GCN2 modulator compounds

Abstract

The disclosure herein relates to novel compounds of formula (1): or salts thereof, wherein X, Y, R 1 、R 2 、R 3 、R 4 and R 5 As defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with general regulatory repressor kinase 2 (GCN2).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to UK patent application number 2002144.0 filed on February 17, 2020 and UK patent application number 2007163.5 filed on May 14, 2020. The disclosures of those applications are hereby incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to novel compounds and their use as general regulatory repressor protein kinase 2 (GCN2) regulators. The compounds described herein can be used to treat or prevent diseases in which GCN2 is involved. The present application also relates to pharmaceutical compositions comprising these compounds, the manufacture of these compounds and compositions, and the use of these compounds and compositions in preventing or treating such diseases in which GCN2 is involved. Background Art

[0004] A wide range of cellular conditions and stresses activate a broadly conserved signaling pathway known as the integrated stress response (ISR) pathway. Activation of the ISR can trigger cell cycle arrest, differentiation, amino acid biosynthesis and transport pathways, compensatory adaptations, or apoptosis, depending on the cell type and the initiating stress.

[0005] GCN2 is one of four stress kinases in the ISR pathway, which senses amino acid availability and controls gene expression in response to amino acid deprivation, UV irradiation, viral infection, proteasome inhibition, hypoxia, glucose deprivation, and oxidative stress. In mammals, GCN2 is also known as EIF2AK4 (eukaryotic translation initiation factor 2α kinase 4).

[0006] GCN2 contains a eukaryotic kinase domain, a pseudokinase domain, and a histidyl-tRNA synthetase (HisRS)-associated domain, which binds uncharged tRNA with a higher affinity than charged tRNA. Sequences at both the N-terminus and C-terminus of GCN2 have been shown to be important for efficient sensing of starvation signals. A lysine residue at the C-terminus has also been shown to be essential for tRNA binding and kinase activity, and residues at the top of the C-terminal region confer GCN2 ribosome binding ability, which is important for translation control.

[0007] In eukaryotes, the mechanism for recognizing essential amino acid deficiency follows a conserved general regulatory system in which uncharged transfer RNA first induces autophosphorylation of GCN2, followed by phosphorylation of eukaryotic initiation factor 2α (eIF2α), leading to reduced globular protein synthesis and, consequently, reduced overall amino acid utilization. Simultaneously, when eIF2α is phosphorylated, a set of stress-responsive mRNAs with upstream open reading frames (uORFs), including ATF4, CHOP, GADD34, and β-secretase BACE-1, are more efficiently translated, which in turn increases amino acid biosynthesis and transport pathways. The GCN2-mediated translational program also controls the host response to infection, immunity, inflammation, and other physiological and pathological processes. A subset of genes upregulated by ATF4 is involved in amino acid import and metabolism, and ATF4- / - cells are hallmarked by impaired amino acid metabolism.

[0008] Therefore, regulation of general regulatory repressor kinase 2 (GCN2) may provide therapeutic strategies for many diseases. Summary of the Invention

[0009] The present invention provides compounds having activity as modulators of general regulatory repressor protein kinase 2 (GCN2).

[0010] Therefore, in some embodiments, the present invention provides a compound of formula (1):

[0011]

[0012] or a salt thereof, wherein;

[0013] R 1 、R 2 、R 3 and R 4 independently selected from H, halo and C optionally substituted with 1-6 fluorine 1-3 Alkyl, where R 1 、R 2 、R 3 and R 4 At least one of them is a halogen group or a C group optionally substituted by 1 to 6 fluorine groups 1-3 Alkyl, or R 4 With R 5 Connected to form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is optionally substituted with halogen and optionally substituted with 1-6 fluorine groups. 1-3 Alkyl substitution; R 5 is selected from H and C optionally substituted by 1-6 fluorine 1-3 alkyl;

[0014] X is a 9- or 10-membered fused heterobicyclic ring containing 1-4 nitrogen heteroatoms, wherein the 9- or 10-membered fused heterobicyclic ring is NR 8 R 9 substituted and optionally substituted by halogen, C 1-3 Alkyl or NH2 further substituted;

[0015] R 8 and R 9 Independently selected from H, C 1-6 Alkyl, -C(O)NH2, -C(O)-C 1-6 Alkyl and 5 or 6 membered carbocyclic or heterocyclic ring, wherein the C 1-6 Alkyl, -C(O)-C 1-6 The alkyl group and the 5- or 6-membered carbocyclic or heterocyclic ring are independently optionally substituted with 1 to 6 substituents selected from halo, OH and phenyl,

[0016] or R 8 and R 9 Together with nitrogen, it forms a 6-membered heterocyclic ring;

[0017] Y is a 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring; or NH2, wherein said 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring is optionally substituted by 1-3 groups selected from halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH;

[0018] R 13 and R 14 are independently H or C 1-3 alkyl; and

[0019] The condition is

[0020] When X is a 9-membered fused heterobicyclic ring containing 1-4 nitrogen heteroatoms, the 9-membered fused heterobicyclic ring is only NR 8 R 9 substituted, and Y is a 6-membered heterocyclic ring containing 1-4 nitrogen heteroatoms, wherein the 6-membered heterocyclic ring is optionally substituted by 1-3 groups selected from halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1-6 substituents selected from halo and OH; and

[0021] When X is a 10-membered fused heterobicyclic ring containing 1-4 ring heteroatoms which are nitrogen, wherein said 10-membered fused heterobicyclic ring is substituted only with NH2, R 1 、R 2 、R 3 and R 4 One of them is a halogen or C 1-3 Alkyl, remaining R 1 、R 2 、R 3 and R 4 It's H, R 5 When Y is a 5- or 6-membered carbocyclic or heterocyclic ring, the 5- or 6-membered carbocyclic or heterocyclic ring is substituted by 2 or 3 groups selected from halogen, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH.

[0022] The compounds of the present invention can be used as GCN2 regulators. The compounds of the present invention can be used as GCN2 inhibitors. The compounds of the present invention can be used as GCN2 antagonists. The compounds of the present invention can be used as GCN2 agonists. The compounds of the present invention can be used to treat diseases or disorders characterized by activation of GCN2. The compounds of the present invention can be used to manufacture medicaments. The compounds or medicaments can be used to treat, prevent, improve, control diseases or disorders in which GCN2 is involved or reduce their risk. The compounds of the present invention can be used as a single agent or in combination with one or more additional agents. Additional agents may include radiotherapy, chemotherapy, immunotherapy or tumor microenvironment regulators. The compounds of the present invention can be used to treat cancer, neurodegenerative diseases, chronic infections or conditions or symptoms associated therewith. The compounds of the present invention can be used to treat breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndrome, myeloproliferative tumors, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, Chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, malignant pleural mesothelioma, head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma, childhood neuroblastoma, or symptoms associated with them. DETAILED DESCRIPTION

[0023] The present invention relates to novel compounds. The present invention also relates to the use of the novel compounds as GCN2 modulators. The present invention further relates to the use of the novel compounds in the manufacture of medicaments for use as GCN2 modulators.

[0024] The present invention further relates to compounds, compositions and agents that can be used to treat cancer, neurodegenerative diseases, chronic infections, or disorders or symptoms associated therewith.

[0025] In one aspect, a compound of formula (1) is provided:

[0026]

[0027] or a salt thereof, wherein;

[0028] R 1 、R 2 、R3 and R 4 independently selected from H, halo and C optionally substituted with 1-6 fluorine 1-3 Alkyl, where R 1 、R 2 、R 3 and R 4 At least one of them is a halogen group or a C group optionally substituted by 1 to 6 fluorine groups 1-3 Alkyl, or R 4 With R 5 Connected to form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is optionally substituted with halogen and optionally substituted with 1-6 fluorine groups. 1-3 Alkyl substitution; R 5 is selected from H and C optionally substituted by 1-6 fluorine 1-3 alkyl;

[0029] X is a 9- or 10-membered fused heterobicyclic ring containing 1-4 nitrogen heteroatoms, wherein the 9- or 10-membered fused heterobicyclic ring is NR 8 R 9 substituted and optionally substituted by halogen, C 1-3 Alkyl or NH2 further substituted;

[0030] R 8 and R 9 Independently selected from H, C 1-6 Alkyl, -C(O)NH2, -C(O)-C 1-6 Alkyl and 5 or 6 membered carbocyclic or heterocyclic ring, wherein the C 1-6 Alkyl, -C(O)-C 1-6 The alkyl group and the 5- or 6-membered carbocyclic or heterocyclic ring are independently optionally substituted with 1 to 6 substituents selected from halo, OH and phenyl,

[0031] or R 8 and R 9 Together with nitrogen, it forms a 6-membered heterocyclic ring;

[0032] Y is a 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring; or NH2, wherein said 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring is optionally substituted by 1-3 groups selected from halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH;

[0033] R 13 and R 14 are independently H or C 1-3 alkyl; and

[0034] The condition is

[0035] When X is a 9-membered fused heterobicyclic ring containing 1-4 nitrogen heteroatoms, the 9-membered fused heterobicyclic ring is only NR 8 R 9 substituted, and Y is a 6-membered heterocyclic ring containing 1-4 nitrogen heteroatoms, wherein the 6-membered heterocyclic ring is optionally substituted by 1-3 groups selected from halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1-6 substituents selected from halo and OH; and

[0036] When X is a 10-membered fused heterobicyclic ring containing 1-4 ring heteroatoms which are nitrogen, wherein said 10-membered fused heterobicyclic ring is substituted only with NH2, R 1 、R 2 、R 3 and R 4 One of them is a halogen or C 1-3 Alkyl, remaining R 1 、R 2 、R 3 and R 4 It's H, R 5 When Y is a 5- or 6-membered carbocyclic or heterocyclic ring, the 5- or 6-membered carbocyclic or heterocyclic ring is substituted by 2 or 3 groups selected from halogen, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH.

[0037] In the descriptions herein, it is understood that each description, variation, embodiment, or aspect of a section can be combined with each description, variation, embodiment, or aspect of any other section, as if each combination of descriptions were specifically and individually listed. For example, each description, variation, embodiment, or aspect of X of formula (1) provided herein can be combined with each description, variation, embodiment, or aspect of Y of formula (1) as if each combination were specifically and individually listed.

[0038] In the compounds described herein, X can be a 9- or 10-membered fused heterobicyclic ring system containing 1-4 N-cyclic heteroatoms. X can be a 9- or 10-membered fused heterobicyclic ring system containing 1 N-heteroatom. X can be a 9- or 10-membered fused heterobicyclic ring system containing 2 N-cyclic heteroatoms. X can be a 9- or 10-membered fused heterobicyclic ring system containing 3 N-cyclic heteroatoms. X can be a 9- or 10-membered fused heterobicyclic ring system containing 4 N-cyclic heteroatoms. X can be a ring system replaced by a group R 6 and R 7 a substituted 9- or 10-membered fused heterobicyclic ring system containing 1-4 N ring heteroatoms; wherein R 6 and R 7 One of them is NR 8 R 9 and the other is H, NH2 or halo.

[0039] X can be a 9- or 10-membered fused heterobicyclic ring system containing 1-4 N ring heteroatoms, said heterobicyclic ring system being NR 8 R 9 and optionally further substituted by halogen, C 1-3 The 9- or 10-membered fused heterobicyclic ring may be aromatic or non-aromatic. In some embodiments, the 9- or 10-membered fused heterobicyclic ring is aromatic.

[0040] X can be a group R 6 and R 7 a substituted 9- or 10-membered fused heterobicyclic ring, wherein R 6 and R 7 One of them is NR 8 R 9 and the other is H, NH2 or halo. In some embodiments, R 8 and R 9 Independently selected from H, C 1-6 Alkyl, -C(O)NH2, -C(O)-C 1-6 Alkyl and 5 or 6 membered carbocyclic or heterocyclic ring, wherein the C 1-6 Alkyl, -C(O)-C 1-6The alkyl group and the 5- or 6-membered carbocyclic or heterocyclic ring are independently optionally substituted with 1-6 substituents selected from halogen, OH and phenyl, or R 8 and R 9 Together with nitrogen, a 6-membered heterocyclic ring is formed. 6 and R 7 Independently selected from: H, NH2, NHCH3, N(CH3)2, F, NHCH2CH2OH, NHCH(CH3)CH2OH, NHCH(CH2OH)2, NHCH(CH2OH)(C6H5), NHCOCH3, NHCOCH2CH3, NHCOCH(CH3)2, NHCOC(CH3)3,

[0041] X can be a 9- or 10-membered fused heterobicyclic ring system containing 1-4 N ring heteroatoms substituted by NH2.

[0042] X may be a 10-membered fused heterobicyclic ring system containing 2 N ring heteroatoms substituted by NH2.

[0043] In some embodiments, the heterobicyclic ring system is selected from the group consisting of quinazoline, quinoline, benzimidazole, isoquinoline, pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pteridine, quinoxaline, purine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, indazole, and pyrrolo[2,3-b]pyridine; and the optional substituent is a group R 6 and R 7 ; where R 6 and R 7 One of them is NR 8 R 9 and the other is H, NH2 or halo.

[0044] In some embodiments, the heterobicyclic ring system is selected from the group consisting of quinazoline, quinoline, benzimidazole, isoquinoline, pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pteridine, quinoxaline, purine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, indazole, and pyrrolo[2,3-b]pyridine; and the optional substituent is a group R 6 and R 7 , R 6 and R 7 One of them is NR 8 R 9 and the other is H, NH2 or halo.

[0045] In some embodiments, the heterobicyclic ring system is selected from the group consisting of quinazoline, quinoline, benzimidazole, isoquinoline, pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pteridine, quinoxaline, purine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, indazole, and pyrrolo[2,3-b]pyridine, each of which is substituted with NH2.

[0046] X may be a substituted quinazoline ring system, wherein the substituent is NH2.

[0047] X can be selected from:

[0048]

[0049] where R 6 and R 7 can be attached at any available position of the bicyclic system, R 6 and R 7 One of them is NR 8 R 9 and the other is H, NH2 or halo.

[0050] X can be:

[0051]

[0052] X can be selected from:

[0053]

[0054]

[0055] In some embodiments, R 6 and R 7 One of them is NR 8 R 9 and the other is H, NH2 or halo. 6 and R 7 Can be independently selected from: H, NH2, NHCH3, N(CH3)2, F, NHCH2CH2OH, NHCH(CH3)CH2OH, NHCH(CH2OH)2, NHCH(CH2OH)(C6H5), NHCOCH3, NHCOCH2CH3, NHCOCH(CH3)2, NHCOC(CH3)3, R 6 Can be H and R 7 It can be NH2.

[0056] In the compounds described herein, R 8 and R9 Can be independently selected from H, C 1-6 Alkyl, -C(O)NH2, -C(O)-C 1-6 Alkyl and 5 or 6 membered carbocyclic or heterocyclic ring, wherein the C 1-6 Alkyl, -C(O)-C 1-6 The alkyl group and the 5- or 6-membered carbocyclic or heterocyclic ring are independently optionally substituted with 1-6 substituents selected from halogen, OH and phenyl, or R 8 and R 9 Together with nitrogen, a 6-membered heterocyclic ring is formed. 8 and R 9 independently selected from H, C optionally substituted by 1 to 6 fluorine atoms or optionally substituted by OH 1-6 alkyl and -C(O)-C optionally substituted by 1 to 6 fluorine atoms or optionally substituted by OH 1-6 Alkyl. R 8 and R 9 can be independently selected from H, CH3, CH2CH2OH, CH(CH3)CH2OH, NHCOCH3, NHCOCH2CH3, NHCOCH(CH3)2, NHCOC(CH3)3 and In some embodiments, NR 8 R 9 Selected from NH2, NHCH3, N(CH3)2, NHCH2CH2OH, NHCH(CH3)CH2OH, NHCH(CH2OH)2, NHCH(CH2OH)(C6H5), NHCOCH3, NHCOCH2CH3, NHCOCH(CH3)2, NHCOC(CH3)3,

[0057] In the compounds described herein, Y can be a 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring; or NH2, wherein the 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring is optionally substituted by 1-3 groups selected from halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, and wherein R 13 and R 14 are independently H or C 1-3The 5-, 6-, 9- or 10-membered heterocyclic ring may have 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0058] The 5 or 6 membered carbocyclic or heterocyclic ring can be an aromatic or non-aromatic monocyclic ring. In some embodiments, the 5 or 6 membered carbocyclic or heterocyclic ring is aromatic. In some embodiments, the 5 or 6 membered carbocyclic or heterocyclic ring is saturated. In some embodiments, the 5 or 6 membered carbocyclic or heterocyclic ring is unsaturated non-aromatic.

[0059] The 9- or 10-membered carbocyclic or heterocyclic ring may be aromatic or a non-aromatic fused bicyclic ring. In some embodiments, the 9- or 10-membered carbocyclic or heterocyclic ring is aromatic. In some embodiments, the 9- or 10-membered carbocyclic or heterocyclic ring is saturated. In some embodiments, the 9- or 10-membered carbocyclic or heterocyclic ring is unsaturated non-aromatic.

[0060] Y may be an optionally substituted 6-membered carbocyclic or heterocyclic ring; or NH2. Y may be an optionally substituted 6-membered carbocyclic or heterocyclic ring. Y may be NH2. Y may be an optionally substituted 6-membered carbocyclic ring. Y may be an optionally substituted 6-membered heterocyclic ring.

[0061] Y may be selected from an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted cyclohexane ring, an optionally substituted piperidine ring, an optionally substituted piperazine ring, an optionally substituted tetrahydropyran ring, an optionally substituted thiazole ring, an optionally substituted morpholine ring, and an optionally substituted thiomorpholine ring; wherein the optional substituent is a group R 10 、R 11 and R 12 , said groups themselves are independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH; wherein R 13 and R 14 are independently H or C 1-3 alkyl.

[0062] R 13 and R 14 may be independently selected from H and CH3.

[0063] In some embodiments, R 10 、R 11 and R 12Can be independently selected from: H, halogen, -C(O)NR 13 R 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1-6 substituents selected from halo and OH. 10 、R 11 and R 12 In some embodiments, R 10 、R 11 and R 12 Independently selected from: H, Cl and OCH3.

[0064] Y may be an optionally substituted phenyl ring or an optionally substituted pyridine ring, wherein the optional substituent is a group R as defined above. 10 、R 11 and R 12 .

[0065] Y may be a group of the formula:

[0066]

[0067] Where Q is C, CH or N and R 10 、R 11 and R 12 is as defined above.

[0068] Q can be C. Q can be N. Q can be CH. Q can be CR 10 .Q can be CR 11 .Q can be CR 12 .Q can be CR 10 , CR 11 , CR 12 , CH or N.

[0069] Y can be selected from:

[0070]

[0071] In the compounds described herein, the following moieties:

[0072]

[0073] Can be selected from:

[0074]

[0075] The following parts:

[0076]

[0077] It can be:

[0078]

[0079] In the compounds described herein, R 1 、R 2 、R 3 and R 4 may be independently selected from H, halogen and C optionally substituted with 1-6 fluorine 1-3 Alkyl, where R 1 、R 2 、R 3 and R 4 At least one of them is a halogen group or a C group optionally substituted by 1 to 6 fluorine groups 1-3 Alkyl, or R 4 With R 5 Connected to form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is optionally substituted with halogen and optionally substituted with 1-6 fluorine groups. 1-3 Alkyl substituted; and R 5 is selected from H and C optionally substituted by 1-6 fluorine 1-3 alkyl.

[0080] In some embodiments, R 1 、R 2 and R 3 may be independently selected from H, halogen and C optionally substituted with 1 to 6 fluorine atoms 1-3 Alkyl. R 1 、R 2 and R 3 R may be independently selected from H, F and CH3. 1 It can be H, F or CH3. 2 It can be H, F or CH3. 3 It can be H, F or CH3. 1 Can be F, R 2 Can be H and R 3 It can be H.

[0081] In some embodiments, R 4 is selected from H, halogen and C optionally substituted by 1 to 6 fluorine atoms 1-3 Alkyl; or with R 5 are connected to form an optionally substituted ring. 4 may be selected from H, halogen and C optionally substituted by 1 to 6 fluorine atoms1-3 Alkyl; or with R 5 Connect to form a ring. 4 may be selected from H, halogen and C optionally substituted by 1 to 6 fluorine atoms 1-3 Alkyl. R 4 Can be used with R 5 are connected to form an optionally substituted ring. 4 R may be selected from H, F and CH3. 4 It can be F. R 4 Can be used with R 5 connected to form a 5-membered ring, which may be optionally substituted by a group R 15 and R 16 Substitution; wherein R 15 and R 16 independently selected from H, halogen and C optionally substituted with 1 to 6 fluorine atoms 1-3 alkyl.

[0082] R 1 、R 2 、R 3 and R 4 R may be independently selected from H, F and CH3. 1 Can be F, R 2 Can be H, R 3 Can be H and R 4 It can be F. R 1 and R 4 Can be F and R 2 and R 3 It can be H.

[0083] In some embodiments, R 5 may be selected from H and C optionally substituted by 1 to 6 fluorine atoms 1-3 Alkyl; or with R 4 are connected to form an optionally substituted ring. 5 may be selected from H and C optionally substituted by 1 to 6 fluorine atoms 1-3 Alkyl; or with R 4 Connect to form a ring. 5 It can be H. R 5 Can be used with R 4 are connected to form an optionally substituted ring. 5 Can be used with R 4 connected to form a 5-membered ring, which may be optionally substituted by a group R 15 and R 16 substituted; wherein R 15 and R 16 independently selected from H, halogen and C optionally substituted with 1 to 6 fluorine atoms 1-3 alkyl.

[0084] R 1 、R 2 and R 3 may be independently selected from H, F and CH3 and R 4 Can be used with R 5 Connect to form a ring.

[0085] In some embodiments, the compound of formula (1) is a compound of formula (1a):

[0086]

[0087] or a salt thereof, wherein:

[0088] R 1 、R 2 、R 3 、R 4 、R 8 、R 9 and Y are as defined in formula (1), and

[0089] The condition is that when R 1 、R 2 、R 3 and R 4 One of them is a halogen or C 1-3 Alkyl, remaining R 1 、R 2 、R 3 and R 4 It's H, R 5 When Y is a 5- or 6-membered carbocyclic or heterocyclic ring, the 5- or 6-membered carbocyclic or heterocyclic ring is substituted by 2 or 3 groups selected from halogen, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH.

[0090] In some embodiments, the compound of formula (1) is a compound of formula (1b):

[0091]

[0092] or a salt thereof, wherein:

[0093] R 1 、R 2 、R3 、R 4 、R 8 and R 9 is as defined in formula (1);

[0094] Q is C or N;

[0095] R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH;

[0096] where R 13 and R 14 are independently H or C 1-3 alkyl, and

[0097] The condition is that when R 1 、R 2 、R 3 and R 4 One of them is a halogen or C 1-3 Alkyl, remaining R 1 、R 2 、R 3 and R 4 When it is H, then R 10 、R 11 and R 12 2 or 3 of them are independently selected from halogen, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH.

[0098] The compound may be a compound of formula (2):

[0099]

[0100] or its salt, wherein Y, R1 、R 2 、R 3 、R 4 and R 5 is as defined in formula (1).

[0101] The compound may be a compound of formula (3):

[0102]

[0103] or a salt thereof, wherein:

[0104] X, R 1 、R 2 、R 3 、R 4 and R 5 is as defined in formula (1);

[0105] Q is C or N;

[0106] R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH;

[0107] where R 13 and R 14 are independently H or C 1-3 alkyl,

[0108] The condition is

[0109] When X is a 9-membered fused heterobicyclic ring containing 1-4 nitrogen heteroatoms, the 9-membered fused heterobicyclic ring is only NR 8 R 9 substituted, and Q is N; and

[0110] When X is a 10-membered fused heterobicyclic ring containing 1-4 ring heteroatoms which are nitrogen, wherein said 10-membered fused heterobicyclic ring is substituted only with NH2, R 1 、R 2 、R 3 and R 4 One of them is a halogen or C 1-3 Alkyl, remaining R1 、R 2 、R 3 and R 4 is H, and R 5 When it is H, then R 10 、R 11 and R 12 2 or 3 of them are independently selected from halogen, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH.

[0111] In some embodiments, the compound of formula (3) is a compound of formula (3a):

[0112]

[0113] or a salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 10 、R 11 and R 12 is as defined above.

[0114] In some embodiments, the compound of formula (3) is a compound of formula (4a):

[0115]

[0116] or a salt thereof, wherein X, Q, R 10 、R 11 and R 12 is as defined above.

[0117] In some embodiments, the compound of formula (3) is a compound of formula (4b):

[0118]

[0119] or its salt, wherein Q, R 10 、R 11 and R 12 is as defined above.

[0120] The compound may be a compound of formula (5) or (5a):

[0121]

[0122] or a salt thereof, wherein X, Y, R 1 、R 2 and R 3 is as defined in formula (1); and

[0123] R 15 and R 16 independently selected from H, halo and C optionally substituted with 1 to 6 fluorine 1-3 alkyl.

[0124] The compound may be a compound of formula (5b) or (5c):

[0125]

[0126] or a salt thereof, wherein X, R 1 、R 2 、R 3 ,Q,R 10 、R 11 、R 12 、R 15 and R 16 is as defined above.

[0127] The compound may be a compound of formula (5d) or (5e):

[0128]

[0129] or a salt thereof, wherein R 1 、R 2 、R 3 ,Q,R 10 、R 11 、R 12 、R 15 and R 16 is as defined above.

[0130] The compound may be a compound of formula (6) or (6a):

[0131]

[0132] or a salt thereof, wherein X, Y, R 1 、R 2 and R 3 is as defined above.

[0133] The compound may be a compound of formula (6b) or (6c):

[0134]

[0135] or a salt thereof, wherein X, R 1 、R 2 、R 3 ,Q,R 10 、R 11 and R 12 is as defined above.

[0136] The compound may be a compound of formula (6d) or (6e):

[0137]

[0138] or a salt thereof, wherein X, R 1 、R 2 、R 3 ,Q,R 10 、R 11 and R 12 is as defined above.

[0139] The compound may be a compound of formula (7):

[0140]

[0141] or a salt thereof, wherein;

[0142] R 1 、R 2 、R 3 、R 4 、R 5 and Y is as defined above;

[0143] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0144] The compound may be a compound of formula (7a):

[0145]

[0146] or a salt thereof, wherein;

[0147] R 1 、R 2 、R 3 、R 4 、R 5 、R 10 、R 11 、R 12 and Q is as defined above;

[0148] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0149] The compound may be a compound of formula (7b):

[0150]

[0151] or a salt thereof, wherein;

[0152] R 1 、R 2 、R 3 、R 4 、R 5 and Y are as defined above.

[0153] The compound may be a compound of formula (7c):

[0154]

[0155] or a salt thereof, wherein;

[0156] R 1 、R 2 、R 3 、R 4 、R 5 、R 10 、R 11 、R 12 and Q are as defined above.

[0157] The compound may be a compound of formula (7d) or (7e):

[0158]

[0159] or a salt thereof, wherein;

[0160] R 1 、R 2 、R 3 、R 15 、R 16 and Y is as defined above;

[0161] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0162] The compound may be a compound of formula (7f) or (7g):

[0163]

[0164] or a salt thereof, wherein;

[0165] R 1 、R 2 、R 3 、R 10 、R 11 、R 12 、R15 、R 16 and Q is as defined above;

[0166] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0167] The compound may be a compound of formula (7h) or (7i):

[0168]

[0169] or a salt thereof, wherein;

[0170] R 1 、R 2 、R 3 、R 15 、R 16 and Y are as defined above.

[0171] The compound may be a compound of formula (7j) or (7k):

[0172]

[0173] or a salt thereof, wherein;

[0174] R 1 、R 2 、R 3 、R 10 、R 11 、R 12 、R 15 、R 16 and Q are as defined above.

[0175] The compound may be a compound of formula (8):

[0176]

[0177] or a salt thereof, wherein;

[0178] R 1 、R 2 、R 3 、R 4 and Y is as defined above;

[0179] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0180] The compound may be a compound of formula (8a):

[0181]

[0182] or a salt thereof, wherein;

[0183] R 1 、R 2 、R 3 、R 4 、R 10 、R 11 、R 12 and Q is as defined above;

[0184] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0185] The compound may be a compound of formula (8b):

[0186]

[0187] or a salt thereof, wherein;

[0188] R 1 、R 2 、R 3 、R 4 and Y are as defined above.

[0189] The compound may be a compound of formula (8c):

[0190]

[0191] or a salt thereof, wherein;

[0192] R 1 、R 2 、R 3 、R 4 、R 10 、R 11 、R 12 and Q are as defined above.

[0193] The compound may be a compound of formula (9):

[0194]

[0195] or a salt thereof, wherein;

[0196] R 1 、R 2 、R 3 、R 4 、R 5 and Y is as defined above;

[0197] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0198] The compound may be a compound of formula (9a):

[0199]

[0200] or a salt thereof, wherein;

[0201] R 1 、R 2 、R 3 、R 4 、R 5 、R 10 、R 11 、R 12 and Q is as defined above;

[0202] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0203] The compound may be a compound of formula (9b):

[0204]

[0205] or a salt thereof, wherein;

[0206] R 1 、R 2 、R 3 、R 4 、R 5 and Y are as defined above.

[0207] The compound may be a compound of formula (9c):

[0208]

[0209] or a salt thereof, wherein;

[0210] R 1 、R 2 、R 3 、R 4 、R 5 、R 10 、R 11 、R 12 and Q are as defined above.

[0211] The compound may be a compound of formula (9d) or (9e):

[0212]

[0213] or a salt thereof, wherein;

[0214] R 1 、R 2 、R 3 、R 15 、R 16 and Y is as defined above;

[0215] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0216] The compound may be a compound of formula (9f) or (9g):

[0217]

[0218] or a salt thereof, wherein;

[0219] R 1 、R 2 、R 3 、R 10 、R 11 、R 12 、R 15 、R 16 and Q is as defined above;

[0220] and W is an optionally substituted 6-membered heteroaryl ring containing 1-3 N heteroatoms.

[0221] The compound may be a compound of formula (9h) or (9i):

[0222]

[0223] or a salt thereof, wherein;

[0224] R 1 、R 2 、R 3 、R 15 、R 16 and Y are as defined above.

[0225] The compound may be a compound of formula (9j) or (9k):

[0226]

[0227] or a salt thereof, wherein;

[0228] R 1 、R 2 、R 3 、R 10 、R 11 、R 12 、R 15 、R 16 and Q are as defined above.

[0229] In the compounds described herein, W can be a substituted 6-membered heteroaromatic ring containing 1-3 N heteroatoms. W can be an optionally substituted 6-membered heteroaromatic ring containing 2 N heteroatoms. W can be a substituted 6-membered heteroaromatic ring containing 2 N heteroatoms. W can be replaced by R6 A substituted 6-membered heteroaromatic ring containing 1-3 N heteroatoms, wherein R 6 is as defined above. W may be 6 A substituted 6-membered heteroaromatic ring containing 2 N heteroatoms, wherein R 6 is as defined above. W may be a 6-membered heteroaromatic ring containing 1-3 N heteroatoms substituted by NH2. W may be a 6-membered heteroaromatic ring containing 2 N heteroatoms substituted by NH2. W may be an optionally substituted pyrimidine ring. W may be a substituted pyrimidine ring. W may be R 6 Substituted pyrimidine ring, wherein R 6 is as defined above. W may be a pyrimidine ring substituted with NH2. W may be 2-aminopyrimidine.

[0230] W can be:

[0231]

[0232] W can be:

[0233]

[0234] The compound may be selected from any one of the exemplary compounds shown in Table 1 or a salt thereof.

[0235] The compound may be selected from:

[0236]

[0237]

[0238]

[0239]

[0240]

[0241] or a salt thereof.

[0242] Treatment

[0243] Further embodiments of the present invention include the use of a compound of formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of formula (1) as a GCN2 regulator. The compounds of the present invention can be used as GCN2 regulators. The compounds of the present invention can be used as GCN2 inhibitors, antagonists or agonists. The compounds of the present invention can be used to treat diseases or disorders characterized by activation of GCN2.

[0244] The compounds of the present invention can be used to treat cancer, neurodegenerative diseases, chronic infections or conditions or symptoms associated therewith. Other aspects of the present invention more generally relate to compounds or compositions for use in therapy, such as compounds of formula (I) or compositions containing them, such as compounds or compositions for use in methods for treating human or animal bodies by therapy. Some embodiments include compounds or compositions (such as compounds of formula (I) or compositions containing them), for use in methods for treating human bodies by therapy.

[0245] The compounds of the present invention can be used to treat cancer. In some embodiments, the compounds of the present invention are used to treat breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndrome, myeloproliferative neoplasms, malignant glioma, non-Hodgkin lymphoma, Hodgkin lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, disease, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, malignant pleural mesothelioma, head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma, childhood neuroblastoma, or conditions or symptoms related thereto.

[0246] In some embodiments, the compounds and compositions detailed herein are used as modulators of GCN2. Provided herein is a method of treating a disease in a subject comprising administering an effective amount of a compound of Formula (I) or any embodiment, variation, or aspect thereof.

[0247] GCN2 has been shown to be an immunomodulatory agent. GCN2 senses the deficiency of tryptophan and L-arginine. Indoleamine 2,3-dioxygenase (IDO) is a potent immunomodulatory enzyme that mediates the conversion of the essential amino acid tryptophan (Trp) to kyneurine, and the expression of kyneurine allows certain macrophages and dendritic cells (DCs) to inhibit T cell proliferation (Grohmann et al., 2003, Mellor and Munn, 2004). IDO and subsequent tryptophan starvation trigger a GCN2-dependent stress signaling pathway that induces severe anergy in responding T cells. GCN2 knockout cells are resistant to IDO-induced cell cycle arrest and anergy. Plasmacytoid DCs expressing IDO are found in tumor-draining lymph nodes and activate the GCN2 kinase pathway in responding T cells. T cells in which GCN2 is targeted for destruction are less susceptible to IDO-mediated proliferation inhibition. (Munn et al., 2005). GCN2 activation through accumulation of uncharged tRNA leads to suppression of CD8+ effector T cells and increased generation and activation of regulatory T cells.

[0248] IFN-γ is a cytokine produced mainly by activated T cells and NK cells and has complex effects on immune cells and non-immune cells. IFN-γ plays an important role in inflammation, which makes it particularly relevant to transplantation and autoimmune diseases. IFN-γ induces Trp metabolism, which then activates GCN2 kinase, leading to phosphorylation of eIF2α (activator of autophagy). In turn, the supplementation of Trp reduces the activation of the GCN2-eIF2α pathway and inhibits autophagy. In addition, targeting GCN2 expression by RNA interference also inhibits IFN-γ-induced autophagy (Fougeray et al., 2012).

[0249] GCN2 plays a central role in regulating cell cycle arrest induced by L-arginine (L-Arg) starvation. L-Arg is a non-essential amino acid that plays a central role in regulating immune responses (Bronte and Zanovello, 2005). In tumor-infiltrating bone marrow cells, L-Arg is converted to urea and ornithine by arginase I and arginase II, and is oxidized to citrulline and nitric oxide by the induced form of nitric oxide synthase. Therefore, in cancer patients after liver transplantation or severe trauma, L-Arg is greatly reduced due to increased production of arginase I (Zea et al., 2005; Roth et al., 1994; Angele et al., 1999). Increased arginase activity is often observed in patients with breast cancer, prostate cancer, lung cancer, and colon cancer (Cederbaum et al., 2004). This leads to reduced T cell proliferation and impaired T cell function. In the absence of L-Arg, GCN2 knockout T cells did not show reduced proliferation (Rodriguez et al., 2006).

[0250] GCN2 activation via L-Arg deprivation has also been shown to occur in astrocytes, similar to how activation of GCN2 kinase mediates proliferation arrest and T cell anergy induction in response to IDO deprivation of Trp. In antigen-activated T cells, L-Arg depletion by arginase 1 in tumor-conditioned GES mediated GCN2 kinase-dependent cell cycle arrest at the G0-G1 phase and downregulation of the ζ chain of the TCR / CD3 complex (Rodriguez et al., 2002).

[0251] In a mouse model of sepsis, GCN2 activation under amino acid deprivation conditions promoted macrophage inflammation and death. GCN2 knockout macrophages showed significantly reduced cytokine gene expression after lipopolysaccharide (LPS) stimulation. When monocyte lineage-specific GCN2 knockout mice were challenged with a lethal dose of LPS, the mice showed a reduced inflammatory response and decreased expression of IL-6 and IL-12, which was associated with a significantly reduced mortality rate (Liu et al., 2014).

[0252] In some embodiments, provided herein is a method of treating a disease mediated by the GCN2 pathway in a subject, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, provided herein is a method of treating a disease in a subject characterized by activation of the GCN2 pathway, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, provided herein is a method for treating a disease in an individual, wherein the individual has a low level of amino acids. In some embodiments, the individual has a low level of non-essential amino acids. In some embodiments, the individual has a low level of L-arginine. In some embodiments, the individual has a low level of L-tryptophan. In some embodiments, the disease causes low levels of arginine in a specific tissue or cell type (such as a tumor or immune cell). In some embodiments, the disease causes low levels of tryptophan in a specific tissue or cell type (such as a tumor or immune cell). In some embodiments, the level of L-tryptophan is less than 200 μM, less than 100 μM, less than 75 μM, less than 50 μM, or less than 25 μM. In some embodiments, the level of L-tryptophan is 10 μM to 75 μM. In some embodiments, the level of L-arginine is less than 200 μM, less than 100 μM, less than 75 μM, less than 50 μM, or less than 25 μM. In some embodiments, the level of L-arginine is 10 μM to 75 μM.

[0255] Also provided herein is a method for treating a disease in an individual, wherein the disease involves overexpression of GCN2. In some embodiments, provided herein is a method for treating a disease in an individual, wherein the disease involves activation of GCN2. In some embodiments, GCN2 is overexpressed and / or activated in a specific tissue or cell type (such as a tumor or immune cell).

[0256] In some embodiments, the methods provided herein inhibit a stress response in a cell. In some embodiments, the stress response is directed to protecting cancer cells. In some embodiments, the stress response is directed to amino acid starvation. In some embodiments, the stress response is an unfolded protein response. In some embodiments, the stress response is an ER stress response.

[0257] In some embodiments, the methods provided herein result in reduced phosphorylation of GCN2. In some embodiments, downstream signaling through GCN2 is reduced. In some embodiments, phosphorylation of eIF2a kinase is reduced.

[0258] It has been described that persistent parasitic or viral infections are associated with local induction of IDO expression, which affects the activation of appropriate immune responses. It has also been demonstrated that severe cutaneous Leishmania infections stimulate IDO expression in local lymph nodes. Induced IDO attenuates the T cell stimulatory function of dendritic cells and suppresses local T cell responses to exogenous and nominal parasite antigens (Makala et al., 2011).

[0259] The role of IDO in leprosy has also been demonstrated. Increased numbers of macrophages and dendritic cells expressing IDO were found in patients with tubercular leprosy reactions compared to patients with reversal reactions. Furthermore, increased IDO expression was found in peripheral blood mononuclear cells stimulated with Mycobacterium leprae. These data suggest that chronic infection with M. leprae activates the inhibitory molecule IDO, which in turn contributes to the specific immunosuppression observed in tubercular leprosy (de Souza et al., 2011).

[0260] It has been described that HIV inhibits CD4+ T cell proliferation by inducing IDO in plasmacytoid dendritic cells, and that inhibition of IDO in vitro leads to increased CD4(+) T cell proliferative responses in peripheral blood mononuclear cells from HIV-infected patients (Boasso et al., 2007).

[0261] Therefore, inhibitors of the IDO / GCN2 pathway as disclosed herein can be used to enhance the immune response to chronic and persistent infections. In some embodiments, the compounds described herein or their salts or compositions described herein can be used in methods for treating or preventing viral infections. In some embodiments, the viral infection is African swine fever virus, dengue virus, enterovirus, hepatitis B virus, hepatitis C virus, influenza virus, tick-borne encephalitis virus, or West Nile virus infection. In some embodiments, the viral infection is caused by a virus that activates GCN2 in infected cells.

[0262] The fundamental mechanism of nutritional stress management mediated by the GCN2 pathway primarily acts to couple cell growth to amino acid utilization (Zhang et al., 2002).

[0263] In the tumor microenvironment, abnormal development of the vasculature leads to insufficient blood supply and deprivation of glucose and amino acids. Both amino acid and glucose deprivation and stress found in solid tumors activate GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. Compared with normal tissues, increased GCN2 activation / overexpression and phospho-eIF2α were observed in human and mouse tumors, and ablation of ATF4 or GCN2 expression significantly inhibited tumor growth in vivo (Ye et al., 2010).

[0264] ATF4 is essential for maintaining amino acid homeostasis in tumor cells, and activation of the GCN2-ATF4-asparagine synthetase (ASNS) pathway promotes tumor cell survival under nutrient (amino acid or glucose) deprivation. The GCN2-eIF2α pathway is activated in various human and mouse tumor tissues. Deficiency of ATF4 or GCN2 severely inhibits tumor growth in vivo. Together, these results suggest that the GCN2-ATF4-ASNS pathway is a promising target for cancer therapy.

[0265] Tumor xenograft studies using head and neck squamous cell carcinoma (HNSCC) or fibrosarcoma (HT1080) cell lines have shown that GCN2 depletion prevents tumor growth and survival (Ye et al., 2010; Wang et al., 2013). Furthermore, in response to vemurafenib, BRAF-mutant melanoma and colorectal cancer cells rapidly induce the ISR as a cytoprotective mechanism by activating GCN2. Silencing GCN2 (but not other eIF2α kinases) specifically prevented the vemurafenib-triggered ISR (an event independent of downstream MEK inhibition). Interestingly, silencing ATF4 by siRNA sensitized BRAF-mutant melanoma cells to vemurafenib. Thus, GCN2-mediated ISR can promote cellular adaptation to vemurafenib-induced stress, providing insights into the development of drug resistance (Nagasawa et al., 2017).

[0266] It has been reported that amino acid deficiency, glucose deprivation, and hypoxia promote tumor growth and angiogenesis through the GCN2 / eIF2α / ATF4 pathway (Wang et al., 2013). GCN2 expression is elevated in human tumors to overcome the stress associated with amino acid deprivation by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis.

[0267] Leukemia cells lack the ability to synthesize asparagine. Therefore, asparaginase (which plays a role by consuming asparagine and glutamine) is a first-line treatment for acute lymphoblastic leukemia (B-ALL) derived from B cells (Terwilliger et al., 2017). In several leukemia cells, it was demonstrated that treatment with asparaginase activated the GCN2 pathway and this was the mechanism (Lough et al., 2018) that tumor cells respond to nutritional stress by reversing chemotherapy amino acid deprivation. The inhibition of GCN2 makes cancer cells with asparagine synthetase (ASNS) expressed at low basal levels sensitive to anti-leukemia agent asparaginase (Nakamura et al., 2018). Therefore, GCN2 inhibitors can be developed as single agent therapy or in combination with asparaginase.

[0268] Without being bound by any particular theory, the GCN2-eIF2α-ATF4 pathway is important for maintaining metabolic homeostasis in tumor cells, making it a novel and attractive target for anti-tumor approaches.

[0269] Compounds disclosed herein as GCN2 modulators can be used as preventive or therapeutic agents for a number of GCN2-related diseases, such as colorectal cancer, gastrointestinal stromal tumors, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer, malignant mesothelioma, primary lung cancer), blood cancer (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic leukemia), malignant lymphoma, Hodgkin's disease, non-Hodgkin's leukemia, chronic myeloproliferative diseases), cancer metastasis, precancerous lesions (e.g., myelodysplastic syndrome), pancreatic cancer (e.g., pancreatic duct cancer, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g., ductal carcinoma), ovarian cancer (e.g., pancreatic duct carcinoma, pancreatic endocrine tumors), esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g., ovarian cancer), ductal carcinoma in situ, inflammatory breast cancer, invasive ductal carcinoma), ovarian cancer (e.g., epithelial ovarian cancer, ovarian germ cell tumor), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer and hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatocellular carcinoma, primary liver cancer), extrahepatic bile duct cancer, thyroid cancer, kidney cancer (e.g., renal cell carcinoma, clear cell renal carcinoma), uterine cancer (e.g., cervical cancer, uterine corpus cancer, uterine sarcoma), brain tumor (e.g., glioma, glioblastoma, medulloblastoma, astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., melanoma, basal cell carcinoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, osteosarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer. In some embodiments, the compounds described herein or their salts, or compositions described herein, can be used in methods of treating cancers such as breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer or adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndrome, myeloproliferative neoplasms, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, In some embodiments, the compound, salt or composition can be used in a method of treating metastatic renal cancer, chronic lymphocytic leukemia, pancreatic adenocarcinoma or non-small cell lung cancer.

[0270] GCN2 regulation provides the opportunity of interfering with tumor growth metabolism, and it can enhance the effect of monotherapy or combination therapy with other anticancer agents at the same time.In some embodiments, compound as herein described or its salt or composition as herein described can be used for other anticancer agents (such as antitumor agent, immune checkpoint inhibitor or any other suitable anticancer agent) combination therapy tumor.Exemplary immune checkpoint inhibitors include anti-PD-1, anti-PD-L1, anti-GITR, anti-OX-40, anti-LAG3, anti-TIM-3, anti-41BB, anti-CTLA-4 antibodies.Exemplary antitumor agents can include, for example, anti-microtubule agents, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, topoisomerase I inhibitors, antimetabolites, antibiotics, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, proteasome inhibitors and cancer metabolism inhibitors. Other anti-cancer agents may include one or more of an immunostimulatory agent, an antibody or fragment thereof (e.g., an anti-CD20, anti-HER2, anti-CD52, or anti-VEGF antibody or fragment thereof), or an immunotoxin (e.g., an anti-CD33 antibody or fragment thereof, an anti-CD22 antibody or fragment thereof, a calicheamicin conjugate, or a Pseudomonas exotoxin conjugate).

[0271] In some embodiments, the compounds described herein, or salts thereof, or compositions described herein, can be used in a method of treating cancer in an individual, wherein the individual's one or more cancer cells are dormant cancer cells. In some embodiments, the one or more dormant cancer cells are disseminated tumor cells or circulating tumor cells. In some embodiments, the one or more dormant cancer cells are disseminated tumor cells.

[0272] In some embodiments, the compound or salt thereof as described herein or the composition as described herein can be used in a method for treating cancer in an individual, wherein the individual has undergone previous treatment. In some embodiments, the cancer is resistant or refractory to the previous treatment. In some embodiments, the cancer has progressed in the previous treatment. In the embodiment, the cancer is a recurrent cancer. In some embodiments, the previous treatment is a treatment with: ubiquitin proteasome pathway inhibitors (e.g., borzotimib), taxanes (e.g., paclitaxel or docetaxel), Cox-2 inhibitors (e.g., celecoxib), platinum anti-tumor drugs (e.g., cisplatin or oxaliplatin), anthracyclines (e.g., doxorubicin), pyrimidine analogs (e.g., 5-fluorouracil or gemcitabine), topoisomerase inhibitors (e.g., etoposide), mTOR inhibitors (e.g., rapamycin), immune checkpoint inhibitors, or agents for immuno-oncology. In some embodiments, the cancer is resistant to treatment with a ubiquitin proteasome pathway inhibitor (e.g., borzotimib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum anti-tumor drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune checkpoint inhibitor, or an agent used in immuno-oncology. In some embodiments, the cancer is resistant to treatment with doxorubicin and / or rapamycin.

[0273] In some embodiments, administration of the compound, salt, or composition reduces tumor growth, tumor proliferation, or tumorigenicity in the individual. In some embodiments, the compound, salt, or composition can be used in a method of reducing tumor growth, tumor proliferation, or tumorigenicity in an individual in need thereof. In some embodiments, tumor growth is slowed or arrested. In some embodiments, tumor growth is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the size of the tumor is reduced. In some embodiments, the size of the tumor is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, tumor metastasis is prevented or slowed. In some embodiments, tumor growth, tumor proliferation, or tumorigenicity is compared to the tumor growth, tumor proliferation, or tumorigenicity in the individual before administration of the compound, salt, or composition. In some embodiments, tumor growth, tumor proliferation, or tumorigenicity is compared to tumor growth, tumor proliferation, or tumorigenicity in a similar individual or group of individuals. Methods of measuring tumor growth, tumor proliferation, and tumorigenicity are known in the art, for example, by repeated imaging of an individual.

[0274] In some embodiments, administration of the compound, salt, or composition induces apoptosis of cancer cells. In some embodiments, apoptosis of cancer cells is increased by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% following administration.

[0275] In some embodiments, administration of the compound, salt, or composition reduces CHOP induction. In some embodiments, CHOP induction is reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% following administration.

[0276] In some embodiments, administration of the compound, salt, or composition does not induce PERK activation. In some embodiments, CHOP production by PERK is not inhibited following administration.

[0277] We recently demonstrated that hepatic GCN2 is activated in fatty liver and that GCN2 deficiency protects against high-fat diet (HFD)-induced hepatic steatosis and insulin resistance, suggesting that the role of GCN2 in the regulation of lipid metabolism is context-dependent.

[0278] After 12 weeks of high-fat diet (HFD) feeding, Gcn2- / - mice were less obese than wild-type (WT) mice, and Gcn2- / - significantly attenuated HFD-induced liver dysfunction, hepatic steatosis, and insulin resistance. In the livers of HFD-fed mice, GCN2 deficiency resulted in higher levels of lipolytic genes, lower expression of genes related to fatty acid synthesis, transport, and lipogenesis, and less induction of oxidative stress. This work also reported that GCN2 knockout attenuated (while GCN2 overexpression exacerbated) palmitic acid-induced steatosis, oxidative and ER stress, and changes in the expression of peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase, and metallothionein in HepG2 cells (Liu et al., 2018). These findings suggest that strategies to inhibit GCN2 activity in the liver may provide new approaches to attenuate the development of non-alcoholic fatty liver disease (NAFLD).

[0279] When mice were fed a medium-fat (22 kcal% fat) diet during perinatal development, GCN2 deficiency reduced hepatic triglyceride storage (Xu et al., 2013).

[0280] It has been reported that GCN2 deficiency attenuates cardiac dysfunction and hyperlipidemia in both type 1 diabetic (T1D) and type 2 diabetic (T2D) mice, and the improved cardiac function in diabetic GCN2- / - mice is associated with reduced hypertrophy, fibrosis, lipid accumulation, oxidative stress, inflammation, and apoptosis. The pathological role of GCN2 in diabetic cardiomyopathy (DCM) has also been validated in H9C2 rat cardiomyocyte cell lines treated with high glucose or palmitic acid (Feng et al., 2019).

[0281] GCN2 deficiency attenuates transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiomyocyte apoptosis by reducing cardiomyocyte apoptosis and myocardial oxidative stress. GCN2 activation impairs the adaptive response to congestive heart failure (Lu et al., 2014). Following doxorubicin-induced cardiac dysfunction, Gcn2- / - mice exhibited less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared with WT mice. In the hearts of Dox-treated mice, GCN2 deficiency attenuated the induction of eIF2α phosphorylation and its downstream targets (activator of transcription 4 (ATF4) and C / EBP homologous protein (CHOP)) and preserved the expression of the anti-apoptotic factors Bcl-2 and mitochondrial uncoupling protein-2 (UCP2) (Wang et al., 2018). These data suggest that strategies to inhibit GCN2 activity in cardiomyocytes may provide a novel approach to attenuate Dox-related cardiotoxicity.

[0282] Therefore, in some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used to treat or prevent metabolic diseases and cardiac diseases.

[0283] It was demonstrated that GCN2 deletion attenuated denervation-induced muscle atrophy. GCN2 deficiency also significantly attenuated the loss of muscle mass in atrophied gastrocnemius and extensor digitorum longus. Similar results were observed 14 days after denervation. Wheat germ agglutinin staining of muscle cryosections showed that TA muscles lacking GCN2 had better myofiber size preservation in response to denervation (Guo et al., 2018). In addition, the deleterious effects of GCN2 in denervation-induced muscle atrophy are associated with FoxO3a activation, which upregulates genes involved in both the ubiquitin-proteasome pathway and autophagy in muscle atrophy (Sandri et al., 2004; Bertaggia et al., 2012; Wei et al., 2013; Guo et al., 2016).

[0284] Thus, in some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used to treat or prevent muscle atrophy.

[0285] The expression of lasting synaptic plasticity and long-term memory (LTM) requires protein synthesis, and protein synthesis can be suppressed by the phosphorylation of eIF2α. In the mice lacking eIF2α kinases (GCN2), the reduction of phosphorylated eIF2α is related to the synaptic plasticity and memory of change. The mice lacking GCN2, wherein eIF2α phosphorylation and ATF4 levels are both reduced, and the threshold value of the lasting long-term potentiation (L-LTP) and LTM in the hippocampus is reduced and this reduction is related to the spatial memory of the weak conditioned reflex of improvement (Costa-Mattioli et al., 2005). This model is supported by the increase in ATF4 expression (which causes the damage of L-LTP and LTM) after being processed with eIF2α phosphatase inhibitor Sal003.

[0286] Thus, in some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used to treat or prevent memory loss.

[0287] In the brain of Alzheimer's disease (AD) patients and Alzheimer's disease model mice, the phosphorylation of eIF2α has been observed to increase. Inhibition of GCN2 prevents the synaptic plasticity damage induced by amyloid beta by reducing the phosphorylation of eIF2α. Senile plaques are mainly composed of beta-amyloid peptide (Aβ) derived from amyloid precursor protein (APP), and the amyloid precursor protein undergoes proteolytic processing by beta-secretase (BACE-1) and gamma-secretase. It has also been reported that the phosphorylation translation of eIF2α increases BACE-1 levels (O'Connor et al., 2008). The inhibition of GCN2 under such disease conditions of promoting the activation of gamma-secretase or the induction of BACE-1 (causing the accumulation of Aβ in the brain and the formation of brain plaques) will provide valuable pathways for responding to or even stopping the progress of neurodegenerative diseases.

[0288] In mice expressing familial AD-associated mutations in amyloid precursor protein (APP) and presenilin-1 (PS1), loss of GCN2 prevented the impairment of synaptic plasticity and spatial memory deficits. In cells with impaired autophagy, PS1 is essential for γ-secretase activity and GCN2 / eIF2α / ATF4 signaling plays an important role in regulating γ-secretase activity (Ohata et al., 2010).

[0289] In addition, the hippocampus LTP defect in APP-PS1 mice is normalized in APP-PS1 mice lacking GCN2. As observed in the Morris water maze task by reduced escape latency, increased platform spanning and target quadrant occupancy (similar to that demonstrated by wild-type mice), spatial learning and memory impairment demonstrated by APP-PS1 mice were prevented in APP-PS1 mice lacking GCN2 (Ma et al., 2013). In short, these findings indicate that the gene removal of eIF2α kinase GCN2 prevents LTP depletion and spatial memory impairment associated with Alzheimer's disease.

[0290] Thus, in some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used to treat neurodegenerative diseases.

[0291] Angiogenesis (neovascularization by endothelial cells (ECs)) is an adaptive response to oxygen / nutrient deprivation induced by GCN2 and coordinated by vascular endothelial growth factor (VEGF) during ischemia or exercise. Angiogenesis in the retina and choroid is a major cause of vision loss in serious eye diseases such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Amino acid restriction triggers angiogenesis via GCN2 / ATF4 regulation of VEGF and hydrogen sulfide production (Longchamp et al., 2018).

[0292] However, retinal angiogenesis is causally and dynamically linked to vascular degeneration, ischemia, and vascular remodeling in retinal tissue (Zhang et al., 2015). ATF4 has been shown to function as an oxygen sensor and interact with HIF-1α to regulate VEGF production (Zhong et al., 2012). Global knockout of ATF4 disrupts lens development and leads to microphthalmia (Masuoka and Townes, 2002). Genetic inhibition of ATF4 activity attenuates diabetes-induced retinal inflammation and vascular leakage, suggesting that upregulation of ATF4 contributes to retinal inflammation and endothelial barrier dysfunction in diabetic retinopathy (Chen et al., 2012).

[0293] Thus, in some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used to treat ocular diseases.

[0294] Because there is increasing evidence that the GCN2 pathway strongly affects the function of the immune system, the present invention encompasses the use of GCN2 regulators for treating or preventing immune-related disorders. In some embodiments, the compounds as described herein or their salts or compositions as described herein can be used to treat or prevent immune-related disorders. In some embodiments, the compounds as described herein or their salts or compositions as described herein can be used to treat or prevent autoimmune diseases, the autoimmune diseases being selected from arthritis, graft-versus-host disease, Crohn's disease, multiple sclerosis, lupus, type 1 diabetes, rheumatoid arthritis, Graves' disease, autoimmune hemolytic anemia, Wegener's granulomatosis, ankylosing spondylitis, aplastic anemia, Behcet's disease, high IgE syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis and psoriasis.

[0295] In some embodiments, the compounds described herein or salts thereof, or compositions described herein, can be used to treat organ rejection, myeloablative and non-myeloablative bone marrow transplant rejection during transplantation.

[0296] In some embodiments, the compounds described herein or their salts or compositions described herein can be used to inhibit the phosphorylation of GCN2. In some embodiments, the compounds described herein or their salts or compositions described herein can be used to promote recovery protein synthesis under amino acid deprivation conditions. In some embodiments, the compounds described herein or their salts or compositions described herein can be used to enhance protein synthesis, and therefore can be used for diseases or disorders mediated by reduced protein synthesis, such as muscle atrophy, muscular dystrophy, cachexia, synaptic plasticity and long-term memory, etc.

[0297] According to the present disclosure, in some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, cattle, sheep, pig, horse, dog, cat, rabbit, or rodent. In some embodiments, the individual is a human. In some embodiments, the individual suffers from any disease or disorder disclosed herein. In some embodiments, the individual is at risk of developing any disease or disorder disclosed herein.

[0298] Also provided herein are uses of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is used to treat a disorder or disease described herein. In some embodiments, the manufacture of a medicament is used to prevent and / or treat a disorder or disease mediated by the GCN2 pathway.

[0299] In some embodiments, the compound as described herein or its salt or composition as described herein can be used as a stand-alone therapy or as a method of combining the treatment of other palliative agents (e.g., agents that alleviate the symptoms of the disorder to be treated) and / or agents for the cause of the disorder. The compound or composition of the present invention can be used or administered in combination with a second therapeutic agent. The compound or composition of the present invention can be used or administered in combination with an anticancer agent, an anti-angiogenic agent, or an agent that targets immune checkpoint proteins. The compound or composition of the present invention can be used or administered in combination with a second therapeutic agent selected from the following: PEG-arginase, asparaginase, anti-angiogenic factor, cysteine ​​enzyme, or sulfasalazine.

[0300] As provided herein, the compounds described herein or their salts and compositions described herein can be administered with a pharmaceutical agent to treat any of the diseases and disorders disclosed herein. In some embodiments, the pharmaceutical agent is an anti-angiogenic agent. In some embodiments, the pharmaceutical agent is an anticancer agent. In some embodiments, the pharmaceutical agent targets an immune checkpoint protein.

[0301] In some embodiments, (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an agent are administered sequentially, concurrently, or simultaneously. In certain embodiments, (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an agent are administered at intervals of about 15 minutes or less (e.g., about 10 minutes, 5 minutes, or 1 minute or less). In certain embodiments, (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an agent are administered at intervals of about 15 minutes or more (e.g., about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, or more). Any of (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an agent may be administered first. In certain embodiments, (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, and (b) an agent are administered simultaneously.

[0302] Provided herein is a method for enhancing an individual's immune response, comprising administering to the individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein and (b) an agent targeting an immune checkpoint protein. In some embodiments, the individual has cancer. In some embodiments, the enhanced immune response is directed against a tumor or cancer cell.

[0303] Also provided herein are methods of treating cancer in an individual in need thereof, comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent targeting an immune checkpoint protein, wherein the individual has an increased immune response.

[0304] In some embodiments, the agent is an anticancer agent. In some embodiments, the anticancer agent is a ubiquitin proteasome pathway inhibitor (e.g., borzotimib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum anti-tumor drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent that regulates the unfolded protein response or the integrated stress response (e.g., IRE1 / XBP1 inhibitor or PERK inhibitor). In some embodiments, the anticancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anticancer agent is an immune checkpoint inhibitor or an agent for immuno-oncology.

[0305] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to one or more anti-cancer therapies.

[0306] In some embodiments, an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein is administered to an individual with cancer to increase sensitivity to radiation. In some embodiments, provided herein are methods of treating cancer in an individual in need thereof, comprising administering to the individual (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein and (b) radiation.

[0307] In some embodiments, an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein is administered to an individual with cancer to increase sensitivity to one or more anticancer agents. In some embodiments, the anticancer agent is an ubiquitin proteasome pathway inhibitor (e.g., borzotimib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum anti-tumor drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent (e.g., IRE1 / XBP1 inhibitor or PERK inhibitor) that regulates the unfolded protein response or the integrated stress response. In some embodiments, the anticancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anticancer agent is an immune checkpoint inhibitor or an agent for immuno-oncology.

[0308] definition

[0309] In this application, the following definitions apply unless otherwise indicated.

[0310] As used herein, the term "GCN2 modulator" refers to any compound that binds to GCN2 and modulates its function. The term "modulator" should be interpreted to include modulation by, but not limited to, antagonists, agonists, partial agonists, and inverse agonists.

[0311] With respect to the use of any compound described herein, including those of formula (1), the term "treatment" is used to describe any form of intervention in the case of administering a compound to a subject suffering from, at risk of, or potentially at risk of developing, the disease or disorder in question (such as cancer or an immune disease). Thus, the term "treatment" covers preventative, prophylactic treatment as well as treatment in the case of symptoms exhibiting a measurable or detectable disease or disorder. Treatment also encompasses reducing one or more symptoms caused by the disease or disorder, alleviating the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the onset or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing relief (partial or complete) from the disease or disorder, reducing the dose of one or more other drugs required to treat the disease or disorder, enhancing the effect of another drug used to treat the disease or disorder, slowing the progression of the disease or disorder, improving the quality of life of the subject, and / or prolonging the survival of the subject.

[0312] In some variations, treatment does not include prevention. Thus, it is understood that, in some variations, treatment refers to the use of any compound described herein (including those of Formula (1)) to describe any form of intervention in the context of administering the compound to a subject having, at risk of, or potentially at risk of developing the disease or disorder in question, such as cancer or an immune disease.

[0313] "Subject" refers to a mammal and includes humans and non-human mammals. Examples of subjects include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, the subject is a human.

[0314] The term "therapeutically effective amount" (e.g., with respect to a method of treating a disease or condition) refers to an amount of a compound effective to produce the desired therapeutic effect. For example, if the condition is pain, a therapeutically effective amount is an amount sufficient to provide the desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or a reduction in the severity of pain. With respect to treatment, if the condition is cancer, a therapeutically effective amount is an amount sufficient to reduce one or more symptoms associated with the cancer (e.g., reduce tumor size or reduce metastasis rate).

[0315] As used herein, "about" a parameter or value includes and describes the parameter or value itself. For example, "about X" includes and describes X itself.

[0316] Unless otherwise indicated, terms such as "heterobicyclic", "heteroaryl", "bicyclic", "heterocycle", "carbocycle", "alkyl", "alkoxy" and "halo" are all used in their conventional sense (e.g., as defined in the IUPAC Gold Book). "Optionally substituted" as applied to any group means that the group may, if desired, be substituted with one or more substituents which may be the same or different.

[0317] In the case of any compound described as having a chiral center, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. Where applicable, any and all stereoisomers of the compounds described herein are also provided herein, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio (including racemic mixtures).

[0318] However, the present invention as described herein relates to all crystal forms, solvates and hydrates of any disclosed compound so prepared. In the case of any compound disclosed herein having an acidic or basic center (such as a carboxylic acid or amino group), all salt forms of the compound are included herein. In the case of pharmaceutical uses, the salts should be regarded as pharmaceutically acceptable salts.

[0319] Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts can be formed in a conventional manner, for example by reacting the free acid or free base form of the compound with one or more equivalents of an appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., vacuum, by freeze drying, or by filtration). Salts can also be prepared by exchanging the counterion of the compound in salt form with another counterion, for example using a suitable ion exchange resin.

[0320] Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids, and salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0321] Examples of acid addition salts include acid addition salts formed with acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+)-camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g.,

[0014] Examples of the present invention include, but are not limited to, D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0322] Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by incorporating molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid state structure (e.g., crystal structure) of the compounds of the invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol) and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or solvent mixture containing a solvating solvent. Whether a solvate has formed in any given case can be determined by analyzing the crystals of the compound using well-known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0323] Solvates can be stoichiometric or non-stoichiometric solvates. Specific solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and methods for preparing and characterizing them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, SSCI, Inc. of West Lafayette, Indiana, USA, 1999, ISBN 0-967-06710-3.

[0324] In the context of the present invention, the term "pharmaceutical composition" means a composition comprising an active agent and further comprising one or more pharmaceutically acceptable carriers suitable for administration to an individual. Depending on the mode of administration and dosage form, the composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, aromatics, antibacterial agents, antifungal agents, lubricants, and dispersants. The composition may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations (including suspensions, sprays, inhalants), tablets, lozenges, emulsions, solutions, cachets, granules, capsules, and suppositories, as well as injectable liquid preparations (including liposomal preparations).

[0325] The compounds of the present invention may contain one or more isotopic substitutions, and reference to a particular element includes within its scope all isotopes of that element. For example, reference to hydrogen includes within its scope all isotopes of that element. 1 H. 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen include within their respective scopes 12 C. 13 C and 14 C and 16 O and 18O. In a similar manner, references to specific functional groups also include isotopic variations within their scope unless the context indicates otherwise. For example, references to alkyl (such as ethyl) or alkoxy (such as methoxy) also include variations in which one or more hydrogen atoms in the group are in the form of deuterated or tritium isotopes, such as, for example, all five hydrogen atoms in the ethyl group are in the form of deuterated isotopes (perdeuteroethyl) or all three hydrogen atoms in the methoxy group are in the form of deuterated isotopes (trideuteromethoxy). The isotopes may be radioactive or non-radioactive.

[0326] The therapeutic dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound being used. Determination of the appropriate dosage for a particular situation is within the skill of the art. Typically, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect for the situation is achieved. For convenience, the total daily dose can be divided and administered in portions throughout the day, if desired.

[0327] Of course, the amplitude of the effective dose of the compound will vary with the nature of the severity of the disease to be treated and the specific compound and its route of administration. The selection of an appropriate dose is within the capabilities of those of ordinary skill in the art without excessive burden. Typically, the daily dose range can be from about 10 μg to about 30 mg per kg of human and non-human animal body weight, preferably from about 50 μg to about 30 mg per kg of human and non-human animal body weight, such as from about 50 μg to about 10 mg per kg of human and non-human animal body weight, such as from about 100 μg to about 30 mg per kg of human and non-human animal body weight, such as from about 100 μg to about 10 mg per kg of human and non-human animal body weight and most preferably from about 100 μg to about 1 mg per kg of human and non-human animal body weight.

[0328] pharmaceutical preparations

[0329] While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation).

[0330] Thus, in some embodiments of the present invention, there is provided a pharmaceutical composition comprising at least one compound of formula (1) as defined above together with at least one pharmaceutically acceptable excipient.

[0331] The one or more pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid, or semisolid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and cosolvents)), granulating agents, binders, flow aids, coating agents, release controlling agents (e.g., release retarding or delaying polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity adjusting agents, thickeners, flavorings, sweeteners, pigments, plasticizers, taste-masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0332] As used herein, the term "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects (e.g., human subjects) without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0333] Pharmaceutical compositions containing compounds of formula (1) can be formulated according to known techniques (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, U.S.A.) The pharmaceutical compositions can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, intravaginal, or transdermal administration.

[0334] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers, or patches (such as buccal patches).

[0335] The composition can be a tablet composition or a capsule composition. Tablet compositions can contain a unit dose of active compound together with an inert diluent or carrier, such as sugar or sugar alcohol (e.g., lactose, sucrose, sorbitol, or mannitol); and / or non-sugar derived diluents (e.g., sodium carbonate, calcium phosphate, calcium carbonate) or cellulose or its derivatives (e.g., microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose), and starch (e.g., corn starch). Tablets can also contain standard ingredients such as: binders and granulating agents (e.g., polyvinyl pyrrolidone), disintegrants (e.g., swellable cross-linked polymers (e.g., cross-linked carboxymethyl cellulose)), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffer), and effervescents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and do not need to be discussed in detail here.

[0336] Tablets can be designed to release the drug upon contact with gastric fluid (immediate-release tablets) or in a controlled manner over a period of time or upon contact with a specific area of ​​the GI tract (controlled-release tablets).

[0337] The pharmaceutical composition typically comprises from about 1% (w / w) to about 95%, preferably % (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g. as defined above) or a combination of such excipients. Preferably, the composition comprises from about 20% (w / w) to about 90% (w / w) active ingredient and from 80% (w / w) to 10% (w / w) pharmaceutically excipient or a combination of excipients. The pharmaceutical composition comprises from about 1% to about 95%, preferably from about 20% to about 90% active ingredient. The pharmaceutical composition according to the present invention can, for example, be in unit dose form, such as in the form of an ampoule, a vial, a suppository, a prefilled syringe, a dragee, a powder, a tablet or a capsule.

[0338] Tablets and capsules can contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers and / or bulking agents (depending on the dosage of the drug). They can also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Sustained-release tablets will typically additionally contain 0-99% (w / w) release-controlling (e.g., delaying) polymers (depending on the dosage). The film coating of the tablet or capsule typically contains 0-10% (w / w) polymers, 0-3% (w / w) pigments and / or 0-2% (w / w) plasticizers.

[0339] The composition can be a parenteral composition. Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether lyophilized). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0340] Pharmaceutical formulations may be presented to the patient in a "patient pack" (usually a blister pack) containing the entire course of treatment in a single package.

[0341] The compound of formula (1) will generally be presented in a unit dosage form and will therefore typically contain enough compound to provide the desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, for example, from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of compound are 0.1 milligram to 2 grams of active ingredient (more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams) or 1 microgram to 20 milligrams (for example, 1 microgram to 10 milligrams, for example, 0.1 milligram to 2 milligrams of active ingredient).

[0342] For oral compositions, unit dosage forms may contain from 1 mg to 2 g, more typically 10 mg to 1 g (e.g. 50 mg to 1 g, for example 100 mg to 1 g) of active ingredient.

[0343] The active compound is administered to a patient in need thereof (eg, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount).The precise amount of compound administered can be determined by the supervising physician according to standard procedures.

[0344] Example

[0345] The invention will now be described with reference to the following examples shown in Table 1 (but not limited thereto).

[0346] Table 1

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361] Preparation of the compounds of the present invention

[0362] Some compounds of formula (1) and their derivatives or synthetic intermediates can be prepared according to synthetic methods known to those skilled in the art. In some embodiments, the present invention provides a method for preparing a compound as defined in formula (1) above. Certain compounds of the present invention can be prepared according to the methods described below.

[0363] Compound 1:

[0364]

[0365] Step 1: Synthesis of 2-bromo-1,3-difluoro-4-nitrobenzene

[0366] To a stirred solution of 2-bromo-1,3-difluorobenzene (1.0 g, 5.18 mmol, 1.0 equivalent) in concentrated sulfuric acid (5 mL) was added potassium nitrate (1.046 g, 10.36 mmol, 2.0 equivalents) at 0 ° C and the mixture was stirred at 0 ° C for 30 min and then at room temperature for 3.5 h. The reaction mixture was added to ice water (50 mL). The precipitated solid was filtered and washed with excess water and dried under vacuum to obtain the title compound. Analytical data: LCMS: 238 [M+H] + .

[0367] Step 2: Synthesis of 3-bromo-2,4-difluoroaniline

[0368] To a stirred solution of 1,3-difluoro-2-bromo-6-nitrobenzene (2.0 g, 8.40 mmol, 1.0 equivalent) in EtOH: water (1: 1, 20 mL) was added Fe (2.37 g, 42.01 mmol, 5.0 equivalents) and ammonium chloride (2.19 g, 42.01 mmol, 5.0 equivalents). The resulting reaction mixture was stirred at reflux for 2 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled, filtered through a diatomaceous earth bed and washed with methanol. The methanol layer was collected and evaporated under reduced pressure to obtain a crude product, to which water and EtOAc were added, the organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude solid. The solid was purified by flash chromatography (using EtOAc / hexane (10%) as eluent) to obtain the title product as a solid. Analytical data: LCMS: 208 [M+H] + .

[0369] Step 3: Synthesis of N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0370] A mixture of 3-bromo-2,4-difluoroaniline (300 mg, 1.44 mmol, 1.0 equivalent) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (180 mg, 1.009 mmol, and 0.7 equivalent) in pyridine was stirred at room temperature overnight. MeOH (10 mL) was added to the mixture and the mixture was stirred at room temperature for 10 min. The mixture was concentrated in rotation. The residue was purified by flash chromatography on silica (n-hexane-ethyl acetate=100: 0-80: 20) to obtain a crude 6 (400 mg) in a solid form. This material was used in the next reaction without further purification. Analytical data: LCMS: 413 [M+H] + .

[0371] Step 4: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine.

[0372] To 6-bromoquinazoline-2-amine (50mg, 0.223mmol, 1.0 equivalent) in 1,4-dioxane (5mL) stirring solution, add potassium acetate (33mg, 0.334mmol, 1.5 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (85mg, 0.334mmol, 1.5 equivalent). Reactant mixture is degassed with nitrogen for 20min and then Pd(PPh3)2Cl2 (8mg, 0.011mmol, 0.05 equivalent). Reactant mixture is degassed for 10min again, then stirred at 100°C overnight. Reactant is diluted with water and extracted by ethyl acetate (3x50mL). The organic layer merged is dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography, to obtain title compound. Analytical data: LCMS: 272 [M+H] + .

[0373] Step 5: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0374] To a stirred solution of N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (100 mg, 0.24 mmol, 1.0 equiv) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (66 mg, 0.24 mmol, 1.0 equiv) in DMF:water (4:1, 5 mL) was added KCO (99 mg, 0.72 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (10 mg, 0.012 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 120 ° C overnight. The reaction progress was monitored by TLC and LCMS. After the reaction is complete, water is added to the reaction mixture and extracted with EtOAc (5x100mL). The organic layers are combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product as a crude residue, which is purified by flash chromatography (using EtOAc / hexane (50%-100%) as eluent) to obtain the title product as a liquid residue. The residue is further purified by reverse phase HPLC to obtain the title product (2.23 mg) as a solid, analytical data: LCMS: 478 [M+H] + , 1H NMR: (400MHz, DMSO-d6) δppm 10.41(br.s.,1H)9.16(s,1H)8.51(d,J=2.63Hz,1H)8.07(d,J=2.63Hz,1H)7.79(s,1H)7.59(d,J=9.2 1Hz, 1H) 7.49 (d, J = 8.33Hz, 1H) 7.33 (d, J = 5.70Hz, 1H) 7.23 (d, J = 9.21Hz, 1H) 7.04 (s, 2H) 3.91 (s, 3H).

[0375] Compound 2:

[0376]

[0377] Step 1: Synthesis of N-(3-bromo-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide

[0378] To a mixture of 3-bromo-2,4-difluoroaniline (200 mg, 0.96 mmol, 1.0 equivalent) in DCM (15 mL) was added pyridine (0.4 mL, 4.80 mmol, 5.0 equivalent) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and then 2,5-dichlorobenzenesulfonyl chloride (233 mg, 0.96 mmol, 1.0 equivalent) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound (200 mg). This material was used in the next reaction without further purification. Analytical data: LCMS: 416 [M+H] + .

[0379] Step 2: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine.

[0380] To a stirred solution of 6-bromoquinazolin-2-amine (100 mg, 0.446 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was added potassium acetate (88 mg, 0.90 mmol, 2.0 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (137 mg, 0.669 mmol, 1.5 equiv). The reaction mixture was degassed with nitrogen for 20 min, and then Pd(dppf)Cl2DCM complex (19 mg, 0.022 mmol, 0.05 equiv) was added. The reaction mixture was degassed again for 10 min, and then stirred at 85 ° C overnight. The reaction mass was treated with KCO (125 mg, 0.892 mmol, 2.0 equivalents) and ethyl acetate was added to the reaction mixture and filtered through a short plug of celite. The celite layer was washed with 2 x 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure and the crude product was used in the next step without further purification.

[0381] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide

[0382] To a stirred solution of N-(3-bromo-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (100 mg, 0.239 mmol, 1.0 equiv) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinazolin-2-amine (66 mg, 0.239 mmol, 1.0 equiv) in DMF:water (4:1, 5 mL) was added KCO (99 mg, 0.717 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (10 mg, 0.012 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 120 ° C overnight. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product as a crude residue, which was purified by reverse phase HPLC to obtain the title product (3.80 mg) as a solid. Analytical data: LCMS: 481 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 10.66(br.s.,1H)9.21(s,1H)7.79-7.89(m,2H)7.70-7.79(m,2H)7.62(br.s.,1H)7.52(d,J=8.77Hz,1H)7.15-7.44(m,4H).

[0383] Compound 3:

[0384]

[0385] Step 1: Synthesis of 5-chloro-N-(3-ethynyl-2,4-difluorophenyl)-2-methoxynicotinamide.

[0386] To a stirred solution of 5-chloro-2-methoxynicotinic acid (100 mg, 0.531 mmol, 1 equivalent) in DMF (2 mL) was added HATU (304 mg, 0.797 mmol, 1.5 equivalents). The mixture was allowed to stir for 5 minutes, then DIPEA (172 mg, 1.33 mmol, 2.5 equivalents) and 3-ethynyl-2,4-difluoroaniline (81 mg, 0.53 mmol, 1 equivalent) were added. The reaction mixture was kept under stirring at room temperature overnight. It was confirmed with TLC and LCMS that the product was formed and the reaction mixture was diluted with water (30 mL) and the precipitated solid was filtered, washed with water and dried under vacuum to obtain the title compound in a solid state. Analytical data: LCMS: 323 [M+H] + Step 2: Synthesis of N-(3-((2-aminopyrimidin-5-yl)ethynyl)-2,4-difluorophenyl)-5-chloro-2-methoxynicotinamide:

[0387] To a stirred solution of 5-chloro-N-(3-ethynyl-2,4-difluorophenyl)-2-methoxynicotinamide (100 mg, 0.310 mmol, 1.0 equivalent) and 5-iodopyrimidine-2-amine (68 mg, 0.310 mmol, 1.0 equivalent) in DMSO (5 mL) was added cesium carbonate (403 mg, 1.24 mmol, 4.0 equivalents). The reaction mixture was purged with nitrogen for 15 minutes, and then Pd(PCy)Cl (11 mg, 0.015 mmol, 0.05 equivalents) was added. The reaction mixture was stirred at 120 ° C for 4 h. The mixture was diluted with water and brine and extracted with EtOAc (2x50 mL). The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to obtain a residue, which was purified using flash chromatography (40%-50% EtOAc / hexane as eluent) to obtain the title compound as an off-white solid. The solid was purified again using reverse phase HPLC to afford the title product as a pure solid (5 mg).

[0388] Analytical data: LCMS: 416 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 4.03(s,3H)7.01(br.s.,1H)7.14-7.42(m,2H)7.90-8.08(m,1H)8.22(d,J=2.63Hz,1H)8.35-8.62(m,2H)8.70(br.s.,1H)10.22(s,1H).

[0389] Compound 4:

[0390]

[0391] Step 1: Synthesis of 3-(6-bromopyridin-3-yl)-2,4-difluoroaniline.

[0392] To a stirred solution of 2,4-difluoro-3-iodoaniline (500mg, 1.96mmol, 1.0 equivalent) in 1,4-dioxane (5mL) was added potassium phosphate (1.2g, 5.88mmol, 3.0 equivalents) and 2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (660mg, 2.352mmol, 1.2 equivalents). The reaction mixture was degassed with nitrogen for 20min, and then Pd(dppf)Cl2.DCM complex (8mg, 0.098mmol) was added. The reaction mixture was degassed again for 10min, and then stirred at 100°C overnight. The reactant was diluted with water and extracted with ethyl acetate (3x50mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography to obtain the title compound (140mg). LCMS: 285[M+H] + .

[0393] Step 2: Synthesis of N-(3-(6-bromopyridin-3-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide:

[0394] To a stirred solution of 3-(6-bromopyridin-3-yl)-2,4-difluoroaniline (140mg, 0.498mmol, 1.0 equivalent) in pyridine, 5-chloro-2-methoxypyridine-3-sulfonyl chloride (118mg, 0.491mmol, 1.0 equivalent) was added and the reaction mixture was stirred at room temperature overnight. MeOH (10mL) was added to the mixture, and the mixture was stirred at room temperature for 10min. The mixture was concentrated under reduced pressure. The crude product was then washed with 2N HCl solution, extracted with ethyl acetate (3x50ml) and reduced under pressure to obtain a residue, to obtain the title product (150mg) as a brown solid. This material was used in the next reaction without further purification. LCMS: 490[M+H] + .

[0395] Step 3: Synthesis of N-(3-(6-(2-aminopyrimidin-5-yl)pyridin-3-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0396] To a stirred solution of N-(3-(6-bromopyridin-3-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (150 mg, 0.305 mmol, 1.0 equiv) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (130 mg, 0.458 mmol, 1.5 equiv) in dioxane:water (4:1, 5 mL) was added KCO (124 mg, 0.917 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Tetrakis (17 mg, 0.0152 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction is complete, water is added to the reaction mixture and extracted with EtOAc (5x100mL). The organic layers are combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product as a crude residue, which is purified by reverse phase HPLC chromatography (using EtOAc / hexane (50%-100%) as eluent) to obtain the title product. The residue is further purified by normal phase silica gel chromatography to remove TPPO to obtain the title product (18 mg) as a white solid. Analytical data: LCMS: 505 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 3.92(s,3H)7.06(s,2H)7.25(t,J=9.65Hz,1H)7.32-7.51(m,1H)7.83(d,J=8.77Hz ,1H)8.01(d,J=8.33Hz,1H)8.08(s,1H)8.44-8.70(m,2H)8.97(s,2H)10.44(s,1H).

[0397] Compound 5:

[0398]

[0399] Step 1: Synthesis of di-Boc protection of 7-bromoquinazolin-2-amine:

[0400] To the stirred solution of 7-bromoquinazoline-2-amine (500mg, 2.23mmol, 1.0 equivalent) in THF (5mL), add DMAP (54mg, 0.44mmol, 0.2 equivalent), TEA (675mg, 6.69mmol, 3.0 equivalent), Boc anhydrides (1.45g, 6.696mmol, 3.0 equivalent) and reaction mixture was at room temperature stirred 4 days.Mixture is extracted and reduced under pressure to obtain resistates by using ethyl acetate (3x50ml), to obtain title product (700mg).This material is not further purified for next reaction.

[0401] Step 2: Synthesis of di-Boc protected boronate ester of 7-bromoquinazolin-2-amine:

[0402] To a stirred solution of tert-butyl (7-bromoquinazoline-2-yl) (tert-butoxycarbonyl)carbamate (200 mg, 0.472 mmol, 1.0 equivalent) and bis(pinacolato)diboron (144 mg, 0.56 mmol, 1.0 equivalent) in dioxane (3 mL) was added KOAc (138 mg, 1.41 mmol, 3.0 equivalents). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl (10 mg, 0.014 mmol, 0.03 equivalents). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C and continued overnight. The reaction process was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (5x100 mL). The organic layers were combined, dried over anhydrous NaSO and evaporated under reduced pressure to obtain the title product (250 mg) as a crude residue.

[0403] Step 3: Synthesis of tert-butyl (tert-butoxycarbonyl)(7-(3-((2,5-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)carbamate

[0404] To a stirred solution of N-(3-bromo-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (150 mg, 0.36 mmol, 1.0 equiv) and (2-(2-(bis(tert-butoxycarbonyl)amino)quinazolin-7-yl)-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl)methylium (204 mg, 0.43 mmol, 1.2 equiv) in DMF:water (4:1, 5 mL) was added KCO (147 mg, 1.08 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (15 mg, 0.05 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture, extracted with EtOAc (5×100 mL).The organic layers were combined, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to afford the title product (300 mg) as a crude residue.

[0405] Step 4: Synthesis of N-(3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide:

[0406] To a stirred solution of tert-butyl (tert-butoxycarbonyl)(7-(3-((2,5-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)carbamate (300 mg, 0.44 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (2 mL). The reaction mixture was then allowed to stir at room temperature overnight. After completion of the reaction, the solvent was evaporated and washed with pentane (5 mL) and ether (5 mL) to obtain a solid, which was purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (7 mg). Analytical data: LCMS: 481 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δppm 6.94(br.s.,2H)7.14-7.29(m,3H)7.34(br.s.,1H)7.61(br.s.,2H)7.77–7.95(m,2H)8.14(s,1H)9.15(s,1H).

[0407] Compound 6:

[0408]

[0409] Step 1: Synthesis of Intermediate A

[0410] To a stirred solution of N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (150 mg, 0.362 mmol, 1.0 equivalent) and diboc-2-amino-quinazoline-7-boronic acid (bronate) ester (206 mg, 0.43 mmol, 1.2 equivalents) in DMF: water (4: 1, 5 mL) was added K2CO3 (150 mg, 1.09 mmol, 3.0 equivalents). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by addition of Pd(dppf)Cl2.DCM complex (15 mg, 0.018 mmol, 0.05 equivalents). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C and continued overnight. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to obtain the title product (300 mg) as a crude residue, which was carried on to the next step without further purification.

[0411] Step 2: Synthesis of N-(3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide:

[0412] To a stirred solution of intermediate A (300 mg, 0.44 mmol, 1.0 equivalent) in DCM (5 mL) was added TFA (2 mL). The reaction mixture was then allowed to stir at room temperature overnight. After the completion of the reaction, the solvent was evaporated, washed with pentane (5 mL) and ether (5 mL) to obtain a solid, which was purified by reverse phase chromatography to obtain the title product N- (3- (2- aminoquinazoline -7- bases) -2,4- difluorophenyl) -2,5- dichlorobenzenesulfonamide (14 mg) as a free base. Analytical data: LCMS: 478 [M + H] + , 1 H NMR(400MHz,DMSO-d6)δppm 3.90(s,3H)6.96(s,2H)7.12(d,J=7.45Hz,1H)7.21(br.s.,1H)7.33(s,1H)7.39(bs,1H),7 .88(d,J=8.33Hz,1H)8.07(d,J=2.63Hz,1H)8.48(br.s.,1H)9.16(s,1H)10.42(br.s.,1H).

[0413] Compound 7:

[0414]

[0415] Step 1: Synthesis of 2,4-difluoro-3-iodobenzoic acid

[0416] To a stirred solution of 2,4-difluorobenzoic acid (3.0 g, 18.97 mmol, 1.0 eq) in HSO (50 mL) was added NIS (8.5 g, 37.97 mmol, 2 eq) dropwise at 0° C. and the reaction was allowed to stir for 2 h at 25° C. After completion of the reaction, the reaction mixture was diluted with cold water (500 mL), the precipitated solid was filtered and dried under vacuum to afford the title compound (3.5 g) as a white solid.

[0417] Step 2: Synthesis of 5-chloro-2-methoxynicotinate

[0418] To a stirred solution of 5-chloro-2-methoxynicotinic acid (2.5 g, 13.29 mmol, 1.0 equivalent) in EtOH (20 mL) was added hydrochloric acid (2 ml) and the reaction was heated at 100 ° C for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum to obtain a crude product, which was diluted with ethyl acetate (50 mL) and water (50 ml). The organic layer was washed with saturated brine and dried over Na2SO4 and concentrated under vacuum to obtain the desired product (2.85 g).

[0419] Step 3 Synthesis of 5-chloro-2-methoxynicotinic acid hydrazide

[0420] At room temperature to the stirring solution of 5-chloro-2-methoxynicotinate (2.85g, 13.19mmol 1 equivalent) in THF, add hydrazine hydrate (2.53ml, 79.14mmol, 6 equivalents).The mixture is stirred at room temperature overnight.After the reaction is completed, the reaction mixture is evaporated under vacuum to obtain crude product, water (25mL) and ethyl acetate (50mL) are added thereto. Each layer is separated and water layer is extracted with ethyl acetate (2x25mL).The organic layer merged is washed with saturated brine, through Na2SO4 drying, concentrated under vacuum to obtain required product (2.5g).

[0421] Step 4: Synthesis of 5-chloro-N'-(2,4-difluoro-3-iodobenzoyl)-2-methoxynicotinic acid hydrazide

[0422] To a stirred solution of 2,4-difluoro-3-iodobenzoic acid (1 g, 3.52 mmol 1 eq) in DMF was added HATU (2 g, 5.28 mmol 1.5 eq) and DIPEA (10.56 mmol 1.5 ml 3 eq) at 25 ° C. The mixture was stirred for 10 min and 5-chloro-2-methoxynicotinic acid hydrazide (711 mg, 3.52 mmol 1 eq) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue, which was purified by flash chromatography (EtOAc in hexane; 30%) to yield the title compound (800 mg) as an off-white solid.

[0423] Step 5 Synthesis of 2-(5-chloro-2-methoxypyridin-3-yl)-5-(2,4-difluoro-3-iodophenyl)-1,3,4-oxadiazole

[0424] To a stirred solution of 5-chloro-N'-(2,4-difluoro-3-iodobenzoyl)-2-methoxynicotinic acid hydrazide (800 mg, 1.70 mmol, 1.0 equiv) in DCM (15 mL) was added NEt at 0 ° C. (0.7 ml, 5.1 mmol, 3.0 equiv) and the mixture was stirred at 0 ° C. for 30 min and p-toluenesulfonyl chloride (0.162 mg, 0.85 mmol, 0.5 equiv) was added. The reaction mixture was stirred overnight. After completion of the reaction, aqueous sodium hydroxide solution was added to the reaction mixture, extracted twice with DCM (2 x 25 mL), the organic layer was washed with saturated brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (500 mg).

[0425] Step 6: Synthesis of 5-((trimethylsilyl)ethynyl)pyrimidin-2-amine

[0426] To a solution of 5-iodopyrimidin-2-amine (500 mg, 2.26 mmol, 1 equivalent) in THF / DMF was added triethylamine (0.85 ml, 6.78 mmol, 3 equivalents), purged with nitrogen 2-3 times, ethynyltriisopropylsilane (0.7 ml, 4.52 mmol, 2 equivalents), CuCl (61 mg, 0.452 mmol, 0.2 equivalents), dikis (793 mg, 1.13 mmol, 0.5 equivalents). The reaction mixture was stirred at 100 ° C for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 ml), and the organic layer was collected and concentrated to give a crude product, which was purified by combiflash chromatography to obtain a pure product (500 mg).

[0427] Step 7: Synthesis of 5-ethynylpyrimidin-2-amine

[0428] To a solution of 5-((trimethylsilyl)ethynyl)pyrimidine-2-amine (500 mg, 2.60 mmol, 1.0 equiv) in THF (10 mL) was added TBAF (0.4 ml, 1.3 mmol, 0.5 equiv). The reaction mixture was purged with nitrogen. The mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer obtained was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound in crude product, which was purified by combi-flash to obtain pure compound (400 mg).

[0429] Step 8: Synthesis of 5-((3-(5-(5-chloro-2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2,6-difluorophenyl)ethynyl)pyrimidin-2-amine

[0430] To a stirred solution of 2-(5-chloro-2-methoxypyridin-3-yl)-5-(2,4-difluoro-3-iodophenyl)-1,3,4-oxadiazole (120 mg 0.27 mmol, 1.0 equivalent) in THF (10 mL) was added triethylamine (0.3 mL, 1.66 mmol, 6 equivalents) and CuCl (6 mg, 0.054 mmol, 0.2 equivalents). The reaction mixture was purged with nitrogen for 15 minutes and then 5-((trimethylsilyl)ethynyl)pyrimidin-2-amine (60 mg, 0.54 mmol, 2 equivalents) and bis(triphenylphosphine)palladium dichloride (95 mg, 0.13 mmol 0.05 equivalents). The mixture was stirred at 100 ° C overnight. The reaction mixture was added to water (25 mL) and the mixture was extracted with ethyl acetate (3x50 mL). The obtained organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by combiflash to obtain the desired product. Analytical data: LCMS: 441.3 (M+H) + , 1 H NMR(400MHz,DMSO-d6)δppm 8.60(d,J=2.63Hz,1H)8.53(d,J=2.63Hz,1H)8.50(s,1H)8.43(t,J=7.67 Hz, 1H) 7.81 (t, J = 10.09 Hz, 1H) 7.51-7.67 (m, 1H) 7.29 (s, 2H) 4.05 (s, 3H).

[0431] Compound 8:

[0432]

[0433] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-2,5-difluorobenzenesulfonamide.

[0434] To a stirred solution of 2,4-difluoro-3-iodoaniline (300mg, 1.4111mmol, 1.0 equivalent) in pyridine (1.5mL) was added 2,5-difluorobenzenesulfonyl chloride (360mg, 1.4111mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound. This material was further purified by flash chromatography to obtain the desired compound (530mg).

[0435] Step 2: Synthesis of N-(6-(3-((2,5-difluorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide:

[0436] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-2,5-difluorobenzenesulfonamide (100 mg, 0.2320 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (164.9 mg, 0.4641 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (96 mg, 0.6962 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes before the addition of Pd(dppf)Cl DCM complex (9.48 mg, 0.0116 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title compound. This compound was used for further reaction without purification (190 mg). Analytical data: LCMS: 533.3 [M+H] + .

[0437] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide

[0438] To a stirred solution of N-(6-(3-((2,5-difluorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (170 mg, crude product) in ethanol (6 mL) was added 2M NaOH (4 mL) at room temperature. The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure, washed with ether (2 ml) and pentane (3 ml) to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide (11 mg), analytical data: LCMS: 449.08 [M+H] + ,NMR: 1 H NMR (400MHz, DMSO-d6) δ10.70(br.s.,1H),9.15(s,1H),7.77(s,1H),7.46-7.65(m,5H),7.32(d,J=6.58Hz,1H),7.24(d,J=9.65Hz,1H),7.03(s,2H).

[0439] Compound 9:

[0440]

[0441] Step 1: Synthesis of 3,4-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide

[0442] 3,4-dichlorobenzenesulfonyl chloride (311.6 mg, 1.2219 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (300 mg, 1.2219 mmol, 1.0 equivalent) in pyridine (2 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexanes) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which was ground together with hexanes to obtain the desired product (220 mg).

[0443] Step 2: Synthesis of N-(6-(3-((3,4-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide:

[0444] To a stirred solution of 3,4-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (200 mg, 0.4310 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (306.25 mg, 0.8620 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (178.7 mg, 1.2931 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (17.59 mg, 0.0215 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product. This compound was used in the next step without purification (350 mg). Analytical data: LCMS: 565.2 [M+H] + .

[0445] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-dichlorobenzenesulfonamide:

[0446] To a stirred solution of N-(6-(3-((3,4-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (350 mg, crude product) in ethanol (6 mL) was added 2M NaOH (4 mL) at room temperature. The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain the product, which was triturated with ether (2 ml) and pentane (3 ml) to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3,4-dichlorobenzenesulfonamide (45 mg) as the title compound. Analytical data: LCMS: 481 [M+H] + ,NMR: 1H NMR (400MHz, DMSO-d6) δ10.47(s,1H),9.14(s,1H),7.88-7.93(m,2H),7.75(s,1H),7.67(dd,J=1 .97,8.55Hz,1H),7.58(d,J=9.21Hz,1H),7.48(d,J=8.77Hz,1H),7.20-7.32(m,2H),7.04(s,2H).

[0447] Compound 10:

[0448]

[0449] Step 1: Synthesis of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-methoxybenzenesulfonamide:

[0450] 5-chloro-2-methoxybenzenesulfonyl chloride (528.8 mg, 2.0738 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (500 mg, 2.0738 mmol, 1.0 equivalent) in pyridine (3 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure and further purified by flash chromatography to obtain the desired product (250 mg).

[0451] Step 2: Synthesis of N-(6-(3-((5-chloro-2-methoxyphenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide:

[0452] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-methoxybenzenesulfonamide (200 mg, 0.4351 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (309.2 mg, 0.8702 mmol, 2.0 equiv) in dioxane:water (5:2, 7 mL) was added KCO (180.4 mg, 1.3053 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (17.76 mg, 0.0217 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. This compound was used for further reaction without purification (350 mg). Analytical data: LCMS: 561.1 [M+H] + .

[0453] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxybenzenesulfonamide:

[0454] To a stirred solution of N-(6-(3-((5-chloro-2-methoxyphenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (60 mg, crude product) in ethanol (5 mL) was added 2M NaOH (3 mL). The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain the product, which was triturated with ether (2 mL) and pentane (3 mL) to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxybenzenesulfonamide (30 mg) as the title compound. Analytical data: LCMS: 477.05 [M+H] + ,NMR: 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.16(s,1H),7.79(s,1H),7.69(dd,J=2.63,8.77Hz, 1H),7.59(br.s.,1H),7.49(d,J=8.77Hz,1H),7.10-7.40(m,3H),7.03(s,2H),3.82(s,3H).

[0455] Compound 11:

[0456]

[0457] Step 1: Synthesis of N-(3-bromo-2-methylphenyl)-2,5-dichlorobenzenesulfonamide

[0458] To a stirred solution of 3-bromo-2-methylaniline (500mg, 2.7mmol, 1.0 equivalent) in pyridine (5mL) was added 2,5-dichlorobenzenesulfonyl chloride (663mg, 2.7mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound. This material was used for the next reaction (700mg) without further purification.

[0459] Step 2: Synthesis of N-(6-bromoquinazolin-2-yl)pivalamide:

[0460] To 6-bromoquinazoline-2-amine (1.0g, 4.46mmol, 1.0 equivalent) stirring solution in pyridine (5mL), add pivaloyl chloride (1.61g, 1.33mmol, 3.0 equivalent).Reactant mixture is stirred at 90 ℃ and spend the night.After reaction is completed, reaction mixture is diluted with water (100mL) and extracted with ethyl acetate (3x500mL), organic layer is washed to remove pyridine with 1N HCl (100mL X 3 times), organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain title compound.This crude product is washed with hexane (20mL) and is not further purified for next reaction (1.2g).

[0461] Step 3: Synthesis of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide:

[0462] To a stirred solution of N-(6-bromoquinazoline-2-yl)pivalamide (1.2 g, 3.90 mmol, 1.0 equivalent) and bis(pinacolato)diboron (1.48 g, 5.86 mmol, 1.5 equivalents) in dioxane (20 mL) was added KOAc (1.14 g, 11.7 mmol, 3.0 equivalents). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl (142 mg, 0.195 mmol, 0.05 equivalents). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C and continued overnight. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (5x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and washed with hexane (20 mL) to obtain the title product (1.1 g) as a crude residue.

[0463] Step 4: Synthesis of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-2-methylphenyl)quinazolin-2-yl)pivalamide:

[0464] To a stirred solution of N-(3-bromo-2-methylphenyl)-2,5-dichlorobenzenesulfonamide (200 mg, 0.50 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (359 mg, 1.01 mmol, 2.0 equiv) in dioxane:water (8:2, 10 mL) was added KCO (207 mg, 1.5 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (20 mg, 0.025 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture, extracted with EtOAc (3×100 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure, which was purified by flash chromatography to obtain the title product (130 mg).

[0465] Step 5: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2-methylphenyl)-2,5-dichlorobenzenesulfonamide.

[0466] To a stirred solution of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-2-methylphenyl)quinazoline-2-yl)pivalamide (130mg, 0.533mmol, 1.0 equivalent) in ethanol (6mL) was added 2M NaOH (4mL). The reaction mixture was then allowed to stir overnight at 90 degrees Celsius. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (2x100mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure, purified by flash chromatography, washed with ether (5ml) and pentane (5ml) to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (70mg) as the title compound. Analytical data: LCMS: 459[M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 2.12(s,3H)6.90(s,3H)7.17(br.s.,2H)7.45(d,J=8.77Hz,1H)7.51-7.63(m ,1H)7.68(d,J=1.75Hz,1H)7.78(s,2H)7.83(s,1H)9.14(s,1H)10.18(s,1H).

[0467] Compound 12:

[0468]

[0469] Step 1: Synthesis of N-(3-bromo-2,6-difluorophenyl)-2,5-dichlorobenzenesulfonamide

[0470] To a stirred solution of 3-bromo-2,6-difluoroaniline (100 mg, 0.480 mmol, 1.0 equivalent) in pyridine (1.5 mL) was added 2,5-dichlorobenzenesulfonyl chloride (141 mg, 0.576 mmol, 1.2 equivalents) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound. This material was used for the next reaction (150 mg) without further purification.

[0471] Step 2: Synthesis of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-2,4-difluorophenyl)quinazolin-2-yl)pivalamide:

[0472] To a stirred solution of N-(3-bromo-2,6-difluorophenyl)-2,5-dichlorobenzenesulfonamide (120 mg, 0.289 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (206 mg, 0.578 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (111 mg, 0.867 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (11 mg, 0.014 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture, extracted with EtOAc (3x100 mL).The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain the title product (50 mg).

[0473] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl)-2,5-dichlorobenzenesulfonamide:

[0474] To a stirred solution of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-2,4-difluorophenyl)quinazolin-2-yl)pivalamide (50 mg, 0.0886 mmol, 1.0 equivalent) in ethanol (4 mL) was added 2M NaOH (4 mL) at room temperature. The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was washed with ether (2 ml) and pentane (3 ml) to obtain N-(3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl)-2,5-dichlorobenzenesulfonamide (22 mg) as the title compound. Analytical data: LCMS: 481 [M+H] + ,NMR: 1H NMR(400MHz,DMSO-d6)δppm 7.27(s,2H)7.29(t,J=8.77Hz,1H)7.51(d,J=8.77Hz,1H)7.57-7.64(m,1H)7.67-7.83(m,3H)7.84-7.98(m,2H)9.21(s,1H)10.59(br.s.,1H).

[0475] Compound 13:

[0476]

[0477] Step 1 Synthesis of N-(3-bromo-2-fluorophenyl)-2,5-dichlorobenzenesulfonamide

[0478] To a stirred solution of 3-bromo-2-fluoroaniline (500 mg, 2.631 mmol, 1.0 equivalent) in pyridine (2.0 mL) was added 2,5-dichlorobenzenesulfonyl chloride (645.984 mg, 2.631 mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC. After the reaction was complete, water (100 ml) was added and filtered, and the residue was washed with water and hexane without further purification for use in the next step (710 mg).

[0479] Step 2: Synthesis of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-2-fluorophenyl)quinazolin-2-yl)pivalamide:

[0480] To a stirred solution of N-(3-bromo-2-fluorophenyl)-2,5-dichlorobenzenesulfonamide (200 mg, 0.501 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (178.043 mg, 0.501 mmol, 1.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (207.52 mg, 1.503 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (40.93 mg, 0.0501 mmol, 0.1 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite bed and the filtrate was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound which was used in the next step without further purification. Analytical data: LCMS: 547.07 [M+H] + .

[0481] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2-fluorophenyl)-2,5-dichlorobenzenesulfonamide.

[0482] To a stirred solution of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-2-fluorophenyl)quinazoline-2-yl)pivalamide (200 mg) in ethanol (4 mL) was added 2M NaOH (4 mL). The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water (20 mL) was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC to obtain the title compound N-(3-(2-aminoquinazoline-6-yl)-2-fluorophenyl)-2,5-dichlorobenzenesulfonamide (4 mg). Analytical data: LCMS: 463.01 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 7.85-7.93 (m, 2H), 7.76 (d, J = 8.77Hz, 1H ),7.54(s,2H),7.46(d,J=8.77Hz,1H),7.08-7.15(m,1H),6.87-7.02(m,5H).

[0483] Compound 14:

[0484]

[0485] Step 1 Synthesis of N-(3-bromo-5-fluorophenyl)-2,5-dichlorobenzenesulfonamide

[0486] To a stirred solution of 3-bromo-5-fluoroaniline (500mg, 2.64mmol, 1.0 equivalent) in pyridine (15mL) was added 3-bromo-5-fluoroaniline (774mg, 3.17mmol, 1.2 equivalents) at room temperature. The resulting reaction mixture was stirred at 90°C overnight. The reaction progress was monitored by TLC. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (5x100mL). The organic layer was combined and treated with 1N HCl to remove pyridine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude compound (0.200g) for the next step without further purification, analytical data: LCMS: 398[M+H] + .

[0487] Step 2: Synthesis of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-5-fluorophenyl)quinazolin-2-yl)pivalamide:

[0488] To a stirred solution of N-(3-bromo-5-fluorophenyl)-2,5-dichlorobenzenesulfonamide (500 mg, 1.26 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (894 mg, 2.51 mmol, 2.0 equiv) in dioxane:water (4:1, 10 mL) was added KCO (521 mg, 3.77 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (51 mg, 0.062 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100 °C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with EtOAc (5x100mL) and extracted with water (2x100mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain the title product N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-5-fluorophenyl)quinazolin-2-yl)pivalamide (0.300g). Analytical data: LCMS: 547[M+H] + .

[0489] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-5-fluorophenyl)-2,5-dichlorobenzenesulfonamide.

[0490] To a stirred solution of N-(6-(3-((2,5-dichlorophenyl)sulfonamido)-5-fluorophenyl)quinazoline-2-yl)pivalamide (500 mg, 0.915 mmol) in ethanol (12 mL) was added 2M NaOH (12 mL). The reaction mixture was then allowed to stir at 90 ° C for 6 h. After completion of the reaction, the solvent was evaporated and dissolved in EtOAc (2x100 mL) and washed with brine (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain the title compound N-(3-(2-aminoquinazoline-6-yl)-5-fluorophenyl)-2,5-dichlorobenzenesulfonamide (0.150 g). Analytical data: LCMS: 463.01 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 11.24(br.s.,1H)9.17(s,1H)8.21(d,J=2.19Hz,1H)7.96(s,1H)7.85(d,J=8.77Hz,1H)7.68- 7.82(m,2H)7.48(d,J=8.33Hz,1H)7.22-7.35(m,2H)7.01(br.s.,2H)6.88(d,J=10.09Hz,1H).

[0491] Compound 15:

[0492]

[0493] Step 1 Synthesis of 2,4-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide.

[0494] To a stirred solution of 2,4-difluoro-3-iodoaniline (415.41 mg, 1.6293 mmol, 1.0 equivalent) in pyridine (2 mL) was added 2,4-dichlorobenzenesulfonyl chloride (400 mg, 1.6293 mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture was stirred overnight at 90 ° C. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound. This material was further purified by flash chromatography to obtain the desired compound (1.2 g).

[0495] Step 2: Synthesis of N-(6-(3-((2,4-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0496] To a stirred solution of 2,4-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (200 mg, 0.4310 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (306.2 mg, 0.8620 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (178.7 mg, 1.2931 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (17.59 mg, 0.0215 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title compound. This compound was used for further reaction without purification (250 mg). Analytical data: LCMS: 565.1 [M+H] + .

[0497] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,4-dichlorobenzenesulfonamide.

[0498] To a stirred solution of N-(6-(3-((2,4-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (250 mg, 0.4432 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (6 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. The progress of the reaction was analyzed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2x30 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and further purified under flash chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,4-dichlorobenzenesulfonamide (49 mg), analytical data: LCMS: 481.0 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.15(s,1H),7.93(d,J=2.19Hz,1H),7.89(d,J=8.33Hz,1H),7.7 6(s,1H),7.52-7.64(m,2H),7.48(d,J=8.77Hz,1H),7.24-7.33(m,1H),7.16-7.24(m,1H),7.03(s,2H).

[0499] Compound 16:

[0500]

[0501] Step 1 Synthesis of N-(3-bromo-4-methylphenyl)-2,5-dichlorobenzenesulfonamide.

[0502] To a stirred solution of 3-bromo-4-methylaniline (379.02 mg, 2.0366 mmol, 1.0 equivalent) in pyridine (3 mL) was added 2,5-dichlorobenzenesulfonyl chloride (500 mg, 2.0366 mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture was stirred at 90 ° C for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure to obtain a crude residue, which was treated with 1N HCl to remove pyridine. The product was extracted with EtOAc, and the organic layer was dried over sodium sulfate and concentrated under vacuum to obtain the desired product, N-(3-bromo-4-methylphenyl)-2,5-dichlorobenzenesulfonamide (600 mg).

[0503] Step 2: Synthesis of N-(6-(5-((2,5-dichlorophenyl)sulfonamido)-2-methylphenyl)quinazolin-2-yl)pivalamide.

[0504] To a stirred solution of N-(3-bromo-4-methylphenyl)-2,5-dichlorobenzenesulfonamide (500 mg, 1.2725 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (904.17 mg, 2.5451 mmol, 2.0 equiv) in dioxane:water (6:2, 8 mL) was added KCO (527.6 mg, 3.8177 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (51.9 mg, 0.0636 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and further purified using flash chromatography to obtain the desired compound N-(6-(5-((2,5-dichlorophenyl)sulfonamido)-2-methylphenyl)quinazolin-2-yl)pivalamide (400 mg), LCMS: 543.1 [M+H] + .

[0505] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-4-methylphenyl)-2,5-dichlorobenzenesulfonamide.

[0506] To a stirred solution of N-(6-(5-((2,5-dichlorophenyl)sulfonamido)-2-methylphenyl)quinazolin-2-yl)pivalamide (230 mg, 0.4242 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (5 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product, extracted with EtOAc (50 mL × 2), dried over sodium sulfate, concentrated under reduced pressure and further purified by using flash chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-4-methylphenyl)-2,5-dichlorobenzenesulfonamide (120 mg), analytical data: LCMS: 459.0 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.76 (s, 1H), 9.13 (s, 1H), 8.01 (d, J = 2.63Hz, 1H), 7.75-7.80(m,1H),7.71(d,J=8.77Hz,1H),7.59(d,J=1.75Hz,1H),7.53(dd ,J=1.75,8.77Hz,1H),7.45(d,J=8.77Hz,1H),7.20(d,J=8.33Hz,1H),7.03 (dd, J=2.19, 8.33Hz, 1H), 6.99 (d, J=2.19Hz, 1H), 6.92 (s, 2H), 2.14 (s, 3H).

[0507] Compound 17:

[0508]

[0509] Step 1: Synthesis of N-(6-bromoquinazolin-4-yl)pivalamide.

[0510] To a stirred solution of 6-bromoquinazoline-4-amine (1g, 4.4642mmol, 1.0 equivalent) in pyridine (4mL) is added pivaloyl chloride (1.6mL, 13.3928mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture is stirred overnight at 90°C. The reaction process is monitored by TLC. After the completion of the reaction, the solvent is concentrated under reduced pressure to obtain a crude residue, which is further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in liquid and the liquid is further processed with 1N HCl to remove pyridine. The product is extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure and further purified by flash chromatography to obtain the desired product (650mg).

[0511] Step 2: Synthesis of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)pivalamide.

[0512] To a stirred solution of N-(6-bromoquinazolin-4-yl)pivalamide (500 mg, 1.6286 mmol, 1.0 eq) in dioxane (7 mL) was added potassium acetate (478.8 mg, 4.8859 mmol, 3.0 eq) and B2Pin2 (620.2 mg, 2.4429 mmol, 1.5 eq) and purged at room temperature under nitrogen atmosphere for 15 min. After 15 min, Pd(dppf)Cl2 (59.5 mg, 0.0814 mmol, 0.05 eq) was added to the reaction mixture and purged again for 5 min, and then the reaction mixture was heated at 100 ° C overnight. The reaction mixture was analyzed by TLC and 1 H NMR analysis reaction progress. After completion of the reaction, the reaction mixture was passed through a bed of celite, then extracted with EtOAc (70 mL x 2), dried over sodium sulfate and concentrated under reduced pressure to obtain the desired product, N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinazoline-4-yl)pivalamide (800 mg), which was used in the next step without any purification.

[0513] Step 3: Synthesis of N-(6-(3-(2,5-dichlorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-4-yl)pivalamide.

[0514] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (522.4 mg, 1.1258 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)pivalamide (800 mg, 2.2519 mmol, 2.0 equiv) in dioxane:water (6:2, 8 mL) was added KCO (466.7 mg, 3.3775 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (45.9 mg, 0.0562 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. This compound was used for further reaction without purification (600 mg).

[0515] Step 4: Synthesis of N-(3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide.

[0516] To a stirred solution of N-(6-(3-(2,5-dichlorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-4-yl)pivalamide (500 mg, 0.8864 mmol, 1.0 equiv) in ethanol (7 mL) was added 2 M NaOH (6 mL). The reaction mixture was then allowed to stir overnight at 90 ° C. The reaction progress was analyzed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was diluted with water and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography (50% EtOAc: hexane) to obtain N-(3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide as the title compound. Analytical data: LCMS: 481.0 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.84(br.s.,1H),8.44(s,1H),8.31(br.s.,1H),7.89(br.s.,3H),7.75(br.s.,3H),7.66(d,J=8.33Hz,1H),7.11-7.40(m,2H).

[0517] Compound 18:

[0518]

[0519] Step 1: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(7-fluoro-1H-benzo[d]imidazol-5-yl)phenyl)benzenesulfonamide.

[0520] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (500 mg, 1.07 mmol, 1.0 equiv) and 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3a,7a-dihydro-1H-benzo[d]imidazole (395 mg, 1.61 mmol, 1.5 equiv) in dioxane:water (4:1, 10 mL) was added KCO (440 mg, 3.23 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (88 mg, 0.107 mmol, 0.1 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (5x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure, and purified by reverse phase chromatography to obtain the title product 2,5-dichloro-N-(2,4-difluoro-3-(7-fluoro-1H-benzo[d]imidazol-5-yl)phenyl)benzenesulfonamide (200 mg). Analytical data: LCMS: 472[M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 12.92(br.s.,1H)10.66(s,1H)8.37(s,1H)7.86(d,J=2.19Hz,1H)7.72- 7.80(m,2H)7.29-7.37(m,2H)7.18-7.24(m,1H)6.96(d,J=10.96Hz,1H).

[0521] Compound 19:

[0522]

[0523] Step 1: Synthesis of N-(3-bromo-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0524] To a stirred solution of 3-bromo-4-fluoroaniline (500mg, 2.6mmol, 1.0 equivalent) in pyridine (3.0mL) was added 5-chloro-2-methoxypyridine-3-sulfonyl chloride (634mg, 2.6mmol, 1.0 equivalent) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound. This material was used for the next reaction (200mg) without further purification, and analytical data: LCMS: 395[M+H] + .

[0525] Step 2: Synthesis of N-(6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)quinazolin-2-yl)pivalamide.

[0526] To a stirred solution of N-(3-bromo-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (200 mg, 0.508 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (360 mg, 1.0 mmol, 2.0 equiv) in dioxane:water (8:2, 10 mL) was added KCO (207 mg, 1.5 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (20 mg, 0.025 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure, and purified by flash chromatography to obtain the title product (120 mg). Analytical data: LCMS: 544.1 [M+H] + .

[0527] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0528] To a stirred solution of N-(6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)quinazoline-2-yl)pivalamide (120 mg, 0.219 mmol, 1.0 equivalent) in ethanol (6 mL) was added 2M NaOH (4 mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 4 h. After the reaction was complete, the solvent was evaporated under vacuum to obtain a crude product, which was extracted with EtOAc (2x50 mL) added with water. The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was then purified by reverse phase silica gel chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,6-difluorophenyl)-2,5-dichlorobenzenesulfonamide (9 mg) as the title compound. Analytical data: LCMS: 460[M+H] + ,NMR: 1 H NMR (400MHz, DMSO-d6) δ10.58(br.s.,1H),9.18(s,1H),8.48(d,J=2.63Hz,1H),8.22(d,J=2.63Hz,1H),7.84(s,1H), 7.72(d,J=9.21Hz,1H),7.50(d,J=8.77Hz,1H),7.17-7.38(m,2H),7.09(d,J=7.89Hz,1H),7.00(s,2H),3.97(s,3H).

[0529] Compound 20:

[0530]

[0531] Step 1 Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine.

[0532] To a stirred solution of 6-bromoquinoline-2-amine (200 mg, 0.8964 mmol, 1.0 equivalent) in dioxane (3 mL) was added B2Pin2 (341.4 mg, 1.3446 mmol, 1.5 equivalents) and potassium acetate (263.5 mg, 2.6893 mmol, 3.0 equivalents), and the reaction mixture was purged with nitrogen for 10 min at room temperature. After 10 min, Pd (dppf) Cl2 (32.7 mg, 0.0448 mmol, 0.05 equivalent) was added to RM and purged again for 5 min under a nitrogen atmosphere. The resulting reaction mixture was heated at 120 ° C for 90 min in a microwave. The reaction process was monitored by TLC and LCMS. After the reaction was complete, RM was extracted twice with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound (400 mg).

[0533] Step 2: Synthesis of N-(3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0534] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide (330 mg, 0.7164 mmol, 1.0 equiv) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinolin-2-amine (387 mg, 1.4328 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (297 mg, 2.1492 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(dppf)Cl DCM complex (29.25 mg, 0.0358 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 120 ° C in a microwave for 90 min. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x50mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by flash chromatography to obtain the desired compound. The compound was then ground using pentane (3mL) to obtain the desired compound N-(3-(2-aminoquinoline-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (47mg). Analytical data: LCMS: 477.3[M+H] + , 1 H NMR (400MHz, DMSO-d6) δ11.96(br.s.,1H),10.42(br.s.,1H),8.51(d,J=2.19Hz,1H),8.06(d,J=2.19Hz,1H),7.92(d,J=8.33Hz,1 H),7.59(br.s.,1H),7.51(br.s.,1H),7.26-7.41(m,2H),7.19(t,J=9.21Hz,1H),6.81(br.s.,1H),6.64(br.s.,1H),3.91(s,3H).

[0535] Compound 44:

[0536]

[0537] Step 1 Synthesis of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine.

[0538] To the stirred solution of 8-bromoquinazoline-2-amine (200mg, 0.8926mmol, 1.0 equivalent) in dioxane (4mL), add B2Pin2 (339.9mg, 1.3389mmol, 1.5 equivalents) and potassium acetate (262.4mg, 2.6778mmol, 3.0 equivalents) and reactant mixture is at room temperature purged with nitrogen for 10min. After 10min, by Pd (dppf) Cl2 (32.6mg, 0.0446mmol, 0.05 equivalent) add in RM and under nitrogen atmosphere, purge 5min again. Gained reaction mixture is heated 90min at 120 ℃ in microwave. Reaction process is monitored by TLC and LCMS. After the completion of the reaction, RM is extracted with EtOAc (50mL × 2). By organic layer through anhydrous sodium sulfate drying and vaporising under reduced pressure, to obtain title compound (420mg).

[0539] Step 2: Synthesis of N-(3-(2-aminoquinazolin-8-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0540] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide (330 mg, 0.7164 mmol, 1.0 equiv) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinazolin-2-amine (388.4 mg, 1.4328 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (297 mg, 2.1492 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(dppf)Cl DCM complex (29.2 mg, 0.0358 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 120 ° C in a microwave for 90 min. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x50mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by flash chromatography to obtain the desired compound, which was ground together with pentane (3mL) and ether (2mL) to obtain the desired compound N-(3-(2-aminoquinazoline-8-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (13mg). Analytical data: LCMS: 478.3[M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.17(s,1H),8.48(d,J=2.63Hz,1H),8.10(d,J=2.63Hz,1H),7.90(dd,J=1. 32,7.89Hz,1H),7.51(d,J=5.70Hz,1H),7.25-7.39(m,2H),7.15(t,J=8.11Hz,1H),6.82(br.s.,2H),3.90(s,3H).

[0541] Compounds 45 and 114:

[0542]

[0543] Step 1: Synthesis of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide.

[0544] To a stirred solution of N-(5-bromoquinazoline-2-yl) pivalamide (500mg, 1.6224mmol, 1.0 equivalent) in dioxane (6mL), B2Pin2 (617.9mg, 2.4336mmol, 1.5 equivalents) and potassium acetate (476.9mg, 4.8672mmol, 3.0 equivalents) was added and the reaction mixture was purged with nitrogen for 10min at room temperature. After 10min, Pd(dppf)Cl2 (59.2mg, 0.0811mmol, 0.05 equivalent) was added to RM and purged again for 5min under a nitrogen atmosphere. The gained reaction mixture was heated overnight at 100°C. The reaction process was monitored by TLC and LCMS. After the reaction was complete, RM was extracted with EtOAc (100mL × 2). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain title compound (960mg).

[0545] Step 2: Synthesis of N-(5-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0546] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide (250 mg, 0.5439 mmol, 1.0 equiv) and N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (386.4 mg, 1.0878 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (225.5 mg, 1.6317 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes followed by the addition of Pd(dppf)Cl DCM complex (22.2 mg, 0.0271 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x70 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title compound. This compound was used in the next step without purification (400 mg). Analytical data: LCMS: 562.1 [M+H] +

[0547] Step 3: Synthesis of N-(3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0548] To a stirred solution of N-(5-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (400 mg, 0.7677 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (4 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C overnight. The progress of the reaction was analyzed by TLC and LCMS. After completion of the reaction, the RM was concentrated under reduced pressure and extracted with EtOAc (2×30 mL). The organic layers were combined, dried over anhydrous Na SO and evaporated under reduced pressure and further purified under flash chromatography to obtain N-(3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (6 mg), analytical data: LCMS: 481.3 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.52(d,J=2.63Hz,1H),8.32(br.s.,1H),8.06(d,J=2.63Hz,1H),7.76(dd, J=7.24,8.55Hz,1H),7.40-7.57(m,2H),7.29(t,J=8.77Hz,1H),7.10(d,J=7.02Hz,1H),7.02(s,2H),3.90(s,3H).

[0549] Compound 46:

[0550]

[0551] Step 1: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide.

[0552] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (60 mg, 0.10 mmol, 1.0 equiv) in DMF (0.3 mL) was added 2-aminoethanol (7 mg, 0.12 mmol, 1.2 equiv), DIPEA (40 mg, 0.31 mmol, 3.0 equiv). The reaction was allowed to stir at 70 ° C for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, ethanol was evaporated and then the reaction was post-processed using ethyl acetate (2x50 ml) and water (20 ml). The separated organic layer was separated over Na2SO4, dried, filtered and concentrated. The crude product was purified by reverse phase HPLC to obtain 5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (11 mg). Analytical data: LCMS: 522.06 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 3.43-3.53(m,2H)3.59(br.s.,2H)3.88(s,3H)4.75(br.s.,1H)7.15(d,J=8.33Hz,1H)7.28(d,J=6.14Hz,1H)7.44(br.s.,1H) 7.53(br.s.,1H)7.60(d,J=8.33Hz,1H)7.79(br.s.,1H)8.05(br.s.,1H)8.44(br.s.,1H)9.14(br.s.,1H)10.42(br.s.,1H).

[0553] Compound 47:

[0554]

[0555] Step 1: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide.

[0556] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (100 mg, 0.209 mmol, 1.0 eq) was added CuI (55.8 mg, 0.293 mmol, 1.4 eq) and purged with N2 gas, isoamyl nitrite (39 mg, 0.334 mmol, 1.6 eq), CH2I2 (335 mg, 1.25 mmol, 6.0 eq) were added to the reaction mixture. After addition, the reaction mixture was allowed to stir at 80°C. After completion of the reaction, water (20 ml) was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the desired product (190 mg), LCMS: 589 [M+H]. +

[0557] Step 2: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(methylamino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide:

[0558] To 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (120 mg, 0.415 mmol, 1.0 equiv) was added a solution of methylamine in ethanol (33% by weight, 1 mL) and allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, ethanol was evaporated under vacuum to obtain a crude product, water (20 ml) was added and extracted with ethyl acetate (2 x 50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain a crude product, which was purified by reverse phase silica gel chromatography (6 mg), analytical data: LCMS: 492 [M+H] + , 1HNMR(400MHz,DMSO-d6)δ9.13(br.s.,1H),8.17(d,J=2.63Hz,1H),7.97(d,J=2.63Hz,1H),7.80(br.s.,1H),7.64(d,J=9.21 Hz,1H),7.54(br.s.,1H),7.41(br.s.,1H),7.11(d,J=5.26Hz,1H),6.72-6.86(m,2H),3.78(s,3H),2.91(d,J=4.82Hz,3H).

[0559] Compound 51:

[0560]

[0561] Step 1: Synthesis of N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-methylphenyl)quinazolin-2-yl)pivalamide:

[0562] To a stirred solution of N-(3-bromo-2-methylphenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (200 mg, 0.512 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (218 mg, 0.615 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (212 mg, 1.536 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (21 mg, 0.025 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step (400 mg) without purification, LCMS: 544 [M+H] +

[0563] Step 2: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2-methylphenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0564] To a stirred solution of N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-methylphenyl)quinazolin-2-yl)pivalamide (400 mg, 0.74 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (4 mL). The reaction mixture was then allowed to stir at 90 ° C for 4 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure, and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-2-methylphenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (30 mg) as the title compound. Analytical data: LCMS: 456 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.17(br.s.,1H),7.93(br.s.,1H),7.48-7.73(m,3H),7.42(d,J=8.77Hz,1 H),7.28(br.s.,1H),6.99(d,J=8.33Hz,1H),6.74-6.94(m,3H),6.68(br.s.,1H),6.51(br.s.,2H),3.82(s,3H).

[0565] Compound 52:

[0566]

[0567] Step 1: Synthesis of N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)quinazolin-2-yl)pivalamide:

[0568] To a stirred solution of N-(3-bromo-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (200 mg, 0.508 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (217 mg, 0.609 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (210 mg, 1.5 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (20 mg, 0.025 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. This material was used in the next reaction (170 mg) without further purification, LCMS: 544 [M+H] +

[0569] Step 2: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0570] To a stirred solution of N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)quinazolin-2-yl)pivalamide (170 mg, 0.312 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaoH (4 mL). The reaction mixture was then allowed to stir at 90 ° C for 4 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (11 mg) as the title compound, analytical data: LCMS: 460[M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.16(s,1H),8.50(d,J=2.63Hz,1H),8.09(d,J=2.63Hz,1H),7.65(d ,1H),7.87(s,1H),7.48(d,J=8.77Hz,1H),7.35(m,1H),7.26(d,J=7.45Hz,2H),6.99(s,2H),3.91(s,3H).

[0571] Compound 58:

[0572]

[0573] Step 1 Synthesis of 5-chloro-2-(trifluoromethyl)benzene-1-sulfonyl chloride

[0574] Part A: Thionyl chloride (8.4 ml) was added dropwise to water (50 ml) at 5 ° C over 60 minutes, maintaining the temperature of the mixture between 0 ° C and 7 ° C. The solution was allowed to warm to 18 ° C over 17 hours. Copper (I) chloride (0.003 g) was added to the mixture and the resulting yellow-green liquid was cooled to -3 ° C using an ice / acetone bath. Part B: Hydrochloric acid (26.5 ml) was added (with stirring) to 5-chloro-2-(trifluoromethyl)aniline (3.0 g), maintaining the temperature of the mixture below 30 ° C with ice cooling. The reaction mixture was cooled to -5 ° C using an ice / acetone bath and a solution of sodium nitrite (3.10 g) in water (40 ml) was added dropwise over 45 minutes, maintaining the temperature of the reaction mixture between -5 ° C and 0 ° C. The resulting slurry was cooled to -2 ° C and stirred for 15 minutes. Part C: The slurry from Part B was cooled to -5 ° C and added to the solution obtained from Part A over 95 minutes, the reaction mixture temperature was maintained between -3 ° to 0 °, and after completion of the reaction, the reaction mass was diluted with water and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography to obtain the title compound 5-chloro-2-(trifluoromethyl)benzene-1-sulfonyl chloride (1.3 g).

[0575] Step 2: Synthesis of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-(trifluoromethyl)benzenesulfonamide.

[0576] By 3-iodo-2,4-difluoroaniline (300mg, 1.25mmol, 1.0 equivalent) and 5-chloro-2-(trifluoromethyl) benzene-1-sulfonyl chloride (450mg, 1.76mmol and 1.5 equivalent) mixture in pyridine at room temperature stir and spend the night.After reaction is completed, add 2N HCl (10mL) and mixture is stirred at room temperature 10min, reaction mass is diluted with water and extracted by ethyl acetate (3x50mL).By the organic layer merged through anhydrous sodium sulfate drying and under reduced pressure concentrate and by combi-flash purifying to obtain title compound (1.03g).

[0577] Step 3: Synthesis of N-(6-(3-(5-chloro-2-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0578] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-(trifluoromethyl)benzenesulfonamide (650 mg, 1.30 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (700 mg, 1.95 mmol, 1.5 equiv) in dioxane:water (4:1, 5 mL) was added KCO (270 mg, 1.95 mmol, 1.5 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(dppf)Cl.DCM complex (56 mg, 0.065 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 130°C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture and extracted with EtOAc (5x100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title product as a crude residue, which was purified by flash chromatography using EtOAc / hexanes (50%-100%) as eluent to obtain the title product (250 mg).

[0579] Step 4: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-(trifluoromethyl)benzenesulfonamide.

[0580] To a stirred solution of N-(6-(3-(5-chloro-2-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (200 mg, 0.34 mmol, 1.0 equiv) in ethanol (5 mL) was added 2M NaOH (2 mL) at room temperature. The reaction mixture was then allowed to stir at 100 ° C for 30 min. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was concentrated under reduced pressure to evaporate ethanol and then extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the crude product. This product was purified by using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-(trifluoromethyl)benzenesulfonamide (34 mg), analytical data: LCMS: 515.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) 7.02 (s, 2H) 7.15 (br.s., 2H) 7.48 (d, J = 9.21Hz, 2H) 7.58 (d, J = 8.33Hz, 1H) 7.76 (s, 2H) 8.01 (s, 1H) 9.15 (s, 1H) 10.65 (br.s., 1H).

[0581] Compound 59:

[0582]

[0583] Step 1 Synthesis of 3,5-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide.

[0584] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.392mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 3,5-dichlorobenzenesulfonyl chloride (96mg, 0.392mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next reaction (130mg) without further purification.

[0585] Step 2: Synthesis of N-(6-(3-((3,5-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0586] To a stirred solution of 3,5-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (125 mg, 0.269 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (114 mg, 0.323 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (111 mg, 0.807 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (10.9 mg, 0.0134 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to a crude product, which was used in the next reaction without further purification (115 mg). LCMS: 565 [M+H] + .

[0587] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-dichlorobenzenesulfonamide.

[0588] To a stirred solution of N-(6-(3-((3,5-dichlorophenyl)sulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (115 mg, 0.0203 mmol, 1.0 equiv) in ethanol (5 mL) was added 2M NaOH (4 mL). The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3,5-dichlorobenzenesulfonamide (15 mg) as the title compound. Analytical data: LCMS: 481 [M+H] +1 H NMR(400MHz,DMSO-d6)δ10.52(br.s.,1H)9.14(s,1H),7.85(br.s.,1H),7.78(s,1H),7.54- 7.71(m,3H),7.48(d,J=8.77Hz,1H),7.21(d,J=6.14Hz,1H),7.05(br.s.,1H),7.00(s,2H).

[0589] Compound 63:

[0590]

[0591] Step 1: Synthesis of 3-chloro-N-(2,4-difluoro-3-iodophenyl)-5-(trifluoromethyl)benzenesulfonamide.

[0592] At room temperature to 2,4-difluoro-3-iodoaniline (136mg, 0.53mmol, 1.0 equivalent) in the stirring solution of pyridine (2mL), add 3-chloro-5-(trifluoromethyl) benzene-1-sulfonyl chloride (150mg, 0.53mmol, 1.0 equivalent), after adding, reactant mixture is stirred at room temperature overnight. Monitor reaction process by TLC and LCMS, after reaction is complete, add 2N HCl (5mL) and mixture is stirred at room temperature 10min, reaction mass is diluted with water and extracted by ethyl acetate (2x15mL).By the organic layer merged through anhydrous Na SO Dry and under reduced pressure concentrate, this material is used for next reaction (260mg) without further purification.

[0593] Step 2: Synthesis of N-(6-(3-(3-chloro-5-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0594] To a stirred solution of 3-chloro-N-(2,4-difluoro-3-iodophenyl)-5-(trifluoromethyl)benzenesulfonamide (260 mg, 0.52 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (204 mg, 0.57 mmol and 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (216 mg, 1.57 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (21 mg, 0.026 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x10mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue, which was purified by flash chromatography to obtain the title product N-(6-(3-(3-chloro-5-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (422 mg). Analytical data: LCMS: 599[M+H] +

[0595] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-chloro-5-(trifluoromethyl)benzenesulfonamide.

[0596] To a stirred solution of N-(6-(3-(3-chloro-5-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (422 mg, 0.705 mmol, 1.0 eq) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature. The reaction mixture was then allowed to stir at 60 ° C for 2 h, and the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (2x10 mL), the organic layers were combined, dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain a crude product, which was purified by using reverse phase chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-chloro-5-(trifluoromethyl)benzenesulfonamide (50 mg), analytical data: LCMS: 515 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 10.75(br.s.,1H)9.15(s,1H)8.19(s,1H)8.02(s,1H)7.78(s,1H)7.60(d,J=8.77Hz,1H)7.49(d,J=8.77Hz,1H)7.15-7.35(m,3H)7.04(s,2H).

[0597] Compound 64:

[0598]

[0599] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)isoquinoline-5-sulfonamide.

[0600] Isoquinoline-5-sulfonyl chloride hydrochloride (248.5 mg, 0.7843 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (200 mg, 0.7843 mmol, 1.0 equivalent) in pyridine (1 mL) at room temperature. The resulting reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexane) to obtain the title compound as a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which was triturated with hexane to obtain the desired product, N-(2,4-difluoro-3-iodophenyl)isoquinoline-5-sulfonamide (220 mg).

[0601] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(isoquinoline-5-sulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0602] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)isoquinoline-5-sulfonamide (220 mg, 0.4930 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (210 mg, 0.5916 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (204.4 mg, 1.4791 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (20.13 mg, 0.0246 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to afford the title product, N-(6-(2,6-difluoro-3-(isoquinoline-5-sulfonamido)phenyl)quinazolin-2-yl)pivalamide (354 mg), which was used in the next step without further purification. LCMS: 548.4 [M+H] +

[0603] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)isoquinoline-5-sulfonamide.

[0604] To a stirred solution of N-(6-(2,6-difluoro-3-(isoquinoline-5-sulfonamido)phenyl)quinazolin-2-yl)pivalamide (350 mg, 0.6391 mmol, 1.0 equiv) in ethanol (6 mL) was added 2 M NaOH (4 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was concentrated under reduced pressure to evaporate ethanol and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 , and evaporated under reduced pressure to obtain the crude product, which was purified by using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)isoquinoline-5-sulfonamide (40 mg). Analytical data: LCMS: 464.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 10.61(br.s.,1H)9.39(s,1H)9.08(s,1H)8.49-8.61(m,2H)8.23-8.35(m,2H)7. 73(t,J=7.89Hz,1H)7.59(s,1H)7.36-7.46(m,2H)7.12-7.21(m,1H)6.96(s,3H).

[0605] Compound 65:

[0606]

[0607] Step 1: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide.

[0608] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (100 mg, 0.21 mmol, 1.0 eq) was added CuI (556 mg, 0.29 mmol, 1.4 eq) and purged with N2 gas. Isoamyl nitrite (39 mg, 0.33 mmol, 1.6 eq) and CHI (335 mg, 1.25 mmol, 6.0 eq) were added to the reaction mixture under N2 atmosphere. After addition, the reaction mixture was allowed to stir at 80 ° C for 3 h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was separated and dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude product, which was purified by using combi-flash (eluent system: 20% EA: hexane) to obtain the desired product (60 mg), LCMS: 589 [M+H] +

[0609] Step 2: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide.

[0610] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (50 mg, 0.085 mmol, 1.0 equiv) in ethanol was added (1r, 4r)-4-aminocyclohexanol (20 mg, 0.169 mmol, 1.0 equiv), DIPEA (32.8 mg, 0.25 mmol, 3.0 equiv). After addition, the reaction was heated at 90 ° C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, ethanol was evaporated and added, and ethyl acetate (2x50 ml) and water (20 ml) were used for post-processing of the reaction. The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase silica gel chromatography to obtain the desired product (16 mg). Analytical data: LCMS: 576 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 1.16-1.44(m,5H)1.77-2.04(m,4H)3.84(br.s.,2H)3.91(s,3H)7.16-7.26(m,1H)7.29-7.41(m,1H)7.62 (br.s.,3H)7.82(br.s.,1H)8.08(d,J=2.19Hz,1H)8.52(d,J=2.63Hz,1H)9.19(br.s.,1H)10.41(s,1H).

[0611] Compound 66:

[0612]

[0613] Step 1: Synthesis of (R)-5-chloro-N-(2,4-difluoro-3-(2-(1-hydroxypropyl-2-ylamino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide:

[0614] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (0.80 mg, 0.136 mmol, 1.0 equiv) in DMF (1.0 ml) was added (R)-2-aminopropan-1-ol (20 mg, 0.272 mmol, 2.0 equiv), DIPEA (52.6 mg, 0.408 mmol, 3.0 equiv). After addition, the reaction was heated at 90 ° C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, water (50 ml) was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography to obtain the desired product (18 mg), analytical data: LCMS: 536 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ=10.43(s,1H),9.14(br.s.,1H),8.39(br.s.,1H),8.04(d,J=2.2Hz,1H),7.78(s,1H),7.60(d,J=8.8Hz,1H),7.51(d,J=7 .9Hz,1H),7.35-7.16(m,2H),7.07(br.s.,1H),4.73(br.s.,1H),4.12(s ,1H),4.14(s,3H),3.86(s,1H),3.53(d,J=5.3Hz,1H),1.31-1.03(m,3H).

[0615] Compound 67:

[0616]

[0617] Step 1: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)benzenesulfonamide.

[0618] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (300 mg, 0.625 mmol, 1.0 eq) was added CuI (166 mg, 0.875 mmol, 1.4 eq) and purged with N2 gas. Under N2 atmosphere, isoamyl nitrite (117 mg, 1.0 mmol, 1.6 eq), CH2I2 (1.0 g, 3.75 mmol, 6.0 eq) were added to the reaction mixture. After addition, the reaction mixture was allowed to stir at 80°C for 3h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude product, which was purified by using combi-flash (eluent system: 20% EA: hexane) to obtain the desired product (190 mg), LCMS: 593[M+H] +

[0619] Step 2: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)benzenesulfonamide.

[0620] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)benzenesulfonamide (40 mg, 0.0679 mmol, 1.0 equiv) in ethanol was added (1r, 4r)-4-aminocyclohexanol (15 mg, 0.135 mmol, 2.0 equiv), DIPEA (26 mg, 0.203 mmol, 3.0 equiv). After addition, the reaction mixture was heated at 90 ° C for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, ethanol was evaporated and water (20 ml) was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4 and concentrated. The crude product was purified by combi flash to obtain the desired product (4 mg), analytical data: LCMS: 579 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 1.13-1.41(m,4H)1.88(br.s.,3H)1.94(br.s.,2H)3.42(br.s.,1H),3.91(br.s.,1H),7.21(br.s.,1H)7.29(d,J=6.14H z,1H)7.43(d,J=8.77Hz,2H)7.49-7.61(m,2H)7.68-7.81(m,2H)7.86(d,J=1.75Hz,1H),9.21(bs,1H),10.67(br.s.,1H).

[0621] Compound 69:

[0622]

[0623] Step 1: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide.

[0624] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide (380 mg, 0.7431 mmol, 1.0 eq) in THF (10 ml) was added CuI (212.3 mg, 1.1147 mmol, 1.5 eq) and purged with N2 gas. Under N2 atmosphere, isoamyl nitrite (130.59 mg, 1.1147 mmol, 1.5 eq), CH2I2 (0.36 mL, 4.4589 mmol, 6.0 eq) were added to the reaction mixture. After addition, the reaction mixture was allowed to stir at 80°C for 2 h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2x100 ml). The separated organic layer was dried over Na 2 SO 4 , filtered and concentrated under vacuum to obtain crude product, which was purified by using combi-flash (eluent system: 20% EA: Hexane) to obtain desired product (60 mg).

[0625] Step 2: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-((1r,4r)-4-hydroxycyclohexylamino)quinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide.

[0626] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide (60 mg, 0.0964 mmol, 1.0 eq) in DMF was added (1r,4r)-4-aminocyclohexanol (22.2 mg, 0.1928 mmol, 2.0 eq), DIPEA (37.39 mg, 0.2892 mmol, 3.0 eq). After addition, the reaction was heated at 90 ° C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum and water (20 ml) was added and extracted with acetate (2 x 50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude product, which was purified by combi flash silica gel chromatography to obtain the desired product (10 mg), analytical data: LCMS: 609.4 [M+H] + ,NMR: 1H NMR(400MHz, DMSO-d6)δppm10.68(s,1H)9.12(br.s.,1H)7.64-7.92(m,3H)7.47-7.63(m,2H)7.42(d,J=7.45Hz,1H)7.25(d,J=6.58Hz,1 H)7.17(br.s.,1H)5.75(t,J=5.70Hz,1H)4.42-4.68(m,3H)3.83(br.s.,1H)3.17(d,J=4.82Hz,1H)1.80-2.06(m,4H)1.15-1.40(m,4H).

[0627] Compound 76:

[0628]

[0629] Step 1 Synthesis of 4-bromo-1-(2,5-dichlorophenylsulfonyl)-1H-indole.

[0630] Under nitrogen atmosphere at 0 DEG C to the stirred solution of 4-bromo-1H-indole (600mg, 3.0461mmol, 1.0 equivalent) in THF (6mL), add NaH (43.8mg, 1.8276mmol, 0.6 equivalent) and stir 10-15min then dropwise add 2,5-dichlorobenzene-1-sulfonyl chloride (1121.7mg, 4.5692mmol, 1.5 equivalent).Then allow reaction mixture to be stirred at room temperature overnight. Monitor reaction process by TLC and HNMR. After the completion of the reaction, add ammonium chloride solution and react by ethyl acetate (2x100ml) after treatment.Organic layers are merged, dried over sodium sulfate and concentrated under reduced pressure to obtain crude product, which is purified by flash chromatography to obtain 4-bromo-1-(2,5-dichlorophenylsulfonyl)-1H-indole (410mg).

[0631] Step 2: Synthesis of N-(6-(1-(2,5-dichlorophenylsulfonyl)-1H-indol-4-yl)quinazolin-2-yl)pivalamide.

[0632] To a stirred solution of 4-bromo-1-(2,5-dichlorophenylsulfonyl)-1H-indole (300 mg, 0.7405 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (315.7 mg, 0.8886 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (307.04 mg, 2.2217 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (30.23 mg, 0.0370 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (340 mg) without further purification, LCMS: 553.2 [M+H] + .

[0633] Step 3: Synthesis of 6-(1-(2,5-dichlorophenylsulfonyl)-1H-indol-4-yl)quinazolin-2-amine.

[0634] To a stirred solution of N-(6-(1-(2,5-dichlorophenylsulfonyl)-1H-indol-4-yl)quinazolin-2-yl)pivalamide (150 mg, 0.0.2710 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaoH (1 mL). The reaction mixture was then allowed to stir at 90 ° C for 30 min. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain 6-(1-(2,5-dichlorophenylsulfonyl)-1H-indol-4-yl)quinazolin-2-amine (20 mg) as the title compound, analytical data: LCMS: 469.4 [M+H] + ,NMR: 1H NMR(400MHz,DMSO-d6)δppm 9.25(s,1H)8.38(d,J=2.19Hz,1H)8.06(s,1H)8.00(d,J=3.51Hz,1H)7.94(d,J=8.77Hz,1H)7.88(dd,J=8.7 7,2.19Hz,1H)7.68-7.80(m,2H)7.56(d,J=8.77Hz,1H)7.39-7.48(m,2H)7.12(br.s.,1H)6.93-7.07(m,2H).

[0635] Compound 81:

[0636]

[0637] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)cyclohexanesulfonamide.

[0638] At room temperature to the stirring solution of 2,4-difluoro-3-iodoaniline (0.153g, 0.60mmol and 1.1 equivalents) in 2mL pyridine, add cyclohexanesulfonyl chloride (100mg, 0.54mmol, 1.0 equivalents).After interpolation, reaction mixture is at room temperature stirred overnight.By TLC and LCMS monitoring reaction process, after the completion of reaction, add 2N HCl (5mL) and reaction mixture is at room temperature stirred to 10min, reaction mass is diluted with water and extracted by ethyl acetate (2x10mL).By the organic layer merged through anhydrous Na sO dry and under reduced pressure concentrate, this material is not further purified for next reaction (153mg).

[0639] Step 2: Synthesis of N-(6-(3-(cyclohexanesulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0640] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)cyclohexanesulfonamide (0.133 gm, 0.33 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (129 mg, 0.36 mmol and 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (137 mg, 0.99 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(dppf)Cl.DCM complex (13 mg, 0.016 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue, which was purified by flash chromatography to obtain the title product N-(6-(3-(cyclohexanesulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (170 mg). Analytical data: LCMS: 503 [M+H] +

[0641] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)cyclohexanesulfonamide.

[0642] To a stirred solution of N-(6-(3-(cyclohexanesulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (170 mg, 0.33 mmol, 1.0 equivalent) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature. The reaction mixture was then allowed to stir at 60 ° C for 2 h, and the progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain a crude product, which was purified using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)cyclohexanesulfonamide (20 mg), analytical data: LCMS: 419 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 1.21-1.33(m,3H)1.34-1.47(m,3H)1.78(d,J=11.84Hz,2H)2.11(d,J=10.52Hz,2H)7.03(s,2H)7.24 (t,J=9.21Hz,1H)7.43-7.56(m,2H)7.72(d,J=8.77Hz,1H)7.90(s,1H)9.19(s,1H)9.66(br.s.,1H).

[0643] Compound 105:

[0644]

[0645] Step 1: Synthesis of N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide

[0646] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide (5 g, 10.85 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (5.4 g, 15.19 mmol, 1.4 equiv) in toluene (30 mL) was added KCO (2.3 g, 16.27 mmol, 1.5 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(PPh) (626 mg, 0.54 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C for 2 days. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, water (150 mL) was added to the reaction mixture and extracted with EtOAc (2 x 200 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude compound, which was purified by column chromatography (elution system: THF / hexane) to obtain the desired product (3.8 g). Analytical data: LCMS: 562.1 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 10.47(s,1H)10.32(s,1H)9.57(s,1H)8.51(d,J=2.63Hz,1H)8.08-8.13(m,2H )7.87-7.93(m,2H)7.38(d,J=6.14Hz,1H)7.27(s,1H)3.91(s,3H)1.27(s,9H).

[0647] Compound 106:

[0648]

[0649] Step 1: Synthesis of N-(6-(3((2,5-dichlorophenyl)sulfonamido)2,6-difluorophenyl)quinazolin-2-yl)acetamide.

[0650] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (40 mg, 0.0831 mmol, 1.0 equiv) in acetic anhydride (0.8 ml) was added DMAP (0.2 mg) and the reaction mixture was heated at 140 ° C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture and extracted with EtOAc (2x20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by using flash chromatography to obtain N(6(3(2,5-dichlorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)acetamide. Analytical data: LCMS: 523.0[M+H] + , 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.18(d,J=2.63Hz,1H),7.98(d,J=9.65Hz,1H),7.75-7.9 3(m,4H),7.63(d,J=8.33Hz,1H),7.40-7.49(m,2H),6.57(d,J=9.21Hz,1H),2.01-2.12(m,3H).

[0651] Compound 107:

[0652]

[0653] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine.

[0654] To a stirred solution of 6-bromoquinoline-2-amine (200 mg, 0.8964 mmol, 1.0 equivalent) in dioxane (3 mL) was added B2Pin2 (341.4 mg, 1.3446 mmol, 1.5 equivalents) and potassium acetate (263.5 mg, 2.6893 mmol, 3.0 equivalents), and the reaction mixture was purged with nitrogen for 10 min at room temperature. After 10 min, Pd (dppf) Cl2 (32.7 mg, 0.0448 mmol, 0.05 equivalent) was added to RM and purged again for 5 min under a nitrogen atmosphere. The resulting reaction mixture was heated at 120 ° C for 90 min in a microwave. The reaction process was monitored by TLC and LCMS. After the reaction was complete, RM was extracted twice with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound (340 mg).

[0655] Step 2: Synthesis of N-(3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide.

[0656] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (290 mg, 0.6249 mmol, 1.0 equiv) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinolin-2-amine (337.6 mg, 1.2498 mmol, 2.0 equiv) in dioxane:water (3:1, 4 mL) was added KCO (259 mg, 1.8747 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(dppf)Cl DCM complex (25.5 mg, 0.0312 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 120 ° C in a microwave for 90 min. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x50mL). The organic layers were merged, dried over anhydrous Na2SO4, evaporated under reduced pressure and purified by flash chromatography to obtain the desired compound, which was ground by using hexane (3mL) and pentane (2mL) to obtain the desired compound N-(3-(2-aminoquinoline-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (13.6mg). Analytical data: LCMS: 480.3[M+H] + , 1H NMR(400MHz,DMSO-d6)δ10.72(br.s.,1H),8.31(br.s.,1H),7.85-7.96(m,2H),7.7 0-7.80(m,3H),7.74(m,1H),7.28-7.40(m,2H),7.24(s,1H),7.06(d,J=8.77Hz,2H).

[0657] Compound 108:

[0658]

[0659] Step 1: Synthesis of 2,5-dichloro-3-(N-(2,4-difluoro-3-(2-pivalamidoquinazolin-6-yl)phenyl)sulfamoyl)benzyl acetate.

[0660] To a stirred solution of 2,5-dichloro-3-(N-(2,4-difluoro-3-iodophenyl)sulfamoyl)benzyl acetate (150 mg, 0.2797 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (198.79 mg, 0.5595 mmol, 2.0 equiv) in dioxane:water (4:1, 5 mL) was added KCO (116 mg, 0.8393 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (11.42 mg, 0.0139 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the desired compound, which was used in the next step without purification (260 mg). Analytical data: LCMS: 637.2 [M+H] +

[0661] Step 2: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide.

[0662] To a stirred solution of 2,5-dichloro-3-(N-(2,4-difluoro-3-(2-pivalamidoquinazolin-6-yl)phenyl)sulfamoyl)benzyl acetate (260 mg, 0.4078 mmol, 1.0 equivalent) in ethanol (4 mL) was added 2M NaOH (6 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. The reaction progress was analyzed by TLC and LCMS. After the reaction was complete, the RM was concentrated under reduced pressure and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and further purified under flash chromatography to obtain the desired compound, which was triturated with hexane (3 mL) and pentane (2 mL) to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide (2 mg). Analytical data: LCMS: 511.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.67(br.s.,1H),9.15(s,1H),7.73-7.84(m,2H),7.59(br.s.,1H),7 .48(d,J=8.33Hz,1H),7.25(br.s.,2H),7.03(br.s.,2H),5.76(s,2H),4.61(d,J=5.70Hz,2H).

[0663] Compound 109:

[0664]

[0665] Step 1: Synthesis of 4-chloro-N-(2,4-difluoro-3-iodophenyl)-2,5-dimethylbenzenesulfonamide

[0666] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.0.392mmol, 1.0 equivalent) in pyridine (1.5mL) stirring solution, add 4-chloro-2,5-dimethylbenzenesulfonyl chloride (93.7mg, 0.392mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next reaction (128mg) without further purification.

[0667] Step 2: Synthesis of N-(6-(3-((4-chloro-2,5-dimethylphenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0668] To a stirred solution of 4-chloro-N-(2,4-difluoro-3-iodophenyl)-2,5-dimethylbenzenesulfonamide (125 mg, 0.273 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (116 mg, 0.327 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (113 mg, 0.819 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (11 mg, 0.0136 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture, extracted with EtOAc (2 x 150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was used in the next reaction without further purification (117 mg).

[0669] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2,5-dimethylbenzenesulfonamide.

[0670] To a stirred solution of N-(6-(3-((4-chloro-2,5-dimethylphenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (117 mg, 0.0209 mmol, 1.0 equiv) in ethanol (5 mL) was added 2M NaOH (4 mL). The reaction mixture was then allowed to stir at 90 ° C for 4 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2,5-dimethylbenzenesulfonamide (15 mg) as the title compound. Analytical data: LCMS: 475 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.41(br.s.,1H),9.14(s,1H),7.77(s,2H),7.63(d,J=9.21Hz,1H),7.46(d,J=9.21Hz,1H),7 .19(s,1H),7.07(dd,J=9.65,15.35Hz,1H),6.92(s,2H),6.69(t,J=9.21Hz,1H),2.12-2.36(m,3H),1.82(br.s.,3H).

[0671] Compound 110:

[0672]

[0673] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-5-fluoro-2-methoxybenzenesulfonamide.

[0674] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.39mmol, 1.0 equivalent) in pyridine (1.5mL) stirring solution, add 5-fluoro-2-methoxybenzene-1-sulfonyl chloride (88mg, 0.39mmol, 1.0 equivalent).Gained reaction mixture is stirred at room temperature overnight.Reaction process is monitored by TLC.After the completion of the reaction, ice-cold water is added to the reaction mixture.The precipitate formed is filtered through using a Buchner funnel and the product is washed with 1N HCl.This material is not further purified for the next reaction (130mg).

[0675] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(5-fluoro-2-methoxyphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide:

[0676] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-5-fluoro-2-methoxybenzenesulfonamide (125 mg, 0.28 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (120 mg, 0.34 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (116 mg, 0.85 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (11.5 mg, 0.014 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x150mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used for the next reaction (110mg) without further purification.

[0677] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methoxybenzenesulfonamide:

[0678] To a stirred solution of N-(6-(2,6-difluoro-3-(5-fluoro-2-methoxyphenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (110 mg, 0.020 mmol, 1.0 equivalent) in ethanol (5 mL) was added 2M NaOH (4 mL). The reaction mixture was then stirred at 90 ° C overnight. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase silica gel chromatography to obtain the title compound N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methoxybenzenesulfonamide (15 mg). Analytical data: LCMS: 461 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 1.89(s,1H)3.75(s,3H)6.98(s,3H)7.07-7.26(m,2H)7.36(br.s.,1H)7.42-7.57(m,2H)7.61(d,J=8.77Hz,1H)7.79(s,1H)9.15(s,1H).

[0679] Compound 111:

[0680]

[0681] Step 1 Synthesis of N-(5-bromoquinazolin-2-yl)pivalamide:

[0682] At room temperature to 5-bromoquinazoline-2-amine (1g, 4.46mmol, 1.0 equivalent) in the stirring solution of pyridine (4mL), add pivaloyl chloride (1.64mL, 13.39mmol, 3.0 equivalent).Gained reaction mixture is heated overnight at 90 ℃.Reaction process is monitored by TLC and LCMS.After reaction is completed, RM is quenched with 1N HCl to remove excessive pyridine, then uses EtOAc (150mL x 2 times) to extract and through dried over sodium sulfate and under reduced pressure, concentrate to obtain crude product, it is further ground together with hexane (2ml) and pentane (3ml) to obtain required compound N-(5-bromoquinazoline-2-yl) pivalamide (1.1g).

[0683] Step 2: Synthesis of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide.

[0684] To a stirred solution of N-(5-bromoquinazoline-2-yl)pivalamide (400 mg, 1.30 mmol, 1.0 equivalent) in dioxane (5 mL) was added B2Pin2 (494 mg, 1.95 mmol, 1.5 equivalents) and potassium acetate (381.5 mg, 3.89 mmol, 3.0 equivalents) and RM was purged under a nitrogen atmosphere for 10 min at room temperature and then Pd(dppf)Cl2 (47.4 mg, 0.065 mmol, 0.05 equivalents) was added. The resulting reaction mixture was purged again with nitrogen for 5 minutes. The reaction mixture was heated to 100 ° C and continued overnight. The reaction process was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was extracted with EtOAc (2x100 mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title compound. This compound was used for further reaction (705 mg) without purification.

[0685] Step 3: Synthesis of N-(5-(3-(2,5-dichlorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0686] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (460 mg, 0.99 mmol, 1.0 equiv) and N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (704 mg, 1.98 mmol, 2.0 equiv) in dioxane:water (6:2, 8 mL) was added KCO (411 mg, 2.97 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (40.4 mg, 0.0495 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100 ° C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and further purified using flash chromatography to obtain the required compound N-(5-(3-(2,5-dichlorophenylsulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (340 mg).

[0687] Step 2: Synthesis of N-(3-(4-aminoquinazolin-5-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide.

[0688] To a stirred solution of N-(5-(3-(2,5-dichlorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (340 mg, 0.60 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (5 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, RM was extracted with EtOAc (2x100 mL) and dried over sodium sulfate. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The compound was purified by using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (20 mg). Analytical data: LCMS: 481.0 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 6.96(br.s.,3H)7.12(d,J=7.45Hz,1H)7.20(br.s.,1H)7.38-7.58(m,3H)7.70-7.78(m,1H)7.90(s,1H)8.52(br.s.,1H)11.95(br.s.,1H).

[0689] Compound 112:

[0690]

[0691] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-3,5-difluorobenzenesulfonamide.

[0692] 3,5-difluorobenzene-1-sulfonyl chloride (83.3 mg, 0.39 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (100 mg, 0.39 mmol, 1.0 equivalent) in pyridine (10 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexanes) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which was ground together with hexane to obtain the desired product N- (2,4-difluoro-3-iodophenyl) -3,5-difluorobenzenesulfonamide (105 mg).

[0693] Step 2: Synthesis of N-(6-(3-(3,5-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0694] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3,5-difluorobenzenesulfonamide (105 mg, 0.24 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (173 mg, 0.49 mmol, 2.0 equiv) in dioxane:water (3:1, 4 mL) was added KCO (101 mg, 0.73 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (10 mg, 0.012 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x50mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain title product N-(6-(3-(3,5-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (230mg). This product was used for the next step without further purification.

[0695] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-difluorobenzenesulfonamide.

[0696] To a stirred solution of N-(6-(3-(3,5-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (230 mg, 0.43 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaOH (6 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was concentrated under reduced pressure to evaporate ethanol and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the crude product. This product was purified by using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-difluorobenzenesulfonamide (10 mg), analytical data: LCMS: 449.06 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 6.81(br.s.,1H)6.94(s,2H)7.12(d,J=6.14Hz,1H)7.29(d,J=6.58Hz,3H)7.47(d ,J=8.77Hz,1H)7.64(d,J=7.89Hz,1H)7.80(s,1H)9.14(s,1H)11.95(br.s.,1H).

[0697] Compound 113:

[0698]

[0699] Step 1 Synthesis of 3,5-dimethyl-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide.

[0700] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.39mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 3,5-dimethylbenzenesulfonyl chloride (80mg, 0.39mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next reaction (128mg) without further purification.

[0701] Step 2: Synthesis of N-(6-(3-((3,5-dimethylphenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0702] To a stirred solution of 3,5-dimethyl-N-(2,4-difluoro-3-iodophenyl)benzenesulfonamide (125 mg, 0.30 mmol, 1.0 equiv) and (4,5,5-trimethyl-2-(2-pivalamidoquinazolin-6-yl)-1,3,2-dioxaborolan-4-yl)methylium (125 mg, 0.35 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (122 mg, 0.89 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (12 mg, 0.015 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used for the next reaction (115 mg) without further purification, LCMS: 525 [M+H] + .

[0703] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-dimethylbenzenesulfonamide.

[0704] To a stirred solution of N-(6-(3-((3,5-dimethylphenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (115 mg, 0.021 mmol, 1.0 equiv) in ethanol (5 mL) was added 2M NaOH (4 mL). The reaction mixture was then allowed to stir overnight at 90 ° C. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase silica gel chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-dimethylbenzenesulfonamide (23 mg) as the title compound. Analytical data: LCMS: 441 [M+H] + ,NMR: 1H NMR(400MHz,DMSO-d6)δppm2.31(s,6H)7.01(s,2H)7.14(br.s.,1H)7.22-7.29(m,2H)7.3 4(s,2H)7.48(d,J=8.77Hz,1H)7.59(br.s.,1H)7.76(s,1H)9.14(s,1H)10.12(br.s.,1H).

[0705] Compound 115:

[0706]

[0707] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-3,4-dimethoxybenzenesulfonamide.

[0708] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.392mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 3,4-dimethoxybenzene-1-sulfonyl chloride (92.8mg, 0.3921mmol, 1.0 equivalent). The resulting reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl. This material is not further purified for the next step (156mg).

[0709] Step 2: Synthesis of N-(6-(3-(3,4-dimethoxyphenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0710] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3,4-dimethoxybenzenesulfonamide (156 mg, 0.3426 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (243.4 mg, 0.6853 mmol, 2.0 equiv) in dioxane:water (4:2, 6 mL) was added KCO (142 mg, 1.0280 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (11.5 mg, 0.014 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was used in the next step without further purification (300 mg). LCMS: 557.3 [M+H] +

[0711] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-dimethoxybenzenesulfonamide.

[0712] To a stirred solution of N-(6-(3-(3,4-dimethoxyphenylsulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (300 mg, 0.5390 mmol, 1.0 equivalent) in ethanol (6 mL) was added 2M NaoH (4 mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 3 hours. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase silica gel chromatography to obtain the title compound N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3,4-dimethoxybenzenesulfonamide (3 mg). Analytical data: LCMS: 473.4 [M+H] + ,NMR: 1 H NMR (400MHz, DMSO-d6) δppm3.74 (s, 3H) 3.82 (s, 3H) 7.03 (s, 2H) 7.11 (d, J = 8.33Hz, 1H) 7.15-7.3 2(m,4H)7.47(d,J=8.77Hz,1H)7.56(d,J=8.33Hz,1H)7.74(s,1H)9.13(s,1H)10.03(br.s.,1H)

[0713] Compound 116:

[0714]

[0715] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-3-fluorobenzenesulfonamide.

[0716] At room temperature to 2,4-difluoro-3-iodoaniline (150mg, 0.5882mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 3-fluorobenzene-1-sulfonyl chloride (144.4mg, 0.5882mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl. This material was used for the next step (192mg) without further purification.

[0717] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(3-fluorophenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0718] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3-fluorobenzenesulfonamide (180 mg, 0.4356 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (185.7 mg, 0.5228 mmol, 1.2 equiv) in dioxane:water (3:1, 4 mL) was added KCO (180.6 mg, 1.3070 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (17.7 mg, 0.0217 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step without further purification (320 mg). LCMS: 515.3 [M+H] +

[0719] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide.

[0720] To a stirred solution of N-(6-(2,6-difluoro-3-(3-fluorophenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (320 mg, 0.6219 mmol, 1.0 equivalent) in ethanol (6 mL) was added 2M NaoH (5 mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 2 hours. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure, and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide (20 mg) as the title compound. Analytical data: LCMS: 431.2[M+H] + ,NMR: 1 H NMR (400MHz, DMSO-d6) δppm 7.00 (s, 2H) 7.09 (t, J = 9.21Hz, 1H) 7.18-7.27 (m, 1H) 7.41-7.64 (m, 7H) 7.76 (s, 1H) 9.14 (s, 1H).

[0721] Compound 117:

[0722]

[0723] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-4-methoxy-3-methylbenzenesulfonamide.

[0724] 4-methoxy-3-methylbenzene-1-sulfonyl chloride (173.07 mg, 0.7843 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (200 mg, 0.7843 mmol, 1.0 equivalent) in pyridine (2 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography (20% EtOAc / hexanes) to obtain the title compound in a liquid and the liquid was further treated with 1N HCl to remove pyridine. The product was extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which was ground together with hexane to obtain the desired product N- (2,4-difluoro-3-iodophenyl) -4-methoxy-3-methylbenzenesulfonamide (340 mg).

[0725] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(4-methoxy-3-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0726] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-4-methoxy-3-methylbenzenesulfonamide (340 mg, 0.7740 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (329.9 mg, 0.9289 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (320.9 mg, 2.3222 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (31.6 mg, 0.0387 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product, N-(6-(2,6-difluoro-3-(4-methoxy-3-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (600 mg). This product was used in the next step without further purification. LCMS: 541.16 [M+H] +

[0727] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-methoxy-3-methylbenzenesulfonamide.

[0728] To a stirred solution of N-(6-(2,6-difluoro-3-(4-methoxy-3-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (600 mg, 1.1098 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaOH (6 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was concentrated under reduced pressure to evaporate ethanol and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the crude product. This product was purified by using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-methoxy-3-methylbenzenesulfonamide (53 mg), analytical data: LCMS: 457.4 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 2.15(s,3H)3.84(s,3H)7.00(s,2H)7.04(s,1H)7.05-7.11(m,2H)7.16-7.26(m,1H)7.45-7.60(m,4H)7.75(s,1H)9.13(s,1H)

[0729] Compound 118:

[0730]

[0731] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-2-methoxy-5-methylbenzenesulfonamide.

[0732] 2-methoxy-5-methylbenzene-1-sulfonyl chloride (173.07 mg, 0.7843 mmol, 1.0 equivalent) is added to a stirred solution of 2,4-difluoro-3-iodoaniline (200 mg, 0.7843 mmol, 1.0 equivalent) in pyridine (2 mL) at room temperature. The resulting reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, the solvent is concentrated under reduced pressure to obtain a crude residue, which is further purified by flash chromatography (20% EtOAc / hexanes) to obtain the title compound in a liquid and the liquid is further treated with 1N HCl to remove pyridine. The product is extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which is ground together with hexane to obtain the desired product N- (2,4-difluoro-3-iodophenyl) -2-methoxy-5-methylbenzenesulfonamide (315 mg).

[0733] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(2-methoxy-5-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0734] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-2-methoxy-5-methylbenzenesulfonamide (315 mg, 0.7171 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (305.7 mg, 0.8606 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (297.3 mg, 2.1515 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (29.28 mg, 0.0358 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product, N-(6-(2,6-difluoro-3-(2-methoxy-5-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (560 mg). This product was used in the next step without further purification. LCMS: 541.4 [M+H] +

[0735] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-methoxy-5-methylbenzenesulfonamide.

[0736] To a stirred solution of N-(6-(2,6-difluoro-3-(2-methoxy-5-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (560 mg, 1.0359 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (7 mL) at room temperature. The reaction mixture was then allowed to stir at 90 ° C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the RM was concentrated under reduced pressure to evaporate ethanol and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the crude product. This product was purified by using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-methoxy-5-methylbenzenesulfonamide (70 mg), analytical data: LCMS: 457.4 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 2.24(s,3H)3.76(s,3H)7.01(br.s.,2H)7.03-7.14(m,2H)7.14-7.30(m,2H)7.36(d ,J=8.33Hz,1H)7.43-7.53(m,2H)7.59(d,J=8.33Hz,1H)7.78(br.s.,1H)9.15(s,1H)

[0737] Compound 119:

[0738]

[0739] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-2,5-dimethoxybenzenesulfonamide.

[0740] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (2.0mL) stirring solution, add 2,5-dimethoxybenzene-1-sulfonyl chloride (185.6mg, 0.7843mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next reaction (287mg) without further purification.

[0741] Step 2: Synthesis of N-(6-(3-(2,5-dimethoxyphenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0742] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-2,5-dimethoxybenzenesulfonamide (287 mg, 0.6304 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (268.7 mg, 0.7565 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (261.3 mg, 1.8914 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (25.7 mg, 0.0315 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step (500 mg) without further purification, LCMS: 557.3 [M+H] + .

[0743] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dimethoxybenzenesulfonamide.

[0744] To a stirred solution of N-(6-(3-(2,5-dimethoxyphenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (500 mg, 0.8983 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaoH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 3 hours. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dimethoxybenzenesulfonamide (90 mg) as the title compound. Analytical data: LCMS: 473.4 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm3.72(s,3H)3.70(s,3H)6.93-7.09(m,5H)7.18-7.28(m,2 H)7.48(d,J=8.77Hz,1H)7.61(d,J=8.77Hz,1H)7.79(s,1H)9.16(s,1H)10.03(s,1H).

[0745] Compound 120:

[0746]

[0747] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-5-ethyl-2-methoxybenzenesulfonamide.

[0748] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (2.0mL) stirring solution, add 5-ethyl-2-methoxybenzene-1-sulfonyl chloride (184.07mg, 0.7843mmol, 1.0 equivalent). The gained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl to remove pyridine. This material is not further purified for the next reaction (212mg).

[0749] Step 2: Synthesis of N-(6-(3-(5-ethyl-2-methoxyphenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0750] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-5-ethyl-2-methoxybenzenesulfonamide (200 mg, 0.4412 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (188.1 mg, 0.5295 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (182.9 mg, 1.3238 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (18.01 mg, 0.0220 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (493 mg) without further purification, LCMS: 555.4 [M+H] + .

[0751] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-ethyl-2-methoxybenzenesulfonamide.

[0752] To a stirred solution of N-(6-(3-(5-ethyl-2-methoxyphenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (490 mg, 0.8835 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaoH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 3 hours. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-ethyl-2-methoxybenzenesulfonamide (14 mg) as the title compound. Analytical data: LCMS: 471.4 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 1.09(t,J=7.24Hz,3H)2.54(d,J=8.33Hz,2H)3.76(br.s.,3H)7.01(br.s.,2H)7.10(d,J=8.77Hz,2H)7.12(s,1H)7.2 7(d,J=5.70Hz,1H)7.41(d,J=7.45Hz,1H)7.46-7.53(m,2H)7.58(d,J=8.33Hz,1H)7.77(br.s.,1H)9.15(br.s.,1H).

[0753] Compound 121:

[0754]

[0755] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-2,5-bis(trifluoromethyl)benzenesulfonamide.

[0756] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (2.0mL) stirring solution, add 2,5-bis(trifluoromethyl)benzene-1-sulfonyl chloride (245.18mg, 0.7843mmol, 1.0 equivalent). The gained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1NHCl to remove pyridine. This material is not further purified for the next step (370mg).

[0757] Step 2: Synthesis of N-(6-(3-(2,5-bis(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0758] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-2,5-bis(trifluoromethyl)benzenesulfonamide (370 mg, 0.6965 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (296.9 mg, 0.8359 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (288.8 mg, 2.0780 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (28.4 mg, 0.0348 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step without further purification (610 mg), LCMS: 633.3 [M+H] + .

[0759] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-bis(trifluoromethyl)benzenesulfonamide.

[0760] To a stirred solution of N-(6-(3-(2,5-bis(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (610 mg, 0.9643 mmol, 1.0 equiv) in ethanol (4 mL) was added 2M NaoH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 2 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-bis(trifluoromethyl)benzenesulfonamide (39 mg) as the title compound. Analytical data: LCMS: 549.5 [M+H] + , 1H NMR(400MHz,DMSO-d6)δppm 7.04 (s, 2H) 7.25 (d, J = 8.77Hz, 1H) 7.35 (d, J = 6.14Hz, 1H) 7.42-7.54 (m, 2H) 7.69 (s, 1H) 8.25 (d, J = 6.58Hz, 3H) 9.13 (s, 1H) 10.80 (br.s., 1H).

[0761] Compound 122:

[0762]

[0763] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)benzofuran-5-sulfonamide.

[0764] Benzofuran-5-sulfonyl chloride (169.8 mg, 0.7843 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (200 mg, 0.7843 mmol, 1.0 equivalent) in pyridine (2.0 mL) at room temperature. The resulting reaction mixture was stirred overnight at room temperature. The reaction process was monitored by TLC. After the reaction was complete, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next reaction (280 mg) without further purification.

[0765] Step 2: Synthesis of N-(6-(3-(benzofuran-5-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0766] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)benzofuran-5-sulfonamide (280 mg, 0.6434 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (274.2 mg, 0.7720 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (266.7 mg, 1.9302 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (26.27 mg, 0.0321 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step without further purification (595 mg), LCMS: 537.3 [M+H] + .

[0767] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)benzofuran-5-sulfonamide.

[0768] To a stirred solution of N-(6-(3-(benzofuran-5-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (595 mg, 1.1089 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaoH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 2 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)benzofuran-5-sulfonamide (9 mg) as the title compound. Analytical data: LCMS: 453.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.02(br.s.,2H)7.09-7.19(m,2H)7.20-7.30(m,1H)7.39-7.53(m,2H)7.63-7.74(m,2H )7.81(d,J=8.77Hz,1H)8.06(br.s.,1H)8.17(br.s.,1H)9.08(s,1H)10.30(br.s.,1H)

[0769] Compound 123:

[0770]

[0771] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-3-fluoro-5-(trifluoromethyl)benzenesulfonamide.

[0772] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (1mL) stirring solution, add 3-fluoro-5-(trifluoromethyl) benzene-1-sulfonyl chloride (205.9mg, 0.7843mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the completion of the reaction, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next step (227mg) without further purification.

[0773] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(3-fluoro-5-(trifluoromethyl)phenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0774] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3-fluoro-5-(trifluoromethyl)benzenesulfonamide (227 mg, 0.4717 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (200.9 mg, 0.5661 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (195.6 mg, 1.4153 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (19.26 mg, 0.0235 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The reaction process was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used for the next reaction (320mg) without further purification, LCMS: 583.12[M+H] + .

[0775] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoro-5-(trifluoromethyl)benzenesulfonamide.

[0776] To a stirred solution of N-(6-(2,6-difluoro-3-(3-fluoro-5-(trifluoromethyl)phenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (320 mg, 0.5493 ​​mmol, 1.0 equiv) in ethanol (5 mL) was added 2M NaoH (5 mL). The reaction mixture was then allowed to stir at 90 ° C for 2 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoro-5-(trifluoromethyl)benzenesulfonamide (48 mg) as the title compound. Analytical data: LCMS: 498.06 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 7.00(s,2H)7.08-7.19(m,1H)7.19-7.31(m,1H)7.45(d,J=8.77Hz,1H)7.55(d,J=8.33Hz,1H)7.7 2(s,1H)7.79(s,1H)7.84(d,J=7.89Hz,1H)8.04(d,J=8.33Hz,1H)9.11(s,1H)10.60(br.s.,1H).

[0777] Compound 124:

[0778]

[0779] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-2,3-difluorobenzenesulfonamide.

[0780] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 2,3-difluorobenzene-1-sulfonyl chloride (166.7mg, 0.7843mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl to remove pyridine. This material was used for the next reaction (266mg) without further purification.

[0781] Step 2: Synthesis of N-(6-(3-(2,3-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0782] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-2,3-difluorobenzenesulfonamide (266 mg, 0.6169 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (262.8 mg, 0.7403 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (255.7 mg, 1.8509 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (25.19 mg, 0.0308 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step without further purification (644 mg), LCMS: 533.2 [M+H] + .

[0783] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-difluorobenzenesulfonamide.

[0784] To a stirred solution of N-(6-(3-(2,3-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (644 mg, 1.2093 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaOH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 2 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-difluorobenzenesulfonamide (40 mg) as the title compound. Analytical data: LCMS: 449.2 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δppm 7.02(br.s.,2H)7.16(t,J=8.99Hz,1H)7.23-7.39(m,2H)7.41-7.59(m,3H)7.74(br.s.,2H)9.13(s,1H)10.74(br.s.,1H)

[0785] Compound 125:

[0786]

[0787] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-3-methylbenzenesulfonamide.

[0788] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 3-methylbenzene-1-sulfonyl chloride (149.5mg, 0.7843mmol, 1.0 equivalent). The obtained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl to remove pyridine. This material is not further purified for the next step (254mg).

[0789] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(3-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0790] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3-methylbenzenesulfonamide (254 mg, 0.6207 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (264.4 mg, 0.7448 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (257.3 mg, 1.8622 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (25.3 mg, 0.0310 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step (600 mg) without further purification, LCMS: 511.3 [M+H] + .

[0791] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-methylbenzenesulfonamide.

[0792] To a stirred solution of N-(6-(2,6-difluoro-3-(3-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (600 mg, 1.1751 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaoH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 2 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-methylbenzenesulfonamide (25 mg) as the title compound. Analytical data: LCMS: 427.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 10.44(br.s.,1H),7.00(br.s.,2H)7.07(t,J=8.77Hz,1H)7.21(d,J=6.14Hz,1 H)7.40(br.s.,2H)7.43-7.66(m,4H)7.76(br.s.,1H)9.14(s,1H),2.34(s,3H).

[0793] Compound 128:

[0794]

[0795] Step 1: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)benzenesulfonamide.

[0796] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide (300 mg, 0.625 mmol, 1.0 eq) was added CuI (166 mg, 0.875 mmol, 1.4 eq) and purged with N2 gas. Under N2 atmosphere, isoamyl nitrite (117 mg, 1.0 mmol, 1.6 eq), CH2I2 (1.0 g, 3.75 mmol, 6.0 eq) were added to the reaction mixture. After addition, the reaction mixture was allowed to stir at 80°C for 3h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude product, which was purified by using combi-flash (eluent system: 20% EA: hexane) to obtain the desired product (190 mg), LCMS: 593[M+H] +

[0797] Step 2: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-(2-hydroxyethylamino)quinazolin-6-yl)phenyl)benzenesulfonamide.

[0798] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)benzenesulfonamide (40 mg, 0.067 mmol, 1.0 equiv) in DMF (1 ml) was added 2-aminoethanol (8 mg, 0.135 mmol, 2.0 equiv), DIPEA (26 mg, 0.203 mmol, 3.0 equiv). After addition, the reaction was heated at 90 ° C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, water (10 ml) was added and extracted with ethyl acetate (1x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase HPLC to obtain the desired product (7 mg), analytical data: LCMS: 525 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 3.47(d,J=5.26Hz,3H)3.59(br.s.,2H)7.20(br.s.,1H)7.28(br.s.,1H)7.46(br.s.,2H)7.53(br.s.,1H )7.59(d,J=7.89Hz,1H)7.78(s,1H)7.75(s,1H)7.87(d,J=1.75Hz,1H)9.14(br.s.,1H)10.67(br.s.,1H).

[0799] Compound 129:

[0800]

[0801] Step 1: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide.

[0802] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (100 mg, 0.209 mmol, 1.0 equiv) was added CuI (55.8 mg, 0.293 mmol, 1.4 equiv) and purged with N2 gas. Under N2 atmosphere, isoamyl nitrite (39 mg, 0.334 mmol, 1.6 equiv), CH2I2 (335 mg, 1.25 mmol, 6.0 equiv) were added to the reaction mixture. After addition, the reaction mixture was allowed to stir at 80°C for 3h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude product, which was purified by using reverse phase HPLC to obtain the desired product (60 mg), LCMS: 589[M+H]. +

[0803] Step 2: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide.

[0804] To a stirred solution of 5-chloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (30 mg, 0.051 mmol, 1.0 equiv) in DMF (1 ml) was added (1s, 4s)-4-aminocyclohexanol hydrochloride (15.4 mg, 0.102 mmol, 1.0 equiv), TEA (15.4 mg, 0.153 mmol, 3.0 equiv). After addition, the reaction mixture was heated at 90 ° C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, ethanol was evaporated and water was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by Combi flash to obtain the desired product (9 mg), analytical data: LCMS: 576 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 1.54(d,J=12.28Hz,3H)1.66(br.s.,4H)1.75(br.s.,2H)3.84(br.s.,2H)3.91(s,3H)7.16-7.26(m,1H)7.29-7.41( m,1H)7.62(br.s.,3H)7.82(br.s.,1H)8.08(d,J=2.19Hz,1H)8.52(d,J=2.63Hz,1H)9.19(br.s.,1H)10.39(s,1H).

[0805] Compound 130:

[0806]

[0807] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)pyridine-3-sulfonamide.

[0808] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.7843mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add pyridine-3-sulfonyl chloride (167.1mg, 0.9411mmol, 1.0 equivalent). The gained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl to remove pyridine. This material is not further purified for the next reaction (165mg).

[0809] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(pyridine-3-sulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0810] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)pyridine-3-sulfonamide (165 mg, 0.4165 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (177.4 mg, 0.4998 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (172.68 mg, 1.2495 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (17 mg, 0.0208 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next step without further purification (265 mg), LCMS: 498.3 [M+H] + .

[0811] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)pyridine-3-sulfonamide.

[0812] To a stirred solution of N-(6-(2,6-difluoro-3-(pyridine-3-sulfonamido)phenyl)quinazolin-2-yl)pivalamide (260 mg, 0.5225 mmol, 1.0 equiv) in ethanol (6 mL) was added 2M NaoH (6 mL). The reaction mixture was then allowed to stir at 90 ° C for 4 hours. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase HPLC to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)pyridine-3-sulfonamide (40 mg) as the title compound. Analytical data: LCMS: 414.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δppm 6.90-7.12(m,3H)7.23(br.s.,1H)7.48(br.s.,1H)7.56(br.s.,2H)7.76(br.s.,1H) 8.06(br.s.,1H)8.71(br.s.,1H)8.85(br.s.,1H)9.14(br.s.,1H)11.22(br.s.,1H)

[0813] Compound 131:

[0814]

[0815] Step 1: Synthesis of N-(2,4-dichlorophenyl)acetamide.

[0816] To a stirred solution of 2,4-dichloroaniline (1.00 g, 6.25 mmol, 1.0 equivalent) in 10 mL of DCM was added TEA (2.55 mL, 18.75 mmol, 3.0 equivalents), the reaction mixture was then cooled to 0 ° C, acetyl chloride (0.44 mL, 6.25 mmol, 1.0 equivalents) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture and extracted with DCM (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain a crude residue, which was purified by combi flash chromatography to obtain N-(2,4-dichlorophenyl)acetamide (1 g). Analytical data: LCMS: 204 [M+H] +

[0817] Step 2: Synthesis of N-(2,4-dichloro-3-iodophenyl)acetamide.

[0818] To a stirred solution of N-(2,4-dichlorophenyl)acetamide (600 mg, 2.970 mmol, 1.0 eq) in THF (5 mL) was added n-BuLi (1.5 M in THF, 6.0 mL, 8.910 mmol, 3.0 eq) under anhydrous conditions at -70 ° C. The reaction mixture was stirred for 2 h at -70 ° C. 1,1,1-trifluoro-2-iodoethane (1.862 mL, 8.910 mmol, 3.0 eq) was added dropwise. After all additions, the reaction mixture was stirred for 1.5 h at -70 ° C. The progress of the reaction was monitored by TLC and LCMS. After completion of the warm reaction, 3N HCl (10 mL) solution was slowly added, the reaction mixture was allowed to reach room temperature and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined, washed with water (20 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue, which was purified by flash chromatography to obtain N-(2,4-dichloro-3-iodophenyl)acetamide (525 mg), analytical data: LCMS: 330.0 [M+H] +

[0819] Step 3: Synthesis of 2,4-dichloro-3-iodoaniline.

[0820] To a stirred solution of N-(2,4-dichloro-3-iodophenyl)acetamide (525 mg, 1.6 mmol, 1.0 equivalent) in MeOH (7 mL) was added concentrated HCl (0.61 mL) dropwise. After addition, the reaction mixture was heated at 70 ° C for 18 hours, and the reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled and the solvent was removed under reduced pressure (water bath below 45 ° C). The residue was cooled with an ice bath and 3N NaOH solution was added to adjust the pH to between 9-10, extracted with ethyl acetate (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue, which was purified by flash chromatography to obtain the title product 2,4-dichloro-3-iodoaniline (400 mg). Analytical data: LCMS: 288 [M+H] +

[0821] Step 4: Synthesis of 5-chloro-N-(2,4-dichloro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide.

[0822] At room temperature to 2,4-dichloro-3-iodoanilines (400mg, 1.39mmol, 1.0 equivalents) in a stirred solution of pyridine (6mL) add 5-chloro-2-methoxypyridine-3-sulfonyl chloride (1.00g, 4.19mmol and 3.0 equivalents), stir at room temperature overnight. Reaction process is monitored by TLC and LCMS. After the completion of the reaction, 2N HCl (10mL) is added and the mixture is stirred at room temperature for 10min, reaction mass is diluted with water and extracted by ethyl acetate (2x15mL). The organic layer merged is dried over anhydrous Na2SO4 and concentrated under reduced pressure and purified by combi-flash to obtain title compound 5-chloro-N-(2,4-dichloro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide (460mg), analytical data: LCMS:493[M+H] +

[0823] Step 5: Synthesis of N-(6-(2,6-dichloro-3-(5-chloro-2-methoxypyridine-3-sulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0824] To a stirred solution of 5-chloro-N-(2,4-dichloro-3-iodophenyl)-2-methoxypyridine-3-sulfonamide (235 mg, 0.47 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (186 mg, 0.52 mmol and 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (197 mg, 1.43 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes and then Pd(dppf)Cl.DCM complex (20 mg, 0.023 mmol, 0.05 equiv) was added. The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 90°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x15mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title product in a crude residue, which was purified by flash chromatography to obtain the title product N-(6-(2,6-dichloro-3-(5-chloro-2-methoxypyridine-3-sulfonamido)phenyl)quinazoline-2-yl)pivalamide (400mg), analytical data: LCMS: 594[M+H] +

[0825] Step 6: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-dichlorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide.

[0826] To a stirred solution of N-(6-(2,6-dichloro-3-(5-chloro-2-methoxypyridine-3-sulfonamido)phenyl)quinazolin-2-yl)pivalamide (300 mg, 0.50 mmol, 1.0 equiv) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature. The reaction mixture was then allowed to stir at 60 ° C for 2 h, and the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x15 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by chromatographic techniques to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-dichlorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (25 mg). Analytical data: LCMS: 510 [M+H] + , 1 H NMR(400MHz,DMSO-d6)d ppm 3.85(s,3H)7.00(s,2H)7.38-7.52(m,3H)7.60-7.66(m,2H)8.08(d,J=2.19Hz,1H)8.50(d,J=2.19Hz,1H)9.14(s,1H)10.42(br.s.,1H).

[0827] Compound 132:

[0828]

[0829] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-3,4-difluorobenzenesulfonamide.

[0830] By 3,4-difluorobenzene-1-sulfonyl chloride (100mg, 0.47mmol, 1.0 equivalent) and the stirring solution of 2,4-difluoro-3-iodoaniline (119mg, 0.47mmol and 1.0 equivalent) in 0.3mL pyridine at room temperature stir and spend the night, monitor reaction process by TLC and LCMS.After reaction is completed, add 2N HCl (5mL) and mixture is at room temperature stirred to 10min, reaction mass is diluted with water and extracted by ethyl acetate (3x10mL).By the organic layer merged through anhydrous Na sO dry and under reduced pressure concentrate.This material is not further purified for next reaction (210mg).

[0831] Step 2: Synthesis of N-(6-(3-(3,4-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0832] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3,4-difluorobenzenesulfonamide (200 mg, 0.46 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (181 mg, 0.51 mmol and 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (192 mg, 1.39 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes before the addition of Pd(dppf)Cl.DCM complex (20 mg, 0.023 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x15 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue, which was purified by flash chromatography to obtain the title product N-(6-(3-(3,4-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (350 mg). Analytical data: LCMS: 533 [M+H] +

[0833] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-difluorobenzenesulfonamide.

[0834] To a stirred solution of N-(6-(3-(3,4-difluorophenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide (350 mg, 0.65 mmol, 1.0 equiv) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature. The reaction mixture was then allowed to stir at 60 ° C for 2 h, and the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain a crude product. This product was purified using reverse phase chromatography to obtain the desired compound N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-difluorobenzenesulfonamide (13 mg), analytical data: LCMS: 449 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δppm 7.02 (s, 2H) 7.12-7.48 (d, J = 8.33Hz, 3H) 7.59 (d, J = 7.02Hz, 2H) 7.78-7.08 (s, 3H) 9.14 (s, 1H) 10.4 (s, 1H).

[0835] Compound 133:

[0836]

[0837] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-5-fluoro-2-methylbenzenesulfonamide.

[0838] At room temperature to the stirring solution of 2,4-difluoro-3-iodoaniline (122mg, 0.47mmol and 1.0 equivalent) in 2mL pyridine, add 5-fluoro-2-methylbenzene-1-sulfonyl chloride (100mg, 0.47mmol, 1.0 equivalent).After interpolation, reaction mixture is stirred at room temperature and spend the night.By TLC and LCMS monitoring reaction process, after the completion of reaction, add 2N HCl (5mL) and mixture is stirred at room temperature 10min, reaction mass is diluted with water and extracted by ethyl acetate (2x15mL).By the organic layer merged through anhydrous Na sO dry and under reduced pressure concentrate, this material is not further purified for next reaction (128mg).

[0839] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(5-fluoro-2-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0840] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-5-fluoro-2-methylbenzenesulfonamide (128 mg, 0.29 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (117 mg, 0.32 mmol and 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (124 mg, 0.89 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes before the addition of Pd(dppf)Cl.DCM complex (12 mg, 0.014 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated to 100° C. overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, water was added to the reaction mixture and extracted with EtOAc (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue, which was purified by flash chromatography to obtain the title product N-(6-(2,6-difluoro-3-(5-fluoro-2-methylphenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (150 mg). Analytical data: LCMS: 529 [M+H] +

[0841] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methylbenzenesulfonamide.

[0842] To a stirred solution of the product N-(6-(2,6-difluoro-3-(5-fluoro-2-methylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide (129 mg, 0.24 mmol, 1.0 equivalent) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature. The reaction mixture was then allowed to stir at 60 ° C for 2 h, and the reaction progress was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (2x10 mL), the organic layers were combined, dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain a crude product, which was purified by using reverse phase chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methylbenzenesulfonamide (10 mg), analytical data: LCMS: 445 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δppm 2.56 (s, 3H) 7.04 (s, 2H) 7.14-7.36 (m, 2H) 7.39-7.60 (m, 5H) 7.74 (s, 1H) 9.14 (s, 1H) 10.45 (s, 1H).

[0843] Compound 134:

[0844]

[0845] Step 1: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide.

[0846] To a stirred solution of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide (120 mg, 0.234 mmol, 1.0 eq) was added CuI (62 mg, 0.328 mmol, 1.4 eq) and purged with N2 gas. Under N2 atmosphere, isoamyl nitrite (43.8 mg, 0.374 mmol, 1.6 eq), CHI (381 mg, 1.428 mmol, 6.0 eq) were added to the reaction mixture. After addition, the reaction mixture was allowed to stir at 80°C for 3h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2x50 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude product, which was purified by using combi-flash (eluent system: 20% EA: hexane) to obtain the desired product (60 mg). LCMS: 622[M+H] +

[0847] Step 2: Synthesis of 2,5-dichloro-N-(2,4-difluoro-3-(2-(2-hydroxyethylamino)quinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide.

[0848] To a stirred solution of 2,5-dichloro-N-(2,4-difluoro-3-(2-iodoquinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide (50 mg, 0.0806 mmol, 1.0 equiv) in DMF (1 ml) was added 2-aminoethanol (10.6 mg, 0.161 mmol, 2.0 equiv) and DIPEA (31 mg, 0.241 mmol, 3.0 equiv) at room temperature. After addition, the reaction was heated at 90 ° C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2x50 ml) and water (20 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase chromatography to obtain the desired product (9 mg), analytical data: LCMS: 555 [M+H] + ,NMR: 1H NMR(400MHz,DMSO-d6)d ppm 11.91(br.s.,1H)9.14(br.s.,1H)7.75-7.90(m,2H)7.65(d,J=7.45Hz,1H)7.45-7.55(m,2H)7.36(br.s.,1H)7.03(dd,J=15.57,8 .99Hz,1H)6.77(t,J=8.99Hz,1H)5.56(t,J=5.92Hz,1H)4.75(br.s.,1H)4.54(d,J=5.26Hz,2H)3.58(br.s.,2H)3.39-3.53(m,2H).

[0849] Compound 135:

[0850]

[0851] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide.

[0852] At room temperature to the stirring solution of 2,4-difluoro-3-iodoaniline (100mg, 0.392mmol, 1.0 equivalent) in pyridine (1.0mL), add 2-fluoro-5-(trifluoromethyl) benzene-1-sulfonyl chloride (103mg, 0.392mmol, 1.0 equivalent). The gained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl. This material is not further purified for the next reaction (125mg).

[0853] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(2-fluoro-5-(trifluoromethyl)phenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0854] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide (120 mg, 0.249 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (97 mg, 0.274 mmol, 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (103 mg, 0.747 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (10 mg, 0.0124 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (170 mg) without further purification. LCMS: 583 [M+H] + .

[0855] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide.

[0856] To a stirred solution of N-(6-(2,6-difluoro-3-(2-fluoro-5-(trifluoromethyl)phenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (160 mg, 0.274 mmol, 1.0 equivalent) in ethanol (5 mL) was added 2M NaoH (2 mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 1 h. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (1x100 mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide (6 mg). Analytical data: LCMS: 499[M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)d ppm 11.89(br.s.,1H)9.14(br.s.,1H)8.02(br.s.,1H)7.78(br.s.,2H)7.61(br .s.,1H)7.33-7.54(m,2H)7.11(br.s.,1H)6.94(br.s.,2H)6.79(br.s.,1H)

[0857] Compound 136:

[0858]

[0859] Step 1 Synthesis of N-(2,4-difluoro-3-iodophenyl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide.

[0860] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.392mmol, 1.0 equivalent) in pyridine (0.5mL) stirring solution, add 4-fluoro-3-(trifluoromethyl) benzene-1-sulfonyl chloride (103mg, 0.3921mmol, 1.0 equivalent). The gained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl. This material is not further purified for the next reaction (130mg).

[0861] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0862] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide (120 mg, 0.249 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (97 mg, 0.274 mmol, 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (103 mg, 0.747 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (10 mg, 0.0124 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used for the next reaction (190 mg) without further purification, LCMS: 583 [M+H] + .

[0863] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide.

[0864] To a stirred solution of N-(6-(2,6-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (160mg, 0.274mmol, 1.0 equivalent) in ethanol (5mL) was added 2M NaOH (2mL). The reaction mixture was then allowed to stir for 1h at 90 degrees Celsius. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (1x100mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide (5mg) as the title compound, analytical data: LCMS:499[M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)d ppm 11.54(br.s.,1H)9.14(s,1H)7.91-8.09(m,2H)7.78(s,1H)7.63(d,J=8.77H z,1H)7.36-7.55(m,2H)7.05-7.15(m,1H)6.94(s,2H)6.77(t,J=9.21Hz,1H).

[0865] Compound 137:

[0866]

[0867] Step 1: Synthesis of 4-chloro-N-(2,4-difluoro-3-iodophenyl)-2-(trifluoromethyl)benzenesulfonamide.

[0868] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.392mmol, 1.0 equivalent) in pyridine (0.5mL) stirring solution, add 4-chloro-2-(trifluoromethyl) benzene-1-sulfonyl chloride (109mg, 0.392mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl. This material was used for the next reaction (150mg) without further purification.

[0869] Step 2: Synthesis of N-(6-(3-(4-chloro-2-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pivalamide.

[0870] To a stirred solution of 4-chloro-N-(2,4-difluoro-3-iodophenyl)-2-(trifluoromethyl)benzenesulfonamide (120 mg, 0.241 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (94 mg, 0.265 mmol, 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (99.7 mg, 0.723 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (9.8 mg, 0.0120 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (160 mg) without further purification. LCMS: 599 [M+H] +

[0871] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2-(trifluoromethyl)benzenesulfonamide.

[0872] To a stirred solution of N-(6-(3-(4-chloro-2-(trifluoromethyl)phenylsulfonamido)-2,6-difluorophenyl)quinazoline-2-yl)pivalamide (160 mg, 0.267 mmol, 1.0 equivalent) in ethanol (5 mL) was added 2M NaoH (2 mL) at room temperature. After addition, the reaction mixture was allowed to stir at 90 degrees Celsius for 1 h. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3-chloro-5-(trifluoromethyl)benzenesulfonamide (15 mg) as the title compound. Analytical data: LCMS: 515 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 11.97(br.s.,1H)9.16(s,1H)8.01-8.12(m,1H)7.69-7.92(m,3H)7.64(d,J=8.33Hz,1H)7.48(d,J=8.77Hz,1H)6.95(br.s.,3H)6.79(br.s.,1H).

[0873] Compound 138:

[0874]

[0875] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)quinoxaline-5-sulfonamide.

[0876] At room temperature to 2,4-difluoro-3-iodoaniline (100mg, 0.392mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add quinoxaline-5-sulfonyl chloride (89.6mg, 0.392mmol, 1.0 equivalent). The resulting reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the reaction is complete, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl. This material is not further purified for the next reaction (100mg).

[0877] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(quinoxaline-5-sulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0878] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)quinoxaline-5-sulfonamide (100 mg, 0.223 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (87 mg, 0.245 mmol, 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (92 mg, 0.669 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (9 mg, 0.0111 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (120 mg) without further purification. LCMS: 549 [M+H] +

[0879] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)quinoxaline-5-sulfonamide.

[0880] To a stirred solution of N-(6-(2,6-difluoro-3-(quinoxaline-5-sulfonamido)phenyl)quinazolin-2-yl)pivalamide (120 mg, 0.21 mmol, 1.0 equivalent) in ethanol (4 mL) was added 2M NaoH (1 mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 1 h. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)quinoxaline-5-sulfonamide (15 mg) as the title compound. Analytical data: LCMS: 465[M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 10.23(br.s.,1H)9.12(s,1H)9.04(s,2H)8.33(d,J=6.58Hz,1H)8.28(d,J=7.89Hz,1H)7.91(t,J= 7.89Hz,1H)7.70(s,1H)7.52(d,J=8.33Hz,1H)7.43(d,J=8.77Hz,1H)7.12-7.25(m,1H)6.98(s,3H)

[0881] Compound 139:

[0882]

[0883] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-3-(trifluoromethoxy)benzenesulfonamide.

[0884] At room temperature to 2,4-difluoro-3-iodoaniline (200mg, 0.784mmol, 1.0 equivalent) in pyridine (1.5mL) stirring solution, add 3-(trifluoromethoxy)benzene-1-sulfonyl chloride (204mg, 0.784mmol, 1.0 equivalent). The obtained reaction mixture is stirred at room temperature overnight. The reaction process is monitored by TLC. After the completion of the reaction, ice-cold water is added to the reaction mixture. The precipitate formed is filtered using a Buchner funnel and the product is washed with 1N HCl. This material is not further purified for the next reaction (300mg).

[0885] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(3-(trifluoromethoxy)phenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0886] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3-(trifluoromethoxy)benzenesulfonamide (300 mg, 0.626 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (244 mg, 0.688 mmol, 1.1 equiv) in dioxane:water (8:2, 10 mL) was added KCO (259 mg, 1.87 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (25 mg, 0.0313 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100 °C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (350 mg) without further purification. LCMS: 581 [M+H] +

[0887] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-(trifluoromethoxy)benzenesulfonamide.

[0888] To a stirred solution of N-(6-(2,6-difluoro-3-(3-(trifluoromethoxy)phenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (350mg, 0.602mmol, 1.0 equivalent) in ethanol (5mL) was added 2M NaoH (1mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 1h. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (1x100mL). The organic layers were merged, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3-(trifluoromethoxy)benzenesulfonamide (25mg) as the title compound, analytical data: LCMS:497[M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 11.43(br.s.,1H)10.47(s,1H)9.19(s,1H)7.75(s,3H)7.62(s,1H)7.52-7.59(m,1H)7.41-7.52(m,1H)7.14-7.41(m,4H)

[0889] Compound 140:

[0890]

[0891] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)thiophene-3-sulfonamide.

[0892] Thiophene-3-sulfonyl chloride (198 mg, 1.17 mmol, 2.0 equivalents) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (150 mg, 0.588 mmol, 1.0 equivalents) in pyridine (1.0 mL) at room temperature. The resulting reaction mixture was stirred overnight at room temperature. The reaction process was monitored by TLC. After the reaction was complete, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl. This material was used for the next reaction (180 mg) without further purification.

[0893] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(thiophene-3-sulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0894] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)thiophene-3-sulfonamide (180 mg, 0.448 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (174 mg, 0.492 mmol, 1.1 equiv) in dioxane:water (4:1, 5 mL) was added KCO (185 mg, 1.344 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (18.2 mg, 0.022 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (290 mg) without further purification. LCMS: 503 [M+H] +

[0895] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-3-sulfonamide.

[0896] To a stirred solution of N-(6-(2,6-difluoro-3-(thiophene-3-sulfonamido)phenyl)quinazoline-2-yl)pivalamide (290 mg, 0.577 mmol, 1.0 equivalent) in ethanol (5 mL) was added 2M NaoH (1 mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 1 h. After completion of the reaction, the solvent was evaporated and water was added to the reaction mixture, which was extracted with EtOAc (1x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)thiophene-3-sulfonamide (28 mg) as the title compound. Analytical data: LCMS: 419 [M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 11.31(br.s.,1H)9.15(s,1H)7.84(br.s.,1H)7.79(br.s.,1H)7.62(d,J=8.77Hz,1H)7 .55(br.s.,1H)7.47(d,J=8.77Hz,1H)7.13-7.29(m,2H)6.97(s,2H)6.85-6.93(m,1H).

[0897] Compound 141:

[0898]

[0899] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)-3-isopropylbenzenesulfonamide.

[0900] At room temperature to 2,4-difluoro-3-iodoaniline (150mg, 0.5882mmol, 1.0 equivalent) in pyridine (1.0mL) stirring solution, add 3-isopropylbenzene-1-sulfonyl chloride (128.6mg, 0.5882mmol, 1.0 equivalent). The resulting reaction mixture was stirred at room temperature overnight. The reaction process was monitored by TLC. After the reaction was completed, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl. This material was used for the next reaction (220mg) without further purification.

[0901] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(3-isopropylphenylsulfonamido)phenyl)quinazolin-2-yl)pivalamide.

[0902] To a stirred solution of N-(2,4-difluoro-3-iodophenyl)-3-isopropylbenzenesulfonamide (200 mg, 0.4574 mmol, 1.0 equiv) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)pivalamide (194.9 mg, 0.5488 mmol, 1.2 equiv) in dioxane:water (4:1, 5 mL) was added KCO (189.6 mg, 1.3722 mmol, 3.0 equiv). The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Pd(dppf)Cl.DCM complex (18.6 mg, 0.0228 mmol, 0.05 equiv). The reaction mixture was purged with nitrogen again for 5 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, water was added to the reaction mixture and extracted with EtOAc (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was used in the next reaction (400 mg) without further purification. LCMS: 539.3 [M+H] +

[0903] Step 3: Synthesis of N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-isopropylbenzenesulfonamide.

[0904] To a stirred solution of N-(6-(2,6-difluoro-3-(3-isopropylphenylsulfonamido)phenyl)quinazoline-2-yl)pivalamide (400mg, 0.7426mmol, 1.0 equivalent) in ethanol (6mL) was added 2M NaOH (5mL). The reaction mixture was then allowed to stir at 90 degrees Celsius for 4h. After the reaction was complete, the solvent was evaporated and water was added to the reaction mixture, extracted with EtOAc (2x100mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by reverse phase silica gel chromatography to obtain N-(3-(2-aminoquinazoline-6-yl)-2,4-difluorophenyl)-3-isopropylbenzenesulfonamide (35mg) as the title compound, analytical data: LCMS:455.4[M+H] + ,NMR: 1 H NMR(400MHz,DMSO-d6)δppm 10.17(br.s.,1H)9.13(br.s.,1H)7.70(br.s.,1H)7.51-7.47(m,7H)7.27(br.s.,1H)7.17(br.s.,1H)7.02(br.s.,2H)1.13(d,J=5.70Hz,6H).

[0905] Compound 142:

[0906]

[0907] Step 1: Synthesis of N-(2,4-difluoro-3-iodophenyl)thiophene-2-sulfonamide.

[0908] Thiophene-2-sulfonyl chloride (143.2 mg, 0.7843 mmol, 1.0 equivalent) was added to a stirred solution of 2,4-difluoro-3-iodoaniline (200 mg, 0.7843 mmol, 1.0 equivalent) in pyridine (1.0 mL) at room temperature. The resulting reaction mixture was stirred overnight at room temperature. The reaction process was monitored by TLC. After the reaction was complete, ice-cold water was added to the reaction mixture. The precipitate formed was filtered using a Buchner funnel and the product was washed with 1N HCl. This material was used for the next reaction (300 mg) without further purification.

[0909] Step 2: Synthesis of N-(6-(2,6-difluoro-3-(thiophene-2-sulfonamido)phenyl)quinazolin-2-yl)pivalamide. [0...

Claims

1. A compound according to formula (I): or a pharmaceutically acceptable salt thereof, wherein; R 1 、R 2 、R 3 and R 4 independently selected from H, halo and C optionally substituted with 1-6 fluorine 1-3 Alkyl, where R 1 、R 2 、R 3 and R 4 At least one of them is a halogen group or a C group optionally substituted by 1 to 6 fluorine groups 1-3 Alkyl, or R 4 With R 5 Connected to form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is optionally substituted with halogen and optionally substituted with 1-6 fluorine groups. 1-3 Alkyl substitution; R 5 is selected from H and C optionally substituted by 1-6 fluorine 1-3 alkyl; X is R 6 is H; R 7 NR 8 R 9 ; R 8 and R 9 Independently selected from H, C 1-6 Alkyl, -C(O)NH2, -C(O)-C 1-6 Alkyl and 5 or 6 membered carbocyclic or heterocyclic ring, wherein the C 1-6 Alkyl, -C(O)-C 1-6 The alkyl group and the 5- or 6-membered carbocyclic or heterocyclic ring are independently optionally substituted with 1 to 6 substituents selected from halo, OH and phenyl, or R 8 and R 9 Together with nitrogen, it forms a 6-membered heterocyclic ring; Y is a 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring; or NH2, wherein said 5-, 6-, 9- or 10-membered carbocyclic or heterocyclic ring is optionally substituted by 1-3 groups selected from halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH; R 13 and R 14 are independently H or C 1-3 alkyl; and The condition is When X is replaced only by NH2, R 1 、R 2 、R 3 and R 4 One of them is a halogen or C 1-3 Alkyl, remaining R 1 、R 2 、R 3 and R 4 It's H, R 5 When Y is a 5- or 6-membered carbocyclic or heterocyclic ring, the 5- or 6-membered carbocyclic or heterocyclic ring is substituted by 2 or 3 groups selected from halogen, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy is substituted with a substituent wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with 1 to 6 substituents selected from halo and OH.

2. The compound according to claim 1, wherein NR 8 R 9 It is NH2, NHCH3, N(CH3)2, NHCH2CH2OH, NHCH(CH3)CH2OH, NHCH(CH2OH)2, NHCH(CH2OH)(C6H5), NHCOCH3, NHCOCH2CH3, NHCOCH(CH3)2, NHCOC(CH3)3, 3. The compound according to claim 1 or 2, wherein R 6 is H and R 7 It's NH2.

4. The compound according to any one of claims 1 to 3, wherein Y is selected from:

5. The compound according to claim 1, which is a compound of formula (1b): or a pharmaceutically acceptable salt thereof, wherein Q is N, C or CH, and R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, wherein R 13 and R 14 are independently H or C 1-3 alkyl.

6. The compound according to claim 1, which is a compound of formula (3a): or a pharmaceutically acceptable salt thereof, wherein Q is N, C or CH, and R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, wherein R 13 and R 14 are independently H or C 1-3 alkyl.

7. The compound according to claim 1, which is a compound of formula (4a): or a pharmaceutically acceptable salt thereof, wherein Q is N, C or CH, and R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, wherein R 13 and R 14 are independently H or C 1-3 alkyl.

8. The compound according to claim 1, which is a compound of formula (4b): or a pharmaceutically acceptable salt thereof, wherein Q is N, C or CH, and R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, wherein R 13 and R 14 are independently H or C 1-3 alkyl.

9. The compound according to any one of claims 5-8, wherein Q is N.

10. The compound according to any one of claims 5 to 9, wherein R 10 、R 11 and R 12 Independently selected from: H, Cl, F, OCH3, CF3, CH3, CH2OH, OH, CONH2, COOH, CONHCH3 and COOCH3.

11. A compound according to any one of claims 5 to 10, wherein the following moiety: Selected from:

12. The compound according to claim 11, wherein the following moiety: yes:

13. A compound according to any one of claims 1 to 6 and claims 9 to 12, wherein R 1 、R 2 、R 3 and R 4 Independently selected from H, F and CH3.

14. The compound according to claim 13, wherein R 1 and R 4 is F and R 2 and R 3 It’s H.

15. A compound according to any one of claims 1 to 14, wherein R 5 It’s H.

16. The compound according to claim 1, which is a compound of formula (5b) or (5c): or a pharmaceutically acceptable salt thereof, wherein Q is N, C or CH; R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, wherein R 13 and R 14 are independently H or C 1-3 alkyl; and R 15 and R 16 independently selected from H, halo and C optionally substituted with 1 to 6 fluorine 1-3 alkyl.

17. The compound according to claim 1, which is a compound of formula (5d) or (5e): or a pharmaceutically acceptable salt thereof, wherein Q is N, C or CH; R 10 、R 11 and R 12 Independently selected from: H, halo, OH, CN, -C(O)NR 13 R 14 、-NR 13 COR 14 、-C(O)OR 13 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted with 1 to 6 substituents selected from halo and OH, wherein R 13 and R 14 are independently H or C 1-3 alkyl; and R 15 and R 16 independently selected from H, halo and C optionally substituted with 1 to 6 fluorine 1-3 alkyl.

18. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient.

20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a composition according to claim 19, in the preparation of a medicament for treating a disease or disorder characterized by activation of GCN2.

21. The use according to claim 20, wherein the disease or disorder is cancer, a neurodegenerative disease or a chronic infection.

22. The use according to claim 20, wherein the disease or disorder is cancer.

23. The method of claim 22, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndrome, myeloproliferative neoplasms, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic myeloid leukemia, Lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, malignant pleural mesothelioma, squamous cell carcinoma of the head and neck, glioblastoma multiforme, sarcoma, or childhood neuroblastoma.

24. The use of any one of claims 20 to 23, wherein the compound or composition is administered in combination with a second therapeutic agent, wherein the second therapeutic agent is PEG-arginase, asparaginase, an anti-angiogenic factor, a caspase, or sulfasalazine.

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