-7.30 (m, 1H), 6.36 (s, 1H), 5.30 (s, 1H), 4.70-4.20 (m, 3H), 3.69 (s, 4H), 2.96 (s, 3H), 2.53 (s, 3H), 2.48 (s, 4H), 2.34 (s, 3H).
D57 D, A.S. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (d, J = 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). MS (ESI/APCI) m/z 455.9 [M+H] ⁺ .
D58 C, BN, AA, AO, BO, AT ^1H NMR (400 MHz, CDCl ₃ ) δ 8.70 (d, J = 4.0 Hz, 1H), 8.01 (d, J = 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, J = 4.4 Hz, 2H), 3.63 (t, J = 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] ⁺ . D59 C, BN, AA, AO, BO, AT ^1H NMR (400 MHz, CDCl ₃ ) δ 8.89 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.67 (d , J = 9.2 Hz, 1H), 7.34-7.31 (m, 1H), 6.25 (s, 1H), 4.61-4.34 (m, 1H), 4.24-3.98 (m, 1H), 3.77 (t, J = 4.4 Hz, 2H), 3.62 (t, J = 4.4 Hz, 2H), 3.03 (s, 3H), 2.98 (s, 3H), 2.64 (s, 3H), 2.56-2.49 (m, 4H), 2.37 (s) , 3H). MS (ESI/APCI) m/z 455.7 [M+H] ⁺ .

biological activity

Example 22: HPB-ALL CXCR4 competitive binding assay

HPB-ALL cells were maintained in RPMI-1640 (Gibico) supplemented with 10% FBS (Hyclone). APC-conjugated anti-human CXCR4 was purchased from Sungene. First, EC ₈₀ for 12G5 binding of CXCR4 was determined. Then, the test compounds were serially diluted in a 1:3 ratio in a 96-well plate. Cells were rinsed once with cold assay buffer (DPBS+2% HI-FBS) and then resuspended in the same buffer at a final concentration of 1 x 10 ⁶ /mL. The cell suspension was then added to the wells and APC-conjugated anti-human CXCR4 clone 12G5 was added with an EC of ₈₀ determined. The mixture of cells, compounds and APC-conjugated anti-human CXCR4 clone 12G5 was incubated at 4°C for 3 hours and then 100 μl of 4% PFA was added. Cells were then rinsed once with assay buffer, resuspended, and analyzed by FACS. The percent effect (%) at each concentration of compound was calculated relative to the amount of calcium produced in the positive and negative control wells contained in each assay plate. A summary of the CXCR4 competitive binding assay results for selected compounds described herein is presented in Table 2, plotting the concentration and percent effect of the test compounds and determining the concentration of compound required for 50% effectiveness (IC ₅₀ ). did. Table 3 summarizes the results of the CXCR4 competitive binding assay for control compounds. Figures 1-2 are IC ₅₀ graphs of compounds A42 and A43.

Table 2. Results of 12G5 binding analysis of selected compounds of the present invention.

compound number IC ₅₀ (nM) compound number IC ₅₀ (nM) compound number IC ₅₀ (nM) A1 45 A2 228 A3 19 A4 229 A5 113 A6 1138 A7 393 A8 242 A9 14 A10 23 A11 26 A12 8000 A13 8000 A14 2253 A15 606 A16 17 A17 2689 A18 43 A19 67 A20 210 A21 790 A22 32 A23 34 A24 42 A25 100 A26 41 A27 7.9 A28 21 A29 78 A30 65 A31 77 A32 22 A33 268 A34 47 A35 106 A36 5735 A37 4432 A38 6940 A39 94 A40 110 A41 97 A42 9.8 A43 11 A44 296 A45 886 A46 161 A47 58 A48 240 A49 123 A50 211 A51 16 A52 27 A53 33 A54 356 A55 44 A56 131 A57 21 A58 19 A59 63 A60 464 A61 8.8 A62 2288 A63 29 A64 21 A65 13 A66 20 A67 12 A68 46 A69 27 A70 54 A71 90 A72 146 A73 32 A74 100 A75 15 A76 220 A77 9 C1 93 C2 9000 C3 9000 C4 2324 C5 20 C6 3235 C7 9000 C8 6957 C9 9000 C10 248 C11 142 C12 165 C13 62 C14 8105 C15 500 C16 7.74 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 D1 18 D2 65 D4 55 D14 57 D20 675 D25 151 D28 338 D30 3822 D36 1171

Table 3. 12G5 binding assay results for selected control compounds.

compound number IC ₅₀ (nM) compound number IC ₅₀ (nM) compound number IC ₅₀ (nM) B1 >10000 B2 >10000 B3 >10000 B4 >10000 B5 >10000 B6 >10000 B7 >10000 B8 >10000

Example 23: FLIPR tetra calcium mobilization assay (mobilization assay)

FLIPR tetra calcium mobilization assay was performed at HD Bioscience. Briefly, The Molecular Devices, Fluorescent Imaging Plate Reader (FLIPR) Tetra was used for this analysis. Excitation was achieved through a unique arrangement of the LEDs in the device, and the emission was captured using a CCD camera (EMCD camera for FI and ICCD camera for luminescence). The homologous FLIPR calcium 4 assay kit from Molecular Devices was used as a fluorescent substance. The compound was dissolved in 100% dimethyl sulfoxide (DMSO) at a concentration of 30 mM. A series of 10-point, quadruple, intermediate dilutions ranging from the highest concentration of 4 mM to the lowest concentration of 0.01 μM were prepared in 100% DMSO. 1 μl of each compound dilution in 100% DMSO was transferred to a Greiner #781201 plate, and ddNARP (near assay ready, direct dilution plate) was prepared from the compound dilution plate. Additionally, each ddNARP plate included positive and negative control wells to determine the upper and lower limits of the assay signal. The final assay concentration of the compounds ranges from 10 μM to 0.035 nM in 0.5% DMSO. Human CD ⁴⁺ T-cells were isolated from human whole blood and then activated and amplified using a CD3/CD28 amplification kit (Life Technologies). Cells were frozen in ThermoFisher-formulated recovered cell culture freezing medium containing 10% dimethyl sulfoxide (DMSO) and 10% fetal bovine serum (FBS) (ThermoFisher Catalog No. 10100147). When used, cells were ^resuspended in 1 2X Calcium 4 dye (20 μl/well) was added and the mixture was centrifuged briefly (~10 seconds) and stopped when 1000 rpm was reached. Compounds were equilibrated prior to addition of compounds and CXCL12 to the plate. Raw data was analyzed using Abase. The percent effect (%) at each concentration of the compound was calculated using Abase and relatively calculated based on the amount of calcium production in the positive and negative control wells included in each assay plate. The concentration and % effect of the test compound were graphed using Abase, and the compound concentration required to achieve 50% of the effect (IC ₅₀ ) was calculated using a 4-parameter logistic concentration response equation. Table 4 summarizes the results of selected compounds in the calcium mobilization assay. Figures 3 and 4 summarize the results of compounds A78 and A83 in calcium mobilization assays.

Table 4. Results of selected compounds of the invention in calcium mobilization assay.

compound number IC ₅₀ (nM) compound number IC ₅₀ (nM) compound number IC ₅₀ (nM) A1 4.5 A22 3.4 A42 0.021 A61 0.024 A75 0.090 A78 0.062 A79 0.22 A80 0.18 A81 4.5 A82 2.5 A83 0.93 A84 3.0 A85 0.99 A86 0.13 A87 0.18 A88 0.30 A89 0.13 A90 0.046 A91 0.032 A92 118 A93 20000 A94 20000 A95 0.13 A96 0.086 A97 0.25 A98 0.15 A99 0.39 A100 0.29 C33 1.1 C34 1.8 C35 2.7 C36 0.5 C37 12 C38 0.2 C39 0.1 D1 1.2 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 D11 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 (21)

Compound of Formula III, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,
A ₁ is CR ₄₄ , A ₂ is N and A ₃ is CR ₄₄ ;

W ₂ is ego;
U is and;
Q is a bond or CH ₂ ;
Each of R ₁ , R ₂ , R ₃ and R ₄ is independently selected from the group consisting of H, deuterium, and C _1-6 alkyl;
Each R ₅ and R ₆ is independently selected from the group consisting of H, deuterium, and C _1-6 alkyl, wherein C _1-6 alkyl is unsubstituted or independently amino, and -NHC(=O ) is substituted with 1-3 groups selected from the group consisting of O(C _1-6 alkyl); or R ₅ is O or CR ₄₅ R ₄₆ , and R ₄ and R ₅ together with the atoms attached to them form a ring;
R ₇ is selected from the group consisting of H, and C _1-6 alkyl, wherein C _1-6 alkyl is unsubstituted or independently selected from the group consisting of C _3-6 cycloalkyl. substituted;
each R ₈ and R ₉ is independently selected from the group consisting of H, deuterium, and C _1-6 alkyl;
R ₄₄ is H, deuterium, halide, -CN, amino, C _1-6 alkyl, C ₃ cycloalkyl, -OCH ₃ , -SCH ₃ , -N(CH ₃ ) ₂ , , , , , -NH(CH ₃ ), , , , -C(CH ₃ ) ₂ , -OCH ₂ CH ₃ , , -CF ₃ , or -CH ₂ (OH), where * indicates the binding position;
Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₅ , R ₂₆ , R ₂₇ , and R ₂₈ is independently selected from the group consisting of H, deuterium, C _1-6 alkyl, and -CH ₂ (OH) being selected;
R' is H, C _1-6 alkyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ (OCH ₃ ), -CH ₂ CH ₂ (CN), -CH(CH ₃ ) ₂ , C ₃ cycloalkyl, and is selected from the group consisting of, where * represents the binding position; or R' and R ₂₁ together with the N atom to which they are attached form a 5-membered heterocycle; and
Each R ₄₅ and R ₄₆ is independently selected from the group consisting of H, deuterium, and C _1-3 alkyl; Or R ₄₅ and R ₄₆ form a ring together with the atoms attached to them. According to paragraph 1,
A compound of formula IIIa, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof:

In the above equation,
each of E ₁ , E ₂ and E ₃ is independently selected from the group consisting of O and CR ₄₅ R ₄₆ ; and
Each R ₄₅ and R ₄₆ is independently selected from the group consisting of H, deuterium, and C _1-3 alkyl; Or R ₄₅ and R ₄₆ form a ring together with the atoms attached to them. According to paragraph 2,
Each of E ₁ , E ₂ and E ₃ is independently CH ₂ , O and is selected from the group consisting of; One or more of E ₁ , E ₂ and E ₃ Phosphorus, a compound, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, selected from the group consisting of the following compounds:



A compound, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, selected from the group consisting of the following compounds:












According to paragraph 1,
A compound, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein the compound is selected from the group consisting of the following compounds:






A therapeutically effective amount of the other compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and
Pharmaceutically acceptable carrier, diluent, adjuvant or excipient
A pharmaceutical composition comprising,
The pharmaceutical composition is for treating diseases, mobilizing stem cells, and treating damaged or burned skin by antagonizing the CXCR4 pathway,
The above diseases include HIV infection, myocardial infarction, hematopoiesis-related disease, inflammation, allergic disease, asthma, allergic pneumonia, interstitial lung disease, lupus erythematosus, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, and severe 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 vitelline 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, cystoid macular edema, glaucoma, branch vein occlusion. , breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell cancer, thyroid cancer, sarcoma, osteosarcoma, dermatofibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, stomach 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 A pharmaceutical composition selected from the group consisting of leukemia, lymphoblastic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorder, brain tumor, astrocytoma, medulloblastoma, schwannoma, primitive neuroectodermal tumor and pituitary adenoma. (a) a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof; and
(b) one or more additional compounds selected from the group consisting of anti-neoplastic agents, anti-cancer agents, anti-bacterial agents, anti-viral agents, central nervous system agents and anti-diabetic agents.
As a combination composition comprising,
The combination composition is intended to treat diseases, mobilize stem cells, and treat damaged or burned skin by antagonizing the CXCR4 pathway,
The above diseases include HIV infection, myocardial infarction, hematopoiesis-related disease, inflammation, allergic disease, asthma, allergic pneumonia, interstitial lung disease, lupus erythematosus, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, and severe 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 vitelline 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, cystoid macular edema, glaucoma, branch vein occlusion. , breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell cancer, thyroid cancer, sarcoma, osteosarcoma, dermatofibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, stomach 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 A combination composition selected from the group consisting of leukemia, lymphoblastic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorder, brain tumor, astrocytoma, medulloblastoma, schwannoma, primitive neuroectodermal tumor, and pituitary adenoma. According to any one of claims 1 to 6,
The compounds are intended to treat diseases, mobilize stem cells, and treat damaged or burned skin by antagonizing the CXCR4 pathway,
The above diseases include HIV infection, myocardial infarction, hematopoiesis-related disease, inflammation, allergic disease, asthma, allergic pneumonia, interstitial lung disease, lupus erythematosus, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, and severe 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 vitelline 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, cystoid macular edema, glaucoma, branch vein occlusion. , breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell cancer, thyroid cancer, sarcoma, osteosarcoma, dermatofibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, stomach 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 A compound selected from the group consisting of leukemia, lymphoblastic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorder, brain tumor, astrocytoma, medulloblastoma, schwannoma, primitive neuroectodermal tumor and pituitary adenoma, or pharmaceutically thereof. Acceptable salts, hydrates, solvates, stereoisomers or tautomers. delete delete delete delete delete delete delete delete delete delete delete delete