Pyrrolo[3,2-c]pyridin-4-one derivatives useful in the treatment of cancer

Abstract

The present disclosure provides chemical entities of formula (I) (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or combinations of the compounds) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2). Such chemical entities are useful, for example, for treating conditions, diseases, or disorders (e.g., cancer) in subjects (e.g., humans) in which elevated (e.g., excessive) EGFR and / or HER2 activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder. The present disclosure also provides compositions containing the chemical entities, as well as methods of using and making the chemical entities. TIFF2023543528001339.tif40128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 082,324, filed September 23, 2020; and U.S. Provisional Patent Application No. 63 / 092,970, filed October 16, 2020; each of which is incorporated by reference herein in its entirety.

[0002] Technical Field The present disclosure provides chemical compounds (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or drug combinations of the compounds) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2). Such chemical compounds are useful, for example, for treating conditions, diseases, or disorders (e.g., cancer) in subjects (e.g., humans) in which elevated (e.g., excessive) EGFR and / or HER2 activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder. The present disclosure also provides compositions containing the chemical compounds, as well as methods of using and making the chemical compounds. [Background technology]

[0003] background Epidermal growth factor receptor (EGFR, ERBB1) and human epidermal growth factor receptor 2 (HER2, ERBB2) are members of a protein family that regulates cellular processes involved in tumor growth, such as proliferation and differentiation. Several researchers have demonstrated the role of EGFR and HER2 in development and cancer (reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232 (Non-Patent Document 1); Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 (Non-Patent Document 2); and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184 (Non-Patent Document 3)). Overexpression of EGFR occurs in at least 70% of human cancers, such as non-small cell lung cancer (NSCLC), breast cancer, glioma, and prostate cancer. HER2 overexpression occurs in approximately 30% of all breast cancers. It is also implicated in other human cancers, such as colon, ovarian, bladder, stomach, esophageal, lung, uterine, and prostate cancers. HER2 overexpression is also correlated with poor prognosis in human cancers, including metastasis and early recurrence.

[0004] Therefore, EGFR and HER2 are widely recognized as targets for the design and development of therapeutic agents that can specifically bind to cancer cells and inhibit their tyrosine kinase activity and signaling pathways, thereby serving as diagnostic or therapeutic agents. For example, EGFR tyrosine kinase inhibitors (TKIs) are effective clinical treatments for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, the vast majority of patients experience disease progression after successful treatment with EGFR TKIs. Common resistance mechanisms include acquired secondary mutations T790M, C797S, and EGFR exon 20 insertion mutations. For example, NSCLC tumors may harbor EGFR exon 20 insertion mutations that are intrinsically resistant to currently used EGFR TKIs.

[0005] Overexpression of another protein, BUB1 (Budding uninhibited by benzimidazole, BUB1) kinase, is often associated with proliferation of cells and tissues, including cancer cells (Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141, 2010). This protein is an essential part of the complex network of proteins that form the mitotic checkpoint. The primary function of an unsatisfied mitotic checkpoint is to maintain the anaphase-promoting complex / cyclosome (APC / C) in an inactive state. As soon as this checkpoint is satisfied, the APC / C ubiquitin ligase targets cyclin B and securin for proteolysis, leading to separation of chromosome pairs and exit from mitosis.

[0006] Defective mitotic checkpoint function is associated with aneuploidy and tumorigenesis (Weaver BA and Cleveland DW, Cancer Res. 67, 10103, 2007 (Non-Patent Document 5); King RW, Biochim Biophys Acta 1786, 4, 2008 (Non-Patent Document 6)). In contrast, complete inhibition of mitotic checkpoints has been recognized to result in severe chromosome missegregation and induction of apoptosis in tumor cells (Kops GJ et al., Nature Rev. Cancer 5, 773, 2005 (Non-Patent Document 7); Schmidt M and Medema RH, Cell Cycle 5, 159, 2006 (Non-Patent Document 8); Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007 (Non-Patent Document 9)). Therefore, mitotic checkpoint inhibition by inhibiting BUB1 kinase represents an approach for the treatment of proliferative disorders, such as solid tumors, e.g., carcinomas, sarcomas, leukemias and lymphoid malignancies, or other disorders associated with uncontrolled cell proliferation. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183 - 232 [Non-Patent Document 2] Klapper, et al., Adv. Cancer Res. (2000) 77, 25 - 79 [Non-Patent Document 3] Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165 - 184 [Non-Patent Document 4] Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141, 2010 [Non-Patent Document 5] Weaver BA and Cleveland DW, Cancer Res. 67、10103, 2007 [Non-Patent Document 6] King RW, Biochim Biophys Acta 1786, 4, 2008 [Non-Patent Document 7] Kops GJ et al., Nature Rev. Cancer 5, 773, 2005 [Non-Patent Document 8] Schmidt M and Medema RH, Cell Cycle 5, 159, 2006 [Non-Patent Document 9] Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007 [Summary of the Invention]

[0008] Summary The present disclosure provides chemical compounds (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or drug combinations) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2). Such chemical compounds are useful, for example, for treating conditions, diseases, or disorders (e.g., cancer) in subjects (e.g., humans) in which elevated (e.g., excessive) EGFR and / or HER2 activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder. The present disclosure also provides compositions containing the chemical compounds, as well as methods of using and making the chemical compounds.

[0009] In one aspect, the present disclosure provides a compound of formula (I): TIFF0007797513000001.tif40128 or a pharmaceutically acceptable salt thereof, wherein R 1c , R 2a , R 2b , R 3a , R 3b , ring A, R 4 , X 1 , R 7 and n can be as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, the present disclosure provides a compound of formula (I): TIFF0007797513000002.tif40128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is:(a)-OL 1 -R 5 ; and Selected from the group consisting of TIFF0007797513000003.tif13128; L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1~10 alkylene; R 5teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 aryl; C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c C is independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; · TIFF0007797513000004.tif16128 (wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -RW or -L 5 -R g2 -R Y selected from the group consisting of: However, L 1 If is a bond, R 5 is the following: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: H; Halo; -OH; -NR e R f ;-R g ;-L 6 -R g ;-R g2 -R W or -R g2 -R Y ;-L 6 -R g2 -R W or -L 6 -R g2 -R Y and each of 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl); L 5 and L 6 are independently -O-, -S(O) 0~2 , -NH or -N(R d )-and; R W Ha-L W -W, where L W is C(=O), S(O) 1~2 ,OC(=O) * , NHC(=O) * , N.R.d C(=O) * , NHS(O) 1~2 * or NR d S(O) 1~2 * where the asterisk represents the point of attachment to W, W is C 2~6 Alkenyl; C 2~6 alkynyl; or C 3~10 arenyl, each of which has 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1~6 alkyl) or S(O)2(C 1~6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y :R g and -(L g ) g -R g selected from the group consisting of: R 1c , R 2a , R 2b , R 3a and R 3b each independently represents: H; halo; —OH; —C(O)OH or —C(O)NH; —CN; —R b ;-L b -R b ;each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -C 1~6 Thioalkoxy;NR e R f ;R g ; and -(L g ) g -R g wherein R is selected from the group consisting of 1cis other than the following: halo, -CN and -C(O)OH; or Or variable part R 1c , R 2a , R 2b , R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (—N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is selected from oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and R d selected from the group consisting of: Each R 7 are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of independently 1~6 Alkyl, C 2~6 Alkenyl or C2~6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1~2 ;C(=O)NH * ;C(=O)NR d* ;S(O) 1~2 NH * ; or S(O) 1~2 N(R d ) * where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R”;-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R e and R f each occurrence independently represents: H; C optionally substituted with 1 to 3 substituents 1~6 Alkyl, each substituent is NR'R", -OH, C 1~6 Alkoxy, C 1~6 independently selected from the group consisting of haloalkoxy and halo; —C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R g Each occurrence of independently: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R cC optionally substituted with 6~10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is a base; Each occurrence of R' and R" independently represents: H; -OH; and C 1~4 selected from the group consisting of alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, R 2a , R 2b , R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 Ga-OL 1 -R 5 and;-L 1 If is CH2: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

[0012] In one aspect, the present disclosure provides a compound of formula (I): TIFF0007797513000005.tif40128 or a pharmaceutically acceptable salt thereof, During the ceremony: X 1 is:(a)-OL 1 -R 5 ; and Selected from the group consisting of TIFF0007797513000006.tif13128; L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1~10 alkylene; R 5 teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 aryl; C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c C is independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; · TIFF0007797513000007.tif16128 (wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R cindependently selected from the group consisting of: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); -R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y selected from the group consisting of: However, L 1 If is a bond, R 5 is the following: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: ·H; ·Halo; ·-OH; -NR e R f ; -R g ; -R w -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -Rg2 -R W or -L 6 -R g2 -R Y ; and Each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl) selected from the group consisting of: L 5 and L 6 are independently -O-, -S(O) 0~2 , -NH or -N(R d )-and; R W Ha-L W -W, where L W is C(=O), S(O) 1~2 ,OC(=O) * , NHC(=O) * , N.R. d C(=O) * , NHS(O) 1~2 * or NR d S(O) 1~2 * where the asterisk represents the point of attachment to W, W is C 2~6 Alkenyl; C 2~6 alkynyl; or C 3~10 arenyl, each of which has 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1~6 alkyl) or S(O)2(C 1~6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y is:-R g and -(Lg ) g -R g selected from the group consisting of: R 1c , R 2a , R 2b , R 3a and R 3b each independently represents: H; halo; —OH; —C(O)OH or —C(O)NH; —CN; —R b ;-L b -R b ;each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -C 1~6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g wherein R is selected from the group consisting of 1c is other than the following: halo, -CN and -C(O)OH; or Variable section R 1c , R 2a , R 2b , R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (—N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and Rd selected from the group consisting of: Each R 7 are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of independently 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1~2 ;C(=O)NH * ;C(=O)NR d* ;S(O) 1~2 NH * ; or S(O) 1~2 N(R d ) * where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 3~5 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O)1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R”;-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R e and R f Each occurrence of is independently: H; 1 to 3 C 1~3 C optionally substituted with alkyl group 3~5 Cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c heterocyclyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: 1~6 alkyl, where each substituent is NR'R", -OH, C 1~6 Alkoxy, C 1~6 C independently selected from the group consisting of haloalkoxy and halo; 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl);-OH;C 1~4 selected from the group consisting of alkoxy; R g Each occurrence of independently: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 alkylene; each g is independently 1, 2, or 3; Each R g2is a divalent R g It is a base; Each occurrence of R' and R" is independently: H; -OH; and C 1~4 selected from the group consisting of alkyl, The present invention features a compound or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, R 2a , R 2b , R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 Ga-OL 1 -R 5 and;-L 1 If is CH2: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

[0014] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0015] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0016] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the EGFR gene, EGFR kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0017] Provided herein is a method for treating an EGFR-related disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR-related disease or disorder a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0018] Also provided herein is a method for treating an EGFR-related disease or disorder in a subject, the method comprising: determining that the subject's cancer is an EGFR-related disease or disorder; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. Further provided herein is a method for treating an EGFR-related cancer in a subject, the method comprising administering to a subject identified or diagnosed with an EGFR-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0019] The present disclosure also provides a method of treating an EGFR-associated cancer in a subject, the method comprising: determining that the subject's cancer is an EGFR-associated cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0020] Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject having clinical documentation indicating that the subject has a dysregulation of the EGFR gene, EGFR kinase, or expression or activity or level of any of them.

[0021] Also provided herein is a method of treating a subject with cancer, comprising: (a) administering to said subject one or more doses of a first EGFR inhibitor for a period of time; (b) after (a), determining whether cancer cells in the sample taken from the subject have at least one EGFR inhibitor resistance mutation that confers on the cancer cells or tumor increased resistance to treatment with the first EGFR inhibitor of step (a); and (c) if the subject is determined to have cancer cells with at least one EGFR inhibitor-resistant mutation that confers on the cancer cells or tumor increased resistance to treatment with the first EGFR inhibitor of step (a), administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anti-cancer agent; or (d) if the subject is not determined to have cancer cells with at least one EGFR inhibitor resistance mutation that confers increased resistance to treatment with the first EGFR inhibitor of step (a), administering an additional dose of the first EGFR inhibitor of step (a) to the subject. The present invention provides a method comprising:

[0022] Further provided herein is a method of treating a subject with cancer, comprising: (a) determining whether cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first EGFR inhibitor have one or more EGFR inhibitor resistance mutations that confer increased resistance to treatment with the first EGFR inhibitor previously administered to the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anti-cancer agent, if the subject is determined to have cancer cells with at least one EGFR inhibitor resistance mutation that confers on the cancer cells or tumor increased resistance to treatment with a first EGFR inhibitor previously administered to the subject; or (c) administering an additional dose of the first EGFR inhibitor to the subject if the subject is not determined to have cancer cells with at least one EGFR inhibitor resistance mutation that confers increased resistance to treatment with the first EGFR inhibitor previously administered to the subject. The present invention provides a method comprising:

[0023] Also provided herein is a method of treating a subject with cancer, comprising: (a) determining that cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first EGFR inhibitor have one or more EGFR inhibitor resistance mutations that confer on the cancer cells or tumor increased resistance to treatment with the first EGFR inhibitor previously administered to the subject; and (b) administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, either as monotherapy or in combination with another anti-cancer agent. The present invention provides a method comprising:

[0024] Further provided herein is a method of treating a subject with cancer, comprising: (a) determining that cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first EGFR inhibitor do not harbor one or more EGFR inhibitor resistance mutations that confer increased resistance to treatment with the first EGFR inhibitor previously administered to the subject; and (b) administering to the subject an additional dose of a first EGFR inhibitor. The present invention provides a method comprising:

[0025] The disclosure also provides a method for inhibiting EGFR in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the HER2 gene, HER2 kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0027] Further provided herein is a method for treating a HER2-associated cancer in a subject, comprising administering to a subject identified or diagnosed with a HER2-associated cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0028] The present disclosure also provides a method for treating a HER2-associated cancer in a subject, comprising: determining that the subject's cancer is a HER2-associated cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0029] Provided herein is a method of treating a subject having cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject having clinical documentation indicating that the subject has dysregulation of the HER2 gene, HER2 kinase, or the expression or activity or levels of either thereof.

[0030] Also provided herein is a method of treating a subject with cancer, comprising: (a) administering to the subject one or more doses of a first HER2 inhibitor for a period of time; (b) after (a), determining whether cancer cells in the sample taken from the subject have at least one HER2 inhibitor resistance mutation that confers increased resistance to treatment with the first HER2 inhibitor of step (a); and (c) if the subject is determined to have cancer cells having at least one HER2 inhibitor-resistant mutation that confers on the cancer cells or tumor increased resistance to treatment with the first HER2 inhibitor of step (a), administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anti-cancer agent; or (d) if the subject is not determined to have cancer cells with at least one HER2 inhibitor resistance mutation that confers increased resistance to treatment with the first HER2 inhibitor of step (a), administering an additional dose of the first HER2 inhibitor of step (a) to the subject. The present invention provides a method comprising:

[0031] Further provided herein is a method of treating a subject with cancer, comprising: (a) determining whether cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first HER2 inhibitor have one or more HER2 inhibitor resistance mutations that confer increased resistance to treatment with the first HER2 inhibitor previously administered to the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anti-cancer agent, if the subject is determined to have cancer cells having at least one HER2 inhibitor resistance mutation that confers on the cancer cells or tumor increased resistance to treatment with a first HER2 inhibitor previously administered to the subject; or (c) administering an additional dose of the first HER2 inhibitor to the subject if the subject is not determined to have cancer cells with at least one HER2 inhibitor resistance mutation that confers on the cancer cells or tumor increased resistance to treatment with the first HER2 inhibitor previously administered to the subject. The present invention provides a method comprising:

[0032] Also provided herein is a method of treating a subject with cancer, comprising: (a) determining that cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first HER2 inhibitor have one or more HER2 inhibitor resistance mutations that confer on the cancer cells or tumor increased resistance to treatment with the first HER2 inhibitor previously administered to the subject; and (b) administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, either as monotherapy or in combination with another anti-cancer agent. The present invention provides a method comprising:

[0033] Further provided herein is a method of treating a subject with cancer, comprising: (a) determining that cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first HER2 inhibitor do not harbor one or more HER2 inhibitor resistance mutations that confer increased resistance to treatment with the first HER2 inhibitor previously administered to the subject; and (b) administering to the subject an additional dose of a first HER2 inhibitor. The present invention provides a method comprising:

[0034] The disclosure also provides a method for inhibiting HER2 in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0035] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression, activity, or level of the EGFR gene, EGFR kinase, or any of them, and that the cancer is associated with dysregulation of the expression, activity, or level of the HER2 gene, HER2 kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0036] Further provided herein are methods for treating EGFR-associated and HER2-associated cancers in a subject, comprising administering to a subject identified or diagnosed with EGFR-associated and HER2-associated cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0037] The present disclosure also provides a method of treating EGFR-associated and HER2-associated cancer in a subject, comprising: determining that the subject's cancer is an EGFR-associated and HER2-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0038] Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject having clinical records indicating that the subject has dysregulation of the expression, activity, or level of the EGFR gene, EGFR kinase, or any of them, and dysregulation of the expression, activity, or level of the HER2 gene, HER2 kinase, or any of them.

[0039] The present disclosure also provides a method for inhibiting EGFR and HER2 in mammalian cells, comprising contacting the mammalian cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0040] In addition to the above, provided herein are methods for inhibiting BUB (mutants defective in benzimidazole-induced germination arrest, BUB1-3) kinase. In some embodiments, the methods provided herein include methods for inhibiting BUB11. For example, a method for inhibiting BUB1 in a mammalian cell includes contacting the mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0041] Other aspects include those described in the detailed description and / or claims.

[0042] Additional definitions To facilitate understanding of the disclosure provided herein, some additional terms are defined below. Generally, the technical terms used herein and the organic chemistry, medicinal chemistry, and pharmacology laboratory procedures described herein are those commonly used and well-known in the art. Unless otherwise defined, all scientific and technical terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, patent applications, published applications, and other publications mentioned throughout this specification and in the appendices is incorporated herein by reference in its entirety.

[0043] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the general well-being of the subject being treated.

[0044] "API" refers to active pharmaceutical ingredient.

[0045] The term "effective amount" or "therapeutically effective amount," as used herein, refers to the amount of a chemical substance administered that is sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated. This result may include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, in therapeutic use, an "effective amount" is the amount of a composition comprising a compound disclosed herein that is required to produce a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using any suitable method, such as a dose escalation study.

[0046] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating agent. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0047] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not eliminate the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, pharmaceutically acceptable salts can be obtained by reacting a compound described herein having an acidic group with a base to form a salt, such as an ammonium salt, an alkali metal salt, such as a sodium salt or a potassium salt, an alkaline earth metal salt, such as a calcium salt or a magnesium salt, a salt with an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and an amino acid, such as arginine or lysine, or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in medicine. Examples of salts that the compounds described herein may form with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may also be acid addition salts, and specific examples include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acid addition salts with natural amino acids such as aspartic acid and glutamic acid.

[0048] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. A pharmaceutical composition facilitates administration of the compound to an organism. Various techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0049] The term "subject" refers to an animal such as, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human.

[0050] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0051] The term "oxo" refers to a divalent oxygen atom having a double bond (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0052] The term "alkyl" refers to an acyclic saturated hydrocarbon residue, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10 indicates that the group can have 1 to 10 (inclusive) carbon atoms. Alkyl groups can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that there are only single bonds between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0053] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0054] The term "alkoxy" refers to an -O-alkyl radical (eg, -OCH3).

[0055] The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl, respectively. For the avoidance of doubt, in "cycloalkylene" and "heterocyclylene," the two atomic groups may be located on the same ring carbon atom (e.g., geminal divalent atomic groups, e.g., TIFF0007797513000008.tif18128) may be present on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)). TIFF0007797513000009.tif18128.

[0056] The term "alkenyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have 2 to 6 (inclusive) carbon atoms. Alkenyl groups may be either unsubstituted or substituted with one or more substituents. Alkenyl groups may be trans or cis.

[0057] The term "alkynyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms. Alkynyl groups may be either unsubstituted or substituted with one or more substituents.

[0058] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); 0, 1, 2, 3, or 4 atoms in each ring may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0059] The term "cycloalkyl," as used herein, refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbon atoms, preferably 3 to 16 ring carbon atoms, and more preferably 3 to 12 ring carbon atoms, 3 to 10 ring carbon atoms, or 3 to 6 ring carbon atoms, wherein the cycloalkyl group is optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. The term "saturated," as used in this context, means that there are only single bonds between the constituent carbon atoms.

[0060] The term "cycloalkenyl," as used herein, refers to a cyclic, partially unsaturated hydrocarbon group having 3 to 20 ring carbon atoms, preferably 3 to 16 ring carbon atoms, more preferably 3 to 12 ring carbon atoms, 3 to 10 ring carbon atoms, or 3 to 6 ring carbon atoms, wherein the cycloalkenyl group is optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a cyclic, partially unsaturated hydrocarbon group, the cycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system is aromatic, and the cycloalkenyl group as a whole is not fully saturated. The cycloalkenyl may contain multiple fused and / or bridged and / or spirocyclic rings.

[0061] The term "heteroaryl," as used herein, refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or alternatively 5, 6, 9, 10, or 14 ring atoms; at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and at least one ring in the system is aromatic (although not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be either unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3 [d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarity, heteroaryl refers to an aromatic lactam, an aromatic cyclic urea, or a vinyl analog thereof, such as a pyridone, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents). TIFF0007797513000010.tif20128, pyrimidon TIFF0007797513000011.tif20128, Pyridazinone TIFF0007797513000012.tif20128, Pyrazinone TIFF0007797513000013.tif20128, and imidazolone Also encompassed are one or more of TIFF0007797513000014.tif17128, where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., where an oxo group (i.e., "=O") is part of a heteroaryl ring).

[0062] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated ring system (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system) having 3 to 16 ring atoms, the heteroatoms being selected from O, N, or S, with 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms that are N, O, or S in the monocyclic, bicyclic, or tricyclic ring, respectively), where 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyls can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyls include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2. ... Examples include hexane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, and 3-oxabicyclo[3.2.1]octane.Heterocyclyl also encompasses spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2 .2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0063] The term "heterocycloalkenyl," as used herein, refers to a partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system), wherein the heteroatoms are selected from O, N, or S, with 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms that are N, O, or S in the monocyclic, bicyclic, or tricyclic ring, respectively), where 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated ring group, a heterocycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present in the ring, no ring in the ring system is aromatic, and the heterocycloalkenyl group as a whole is not fully saturated. A heterocycloalkenyl may contain multiple fused and / or bridged and / or spirocyclic rings.

[0064] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0065] As used herein, when a ring is described as being "partially unsaturated," this means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation inherent in the ring itself; for example, one or more double or triple bonds between constituent ring atoms), but the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0066] For the avoidance of doubt, unless otherwise indicated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are not limited to those having fused rings, e.g., those in which the points of fusion are (i) on adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents zero atom bridging). TIFF0007797513000015.tif13128); (ii) those present on a single ring atom (spiro-fused ring systems) TIFF0007797513000016.tif18128 or (iii) present on a series of consecutive ring atoms (bridged ring systems with a total bridge length > 0). Please understand that this includes TIFF0007797513000017.tif14128.

[0067] Furthermore, atoms constituting the compounds of the various aspects of the present invention are intended to encompass all isotopic forms of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include tetrahydrogen, tetrahydrofuran ... 13 C and 14 C is one example.

[0068] Additionally, compounds disclosed generically or specifically herein are intended to encompass all tautomeric forms. Thus, by way of example, the moiety: The compound containing TIFF0007797513000018.tif15128 is part: TIFF0007797513000019.tif16128. Similarly, a pyridinyl or pyrimidinyl moiety that is described as being optionally substituted with a hydroxyl includes the pyridone or pyrimidone tautomeric forms.

[0069] The compounds provided herein can include various stereochemical forms.These compounds also include the diastereomers and optical isomers that result from the structural asymmetry of certain compounds, such as enantiomeric mixtures, for example, racemic mixtures and individual enantiomers and diastereomers.Unless otherwise stated, when the disclosed compounds are named without specifying stereochemistry or their structures are depicted, and when they have one or more chiral centers, they should be understood to represent all possible stereoisomers of the compounds.

[0070] [The present invention 1001] Formula (I): TIFF0007797513000020.tif40128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is:(a)-OL 1 -R 5 ; and TIFF0007797513000021.tif13128 selected from the group consisting of: L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1~10 alkylene; R 5 teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are each independently N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 aryl; ·C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c C is independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; · TIFF0007797513000022.tif16128 (wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X In addition to the nitrogen atom in the ring bonded to d ), O and S(O) 0~2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is: oxo and -R c independently selected from the group consisting of: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); ·-R W ·-R g2 -R W or -R g2 -R Y ; ·-L 5 -R g ; and ·-L 5 -R g2 -R W or -L 5 -R g2 -R Y selected from the group consisting of: However, L 1 If is a bond, R5 is the following: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: ·H; ·Halo; ·-OH; -NR e R f ; ·-R g ; ·-R w ·-L 6 -R g ; ·-R g2 -R W or -R g2 -R Y ; ·-L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and Each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl) selected from the group consisting of: L 5 and L 6 are independently -O-, -S(O) 0~2 , -NH or -N(R d )-and; R W Ha-L W -W, where L W is C(=O), S(O) 1~2 ,OC(=O) * , NHC(=O) * , N.R. d C(=O) * , NHS(O) 1~2 * or NR d S(O) 1~2 * where the asterisk represents the point of attachment to W, W is C 2~6 Alkenyl; C 2~6 alkynyl; or C 3~10 arenyl, each of which has 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1~6 alkyl) or S(O) 2 (C 1~6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y is:-R g and -(L g ) g -R g selected from the group consisting of: R 1c 、R 2a 、R 2b 、R 3a and R 3b each independently represents: H; halo; —OH; —C(O)OH or —C(O)NH 2 ;-CN;-R b ;-L b -R b ;each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -C 1~6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g wherein R is selected from the group consisting of 1c is other than the following: halo, -CN and -C(O)OH; or Variable section R 1c 、R 2a 、R 2b 、R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (—N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is oxo, R c and RW and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and R d selected from the group consisting of: Each R 7 are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of independently 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1~2 ;C(=O)NH * ;C(=O)NR d* ;S(O) 1~2 NH * ; or S(O) 1~2 N(R d ) * where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 3~5 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R”;-C 1~4 Thioalkoxy;-NO 2 ;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF 5 selected from the group consisting of: R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R e and R f Each occurrence of is independently: H; 1 to 3 C 1~3 C optionally substituted with alkyl group 3~5 Cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c heterocyclyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: 1~6 alkyl, where each substituent is NR'R", -OH, C1~6 Alkoxy, C 1~6 C independently selected from the group consisting of haloalkoxy and halo; 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R g Each occurrence of independently: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is a base; Each occurrence of R' and R" is independently: H; -OH; and C 1~4 selected from the group consisting of alkyl; However, R 2a 、R 2b 、R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 Ga-OL 1 -R 5 and;-L 1 is CH 2 If: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; A compound or a pharmaceutically acceptable salt thereof. [The present invention 1002] X 1 Ga-OL 1 -R 5 The compound of the present invention 1001, [The present invention 1003] R 5 is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of the present invention 1001 or 1002, [The present invention 1004] R 5 is a monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of any one of the present inventions 1001 to 1003, [The present invention 1005] R 5 is a monocyclic heteroaryl containing 5 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of any one of 1001 to 1004 of the present invention, [The present invention 1006] R 5 is selected from the group consisting of furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, and thiazolyl, each of which is selected from the group consisting of 1 to 2 R cA The ring nitrogen may be substituted with R d where each R cA are independently selected R c The compound of any one of 1001 to 1005 of the present invention, [The present invention 1007] R 5 but, Each has 1-2 R cA may be substituted with TIFF0007797513000023.tif23159 wherein each R cA are independently selected R c The compound of any one of 1001 to 1006 of the present invention, [The present invention 1008] R 5 is a monocyclic heteroaryl containing 6 ring atoms, of which 1 to 4 ring atoms are nitrogen ring atoms, and the heteroaryl is cA where each R cA are independently selected R c The compound of any one of 1001 to 1004 of the present invention, [The present invention 1009] R 5 However, each has 1 to 3 R cA and R is selected from the group consisting of pyridyl, pyridonyl, pyrimidyl, pyrazinyl, and pyridazinyl, optionally substituted with cA are independently selected R c The compound of any one of 1001 to 1004 or 1008 of the present invention, [The present invention 1010] R 5 but: TIFF0007797513000024.tif44128 each of which is selected from the group consisting of R cA wherein each R cA are independently selected R c The compound of any one of 1001 to 1004 or 1008 to 1009 of the present invention, [The present invention 1011] R 5 but: TIFF0007797513000025.tif23131 each of which is selected from the group consisting of R cA wherein each R cA are independently selected R c The compound of any one of 1001 to 1004 or 1008 to 1009 of the present invention, [The present invention 1012] R 5 is a bicyclic heteroaryl containing 8 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of any one of the present inventions 1001 to 1003, [The present invention 1013] R 5 is a bicyclic heteroaryl containing 8 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of any one of 1001 to 1003 or 1012 of the present invention, [The present invention 1014] R 5 but: TIFF0007797513000026.tif17128 each of which is selected from the group consisting of 1 to 2 R cA wherein each R cA are independently selected R c The compound of any one of 1001 to 1003 and 1012 to 1013 of the present invention, [The present invention 1015] R 5 but: TIFF0007797513000027.tif41128 each of which is selected from the group consisting of 1 to 2 R cA wherein each R cA are independently selected R c The compound of any one of 1001 to 1002 or 1012 to 1013 of the present invention, [The present invention 1016] R 5 is a bicyclic heteroaryl containing 9 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of any one of 1001 to 1003 or 1012 of the present invention, [The present invention 1017] R 5 is imidazolopyridinyl, pyrazolopyridinyl, or benzotriazolyl, each of which is selected from the group consisting of 1 to 2 R cA where each R cA are independently selected R c The compound of any one of 1001 to 1003, 1012 and 1016 of the present invention, [The present invention 1018] R 5 but TIFF0007797513000028.tif24128 and each of these contains 1 to 2 R cA where each R cA are independently selected R c The compound of any one of 1001 to 1003, 1012, or 1016 to 1017 of the present invention, [The present invention 1019] R 5 is a bicyclic 10-membered heteroaryl in which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of any one of the present inventions 1001 to 1003, [The present invention 1020] Each R cA are independently: halo; cyano; -OH; 1 to 6 independently selected R a C optionally substituted with 1~6 Alkyl; C1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Any of compounds 1003 to 1019 of the present invention, selected from the group consisting of haloalkoxy; and —C(═O)NR′R″. [The present invention 1021] R cA The compound of any of claims 1003-1020, wherein one occurrence of is independently selected halo, for example, -F or -Cl. [The present invention 1022] R cA The compound of any one of claims 1003 to 1021, wherein one occurrence of is cyano. [The present invention 1023] R cA One occurrence of is selected from 1 to 6 independently selected R a C optionally substituted with 1~6 The compound of any one of 1003 to 1022 of the present invention, which is alkyl. [The present invention 1024] R cA One occurrence of C 1~6 Alkyl, e.g., C 1~3 The compound of any one of claims 1003 to 1023 of the present invention, which is alkyl. [The present invention 1025] R cA One occurrence of -OH or -NR e R f C is replaced by 1~6 Alkyl, e.g., —OH or NH 2 C is replaced by 1~3 The compound of any one of claims 1003 to 1023 of the present invention, which is alkyl. [The present invention 1026] R cA One occurrence of C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy, e.g., R cA One occurrence of C 1~4 The compound of any one of claims 1003 to 1025, which is alkoxy, for example, methoxy or ethoxy. [The present invention 1027] R cA One occurrence of -C(=O)NR'R", e.g., C(=O)NH2 The compound of any one of claims 1003 to 1026 of the present invention, [The present invention 1028] R 5 but TIFF0007797513000029.tif16128 wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c The compound of the present invention 1001 or 1002, independently selected from the group consisting of: [The present invention 1029] R 5 but TIFF0007797513000030.tif20128 This is one to two R c wherein x1 and x2 are each independently 0, 1, or 2. [The present invention 1030] The compound of the present invention 1029, wherein x1=0 and x2=0. [The present invention 1031] The compound of the present invention 1029, wherein x1=0 and x2=1. [The present invention 1032] The compound of the present invention 1029, wherein x1=0 and x2=2. [The present invention 1033] R 5 but: TIFF0007797513000031.tif39128 The compound of any one of 1001 to 1002 and 1028 to 1029 of the present invention selected from the group consisting of: [The present invention 1034] R X is C(=O)(C 1~4 alkyl) or S(O) 2 (C 1~4 The compound of any one of claims 1028 to 1033 of the present invention, wherein the aryl group is aryl, ... [This invention 1035] R X is C(=O)(C 1~4 The compound of any one of claims 1028 to 1034, wherein the aryl group is C(=O)Me or C(=O)Et. [The present invention 1036] RX is S(O) 2 (C 1~4 alkyl), e.g., S(O) 2 The compound of any one of claims 1028 to 1034, wherein Me. [This invention 1037] R 5 Ga-R g2 -R W The compound of the present invention 1001 or 1002, [The present invention 1038] R 5 Ga-R g2 -R W and;-R g2 -R W -R g2 is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is independently selected from the group consisting of oxo and R c The compound of any one of 1001 to 1002 or 1037 of the present invention, which may be substituted with 1 to 4 substituents independently selected from the group consisting of: [This invention 1039] -R 5 but TIFF0007797513000032.tif16128 wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c The compound of any one of 1001 to 1002 and 1037 to 1038 of the present invention, independently selected from the group consisting of: [The present invention 1040] -R 5 But 1-2 R c may be substituted with TIFF0007797513000033.tif20128 wherein x1 and x2 are each independently 0, 1, or 2. [The present invention 1041] Compound 1040 of the present invention, wherein x1=0 and x2=0. [The present invention 1042] 1040. The compound of claim 10, wherein x1=0 and x2=1; or x1=0 and x2=2. [This invention 1043] R 5 but: TIFF0007797513000034.tif60146 The compound of any one of 1001 to 1002 and 1037 to 1042 of the present invention selected from the group consisting of: [This invention 1044] R 5 R W The compound of any one of 1001 and 1002 of the present invention, [This invention 1045] R W Ga-L W -W;L W is C(=O)NHC(=O) * or NHS(O) 1~2 * wherein the asterisk represents the point of attachment to W. [The present invention 1046] W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W Any of the compounds of 1037 to 1045 of the present invention, which is bound to [This invention 1047] W is C 2~4 Alkenyl or C 2~4 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W Any of the compounds of 1037 to 1046 of the present invention, which is bound to [This invention 1048] W is CH=CH 2 , CH=CHCH 2 NMe 2 or TIFF0007797513000035.tif7128 The compound of any one of claims 1037 to 1047 of the present invention, [This invention 1049] -L W -W is -C(=O)CH=CH 2 , -C(=O)CH=CHCH 2 NMe 2 or TIFF0007797513000036.tif14128 The compound of any one of 1037 to 1048 of the present invention, [The present invention 1050] R 5 Ga-R g2 -R Y The compound of the present invention 1001 or 1002, [This invention 1051] R 5 Ga-R g2 -R Y where -R g2 -R Y -R g2 is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is independently selected from the group consisting of oxo and R c The compound of any one of 1001 to 1002 or 1050 of the present invention, which may be substituted with 1 to 3 substituents independently selected from the group consisting of: [This invention 1052] -R 5 but TIFF0007797513000037.tif16128 wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R Y ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c The compound of any one of 1001 to 1002 or 1050 to 1051 of the present invention, independently selected from the group consisting of: [This invention 1053] -R 5 But 1-2 R c may be substituted with TIFF0007797513000038.tif20128 wherein x1 and x2 are each independently 0, 1, or 2. [This invention 1054] The compound of the present invention 1053, wherein x1=0 and x2=0. [This invention 1055] The compound of the present invention 1053, wherein x1=0 and x2=1. [This invention 1056] The compound of the present invention 1053, wherein x1=0 and x2=2. [This invention 1057] R 5 but: TIFF0007797513000039.tif38128 The compound of any one of 1001 to 1002 and 1050 to 1053 of the present invention selected from the group consisting of: [This invention 1058] R 5 Ga-R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 3 R c The compound of any one of 1001 to 1002 or 1050 of the present invention, which may be substituted with [This invention 1059] R 5 Ga-R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing five ring atoms, of which one to four ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 2 R c The compound of any one of 1001 to 1002, 1050 and 1058 of the present invention, which may be substituted with [The present invention 1060] R 5 but: TIFF0007797513000040.tif18128 The compound of any one of 1001 to 1002, 1050, and 1058 to 1059 of the present invention selected from the group consisting of: [This invention 1061] -R Y Ga-R g The compound of any one of 1050 to 1060 of the present invention, [This invention 1062] -R Y but: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl Any of the compounds of 1050 to 1061 of the present invention selected from the group consisting of: [This invention 1063] -R Y However, 1 to 4 R c C optionally substituted with 6~10 The compound of any one of 1050 to 1062 of the present invention, which is aryl. [The present invention 1064] -R Y However, 1 to 3 R c The compound of any one of claims 1050 to 1063, wherein the compound is phenyl which may be substituted by [This invention 1065] -R Y is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c The compound of any one of 1050 to 1062 of the present invention, which may be substituted with [The present invention 1066] -R Y is a monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c The compound of any one of 1050 to 1062 or 1065 of the present invention, which may be substituted with [This invention 1067] -R Y is selected from the group consisting of pyridyl and pyrazolyl, each of which is selected from the group consisting of 1 to 2 R c The compound of any one of 1050 to 1062 or 1065 to 1066 of the present invention, which may be substituted with [The present invention 1068] R 5 C, each of which may be substituted with 1 to 4 substituents 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each substituent being: oxo and R c The compound of the present invention 1001 or 1002, independently selected from the group consisting of: [The present invention 1069] R 5 is substituted with 1 to 4 substituents 3~10 cycloalkyl, each substituent being: oxo and R c The compound of any one of 1001 to 1002 or 1068 of the present invention, independently selected from the group consisting of: [The present invention 1070] R 5 But C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 3~6 is cycloalkyl; R 5 is optionally further substituted with 1 to 2 substituents, each of which is selected from: oxo and R c The compound of any one of 1001 to 1002 or 1068 to 1069 of the present invention, independently selected from the group consisting of: [This invention 1071] R 5 But C 1~4 Alkoxy or C 1~4 cyclopropyl substituted with haloalkoxy; TIFF0007797513000041.tif17128 The compound of any one of 1001 to 1002 and 1068 to 1070 of the present invention, [This invention 1072] R 5 However, 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 The compound of the present invention 1001 or 1002, wherein [This invention 1073] R 5 However, 1 to 6 R a -S(O) optionally substituted with 2 (C 1~6 The compound of any one of claims 1001 to 1002 or 1072 of the present invention, wherein the compound is alkyl. [This invention 1074] R5 -S(O) 2 (C 1~6 alkyl), e.g., -S(O) 2 (C 1~3 The compound of any one of 1001 to 1002 or 1072 to 1073 of the present invention, wherein the compound is alkyl. [This invention 1075] R 5 But -L 5 -R g 、-L 5 -R g2 -R Y and -L 5 -R g2 -R W The compound of the present invention 1001 or 1002, selected from: [This invention 1076] R 5 Ga-L 5 -R g The compound of any one of 1001 to 1002 or 1075 of the present invention, [This invention 1077] R 5 -OR g The compound of any one of 1001 to 1002 and 1075 to 1076 of the present invention, [This invention 1078] R 5 -OR g and;-OR g R exists in g C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c The compound of any one of 1001 to 1002 and 1075 to 1077 of the present invention, independently selected from the group consisting of: [This invention 1079] R 5 -O-(C 3~6 cycloalkyl), and the C 3~6 Cycloalkyl has 1 to 3 R c The compound of any one of 1001 to 1002 or 1075 to 1078 of the present invention, which may be substituted with [The present invention 1080] R 5 but TIFF0007797513000042.tif9128 The compound of any one of 1001 to 1002 and 1075 to 1079 of the present invention, [This invention 1081] L 1 However, 1 to 6 R a C optionally substituted with 1~10 The compound of any one of 1001 to 1080 of the present invention, which is alkylene. [This invention 1082] L 1 However, 1 to 6 R a C optionally substituted with 1~6 The compound of any one of 1001 to 1081 of the present invention, which is alkylene. [This invention 1083] L 1 However, 1 to 6 R a C optionally substituted with 1~4 The compound of any one of 1001 to 1082 of the present invention, which is alkylene. [This invention 1084] L 1 C 1~4 The compound of any one of 1001 to 1083 of the present invention, which is alkylene. [This invention 1085] L 1 Ga-CH 2 -or-CH 2 CH 2 Any of the compounds of the present invention 1001 to 1084, wherein [This invention 1086] L 1 but TIFF0007797513000043.tif11128 where the asterisk is R W The compound of any one of claims 1001 to 1084 of the present invention, wherein the point of attachment to [This invention 1087] L 1 The compound of any one of claims 1001 to 1080, wherein is a bond. [This invention 1088] X 1 but TIFF0007797513000044.tif12128 The compound of the present invention 1001, [This invention 1089] R 6 R g The compound of the present invention 1001 or 1088, [The present invention 1090] R 6 is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c The compound of any one of 1001 and 1088 to 1089 of the present invention, which may be substituted with 1 to 4 substituents independently selected from the group consisting of: [This invention 1091] R 6 is a heterocyclyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 6 is a heterocyclyl containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c The compound of any one of 1001 and 1088 to 1090 of the present invention, which may be substituted with 1 to 2 substituents independently selected from the group consisting of: [This invention 1092] R 6 is selected from the group consisting of pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, which are each selected from the group consisting of oxo and R c and the nitrogen atom in the pyrrolidinyl or piperidinyl ring is optionally substituted with 1 to 2 substituents independently selected from the group consisting of R d may be substituted with, for example, R 6 teeth TIFF0007797513000045.tif41128 The compound of any one of the present invention 1001 and 1088 to 1091, [This invention 1093] R 6 is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 Rc may be substituted with, for example: R 6 is a heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be substituted with, for example: R 6 teeth TIFF0007797513000046.tif19128 The compound of any one of the present invention 1001 and 1088 to 1089, [This invention 1094] R 6 Ga-R g2 -R W or -R g2 -R Y The compound of the present invention 1001 or 1088, [This invention 1095] R 6 Ga-R g2 -R W Any of compounds 1001, 1088 or 1094 of the present invention, [This invention 1096] -R 6 but TIFF0007797513000047.tif16128 wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: 6 is a monocyclic heterocyclylene ring containing 3 to 10 ring atoms as defined above, and R W a monocyclic heterocyclylene ring having a nitrogen atom bonded to TIFF0007797513000048.tif39147 and optionally, -R 6 is a bicyclic heterocyclylene ring containing 3 to 10 ring atoms as defined above, and R W a bicyclic heterocyclylene ring having a nitrogen atom bonded to TIFF0007797513000049.tif87160 The compound of any one of 1001, 1088, and 1094 to 1095 of the present invention, [This invention 1097] -R 6 But 1-2 R c may be substituted with TIFF0007797513000050.tif20128 wherein x1 and x2 are each independently 0, 1 or 2. [This invention 1098] 1097. The compound of the present invention, wherein x1=0 and x2=0; or x1=0 and x2=1; or x1=0 and x2=2. [This invention 1099] R 6 but: TIFF0007797513000051.tif58159 The compound of the present invention, any one of 1001, 1088, and 1094 to 1098, selected from the group consisting of: [The present invention 1100] R 6 But R W C is replaced by 3 ~C 6 cycloalkyl (e.g., cyclobutyl); or R W oxetanyl substituted with R W The compound of any one of claims 1001, 1088, and 1094 to 1095 of the present invention, which is tetrahydrofuryl substituted with [The present invention 1101] R 6 Ga-R W The compound of any of claims 1001 and 1088 of the present invention, [The present invention 1102] -R W Ga-L W -W;L W is C(=O)NHC(=O) * , N.R. d C(=O) * (e.g., NMeC(=O) * ) or NHS(O) 1~2 * wherein the asterisk represents the point of attachment to W. [The present invention 1103] W is C 2~6 Alkenyl or C 2~6 This means that 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W The compound of any one of claims 1094 to 1102, wherein the compound is bound to [The present invention 1104] W is C 2~4 Alkenyl (e.g., CH=CH 2 ) or C 2~4 Alkynylalkynyl TIFF0007797513000052.tif8128 This means that 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W The compound of any one of claims 1094 to 1103, wherein the compound is bound to [This invention 1105] -L W -W TIFF0007797513000053.tif57128 The compound of any one of 1094 to 1104 of the present invention, [The present invention 1106] R 6 However, each has 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 The compound of the present invention 1001 or 1088, wherein the aryl group is alkyl. [This invention 1107] R 6 Ga-C 1~6 Alkoxy, e.g., -C 1~3 A compound of any of claims 1001, 1088 or 1106 which is alkoxy, for example methoxy. [This invention 1108] L 2 The compound of any one of 1001 and 1088 to 1107 of the present invention, wherein is a bond. [This invention 1109] L 2 However, 1 to 6 R a C optionally substituted with1~10 alkylene, where R a Ha-NR e R f (e.g., NMe 2 ), halo (e.g., fluoro), alkoxyl (e.g., methoxy). [The present invention 1110] L 2 However, 1 to 6 R a C optionally substituted with 1~6 alkylene, where R a Ha-NR e R f (e.g., NMe 2 ), halo (e.g., fluoro), alkoxyl (e.g., methoxy). [The present invention 1111] L 2 However, 1 to 6 R a Branch C optionally substituted with 3~6 alkylene, where R a Ha-NR e R f (e.g., NMe 2 ), halo (e.g., fluoro), alkoxyl (e.g., methoxy). [The present invention 1112] L 2 but TIFF0007797513000054.tif62166 The compound of any one of the present inventions 1001, 1088 to 1107, and 1109 to 1111, wherein [The present invention 1113] The compound of any one of 1001 to 1112 of the present invention, wherein n is 0. [This invention 1114] The compound of any one of 1001 to 1112 of the present invention, wherein n is 1 or 2. [This invention 1115] The compound of any one of 1001 to 1112 or 1114 of the present invention, wherein n is 1. [The present invention 1116] TIFF0007797513000055.tif15128 Part TIFF0007797513000056.tif15128 The compound of any one of 1001 to 1112 and 1114 to 1115 of the present invention, [This invention 1117] R 7 One occurrence of NR e R f , for example:NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 The compound of any one of 1001 to 1112 and 1114 to 1116 of the present invention, [This invention 1118] R 7 One occurrence of NH 2 or NH(C 1~3 alkyl), e.g., R 7 One occurrence of NH 2 The compound of any one of 1001 to 1112 or 1114 to 1117 of the present invention, [This invention 1119] TIFF0007797513000057.tif15128 Part TIFF0007797513000058.tif15128 and;R 7 NR e R f The compound of any one of the present inventions 1001 to 1112, [The present invention 1120] R 7 NH 2 or NH(C 1~3 alkyl), e.g., R 7 NH 2 The compound of the present invention 1119. [This invention 1121] R 1c The compound of any one of claims 1001 to 1120, wherein is H. [This invention 1122] R 2a and R 2b The compound of any one of claims 1001 to 1121 of the present invention, wherein is H. [This invention 1123] R 2a and R 2b The compound of any one of 1001 to 1121 of the present invention, wherein one or two of the groups are substituents other than H. [This invention 1124] R 2a and R 2b One of them has 1 to 3 R a C optionally substituted with 1~3 Alkyl, e.g., C 1~3 alkyl; R 2a and R 2b The compound of the present invention 1123, wherein the other of [Invention 1125] R 3a and R 3b The compound of any one of claims 1001 to 1124 of the present invention, wherein is H. [Invention 1126] R 3a and R 3b The compound of any one of 1001 to 1124 of the present invention, wherein one or two of the above are substituents other than H. [This invention 1127] R 3a and R 3b One of them has 1 to 3 R a C optionally substituted with 1~3 Alkyl, for example, C optionally substituted with 1 to 3 -F 1~3 alkyl; R 2a and R 2b The compound of the present invention 1126, wherein the other of [This invention 1128] R 3a and R 3b are bonded to the ring atoms of ring B to form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each an independently selected heteroatom, and each of the independently selected heteroatoms is N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Any of compounds 1001 to 1124 of the present invention. [This invention 1129] R 3a and R 3b are bonded to ring B and together form a saturated fused ring of 4 to 8 ring atoms; 0 to 2 of the ring atoms are each an independently selected heteroatom, and each of the independently selected heteroatoms is N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated fused ring having 4 to 8 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: The compound of any one of 1001 to 1124 or 1128 of the present invention. [The present invention 1130] R 3a and R 3b together with the ring atom of ring B to which each is attached: TIFF0007797513000059.tif21128 which forms oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: p1 and p2 are independently 0, 1, or 2; R Q is H, R d , C(=O)-W or S(O) 2 W; cc is C(R 2a R 2b ) and the point of attachment. The compound of any one of 1001 to 1124 or 1128 to 1129 of the present invention. [This invention 1131] R 3a and R 3b are bonded to the ring atoms of ring B, TIFF0007797513000060.tif23128 where R Q is H, R d , C(=O)-W or S(O) 2 W; cc is C(R 2a R 2b ) represents the point of attachment to the compound of any one of 1001 to 1124 or 1128 to 1130 of the present invention. [This invention 1132] R3a and R 3b together with the ring atom of ring B to which each is attached: TIFF0007797513000061.tif99159 wherein R Q is H, R d , C(=O)-W or S(O) 2 W; cc is C(R 2a R 2b ) represents the point of attachment to the compound of any one of 1001 to 1124 or 1128 to 1130 of the present invention. [This invention 1133] R Q The compound of any one of 1130 to 1132 of the present invention, wherein is H. [This invention 1134] R Q R d The compound of any one of 1130 to 1132 of the present invention, [This invention 1135] R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 The compound of any one of 1130 to 1132 or 1134 of the present invention, wherein the compound is alkyl. [This invention 1136] R Q is C(=O)-W or S(O) 2 The compound of any one of 1130 to 1132 of the present invention, wherein W is [This invention 1137] W is C 2~4 Compounds of any one of 1130 to 1132 or 1136 of the present invention, which are alkenyl. [This invention 1138] R Q is C(=O)-CH 2 =CH 2 The compound of any one of 1130 to 1132 and 1136 to 1137 of the present invention, [This invention 1139] Ring A TIFF0007797513000062.tif16128 where each R cB are independently selected R c and m is 0, 1, 2, 3 or 4. [This invention 1140] 1139. The compound of claim 1139, wherein m is 1, 2 or 3. [This invention 1141] The compound of invention 1139 or 1140, wherein m is 1 or 2, for example 2. [This invention 1142] Ring A TIFF0007797513000063.tif23128 where each R cB are independently selected R c The compound of any one of claims 1001 to 1141 of the present invention, [This invention 1143] Each R cB are independently: -halo, e.g., -Cl and -F; -CN; C 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~3 alkyl; and C substituted with 1 to 6 independently selected halo 1~3 The compound of any one of 1139 to 1142 of the present invention, selected from the group consisting of alkyl. [This invention 1144] Ring A TIFF0007797513000064.tif16128 where R cB1 is R c and;R cB2 is H or R c The compound of any one of claims 1001 to 1143 of the present invention, [Invention 1145] R cB1 1144. Compounds of the invention wherein is halo, for example -F or -Cl, for example -F. [Invention 1146] R cB2 C 1~4 Alkoxy or C 1~4 Haloalkoxy, e.g., C 1~4 The compound of the invention 1144 or 1145, which is alkoxy, for example methoxy. [This invention 1147] Ring A TIFF0007797513000065.tif19128 The compound of any one of claims 1001 to 1146 of the present invention, [This invention 1148] Ring A is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be replaced by, for example: Ring A is a bicyclic heteroaryl containing 9-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be replaced by, for example: Ring A is: TIFF0007797513000066.tif87153 each of which is selected from the group consisting of R c The compound of any one of 1001 to 1138 of the present invention, which may be further substituted with: [This invention 1149] The compound of formula (I) is of formula (Ia) TIFF0007797513000067.tif46128 or a pharmaceutically acceptable salt thereof, wherein ring D1 is: Monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA monocyclic heteroaryl, optionally substituted with ·-R g2 -R Y where -R g2 -R Y -R g2 is a monocyclic heteroarylene containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 3 R cA optionally substituted with -R g2 -R Y selected from the group consisting of Each R cA are independently selected R c and; L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 is alkylene, 1001 compounds of the present invention. [This invention 1150] Ring D1 is a monocyclic heteroaryl containing 5 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA 1149 compounds of the present invention, optionally substituted with [This invention 1151] Ring D1 is Each has 1-2 R cA may be substituted with TIFF0007797513000068.tif23159 1149 or 1150, a compound of the present invention selected from the group consisting of: [This invention 1152] Ring D1 is a monocyclic heteroaryl containing 6 ring atoms, of which 1 to 4 ring atoms are nitrogen ring atoms, and the heteroaryl is cA 1149 compounds of the present invention, optionally substituted with [This invention 1153] Ring D1 is: TIFF0007797513000069.tif75138 each of which is selected from the group consisting of R cA The compound of the present invention 1149 or 1152, which may be further substituted with: [This invention 1154] Ring D1 is -R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 3 R cA 1149 compounds of the present invention, optionally substituted with [This invention 1155] Ring D1 is -R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing five ring atoms, of which one to four ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 2 R cA The compound of the present invention 1149 or 1154, optionally substituted with [Invention 1156] R Y but: 1 to 3 R c phenyl optionally substituted with Monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c monocyclic heteroaryl optionally substituted with The compound of any one of 1149 to 1155 of the present invention selected from the group consisting of: [This invention 1157] The compound of any one of 1149 to 1156 of the present invention, wherein n is 0. [This invention 1158] The compound of any one of claims 1149 to 1156, wherein n is 1 or 2, for example, n is 1. [This invention 1159] TIFF0007797513000070.tif33128 but TIFF0007797513000071.tif33128 The compound of any one of 1149 to 1156 or 1158 of the present invention, [The present invention 1160] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1149 to 1156 or 1158 to 1159 of the present invention, [This invention 1161] The compound of formula (I) is of formula (Ib) TIFF0007797513000072.tif47128 or a pharmaceutically acceptable salt thereof, wherein ring D2 is a bicyclic heteroaryl containing 8 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c and; L1 is a bond or 1 to 6 R a C optionally substituted with 1~3 is alkylene, 1001 compounds of the present invention. [This invention 1162] Ring D2 is a heteroaryl containing 8 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of the present invention 1161. [This invention 1163] Ring D2 is: TIFF0007797513000073.tif17128 each of which is selected from the group consisting of 1 to 2 R cA wherein each R cA are independently selected R c The compound of the present invention 1161 or 1162, [This invention 1164] Ring D2 is: TIFF0007797513000074.tif40128 each of which is selected from the group consisting of 1 to 2 R cA wherein each R cA are independently selected R c The compound of the present invention 1161 or 1162, [Invention 1165] Ring D2 is a bicyclic heteroaryl containing 9 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c The compound of the present invention 1161. [Invention 1166] Ring D2 is imidazolopyridinyl, pyrazolopyridinyl, or benzotriazolyl, each of which is substituted with 1 to 2 R cA where each R cA are independently selected R c The compound of the present invention 1161 or 1165, [This invention 1167] Ring D2 TIFF0007797513000075.tif24128 and each of these contains 1 to 2 R cA where each R cA are independently selected R c The compound of any one of the compounds 1161 and 1165 to 1166 of the present invention, [Invention 1168] The compound of any one of 1161 to 1167 of the present invention, wherein n is 0. [This invention 1169] The compound of any one of claims 1161 to 1167, wherein n is 1 or 2, for example, n is 1. [This invention 1170] TIFF0007797513000076.tif33128 but TIFF0007797513000077.tif33128 The compound of any one of 1161 to 1167 or 1169 of the present invention, [This invention 1171] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1161 to 1167 or 1169 to 1170 of the present invention, [This invention 1172] Each R cA are independently: halo; cyano; -OH; 1 to 6 independently selected R a C optionally substituted with 1~6 Alkyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 The compound of any one of claims 1149 to 1171, wherein the compound is selected from the group consisting of haloalkoxy; and -C(=O)NR'R". [This invention 1173] The compound of formula (I) is represented by the formula (Ic) TIFF0007797513000078.tif52128 or a pharmaceutically acceptable salt thereof, In the formula, ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R Z ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: R Z is R X or R Y and; L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 is alkylene, 1001 compounds of the present invention. [This invention 1174] R Z R X The compound of the present invention 1173, [This invention 1175] R Z is C(=O)(C 1~4 The compound of the present invention 1173 or 1174, wherein the aryl group is alkyl. [Invention 1176] R Z is S(O) 2 (C 1~4 The compound of the present invention 1173 or 1174, wherein the aryl group is alkyl. [This invention 1177] R Z R Y The compound of the present invention 1173, [This invention 1178] R Z R g The compound of the present invention 1173 or 1177, [This invention 1179] R Z but: 1 to 3 R c phenyl optionally substituted with Monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c monocyclic heteroaryl optionally substituted with The compound of the present invention 1173 or any one of 1177 to 1178 selected from the group consisting of: [This invention 1180] The compound of any one of claims 1173 to 1179, wherein n is 0. [This invention 1181] The compound of any one of claims 1173 to 1179, wherein n is 1 or 2, for example, n is 1. [This invention 1182] TIFF0007797513000079.tif38128 but TIFF0007797513000080.tif38128 The compound of any one of 1173 to 1179 or 1181 of the present invention, [This invention 1183] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1173 to 1179 or 1181 to 1182 of the present invention, [This invention 1184] The compound of formula (I) is of formula (Id) TIFF0007797513000081.tif52128 or a pharmaceutically acceptable salt thereof, In the formula, ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 is alkylene, 1001 compounds of the present invention. [This invention 1185] R W Ga-L W -W;L W is C(=O), compound 1184 of the present invention. [Invention 1186] W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W The compound of claim 1184 or 1185, wherein the compound is bound to [This invention 1187] W is CH=CH 2 , CH=CHCH 2 NMe 2 or TIFF0007797513000082.tif7128 The compound of any one of 1184 to 1186 of the present invention, [This invention 1188] The compound of any one of 1184 to 1187 of the present invention, wherein n is 0. [This invention 1189] The compound of any one of claims 1184 to 1187, wherein n is 1 or 2, for example, n is 1. [This invention 1190] TIFF0007797513000083.tif37128 but TIFF0007797513000084.tif37128 The compound of any one of 1184 to 1187 or 1189 of the present invention, [This invention 1191] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1184 to 1187 or 1189 to 1190 of the present invention, [This invention 1192] Ring D TIFF0007797513000085.tif19128 This is one to two R c wherein x1 and x2 are each independently 0, 1, or 2. [This invention 1193] The compound of the present invention 1192, wherein x1 is 0. [This invention 1194] Ring D is: TIFF0007797513000086.tif60166 Any of the compounds of 1173 to 1193 of the present invention selected from the group consisting of: [This invention 1195] The compound of formula (I) may be of formula (Ie): TIFF0007797513000087.tif38128 or a pharmaceutically acceptable salt thereof, In the formula, R 5A Ha-L 5 -R g , or 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); L 1 is 1 to 6 R a C optionally substituted with 1~10 is alkylene, 1001 compounds of the present invention. [This invention 1196] R 5A Ga-L 5 -R g The compound of the present invention 1195, [This invention 1197] R 5A -OR g The compound of the present invention 1195 or 1196, [This invention 1198] R 5A -ORg and;-OR g R exists in g C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c Any of the compounds of 1195 to 1197 of the present invention, independently selected from the group consisting of: [This invention 1199] R 5A -O-(C 3~6 cycloalkyl), and the C 3~6 Cycloalkyl has 1 to 3 R c may be substituted with, for example, R 5 teeth TIFF0007797513000088.tif9128 The compound of any one of 1195 to 1198 of the present invention, [The present invention 1200] R 5A However, 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 The compound of the present invention 1195, wherein the aryl group is alkyl. [The present invention 1201] R 5A However, 1 to 6 R a -S(O) optionally substituted with 2 (C 1~6 The compound of the present invention 1195 or 1200, wherein the aryl group is alkyl. [This invention 1202] R 5A -S(O) 2 (C 1~3 alkyl), e.g., -S(O) 2 The compound of any one of 1195 and 1200 to 1201 of the present invention, wherein Me. [This invention 1203] The compound of any one of 1195 to 1202 of the present invention, wherein n is 0. [The present invention 1204] The compound of any one of 1195 to 1202 of the present invention, wherein n is 1 or 2, for example, n is 1. [This invention 1205] TIFF0007797513000089.tif24128 but TIFF0007797513000090.tif24128 The compound of any one of 1195 to 1202 or 1204 of the present invention, [This invention 1206] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1195 to 1202 and 1204 to 1205 of the present invention, [This invention 1207] L 1 However, 1 to 6 R a C optionally substituted with 1~3 The compound of any one of 1149 to 1206 of the present invention, which is alkylene. [This invention 1208] L 1 C 1~3 The compound of any one of 1149 to 1207 of the present invention, which is alkylene. [This invention 1209] L 1 Ga-CH 2 - Any of the compounds of the present invention 1149 to 1208, wherein [The present invention 1210] L 1 Ga-CH 2 CH 2 - Any of the compounds of the present invention 1149 to 1208, wherein [The present invention 1211] L 1 The compound of any one of claims 1149 to 1194, wherein is a bond. [The present invention 1212] The compound of formula (I) has the formula (If): TIFF0007797513000091.tif40128 or a pharmaceutically acceptable salt thereof, In the formula, ring D3 is C substituted with 1 to 4 substituents. 3~10 cycloalkyl, each substituent independently being: oxo and R c selected from the group consisting of 1001 compounds of the present invention. [This invention 1213] Ring D3 is C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 3~6 is cycloalkyl; R 5 is optionally further substituted with 1 to 2 substituents, each of which is selected from: oxo and R c 1212. A compound of the present invention, independently selected from the group consisting of: [This invention 1214] R 5 But C 1~4 Alkoxy or C 1~4 cyclopropyl substituted with haloalkoxy; TIFF0007797513000092.tif17128 The compound of the present invention 1212 or 1213, [This invention 1215] The compound of any one of 1212 to 1214 of the present invention, wherein n is 0. [This invention 1216] The compound of any one of 1212 to 1214 of the present invention, wherein n is 1 or 2, for example, n is 1. [This invention 1217] TIFF0007797513000093.tif27128 but TIFF0007797513000094.tif27128 The compound of any one of 1212 to 1214 or 1216 of the present invention, [This invention 1218] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1212 to 1214 and 1216 to 1217 of the present invention, [This invention 1219] The compound of formula (I) may be of formula (Ig): TIFF0007797513000095.tif38128 or a pharmaceutically acceptable salt thereof, In the formula, L 2 is 1 to 6 R a C optionally substituted with 1~6 is alkylene; R 6A is 1 to 6 R a may be substituted with -C 1~6 Alkoxy;NR e R f H; halo; and -OH, 1001 compounds of the present invention. [The present invention 1220] R 6A However, 1 to 6 R a may be substituted with -C 1~6 1219 compounds of the present invention, which are alkoxy. [This invention 1221] R 6A Ga-C 1~3 The compound of the present invention 1219 or 1220, which is alkoxy. [The present invention 1222] R 6A NR e R f The compound of the present invention 1219. [This invention 1223] R 6A 1219 compounds of the present invention, wherein is H, halo, or -OH. [This invention 1224] L 2 is branch C 3~6 The compound of any one of 1219 to 1223 of the present invention, which is alkylene. [This invention 1225] L 2 but TIFF0007797513000096.tif11128 The compound of any one of claims 1219 to 1224 of the present invention, [This invention 1226] L 2 C 1~3 Alkylene, e.g., -CH 2 Any of compounds 1219 to 1223 of the present invention, wherein [This invention 1227] The compound of any one of 1219 to 1226 of the present invention, wherein n is 0. [This invention 1228] The compound of any one of claims 1219 to 1226, wherein n is 1 or 2, for example, n is 1. [This invention 1229] TIFF0007797513000097.tif23128 but TIFF0007797513000098.tif23128 The compound of any one of 1219 to 1226 or 1228 of the present invention, [This invention 1230] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1219 to 1226 and 1228 to 1229 of the present invention, [This invention 1231] The compound of formula (I) may be of formula (Ih): TIFF0007797513000099.tif45128 or a pharmaceutically acceptable salt thereof, In the formula, ring D4 is R g That is, 1001 compounds of the present invention. [This invention 1232] Ring D4 is: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; and Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of 1231 compounds of the present invention selected from the group consisting of: [This invention 1233] Ring D4 is a heterocyclyl containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c The compound of the present invention 1231 or 1232, which may be substituted with 1 to 4 substituents independently selected from the group consisting of: [This invention 1234] Ring D4 is selected from the group consisting of pyrrolidinyl, piperidinyl, oxentanyl, tetrahydrofuranyl, and tetrahydropyranyl, which are each selected from oxo and R c and the nitrogen atom in the pyrrolidinyl or piperidinyl ring is optionally substituted with 1 to 2 substituents independently selected from the group consisting of R d For example, ring D4 may be substituted with: TIFF0007797513000100.tif41128 The compound of any one of 1231 to 1233 of the present invention, [This invention 1235] Ring D4 is a heteroaryl containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be substituted with, for example: R 6 teeth TIFF0007797513000101.tif19128 The compound of the present invention 1231, [This invention 1236] The compound of any one of 1231 to 1235 of the present invention, wherein n is 0. [This invention 1237] The compound of any one of 1231 to 1235 of the present invention, wherein n is 1 or 2, for example, n is 1. [This invention 1238] TIFF0007797513000102.tif32128 but TIFF0007797513000103.tif32128 The compound of any one of 1231 to 1235 and 1237 of the present invention, [This invention 1239] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1231 to 1235 and 1237 to 1238 of the present invention, [This invention 1240] The compound of formula (I) is represented by the formula (Ii) TIFF0007797513000104.tif51128 or a pharmaceutically acceptable salt thereof, In the formula, ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c Independently selected from the group consisting of: 1001 compounds of the present invention. [This invention 1241] R W Ga-L W -W;L W is C(=O), compound 1240 of the present invention. [This invention 1242] W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W 1240 or 1241, a compound of the present invention, which is bound to [This invention 1243] W is CH=CH 2 , CH=CHCH 2 NMe 2 or TIFF0007797513000105.tif7128 The compound of any one of 1240 to 1242 of the present invention, [This invention 1244] Ring D is 1 to 2 R c may be substituted with TIFF0007797513000106.tif19128 wherein x1 and x2 are each independently 0, 1 or 2. [Invention 1245] The compound of the present invention 1244, wherein x1 is 0. [Invention 1246] Ring D is: TIFF0007797513000107.tif60166 Any of the compounds of 1240 to 1245 of the present invention selected from the group consisting of: [Invention 1247] The compound of any one of 1240 to 1246 of the present invention, wherein n is 0. [Invention 1248] The compound of any one of 1240 to 1246 of the present invention, wherein n is 1 or 2, for example, n is 1. [Invention 1249] TIFF0007797513000108.tif37128 but TIFF0007797513000109.tif37128 The compound of any one of 1240 to 1246 or 1248 of the present invention, [This invention 1250] R 7 NR e R f , e.g., NH 2 , NH(C 1~3 alkyl) or N(C 1~3 alkyl) 2 For example, R 7 NH 2 The compound of any one of 1240 to 1246 or 1248 of the present invention, [This invention 1251] The compound of formula (I) is represented by the formula (Ij) TIFF0007797513000110.tif38128 or a pharmaceutically acceptable salt thereof, In the formula, L 2 is 1 to 6 R a C optionally substituted with 1~6 alkylene; R 6B Ha-R W That is, 1001 compounds of the present invention. [This invention 1252] R W Ga-L W -W;L W C(=O), NHC(=O) * or NHS(O)1~2 * wherein the asterisk represents the point of attachment to W. 1251 Compounds of the present invention. [Invention 1253] W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W 12. The compound of claim 1251 or 1252, wherein the compound is linked to: [Invention 1254] W is CH=CH 2 , CH=CHCH 2 NMe 2 or TIFF0007797513000111.tif7128 The compound of any one of 1251 to 1253 of the present invention, which may be: [Invention 1255] -L W -W is -C(=O)CH=CH 2 , -NHSO 2 CH=CH 2 , -C(=O)CH=CHCH 2 NMe 2 or TIFF0007797513000112.tif14128 The compound of any one of 1251 to 1254 of the present invention, [Invention 1256] L 2 However, 1 to 6 R a C optionally substituted with 1~3 alkylene, where R a Ha-NR e R f (e.g., NMe 2 ), halo (e.g., fluoro), or alkoxyl (e.g., methoxy). [Invention 1257] L 2 but TIFF0007797513000113.tif76169 The compound of any one of 1251 to 1256 of the present invention, [Invention 1258] The compound of any one of 1251 to 1257 of the present invention, wherein n is 0. [Invention 1259] The compound of any one of 1251 to 1257 of the present invention, wherein n is 1 or 2, for example, n is 1. [This invention 1260] TIFF0007797513000114.tif24128 but TIFF0007797513000115.tif24128 The compound of any one of 1251 to 1258 of the present invention, [This invention 1261] The compound of formula (I) may be of formula (Ik): TIFF0007797513000116.tif48128 or a pharmaceutically acceptable salt thereof, In the formula, ring D5 is R g2 That is, 1001 compounds of the present invention. [This invention 1262] Ring D5 is: oxo and R, respectively c C 3~10 Cycloalkylene or C 3~10 cycloalkenylene; and Heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is independently selected from the group consisting of oxo and R c Heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of 1261. A compound of the present invention selected from the group consisting of: [This invention 1263] Ring D5 is a heterocyclylene containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c The compound of the present invention 1261 or 1262, which may be substituted with 1 to 4 substituents independently selected from the group consisting of: [Invention 1264] Ring D5 is C 3 ~C 6 Compounds of the present invention 1261 or 1262 which are cycloalkylene (eg, cyclobutylene), oxetanylene, or tetrahydrofurylene. [Invention 1265] R W Ga-L W -W;L W is C(=O) or NHC(=O)* , N.R. d C(=O) * , NHS(O) 1~2 * wherein the asterisk represents the point of attachment to W. [Invention 1266] W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W Any of the compounds of 1261 to 1265 of the present invention, which is bound to [Invention 1267] W is CH=CH 2 , CH=CHCH 2 NMe 2 or TIFF0007797513000117.tif7128 The compound of any one of claims 1261 to 1266 of the present invention, [Invention 1268] -L W -W is -C(=O)CH=CH 2 , -C(=O)CH=CHCH 2 NMe 2 or TIFF0007797513000118.tif14128 The compound of any one of claims 1261 to 1267 of the present invention, [Invention 1269] The compound of any one of 1184 to 1187 of the present invention, wherein n is 0. [This invention 1270] TIFF0007797513000119.tif37128 but TIFF0007797513000120.tif38128 The compound of any one of 1184 to 1187 or 1189 of the present invention, [This invention 1271] R 1c The compound of any one of claims 1149 to 1270, wherein is H. [Invention 1272] R 2a and R 2b The compound of any one of claims 1149 to 1271 of the present invention, wherein is H. [This invention 1273] R 3a and R 3b The compound of any one of claims 1149 to 1272 of the present invention, wherein is H. [Invention 1274] R 3a and R 3b are bonded to ring B and together form a saturated fused ring of 4 to 8 ring atoms; 0 to 2 of the ring atoms are each an independently selected heteroatom, and each of the independently selected heteroatoms is N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated fused ring having 4 to 8 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Any of the compounds 1149 to 1272 of the present invention. [Invention 1275] R 3a and R 3b are bonded to the ring atom of ring B to form oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: TIFF0007797513000121.tif21128 where: p1 and p2 are independently 0, 1, or 2; R Q is H, R d , C(=O)-W or S(O) 2 W; cc is C(R 2a R 2b ) and the point of attachment. The compound of any one of 1149 to 1272 or 1274 of the present invention. [Invention 1276] R 3a and R 3b are bonded to the ring atoms of ring B, TIFF0007797513000122.tif23128 where R Q is H, Rd , C(=O)-W or S(O) 2 W; cc is C(R 2a R 2b ) and the point of attachment. The compound of any one of 1149 to 1272 or 1274 to 1275 of the present invention. [Invention 1277] R 3a and R 3b together with the ring atom of ring B to which each is attached: TIFF0007797513000123.tif100151 wherein R Q is H, R d , C(=O)-W or S(O) 2 W; cc is C(R 2a R 2b ) and the point of attachment. The compound of any one of 1149 to 1272 or 1274 to 1275 of the present invention. [Invention 1278] R Q The compound of any one of claims 1275 to 1277, wherein is H. [Invention 1279] R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 The compound of any one of 1275 to 1277 of the present invention, which is alkyl. [This invention 1280] R Q is C(=O)-W or S(O) 2 W, and optionally W is C 2~4 The compound of any one of 1275 to 1277 of the present invention, which is alkenyl. [This invention 1281] R Q is C(=O)-CH 2 =CH 2 The compound of any one of 1275 to 1277 or 1280 of the present invention, [This invention 1282] Ring A TIFF0007797513000124.tif16128 where each R cB are independently selected R c and m is 1, 2 or 3. [This invention 1283] 1282. A compound of the present invention, wherein m is 1 or 2, for example 2. [This invention 1284] Ring A TIFF0007797513000125.tif23128 where each R cB are independently: -halo, e.g., -Cl and -F; -CN; C 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~3 alkyl; and C substituted with 1 to 6 independently selected halo 1~3 The compound of any one of claims 1149 to 1283 of the present invention, selected from the group consisting of alkyl. [Invention 1285] Ring A TIFF0007797513000126.tif16128 where R cB1 is R c and;R cB2 is H or R c The compound of any one of claims 1149 to 1284 of the present invention, [Invention 1286] R cB1 1285 compounds of the invention wherein is halo, for example -F or -Cl, for example -F. [This invention 1287] R cB2 C 1~4 Alkoxy or C 1~4 Haloalkoxy, e.g., C 1~4 The compound of the present invention 1285 or 1286, which is alkoxy, for example methoxy. [This invention 1288] Ring A TIFF0007797513000127.tif19128 The compound of any one of claims 1149 to 1287 of the present invention, [This invention 1289] Ring A is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c The compound of any one of 1149 to 1281 of the present invention, which may be substituted with [This invention 1290] Ring A is a bicyclic heteroaryl containing 9 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c The compound of any one of 1149 to 1281 or 1289 of the present invention, which may be substituted with [This invention 1291] Ring A is: TIFF0007797513000128.tif65136 each of which is selected from the group consisting of R c The compound of any one of 1149 to 1281 or 1289 to 1290 of the present invention, which may be further substituted with: [This invention 1292] R 4 The compound of any one of claims 1001 to 1291 of the present invention, wherein is H. [This invention 1293] 1001. A compound of the present invention selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt thereof. [Invention 1294] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1293 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. [This invention 1295] A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention 1294. [Invention 1296] A method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the EGFR gene, EGFR kinase, or the expression, activity, or level of any of them; and (b) administering to the subject a therapeutically effective amount of any of compounds 1001 to 1293 of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of 1294 of the present invention. [Invention 1297] A method for treating EGFR-related cancer in a subject, comprising administering to a subject identified or diagnosed as having EGFR-related cancer a therapeutically effective amount of any of compounds 1001 to 1293 of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of 1294 of the present invention. [Invention 1298] 1. A method of treating an EGFR-associated cancer in a subject, comprising: (a) determining that the cancer in the subject is an EGFR-associated cancer; and (b) administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention 1294. A method comprising: [This invention 1299] A method for treating a subject, comprising administering a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention 1294, to the subject having clinical records indicating that the subject has abnormal regulation of the expression, activity or level of the EGFR gene, EGFR kinase, or any of them. [The present invention 1300] The method of any of claims 1296 and 1298, wherein the step of determining that the cancer in the subject is an EGFR-related cancer comprises performing an assay in a sample from the subject to detect dysregulation of the expression or activity or level of the EGFR gene, EGFR kinase protein, or any of them. [This invention 1301] The method of claim 1300, further comprising obtaining a sample from the subject. [This invention 1302] The method of claim 1301, wherein the sample is a biopsy sample. [This invention 1303] 13. The method of any of claims 1300 to 1302, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). [The present invention 1304] The method of the present invention 1303, wherein the FISH is a break-apart FISH analysis. [This invention 1305] The method of claim 1303, wherein the sequencing is pyrosequencing or next generation sequencing. [Invention 1306] The method of any of claims 1296, 1299 and 1300, wherein the dysregulation of the expression or activity or levels of the EGFR gene, EGFR kinase protein or any thereof is one or more point mutations in the EGFR gene. [This invention 1307] The method of claim 1306, wherein said one or more point mutations in the EGFR gene result in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the amino acid positions exemplified in Table 1a and Table 1b below. [This invention 1308] 1307. The method of claim 1307, wherein said one or more point mutations are selected from the mutations in Table 1a and Table 1b (e.g., L858R, G719S, G719C, G719A, L861Q, exon 19 deletions and / or exon 20 insertions). [This invention 1309] 1307. The method of claim 1307, wherein said one or more point mutations are EGFR inhibitor resistance mutations (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A). [The present invention 1310] 1307. The method of claim 1307, wherein said one or more point mutations in the EGFR gene comprise an exon 19 deletion of the human EGFR gene. [This invention 1311] 1307. The method of claim 1307, wherein said one or more mutations is an EGFR exon 20 insertion in the human EGFR gene. [This invention 1312] 1311. The method of claim 1311, wherein the exon 20 insertion of the human EGFR gene is selected from: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX and H773_V774insX. [This invention 1313] 1313. The method of claim 1311 or 1312, wherein the exon 20 insertion of the human EGFR gene is selected from: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP and P780_Y781insGSP. [This invention 1314] Any of the methods of inventions 1297, 1298 and 1300 to 1313, wherein the EGFR-related cancer is selected from the group consisting of oral cavity cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, genitourinary cancer, digestive cancer, cancer of the tissues of the central or peripheral nervous system, cancer of the endocrine or neuroendocrine system, hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, kidney cancer, bile duct cancer, pheochromocytoma-Li-Fraumeni tumor, thyroid cancer, parathyroid cancer, pituitary tumor, adrenal tumor, osteogenic sarcoma tumor, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, gastric cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer and skin cancer. [This invention 1315] The method of any of claims 1297, 1298 and 1300-1314, wherein the EGFR-related cancer is selected from the group consisting of: lung cancer, pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, glioblastoma or breast cancer. [Invention 1316] The method of any one of claims 1314 to 1315, wherein the lung cancer is non-small cell lung cancer. [This invention 1317] The method of any one of claims 1295 to 1316, wherein the cancer is a HER2-related cancer. [This invention 1318] The method of claim 1317, wherein the HER2-associated cancer is associated with dysregulation of the expression or activity or levels of the HER2 gene, HER2 kinase, or any of them. [This invention 1319] Any of the methods of claims 1317 and 1318, wherein determining that the cancer in the subject is a HER2-associated cancer comprises performing an assay in a sample from the subject to detect dysregulation of the expression or activity or level of the HER2 gene, HER2 kinase protein, or any of them. [This invention 1320] The method of claim 1319, further comprising obtaining a sample from the subject. [This invention 1321] The method of claim 1320, wherein the sample is a biopsy sample. [This invention 1322] 1322. The method of any of claims 1319 to 1321, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). [This invention 1323] The method of claim 1322, wherein the sequencing is pyrosequencing or next-generation sequencing. [This invention 1324] 13. The method of any of claims 1318 to 1323, wherein the dysregulation of the expression or activity or level of the HER2 gene, the HER2 kinase protein, or any of them is one or more point mutations in the HER2 gene. [Invention 1325] 1324. The method of claim 1324, wherein said one or more point mutations in the HER2 gene result in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3: [Invention 1326] 1325. The method of claim 1325, wherein said one or more point mutations are selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I). [This invention 1327] 17. The method of any of claims 1295 to 1326, wherein the cancer is selected from the group consisting of non-small cell lung cancer, pancreatic cancer, and colorectal cancer. [This invention 1328] The method of any of claims 1295 to 1327, further comprising administering to the subject an additional therapy or therapeutic agent. [This invention 1329] 1328. The method of claim 1328, wherein said additional therapy or therapeutic agent is selected from radiation therapy, a cytotoxic chemotherapeutic agent, a kinase targeted therapy, an apoptosis modulator, a signal transduction inhibitor, an immune targeted therapy, and an angiogenesis targeted therapy. [This invention 1330] 1329. The method of claim 1329, wherein said additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents. [This invention 1331] 1330. The method of claim 1330, wherein said additional therapeutic agent is a tyrosine kinase inhibitor. [This invention 1332] 1331. The method of claim 1331, wherein said additional therapeutic agent is a second EGFR inhibitor. [This invention 1333] 1328. The method of claim 1328, wherein said additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof. [This invention 1334] The method of claim 1328, wherein said additional therapeutic agent is a second compound of any one of claims 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 1294. [This invention 1335] 1329. The method of any one of claims 1328 to 1329, wherein said additional therapeutic agent is a HER2 inhibitor. [Invention 1336] 1335. The method of claim 1335, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib, KU004, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-22261 1 and AEE-788. [This invention 1337] The method of any of claims 1328 to 1336, wherein the compound of any of claims 1001 to 1293 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 1274 and the additional therapeutic agent are administered simultaneously as separate dosage forms. [This invention 1338] Any of the methods of the present inventions 1328 to 1336, wherein the compound of any of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention 1274 and the additional therapeutic agent are administered sequentially in any order as separate dosage forms. [This invention 1339] 1. A method of treating a subject having cancer, comprising: (a) administering to said subject one or more doses of a first EGFR inhibitor for a period of time; (b) after (a), determining whether cancer cells in the sample taken from the subject have at least one EGFR inhibitor resistance mutation that confers on the cancer cells or tumor increased resistance to treatment with the first EGFR inhibitor of step (a); and (c) administering to the subject any of the compounds of present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof as monotherapy or in combination with another anticancer agent if the subject is determined to have cancer cells having at least one EGFR inhibitor-resistant mutation that confers on the cancer cells or tumor increased resistance to treatment with the first EGFR inhibitor of step (a); or (d) if the subject is not determined to have cancer cells with at least one EGFR inhibitor resistance mutation that confers increased resistance to treatment with the first EGFR inhibitor of step (a), administering an additional dose of the first EGFR inhibitor of step (a) to the subject. A method comprising: [This invention 1340] 1339. The method of claim 1339, wherein the anti-cancer agent in step (c) is a second EGFR inhibitor, an immunotherapy, a HER2 inhibitor, or a combination thereof. [This invention 1341] The method of claim 1339, wherein the anticancer agent in step (c) is the first EGFR inhibitor administered in step (a). [This invention 1342] 1339. The method of claim 1339, wherein the subject is administered an additional dose of the first inhibitor of EGFR in step (a), and the method further comprises (e) administering to the subject another anti-cancer agent. [This invention 1343] The method of claim 1342, wherein the anti-cancer agent in step (e) is a second EGFR inhibitor, immunotherapy, or a combination thereof. [This invention 1344] The method of the present invention 1342, wherein the anticancer drug in the step (e) is any of the compounds of the present invention 1001 to 1313 or a pharmaceutically acceptable salt thereof. [Invention 1345] Any of the methods of 1339 to 1344 of the present invention, wherein the EGFR inhibitor resistance mutation is an amino acid substitution at position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A). [Invention 1346] A method for treating EGFR-related cancer in a subject, comprising administering to a subject identified or diagnosed as having an EGFR-related cancer with one or more EGFR inhibitor-resistant mutations a therapeutically effective amount of any of compounds 1001 to 1313 of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compound 1294 of the present invention. [Invention 1347] 1. A method of treating an EGFR-associated cancer in a subject, comprising: (a) determining that the cancer in the subject has one or more EGFR inhibitor resistance mutations; and (b) administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention 1294. A method comprising: [Invention 1348] 1. A method of treating a subject having cancer, comprising: (a) determining whether cancer cells in a sample taken from a subject having cancer and who has previously been administered one or more doses of a first EGFR inhibitor have one or more EGFR inhibitor resistance mutations that confer increased resistance to treatment with the first EGFR inhibitor previously administered to the subject; and (b) administering to the subject any of compounds of present inventions 1001-1293 or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anti-cancer agent, if the subject is determined to have cancer cells with at least one EGFR inhibitor-resistant mutation that confers on the cancer cells or tumor increased resistance to treatment with the first EGFR-modulating agent previously administered to the subject; or (c) administering an additional dose of the first EGFR modulator to the subject if the subject is not determined to have cancer cells with at least one EGFR modulator resistance mutation that confers increased resistance to treatment with the first EGFR modulator previously administered to the subject. A method comprising: [Invention 1349] The method of claim 1348, wherein the anti-cancer agent in step (b) is a second EGFR inhibitor, immunotherapy, a HER2 inhibitor, or a combination thereof. [This invention 1350] The method of claim 1348, wherein the anti-cancer agent in step (b) is a first EGFR inhibitor previously administered to the subject. [Invention 1351] The method of claim 1348, wherein the subject is administered an additional dose of a first EGFR inhibitor previously administered to the subject, and the method further comprises (d) administering to the subject another anti-cancer agent. [Invention 1352] 1351. The method of claim 1351, wherein the anti-cancer agent in step (d) is a second EGFR inhibitor, an immunotherapy, or a combination thereof. [This invention 1353] The method of present invention 1351, wherein the anticancer agent in step (d) is any of the compounds of present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof. [Invention 1354] 1353. The method of claim 1353, wherein the second EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof. [Invention 1355] The method of any of claims 1346 to 1354, wherein the cancer is selected from the group consisting of non-small cell lung cancer, pancreatic cancer, and colorectal cancer. [Invention 1356] 6. The method of any of claims 1346 to 1355, wherein the cancer is associated with the HER2 gene, the HER2 kinase, or dysregulation of the expression or activity or level of either thereof. [Invention 1357] 1356. The method of claim 1356, wherein the dysregulation of the expression or activity or level of the HER2 gene, the HER2 kinase protein, or either thereof is one or more point mutations in the HER2 gene. [Invention 1358] 1357. The method of claim 1357, wherein said one or more point mutations in the HER2 gene result in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3: [Invention 1359] 1358. The method of claim 1358, wherein said one or more point mutations are selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I). [Invention 1360] A method for regulating EGFR in mammalian cells, comprising contacting the mammalian cells with an effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof. [Invention 1361] The method of claim 1360, wherein the contacting is performed in vivo. [Invention 1362] The method of claim 1360, wherein the contacting is performed in vitro. [Invention 1363] The method according to any one of claims 1360 to 1362, wherein the mammalian cells are mammalian cancer cells. [Invention 1364] The method of claim 1363, wherein the mammalian cancer cell is an EGFR-associated mammalian cancer cell. [Invention 1365] The method of any of claims 1360 to 1363, wherein said cell has a dysregulation of the EGFR gene, the EGFR kinase protein, or the expression or activity or level of either thereof. [Invention 1366] The method of claim 1365, wherein the dysregulation of the expression or activity or levels of the EGFR gene, the EGFR kinase protein, or either thereof is one or more point mutations in the EGFR gene. [Invention 1367] The method of the present invention 1366, wherein said one or more point mutations in the EGFR gene result in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the amino acid positions exemplified in Table 1a and Table 1b below. [Invention 1368] 1366. The method of claim 1366, wherein said one or more point mutations are selected from the mutations in Table 1a and Table 1b (e.g., L858R, G719S, G719C, G719A, L861Q, exon 19 deletions and / or exon 20 insertions). [Invention 1369] 1366. The method of claim 1366, wherein said one or more point mutations are EGFR inhibitor resistance mutations (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A). [This invention 1370] 1366. The method of claim 1366, wherein said one or more point mutations in the EGFR gene comprise an exon 19 deletion of the human EGFR gene. [Invention 1371] 1366. The method of claim 1366, wherein said one or more point mutations are EGFR exon 20 insertions in the human EGFR gene. [Invention 1372] 1371. The method of claim 1371, wherein the exon 20 insertion of the human EGFR gene is selected from: A767_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX and H773_V774insX. [This invention 1373] 1372. The method of claim 1372, wherein the exon 20 insertion of the human EGFR gene is selected from: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH and P772_H773insPNP. [Invention 1374] A method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the HER2 gene, HER2 kinase, or the expression, activity, or level of any of them; and (b) administering to the subject a therapeutically effective amount of any of compounds of present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of present invention 1294. [Invention 1375] A method for treating HER2-related cancer in a subject, comprising administering to a subject identified or diagnosed as having HER2-related cancer a therapeutically effective amount of any of compounds 1001 to 1293 of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of 1294 of the present invention. [Invention 1376] (a) determining that the cancer in the subject is a HER2-associated cancer; and (b) administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention 1294. 10. A method for treating HER2-associated cancer in a subject, comprising: [Invention 1377] A method for treating a subject, comprising administering a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention 1294, to said subject having clinical records indicating that the subject has abnormal regulation of the HER2 gene, HER2 kinase, or the expression, activity, or level of either of them. [Invention 1378] Any of the methods of claims 1374 and 1376, wherein the step of determining that the cancer in the subject is a HER2-associated cancer comprises performing an assay in a sample from the subject to detect dysregulation of the expression or activity or level of the HER2 gene, the HER2 kinase protein, or any of them. [This invention 1379] The method of claim 1378, further comprising obtaining a sample from the subject. [This invention 1380] 1379. The method of claim 1379, wherein the sample is a biopsy sample. [This invention 1381] 13. The method of any of claims 1374 to 1380, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). [This invention 1382] 1381. The method of the present invention, wherein the FISH is a break-apart FISH analysis. [This invention 1383] 1381. The method of claim 1381, wherein the sequencing is pyrosequencing or next generation sequencing. [Invention 1384] The method of any of claims 1374, 1377 and 1378, wherein the dysregulation of the expression or activity or level of the HER2 gene, the HER2 kinase protein, or either thereof is one or more point mutations in the HER2 gene. [Invention 1385] The method of claim 1384, wherein said one or more point mutations in the HER2 gene result in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3: [Invention 1386] 1384. The method of claim 1384, wherein said one or more point mutations are selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I). [Invention 1387] The method of any of claims 1373, 1376 and 1377, wherein the dysregulation of the expression or activity or level of the HER2 gene, the HER2 kinase protein or either thereof is an exon 20 insertion in the human HER2 gene. [Invention 1388] 1387. The method of claim 1387, wherein the exon 20 insertion of the human HER2 gene is a deletion of an amino acid at a position selected from: positions 774, 775, 776, 777, 778, and 780. [Invention 1389] 1388. The method of claim 1388, wherein the exon 20 insertion of the human HER2 gene is selected from: M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG and P780_Y781insGSP. [This invention 1390] The method of any of claims 1375, 1376 and 1378, wherein the HER2-associated cancer is selected from the group consisting of: colon cancer, lung cancer or breast cancer. [This invention 1391] The method of claim 1390, wherein the lung cancer is non-small cell lung cancer. [Invention 1392] The method of any of claims 1377 to 1391, further comprising administering an additional therapy or therapeutic agent to the subject. [This invention 1393] 1392. The method of claim 1392, wherein said additional therapy or therapeutic agent is selected from radiation therapy, a cytotoxic chemotherapeutic agent, a kinase targeted therapy, an apoptosis modulator, a signal transduction inhibitor, an immune targeted therapy, and an angiogenesis targeted therapy. [Invention 1394] The method of invention 1392, wherein said additional therapeutic agent is a second compound of any one of inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of invention 1274. [Invention 1395] 1392. The method of claim 1392, wherein said additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents. [Invention 1396] 1392. The method of claim 1392, wherein said additional therapeutic agent is a tyrosine kinase inhibitor. [Invention 1397] 1392. The method of claim 1392, wherein said additional therapeutic agent is an EGFR inhibitor. [Invention 1398] 1392. The method of claim 1392, wherein said additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof. [Invention 1399] 1392. The method of claim 1392, wherein said additional therapeutic agent is a HER2 inhibitor. [The present invention 1400] 1399. The method of claim 1399, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib, KU004, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-22261 1 and AEE-788. [The present invention 1401] The method of any of claims 1395 to 1400, wherein the compound of any of claims 1001 to 1293 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 1274 and the additional therapeutic agent are administered simultaneously as separate dosage forms. [The present invention 1402] Any of the methods of the present inventions 1395 to 1400, wherein the compound of any of the present inventions 1001 to 1293 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention 1274 and the additional therapeutic agent are administered sequentially in any order as separate dosages. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0071] Detailed Description The present disclosure provides chemical compounds (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or combinations of the compounds) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2). Such chemical compounds are useful, for example, for treating conditions, diseases, or disorders (e.g., cancer) in subjects (e.g., humans) in which hyperactive (e.g., excessive) EGFR and / or HER2 activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder. In some embodiments, the chemical compounds provided herein can inhibit EGFR kinase and / or HER2 kinase harboring an exon 20 mutation (e.g., any of the exon 20 mutations described herein). Exon 20 mutations may confer intrinsic resistance to EGFR and / or HER2 inhibitors, and currently, only a limited number of targeted therapeutics are approved for subjects harboring such mutations. The present disclosure also provides compositions comprising the chemical compounds provided herein, as well as methods for using and making the same.

[0072] Compounds of formula (I) In one aspect, the present disclosure provides a compound of formula (I): TIFF0007797513000129.tif40128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is:(a)-OL 1 -R 5 ; and Selected from the group consisting of TIFF0007797513000130.tif13128; L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1~10 alkylene; R 5 teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 aryl; C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c C is independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; · TIFF0007797513000131.tif16128 (wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L5 -R g2 -R Y selected from the group consisting of: However, L 1 If is a bond, R 5 is the following: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: ·H; ·Halo; ·-OH; -NR e R f ; -R g ; -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and Each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl) selected from the group consisting of: L 5 and L 6 are independently -O-, -S(O) 0~2 , -NH or -N(R d )-and; R W Ha-L W-W, where L W is C(=O), S(O) 1~2 ,OC(=O) * , NHC(=O) * , N.R. d C(=O) * , NHS(O) 1~2 * or NR d S(O) 1~2 * where the asterisk represents the point of attachment to W, W is C 2~6 Alkenyl; C 2~6 alkynyl; or C 3~10 arenyl, each of which has 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1~6 alkyl) or S(O)2(C 1~6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y is:-R g and -(L g ) g -R g selected from the group consisting of: R 1c , R 2a , R 2b , R 3a and R 3b each independently represents: H; halo; —OH; —C(O)OH or —C(O)NH; —CN; —R b ;-L b -R b ;each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -C 1~6 Thioalkoxy; -NR e R f ;-R g; and -(L g ) g -R g wherein R is selected from the group consisting of 1c is other than the following: halo, -CN and -C(O)OH; or Or variable part R 1c , R 2a , R 2b , R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (—N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and R d selected from the group consisting of: Each R 7 are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4alkyl); and cyano; R b Each occurrence of independently 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1~2 ;C(=O)NH * ;C(=O)NR d* ;S(O) 1~2 NH * ; or S(O) 1~2 N(R d ) * where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R”;-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R e and R f each occurrence independently represents: H; C optionally substituted with 1 to 3 substituents 1~6 Alkyl, each substituent is NR'R", -OH, C 1~6 Alkoxy, C 1~6 independently selected from the group consisting of haloalkoxy and halo; —C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R g Each occurrence of independently: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is a base; Each occurrence of R' and R" is independently: H; -OH; and C 1~4 selected from the group consisting of alkyl, The present invention features a compound or a pharmaceutically acceptable salt thereof.

[0073] In one aspect, the present disclosure provides a compound of formula (I): TIFF0007797513000132.tif40128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is:(a)-OL 1 -R 5 ; and Selected from the group consisting of TIFF0007797513000133.tif13128; L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1~10 alkylene; R 5 teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O)0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 aryl; C 3~10 Cycloalkyl or C 3~10 Cycloalkenyl, each of which is: oxo and R c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; · TIFF0007797513000134.tif16128 (wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y selected from the group consisting of: However, L 1If is a bond, R 5 is the following: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: ·H; ·Halo; ·-OH; -NR e R f ; -R g ; -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and Each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl) selected from the group consisting of: L 5 and L 6 are independently -O-, -S(O) 0~2 , -NH or -N(R d )-and; R W Ha-L W -W, where L W is C(=O), S(O) 1~2 ,OC(=O) * , NHC(=O) *, N.R. d C(=O) * , NHS(O) 1~2 * or NR d S(O) 1~2 * where the asterisk represents the point of attachment to W, W is C 2~6 Alkenyl; C 2~6 alkynyl; or C 3~10 arenyl, each of which has 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1~6 alkyl) or S(O)2(C 1~6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y :R g and -(L g ) g -R g selected from the group consisting of: R 1c , R 2a , R 2b , R 3a and R 3b each independently represents: H; halo; —OH; —C(O)OH or —C(O)NH; —CN; —R b ;-L b -R b ;each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -C 1~6 Thioalkoxy;NR e R f ;-R g ; and -(L g ) g -R g wherein R is selected from the group consisting of 1cis other than the following: halo, -CN and -C(O)OH; or Or variable part R 1c , R 2a , R 2b , R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (—N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is selected from oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and R d selected from the group consisting of: Each R 7 are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of independently 1~6 Alkyl, C 2~6 Alkenyl or C2~6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1~2 ;C(=O)NH * ;C(=O)NR d* ;S(O) 1~2 NH * ; or S(O) 1~2 N(R d ) * where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R”;-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R e and R f each occurrence independently represents: H; C optionally substituted with 1 to 3 substituents 1~6 Alkyl, each substituent is NR'R", -OH, C 1~6 Alkoxy, C 1~6 independently selected from the group consisting of haloalkoxy and halo; —C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R g Each occurrence of independently: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R cC optionally substituted with 6~10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is a base; Each occurrence of R' and R" is independently: H; -OH; and C 1~4 selected from the group consisting of alkyl, The present invention features a compound or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, R 2a , R 2b , R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 Ga-OL 1 -R 5 and;-L 1 If is CH2: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

[0075] In one aspect, the present disclosure provides a compound of formula (I): TIFF0007797513000135.tif40128 or a pharmaceutically acceptable salt thereof, wherein: X 1is:(a)-OL 1 -R 5 ; and Selected from the group consisting of TIFF0007797513000136.tif13128; L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1~10 alkylene; R 5 teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 aryl; C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c C is independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; · TIFF0007797513000137.tif16128 (wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: 1 to 6 Ra -S(O) optionally substituted with 0~2 (C 1~6 alkyl); -R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y selected from the group consisting of: However, L 1 If is a bond, R 5 is the following: 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: ·H; ·Halo; ·-OH; -NR e R f ; -R g ; -R w -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -Rg2 -R Y ; and Each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl) selected from the group consisting of: L 5 and L 6 are independently -O-, -S(O) 0~2 , -NH or -N(R d )-and; R W Ha-L W -W, where L W is C(=O), S(O) 1~2 ,OC(=O) * , NHC(=O) * , N.R. d C(=O) * , NHS(O) 1~2 * or NR d S(O) 1~2 * where the asterisk represents the point of attachment to W, W is C 2~6 Alkenyl; C 2~6 alkynyl; or C 3~10 arenyl, each of which has 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1~6 alkyl) or S(O)2(C 1~6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y is:-R g and -(L g ) g -R g selected from the group consisting of: R 1c , R 2a , R 2b , R 3a and R 3b each independently represents: H; halo; —OH; —C(O)OH or —C(O)NH; —CN; —R b ;-L b -R b ;each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -C 1~6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g wherein R is selected from the group consisting of 1c is other than the following: halo, -CN and -C(O)OH; or Variable section R 1c , R 2a , R 2b , R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (—N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and R d selected from the group consisting of: Each R 7are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of independently 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1~2 ;C(=O)NH * ;C(=O)NR d* ;S(O) 1~2 NH * ; or S(O) 1~2 N(R d ) * where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 3~5 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R”;-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 selected from the group consisting of alkoxy; R e and R f Each occurrence of is independently: H; 1 to 3 C 1~3 C optionally substituted with alkyl group 3~5 Cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c heterocyclyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: 1~6 alkyl, where each substituent is NR'R", -OH, C 1~6 Alkoxy, C 1~6 C independently selected from the group consisting of haloalkoxy and halo; 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R";-S(O) 1~2 NR'R”;-S(O)1~2 (C 1~4 alkyl);-OH;C 1~4 selected from the group consisting of alkoxy; R g Each occurrence of independently: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is a base; Each occurrence of R' and R" is independently: H; -OH; and C 1~4 selected from the group consisting of alkyl, The present invention features a compound or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, R 2a , R 2b , R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 but -OL 1 -R 5 and;-L 1 If is CH2: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

[0077] In some embodiments, R 5 or R 6 When is a heteroaryl, the heteroaryl can be any of the following: aromatic lactams in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), aromatic cyclic ureas and their vinyl analogs, and pyridones in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., where an oxo group (i.e., "=O") is a member of the heteroaryl ring). TIFF0007797513000138.tif20128, pyrimidon TIFF0007797513000139.tif20128, Pyridazinone TIFF0007797513000140.tif20128, Pyrazinone TIFF0007797513000141.tif20128, and imidazolone TIFF0007797513000142.tif17128, other than one or more of:

[0078] In some embodiments, R 5 or R 6 When is heteroaryl, said heteroaryl is not substituted with -OH.

[0079] Variable part X 1 X 1 Ga-OL 1 -R 5 The circumstances in which In some embodiments, X 1 Ha-OL 1 -R 5 is.

[0080] In certain of these embodiments, R 5 is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0081] In certain embodiments, R 5 is a monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0082] In certain of the foregoing embodiments, R 5 is a monocyclic heteroaryl containing five ring atoms, of which one to four ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0083] In certain embodiments, R 5 is selected from the group consisting of furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, and thiazolyl, each of which is selected from the group consisting of 1 to 2 R cA The ring nitrogen may be substituted with R d where each R cA are independently selected R c is.

[0084] As a non-limiting example of the foregoing embodiment, R 5 teeth: Each has 1-2 R cA may be substituted with TIFF0007797513000143.tif43128, wherein each R cA are independently selected R c is.

[0085] In certain embodiments, R 5 is selected from the group consisting of furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, and thiazolyl, each of which is selected from the group consisting of 1 to 2 R cA The ring nitrogen may be substituted with R d where each R cA are independently selected R c is.

[0086] As a non-limiting example of the foregoing embodiment, R 5 teeth: Each has 1-2 R cA may be substituted with TIFF0007797513000144.tif18128, wherein each R cA are independently selected R c For example, R 5 teeth TIFF0007797513000145.tif11128. As an additional non-limiting example, R 5 teeth TIFF0007797513000146.tif18128; optionally, R d is C 1~3 It can be alkyl.

[0087] In certain embodiments, R 5 is a monocyclic heteroaryl containing 6 ring atoms, of which 1 to 4 ring atoms are nitrogen ring atoms, and the heteroaryl is cA where each R cA are independently selected R c is.

[0088] In certain embodiments, R 5 Each contains 1 to 3 R cA and R is selected from the group consisting of pyridyl, pyridonyl, pyrimidyl, pyrazinyl, and pyridazinyl, optionally substituted with cA are independently selected R c is.

[0089] As a non-limiting example of the foregoing embodiment, R 5 teeth: Each one is R cA may be further substituted with TIFF0007797513000147.tif44128, wherein each R cA are independently selected R c is.

[0090] In certain of these embodiments, R 5 Each contains 1 to 3 R cA and R is selected from the group consisting of pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, optionally substituted with cA are independently selected R c is.

[0091] As a non-limiting example of the foregoing embodiment, R 5 teeth: TIFF0007797513000148.tif44128, each of which may be selected from the group consisting of R cA wherein each R cA are independently selected R c is.

[0092] As a further non-limiting example, R 5 teeth: TIFF0007797513000149.tif23128, each of which may be selected from the group consisting of R cA wherein each R cA are independently selected R c is.

[0093] In certain embodiments, R 5 is a bicyclic heteroaryl containing 8 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0094] In certain of these embodiments, R 5 is a bicyclic heteroaryl containing 8 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0095] As a non-limiting example of the foregoing embodiment, R 5 teeth: TIFF0007797513000150.tif17128, each of which may contain 1 to 2 R cA wherein each R cA are independently selected R c is.

[0096] As a further non-limiting example, R 5 teeth, TIFF0007797513000151.tif40133, each of which may contain 1 to 2 R cA wherein each R cA are independently selected R c is.

[0097] In certain embodiments, R 5 is a bicyclic heteroaryl containing 9 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0098] In certain of these embodiments, R 5 is imidazolopyridinyl, pyrazolopyridinyl, or benzotriazolyl, each of which is selected from the group consisting of 1 to 2 R cA where each R cA are independently selected Rc is.

[0099] As a non-limiting example of the foregoing embodiment, R 5 teeth TIFF0007797513000152.tif24128, each of which contains 1-2 R cA where each R cA are independently selected R c is.

[0100] In certain embodiments, R 5 is a bicyclic 10-membered heteroaryl in which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0101] In certain embodiments, each R cA are independently: halo; cyano; -OH; 1 to 6 independently selected R a C optionally substituted with 1~6 Alkyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4 haloalkoxy; and —C(═O)NR′R″.

[0102] In certain embodiments, R cA One occurrence of is an independently selected halo, for example, -F or -Cl.

[0103] In certain embodiments, R cA One occurrence of is cyano.

[0104] In certain embodiments, R cA A single occurrence of is selected from 1 to 6 independently selected R aC optionally substituted with 1~6 It is alkyl.

[0105] In certain embodiments, R cA One occurrence of C 1~6 Alkyl, e.g., C 1~3 It is alkyl.

[0106] In certain embodiments, R cA A single occurrence of -OH or -NR e R f C is replaced by 1~6 alkyl. For example, R cA One occurrence of C is substituted with -OH or NH 1~3 It can be alkyl.

[0107] In certain embodiments, R cA One occurrence of C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy. For example, R cA One occurrence of C 1~4 It can be alkoxy (eg, methoxy or ethoxy).

[0108] In certain embodiments, R cA One occurrence of is -C(=O)NR'R" (e.g., C(=O)NH2).

[0109] In certain embodiments, R 5 but TIFF0007797513000153.tif16128, wherein ring D is a heterocyclylene or heterocycloalkenylene (e.g., heterocyclylene) containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2and wherein the heterocyclylene or heterocycloalkenylene (e.g., heterocyclylene) is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c are independently selected from the group consisting of:

[0110] In certain of these embodiments, R 5 But 1-2 R c may be substituted with TIFF0007797513000154.tif20128, where x1 and x2 are each independently 0, 1, or 2.

[0111] In certain of the foregoing embodiments, x1=0 and x2=0.

[0112] In certain embodiments, x1=0 and x2=1.

[0113] In certain embodiments, x1=0 and x2=2.

[0114] As a non-limiting example, R 5 but If it is TIFF0007797513000155.tif22128, R 5 teeth: TIFF0007797513000156.tif39134.

[0115] In certain embodiments, R X is C(=O)(C 1~4 alkyl) or S(O)2(C 1~4 alkyl).

[0116] In certain of these embodiments, R X is C(=O)(C 1~4 alkyl) (e.g., C(=O)Me or C(=O)Et).

[0117] In certain embodiments, R X is S(O)2(C 1~4alkyl) (e.g., S(O)Me).

[0118] In certain embodiments, R 5 Ga-R g2 -R W is.

[0119] In certain of these embodiments, R 5 Ga-R g2 -R W and;-R g2 -R W -R g2 is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is independently selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0120] In certain of the foregoing embodiments, -R 5 but TIFF0007797513000157.tif16128, wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c are independently selected from the group consisting of:

[0121] In certain of these embodiments, -R 5 But 1-2 R c may be substituted with TIFF0007797513000158.tif20128, where x1 and x2 are each independently 0, 1, or 2.

[0122] In certain of the foregoing embodiments, x1=0 and x2=0.

[0123] In certain embodiments, x1=0 and x2=1.

[0124] In certain embodiments, x1=0 and x2=2.

[0125] In certain embodiments, x1=0 and x2=1; or x1=0 and x2=2.

[0126] As a non-limiting example, R 5 but If it is TIFF0007797513000159.tif22128, R 5 teeth: TIFF0007797513000160.tif39137.

[0127] As a non-limiting example, R 5 but If it is TIFF0007797513000161.tif22128, R 5 teeth: TIFF0007797513000162.tif17128TIFF0007797513000163.tif38150.

[0128] In some embodiments, R 5 is R W is.

[0129] In certain embodiments, R W Ga-L W -W;L W is C(=O).

[0130] In certain embodiments, R W Ga-L W-W;L W is C(=O)NHC(=O) * or NHS(O) 1~2 * where the asterisk indicates the point of attachment to W.

[0131] In certain of these embodiments, W is C 2~6 alkenyl, which is a group consisting of 1 to 3 R a and R g where W is sp 2 L through the hybridized carbon atom W is connected to

[0132] In certain of these embodiments, W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W is connected to

[0133] In certain of the foregoing embodiments, W is C 2~4 alkenyl, which is a group consisting of 1 to 3 R a and R g where W is sp 2 L through the hybridized carbon atom W As a non-limiting example of the foregoing embodiment, W can be CH=CH2.

[0134] In certain of these aforementioned embodiments, W is C 2~4 Alkenyl or C 2~4 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms WAs a non-limiting example of the foregoing embodiment, W is CH=CH2, CH=CHCH2NMe2 or It could be TIFF0007797513000164.tif7128.

[0135] In certain embodiments, -L W -W is -C(=O)CH=CH2.

[0136] As a non-limiting example, -L W -W is -C(=O)CH=CH2, -C(=O)CH=CHCH2NMe2 or It could be TIFF0007797513000165.tif14128.

[0137] In certain embodiments, R 5 Ga-R g2 -R Y is.

[0138] In certain of these embodiments, R 5 Ga-R g2 -R Y where -R g2 -R Y -R g2 is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is independently selected from the group consisting of oxo and R c and the like. The group consisting of the following may be substituted with 1 to 3 substituents independently selected from the group consisting of:

[0139] Specific Aspects (R 5 Ga-R g2 -R Y If -R 5 but TIFF0007797513000166.tif16128, wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R Y ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c are independently selected from the group consisting of:

[0140] In certain of the foregoing embodiments, -R 5 But 1-2 R c may be substituted with TIFF0007797513000167.tif20128, where x1 and x2 are each independently 0, 1, or 2.

[0141] In certain such embodiments, x1=0 and x2=0.

[0142] In certain embodiments, x1=0 and x2=1.

[0143] In certain embodiments, x1=0 and x2=2.

[0144] As a non-limiting example, R 5 but If it is TIFF0007797513000168.tif22128, R 5 teeth: TIFF0007797513000169.tif39136.

[0145] In certain embodiments, R 5 Ga-R g2 -R Y and;-R g2 -R Y -R g2is a monocyclic heteroarylene containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 3 R c may be substituted with.

[0146] In certain of these embodiments, R 5 Ga-R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing five ring atoms, of which one to four ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 2 R c may be substituted with.

[0147] As a non-limiting example of the foregoing embodiment, R 5 teeth: TIFF0007797513000170.tif18128.

[0148] Specific Aspects (R 5 Ga-R g2 -R Y If -R Y Ga-R g is.

[0149] In certain of these embodiments, -R Y but: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with 1 to 4 R cC optionally substituted with 6~10 Aryl is selected from the group consisting of:

[0150] In certain of the foregoing embodiments, -R Y However, 1 to 4 R c C optionally substituted with 6~10 It is aryl.

[0151] As a non-limiting example of the foregoing embodiment, -R Y is 1 to 3 R c It may be phenyl optionally substituted with

[0152] In certain embodiments, -R Y is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be substituted with.

[0153] In certain of these embodiments, -R Y is a monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be substituted with.

[0154] Non-limiting examples of the foregoing embodiments include -R Y may be selected from the group consisting of pyridyl and pyrazolyl, each of which may contain 1 to 2 R c may be substituted with.

[0155] In certain embodiments, R 5 C, each of which is optionally substituted with 1 to 4 substituents 3~10 Cycloalkyl or C 3~10cycloalkenyl, each substituent being: oxo and R c are independently selected from the group consisting of:

[0156] In certain of these embodiments, R 5 is a C substituted with 1 to 4 substituents 3~10 cycloalkyl, each substituent independently being: oxo and R c is selected from the group consisting of:

[0157] In certain embodiments, R 5 is C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 3~6 is cycloalkyl; R 5 is optionally further substituted with 1 to 2 substituents, each of which is selected from: oxo and R c are independently selected from the group consisting of:

[0158] In certain embodiments, R 5 But C 1~4 Alkoxy or C 1~4 cyclopropyl substituted with haloalkoxy. For example, R 5 teeth It could be TIFF0007797513000171.tif17128.

[0159] In certain embodiments, R 5 However, 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl).

[0160] In certain of these embodiments, R 5 However, 1 to 6 R a may be substituted with -S(O)2(C 1~6 alkyl).

[0161] As a non-limiting example of the foregoing embodiment, R 5 is -S(O)2(C 1~6 alkyl) (e.g., -S(O)2(C1~3 alkyl).

[0162] In certain embodiments, R 5 But:-L 5 -R g , -L 5 -R g2 -R Y and -L 5 -R g2 -R W is selected from the group consisting of:

[0163] In certain of these embodiments, R 5 Ga-L 5 -R g In certain of the foregoing embodiments, R 5 -OR g is.

[0164] In certain embodiments, R 5 -OR g and;-OR g R exists in g C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c are independently selected from the group consisting of:

[0165] In certain embodiments, R 5 -O-(C 3~6 cycloalkyl), and the C 3~6 Cycloalkyl has 1 to 3 R c For example, R 5 teeth It could be TIFF0007797513000172.tif9128.

[0166] In some embodiments, L 1 is 1 to 6 R a C optionally substituted with 1~10 It is alkylene.

[0167] In certain of these embodiments, L 1 However, 1 to 6 R a C optionally substituted with 1~6 In certain of the above embodiments, L is alkylene. 1 However, 1 to 6 R a C optionally substituted with 1~3 In certain embodiments, L is alkylene. 1 C 1~3 alkylene. For example, L 1 In another non-limiting example, L 1 can be -CH2CH2-.

[0168] In certain of these embodiments, L 1 However, 1 to 6 R a C optionally substituted with 1~4 In certain of these foregoing embodiments, L is alkylene. 1 C 1~4 As a non-limiting example of the foregoing embodiment, L 1 can be -CH2- or -CH2CH2-. As another non-limiting example of the foregoing embodiment, L 1 teeth TIFF0007797513000173.tif11128, where the asterisk is R W Represents the point of attachment to

[0169] In some embodiments, L 1 is a bond.

[0170] X 1 but When the file is TIFF0007797513000174.tif12128 In some embodiments, X 1 teeth The file is TIFF0007797513000175.tif11128.

[0171] In certain of these embodiments, R 6 R g is.

[0172] In certain embodiments, R 6 is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0173] In certain embodiments, R 6 is a heterocyclyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0174] In certain of these embodiments, R 6 is a heterocyclyl containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c It may be substituted with 1 to 2 substituents independently selected from the group consisting of:

[0175] In certain embodiments, R 6 are oxo and R c and wherein the nitrogen atom in the ring of said pyrrolidinyl or piperidinyl is selected from the group consisting of pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted by one or two substituents independently selected from the group consisting of R d may be substituted with, for example, R 6 teeth The file is TIFF0007797513000176.tif37128.

[0176] In certain of the foregoing embodiments, R 6 are oxo and R c and wherein the nitrogen atom in the ring of said pyrrolidinyl or piperidinyl is selected from the group consisting of pyrrolidinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted by one or two substituents independently selected from the group consisting of R d As a non-limiting example of the foregoing embodiment, R 6 teeth TIFF0007797513000177.tif20128. In another non-limiting example, R 6 but It could be TIFF0007797513000178.tif23128.

[0177] Specific Aspects (R 6 R g In this case, R 6 C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, each of which is oxo and R c In certain of these embodiments, R 6 But 1-2 R c C optionally substituted with 3~8 cycloalkyl The file is TIFF0007797513000179.tif17128.

[0178] Specific Aspects (R 6 R g In this case, R 6 is a heteroaryl containing 5 to 10 (e.g., 5 to 6) ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 Rc In certain of these embodiments, R 6 is a heteroaryl containing five ring atoms, of which one to four are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 2 R c For example, R 6 teeth TIFF0007797513000180.tif22128. As another non-limiting example, R 6 teeth It could be TIFF0007797513000181.tif16128.

[0179] In certain embodiments, R 6 is a heteroaryl containing 6 ring atoms, of which 1 to 4 ring atoms are nitrogen ring atoms, and the heteroaryl is c For example, R 6 teeth It could be TIFF0007797513000182.tif19128.

[0180] In certain embodiments, R 6 Ga-R g2 -R W or -R g2 -R Y is.

[0181] In certain of these embodiments, R 6 Ga-R g2 -R W is.

[0182] In certain of the foregoing embodiments, -R 6 but TIFF0007797513000183.tif16128, wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c are independently selected from the group consisting of:

[0183] In certain of the foregoing embodiments, -R 6 but TIFF0007797513000184.tif16128, wherein ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: 6 contains 3 to 10 ring atoms as defined above, and R W a monocyclic heterocyclylene ring having a nitrogen atom bonded to TIFF0007797513000185.tif39128; optionally, -R 6 contains 3 to 10 ring atoms as defined above, and R W a bicyclic heterocyclylene ring having a nitrogen atom bonded to The file is TIFF0007797513000186.tif66153.

[0184] In certain of these embodiments, -R 6 But 1-2 R c may be substituted with TIFF0007797513000187.tif20128, where x1 and x2 are each independently 0, 1, or 2.

[0185] In certain embodiments, x1 = 0 and x2 = 0. In certain embodiments, x1 = 0 and x2 = 1. In certain embodiments, x1 = 0 and x2 = 2.

[0186] In certain embodiments, x1=0 and x2=0; or x1=0 and x2=1; or x1=0 and x2=2.

[0187] As a non-limiting example, R 6 but If it is TIFF0007797513000188.tif22128, R 6 teeth: TIFF0007797513000189.tif39137.

[0188] As a non-limiting example, R 6 but If it is TIFF0007797513000190.tif22128, R 6 teeth: TIFF0007797513000191.tif15128 for example TIFF0007797513000192.tif58151.

[0189] In certain embodiments, R 6 But R W C3-C6 cycloalkyl (e.g., cyclobutyl) substituted with; or R W oxetanyl substituted with R W and tetrahydrofuryl substituted with

[0190] In certain embodiments, R 6 Ga-R W is.

[0191] Specific Aspects (R 6 Ga-R g2 -R W If -R W Ga-L W -W;L W is C(=O).

[0192] In certain embodiments, (R 6 Ga-R g2 -R W or R 6 R W ), -R W Ga-L W -W;L W is C(=O)NHC(=O) * , N.R. d C(=O) * (e.g., NMeC(=O) * ) or NHS(O) 1~2 * where the asterisk indicates the point of attachment to W.

[0193] In certain of these embodiments, W is C 2~6 alkenyl, which is a group consisting of 1 to 3 R a and R g where W is sp 2 L through the hybridized carbon atom W is connected to

[0194] In certain of these embodiments, W is C 2~6 Alkenyl or C 2~6 This means that 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W is connected to

[0195] In certain of the foregoing embodiments, W is C 2~4 alkenyl, which is a group consisting of 1 to 3 R a and R g where W is sp 2 L through the hybridized carbon atom W For example, W can be CH=CH2.

[0196] In certain of the foregoing embodiments, W is C 2~4 Alkenyl (e.g., CH=CH2) or C 2~4 Alkynylalkynyl TIFF0007797513000193.tif8128, which contains 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W is connected to

[0197] In certain embodiments, -L W -W is -C(=O)CH=CH2.

[0198] In certain embodiments, -L W -W The file is TIFF0007797513000194.tif39156.

[0199] In certain embodiments, R 6 Each contains 1 to 6 R a may be substituted with -C 1~6 Alkoxy or -S(O) 0~2 (C 1~6 alkyl).

[0200] In certain of these embodiments, R 6 Ga-C 1~6 Alkoxy. For example, R 6 Ha-C 1~3 It can be alkoxy (eg, methoxy).

[0201] In certain embodiments, L 2 is a bond.

[0202] In certain embodiments, L 2 However, 1 to 6 R a C optionally substituted with 1~10 It is alkylene.

[0203] In certain embodiments, L2 However, 1 to 6 R a C optionally substituted with 1~10 alkylene, where R a Ha-NR e R f (e.g., NMe2), halo (e.g., fluoro), alkoxyl (e.g., methoxy).

[0204] In certain of these embodiments, L 2 However, 1 to 6 R a C optionally substituted with 1~6 In certain of the above embodiments, L is alkylene. 2 is branch C 3~6 As a non-limiting example of the foregoing embodiment, L 2 teeth It could be TIFF0007797513000195.tif11128.

[0205] In certain embodiments, L 2 However, 1 to 6 R a C optionally substituted with 1~6 alkylene, where R a Ha-NR e R f (e.g., NMe), halo (e.g., fluoro), alkoxyl (e.g., methoxy). In certain of these foregoing embodiments, L 2 However, 1 to 6 R a Branch C optionally substituted with 3~6 alkylene, where R a Ha-NR e R f (e.g., NMe2), halo (e.g., fluoro), alkoxyl (e.g., methoxy).

[0206] As a non-limiting example of the foregoing embodiment, L 2 teeth It could be TIFF0007797513000196.tif76166.

[0207] Variable section R 1c , R 2a , R2b , R 3a and R 3b In some embodiments, R 1c is H.

[0208] In some embodiments, R 2a and R 2b is H.

[0209] In some embodiments, R 2a and R 2b One to two (for example, one) of the groups are substituents other than H.

[0210] In certain of these embodiments, R 2a and R 2b One of them has 1 to 3 R a C optionally substituted with 1~3 Alkyl (e.g., C 1~3 alkyl); R 2a and R 2b The other of these is H.

[0211] In some embodiments, R 3a and R 3b is H.

[0212] In some embodiments, R 3a and R 3b One to two (for example, one) of the groups are substituents other than H.

[0213] In certain of these embodiments, R 3a and R 3b One of them has 1 to 3 R a C optionally substituted with 1~3 Alkyl (e.g., C optionally substituted with 1 to 3 -F) 1~3 alkyl); R 2a and R 2b The other of these is H.

[0214] In some embodiments, R 3a and R 3bare bonded to ring B and together form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each an independently selected heteroatom, and each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated or unsaturated fused ring having 3 to 12 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0215] In certain embodiments, R 3a and R 3b are bonded to ring B and together form a saturated fused ring of 4 to 8 ring atoms; 0 to 2 of the ring atoms are each an independently selected heteroatom, and each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated fused ring having 4 to 8 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0216] In certain of these embodiments, R 3a and R 3b are bonded to the ring atom of ring B to form oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: This forms TIFF0007797513000197.tif21128, where: p1 and p2 are independently 0, 1, or 2; R Q is H, R d , C(=O)-W or S(O)W; cc is C(R 2a R2b ) represents the point of attachment.

[0217] In certain of these embodiments, R Q is H. In certain embodiments, R Q R d In certain embodiments, R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 In certain embodiments, R Q is C(=O)-W or S(O)W. In certain of these embodiments, W is C 2~4 alkenyl. For example, R Q can be C(=O)-CH2=CH2.

[0218] In certain of these embodiments, R 3a and R 3b are bonded to the ring atoms of ring B, TIFF0007797513000198.tif23128 is formed, and here R Q is H, R d , C(=O)-W or S(O)W; cc is C(R 2a R 2b ) represents the point of attachment to the aryl group. Q is H. In certain embodiments, R Q R d In certain embodiments, R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 In certain embodiments, R Q is C(=O)-W or S(O)W. In certain of these embodiments, W is C 2~4 alkenyl. For example, R Q can be C(=O)-CH2=CH2.

[0219] In certain embodiments, R 3a and R 3b together with the ring atom of ring B to which each is attached: TIFF0007797513000199.tif98146, wherein R Q is H, R d , C(=O)-W or S(O)W; cc is C(R 2a R 2b ) represents the point of attachment to the aryl group. Q is H. In certain embodiments, R Q R d In certain embodiments, R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 In certain embodiments, R Q is C(=O)-W or S(O)W. In certain of these embodiments, W is C 2~4 alkenyl. For example, R Q can be C(=O)-CH2=CH2.

[0220] Variable ring A In some embodiments, ring A is TIFF0007797513000200.tif16128, where each R cB are independently selected R c and m is 0, 1, 2, 3 or 4.

[0221] In certain such embodiments, m is 1, 2, or 3. For example, m can be 1 or 2 (e.g., 2).

[0222] In certain embodiments, ring A is TIFF0007797513000201.tif23128, where each R cB are independently selected R c is.

[0223] In certain embodiments, each R cB -halo, e.g. -Cl and -F; -CN; C 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~3alkyl; and C substituted with 1 to 6 independently selected halo 1~3 alkyl.

[0224] In certain embodiments, ring A is TIFF0007797513000202.tif16128, where R cB1 is R c and;R cB2 is H or R c is.

[0225] In certain of these embodiments, R cB1 is halo (e.g., —F or —Cl (e.g., —F)).

[0226] In certain embodiments, R cB2 C 1~4 Alkoxy or C 1~4 Haloalkoxy (e.g., C 1~4 alkoxy (e.g., methoxy).

[0227] As a non-limiting example of the foregoing embodiment, ring A is It could be TIFF0007797513000203.tif19128.

[0228] In certain embodiments, ring A is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be substituted with.

[0229] In certain of these embodiments, ring A is a bicyclic heteroaryl containing 9-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cmay be substituted with.

[0230] As a non-limiting example of the foregoing embodiment, each ring A may contain 1 to 2 R c and the ring nitrogen may be quinolinyl, indazolyl, pyrazolopyridyl, or isothiazolopyridyl, optionally substituted with R d For example, ring A may be substituted with: TIFF0007797513000204.tif67147, which are R c In another non-limiting example, ring A may be further substituted with R c may be further substituted with It could be TIFF0007797513000205.tif16128.

[0231] Variable part n, R 7 and R 4 In some embodiments, n is 0. In some embodiments, n is 1 or 2. In certain such embodiments, n is 1. In certain embodiments, R 7 One occurrence of NR e R f (e.g., NH2, NH(C 1~3 alkyl) or N(C 1~3 In certain of these embodiments, R 7 One occurrence of NH2 or NH(C 1~3 alkyl). For example, R 7 One occurrence of may be NH2.

[0232] In certain embodiments, TIFF0007797513000206.tif15128 part TIFF0007797513000207.tif15128. In certain of these embodiments, R 7 One occurrence of NR e R f (e.g., NH2, NH(C 1~3 alkyl) or N(C 1~3In certain of the above embodiments, R 7 One occurrence of NH2 or NH(C 1~3 alkyl). For example, R 7 One occurrence of may be NH2.

[0233] In some embodiments, R 4 is H.

[0234] Non-limiting combinations In certain embodiments, the compound of formula (I) has the formula (Ia) TIFF0007797513000208.tif47128 or a pharmaceutically acceptable salt thereof, wherein ring D1 is: Monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA monocyclic heteroaryl, optionally substituted with -R g2 -R Y and -R g2 -R Y -R g2 is a monocyclic heteroarylene containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 3 R cA optionally substituted with -R g2 -R Y selected from the group consisting of Here, each R cA are independently selected R c and; L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 It is alkylene.

[0235] In certain embodiments of Formula (Ia), ring D1 is a monocyclic heteroaryl containing 5 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S, wherein the heteroaryl is selected from the group consisting of 1 to 4 R cA may be substituted with.

[0236] As a non-limiting example of the foregoing embodiment, ring D1 is: Each has 1-2 R cA may be substituted with TIFF0007797513000209.tif23154.

[0237] As a non-limiting example of the foregoing embodiment, ring D1 is: Each has 1-2 R cA may be substituted with TIFF0007797513000210.tif18128.

[0238] In certain embodiments of Formula (Ia), ring D1 is a monocyclic heteroaryl containing 6 ring atoms, of which 1 to 4 ring atoms are nitrogen ring atoms, and the heteroaryl is cA may be substituted with.

[0239] As a non-limiting example of the foregoing embodiment, ring D1 is: Each one is R cA may be further substituted with TIFF0007797513000211.tif76152.

[0240] As a non-limiting example of the foregoing embodiment, ring D1 is: Each one is R cA may be further substituted with TIFF0007797513000212.tif75145.

[0241] In certain embodiments of Formula (Ia), ring D1 is -R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 3 R cA may be substituted with.

[0242] In certain of these embodiments, ring D1 is -R g2 -R Y and;-R g2 -R Y -R g2 is a monocyclic heteroarylene containing five ring atoms, of which one to four are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S, and the heteroarylene is selected from the group consisting of 1 to 2 R cA For example, ring D1 may be substituted with It could be TIFF0007797513000213.tif18128.

[0243] Certain embodiments of formula (Ia) (wherein ring D1 is -R g2 -R Y In this case, R Y but: 1 to 3 R c phenyl optionally substituted with Monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c monocyclic heteroaryl optionally substituted with is selected from the group consisting of:

[0244] In certain embodiments of Formula (Ia), n is 0.

[0245] In certain embodiments of Formula (Ia), n is 1 or 2. For example, n can be 1.

[0246] In certain embodiments of formula (Ia), TIFF0007797513000214.tif33128 The file is TIFF0007797513000215.tif33128.

[0247] In certain embodiments of Formula (Ia), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0248] In certain embodiments, the compound of formula (I) has the formula (Ib) TIFF0007797513000216.tif47128 or a pharmaceutically acceptable salt thereof, wherein ring D2 is a bicyclic heteroaryl containing 8 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c and; L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 It is alkylene.

[0249] In certain embodiments of Formula (Ib), ring D2 is a heteroaryl containing 8 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0250] As a non-limiting example of the foregoing embodiment, ring D2 is: 1 to 2 R each cA may be further substituted with TIFF0007797513000217.tif17128, wherein each R cA are independently selected R c is.

[0251] As a further non-limiting example, ring D2 can be: 1 to 2 R each cA may be further substituted with TIFF0007797513000218.tif40128, wherein each R cA are independently selected R c is.

[0252] In certain embodiments of Formula (Ib), ring D2 is a bicyclic heteroaryl containing 9 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c is.

[0253] In certain of these embodiments, rings D2 each contain 1 to 2 R cAimidazolopyridinyl, pyrazolopyridinyl, or benzotriazolyl, wherein each R cA are independently selected R c is.

[0254] As a non-limiting example of the foregoing embodiment, ring D2 is Each has 1-2 R cA may be substituted with TIFF0007797513000219.tif24128, where each R cA are independently selected R c is.

[0255] In certain embodiments of Formula (Ib), n is 0.

[0256] In certain embodiments of Formula (Ib), n is 1 or 2. For example, n can be 1.

[0257] In certain embodiments of formula (Ib), TIFF0007797513000220.tif32128 The file is TIFF0007797513000221.tif33128.

[0258] In certain embodiments of Formula (Ib), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0259] In certain embodiments of formula (Ia) or (Ib), each R cA is: halo; cyano; -OH; 1 to 6 independently selected R a C optionally substituted with 1~6 Alkyl; C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy;C 1~4haloalkoxy; and —C(═O)NR′R″.

[0260] In certain embodiments, R cA is an independently selected halo, e.g., —F or —Cl. In certain embodiments, R cA is cyano. In certain embodiments, R cA One occurrence of is selected from 1 to 6 independently selected R a C optionally substituted with 1~6 In certain embodiments, R cA One occurrence of C 1~6 Alkyl, e.g., C 1~3 In certain embodiments, R cA One occurrence of -OH or -NR e R f C is replaced by 1~6 alkyl. For example, R cA One occurrence of C is substituted with -OH or NH 1~3 In certain embodiments, R cA One occurrence of C 1~4 Alkoxy or C 1~4 C optionally substituted with haloalkoxy 1~4 Alkoxy. For example, R cA One occurrence of C 1~4 It can be alkoxy (eg, methoxy or ethoxy).

[0261] In certain embodiments, the compound of formula (I) has the formula (Ic): TIFF0007797513000222.tif52128 or a pharmaceutically acceptable salt thereof; In the formula, ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R Z ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: R Z is R X or R Y and; L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 It is alkylene.

[0262] In certain embodiments of Formula (Ic), R Z R X is.

[0263] In certain of these embodiments, R Z is C(=O)(C 1~4 alkyl).

[0264] In certain embodiments, R Z is S(O)2(C 1~4 alkyl).

[0265] In certain embodiments of Formula (Ib), R Z R Y is.

[0266] In certain of these embodiments, R Z R g is.

[0267] In certain of the foregoing embodiments, R Z but: 1 to 3 R c phenyl optionally substituted with Monocyclic heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c monocyclic heteroaryl optionally substituted with is selected from the group consisting of:

[0268] In certain embodiments of Formula (Ic), n is 0.

[0269] In certain embodiments of Formula (Ic), n is 1 or 2, for example, n is 1.

[0270] In certain embodiments of formula (Ic), TIFF0007797513000223.tif38128 The file is TIFF0007797513000224.tif38128.

[0271] In certain embodiments of Formula (Ic), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0272] In certain embodiments, the compound of formula (I) has the formula (Id): TIFF0007797513000225.tif52128 or a pharmaceutically acceptable salt thereof, In the formula, ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: L 1 is a bond or 1 to 6 R a C optionally substituted with 1~3 It is alkylene.

[0273] In certain embodiments of formula (Id), RW Ga-L W -W;L W is C(=O).

[0274] In certain of these embodiments, W is C 2~6 alkenyl, which is a group consisting of 1 to 3 R a and R g where W is sp 2 L through the hybridized carbon atom W For example, W can be CH=CH2.

[0275] In certain of these embodiments, W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W As a non-limiting example, W can be CH=CH2, CH=CHCH2NMe2 or It could be TIFF0007797513000226.tif7128.

[0276] In certain embodiments of formula (Ic) or (Id), ring D is selected from the group consisting of 1 to 2 R c may be substituted with TIFF0007797513000227.tif19128, where x1 and x2 are each independently 0, 1, or 2. In certain such embodiments, x1 is 0.

[0277] As a non-limiting example of the foregoing embodiment, ring D is: TIFF0007797513000228.tif40128.

[0278] In a further non-limiting example of the above embodiment, ring D is: TIFF0007797513000229.tif60159.

[0279] In certain embodiments of formula (Id), n is 0.

[0280] In certain embodiments of Formula (Id), n is 1 or 2. For example, n can be 1.

[0281] In certain embodiments of formula (Id), TIFF0007797513000230.tif37128 The file is TIFF0007797513000231.tif37128.

[0282] In certain embodiments of formula (Id), TIFF0007797513000232.tif37128 The file is TIFF0007797513000233.tif37128.

[0283] In certain embodiments of formula (Id), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0284] In certain embodiments, the compound of formula (I) has the formula (Ie): TIFF0007797513000234.tif38128 or a pharmaceutically acceptable salt thereof, In the formula, R 5A Ha-L 5 -R g or 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 alkyl); L 1 is 1 to 6 R a C optionally substituted with 1~10 It is alkylene.

[0285] In certain embodiments of formula (Ie), R 5A Ga-L 5 -R g In certain of these embodiments, R 5A -OR g is.

[0286] In certain of the foregoing embodiments, R 5A -OR g and;-OR g R exists in g C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c are independently selected from the group consisting of:

[0287] In certain embodiments, R 5A -O-(C 3~6 cycloalkyl), and the C 3~6 Cycloalkyl has 1 to 3 R c For example, R 5 teeth It could be TIFF0007797513000235.tif9128.

[0288] In certain embodiments of formula (Ie), R 5A However, 1 to 6 R a -S(O) optionally substituted with 0~2 (C 1~6 In certain of these embodiments, R 5A However, 1 to 6 R a may be substituted with -S(O)2(C 1~6 As a non-limiting example of the foregoing embodiment, R 5A is -S(O)2(C 1~3 alkyl) (e.g., —S(O)2Me).

[0289] In certain embodiments of Formula (Ie), n is 0.

[0290] In certain embodiments of formula (Ie), n is 1 or 2, for example, n is 1.

[0291] In certain embodiments of formula (Ie), TIFF0007797513000236.tif24128 The file is TIFF0007797513000237.tif24128.

[0292] In certain embodiments of formula (Ie), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0293] In certain embodiments of formula (Ia), (Ib), (Ic), (Id) or (Ie), L 1 However, 1 to 6 R a C optionally substituted with 1~3 It is alkylene.

[0294] In certain of these embodiments, L 1 C 1~3 alkylene. For example, L 1 In another non-limiting example, L 1 can be -CH2CH2-.

[0295] In certain embodiments of formula (Ia), (Ib), (Ic), (Id) or (Ie), L 1 is a bond.

[0296] In certain embodiments, the compound of formula (I) has the formula (If): TIFF0007797513000238.tif41128 or a pharmaceutically acceptable salt thereof, In the formula, ring D3 is C substituted with 1 to 4 substituents. 3~10cycloalkyl, each substituent independently being: oxo and R c is selected from the group consisting of:

[0297] In certain embodiments of formula (If), ring D3 is C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 3~6 is cycloalkyl; R 5 is optionally further substituted with 1 to 2 substituents, each of which is: oxo and R c are independently selected from the group consisting of:

[0298] In certain of these embodiments, R 5 But C 1~4 Alkoxy or C 1~4 cyclopropyl substituted with haloalkoxy. For example, R 5 teeth: It could be TIFF0007797513000239.tif17128.

[0299] In certain embodiments of formula (If), n is 0.

[0300] In certain embodiments of formula (If), n is 1 or 2, for example, n is 1.

[0301] In certain embodiments of formula (If), TIFF0007797513000240.tif27128 The file is TIFF0007797513000241.tif27128.

[0302] In certain embodiments of formula (If), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0303] In certain of these embodiments, the compound of formula (I) has the formula (Ig): TIFF0007797513000242.tif38128 or a pharmaceutically acceptable salt thereof, In the formula, L 2 is 1 to 6 R a C optionally substituted with 1~6 is alkylene; R 6A is 1 to 6 R a may be substituted with -C 1~6 Alkoxy;NR e R f ;H; halo; and -OH.

[0304] In certain embodiments of Formula (Ig), R 6A However, 1 to 6 R a may be substituted with -C 1~6 It is an alkoxy.

[0305] In certain of these embodiments, R 6A Ga-C 1~3 Alkoxy (eg, methoxy).

[0306] In certain embodiments, R 6A NR e R f is.

[0307] In certain embodiments, R 6A is H, halo, or -OH.

[0308] In certain embodiments of Formula (Ig), L 2 is branch C 3~6 As a non-limiting example of the foregoing embodiment, L 2 teeth It could be TIFF0007797513000243.tif11128.

[0309] In certain embodiments of Formula (Ig), L 2 C 1~3 Alkylene, for example -CH2-.

[0310] In certain embodiments of Formula (Ig), n is 0.

[0311] In certain embodiments of formula (Ig), n is 1 or 2, for example, n is 1.

[0312] In certain embodiments of formula (Ig), TIFF0007797513000244.tif23128 The file is TIFF0007797513000245.tif23128.

[0313] In certain embodiments of Formula (Ig), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0314] In certain embodiments, the compound of formula (I) has the formula (Ih): TIFF0007797513000246.tif46128 or a pharmaceutically acceptable salt thereof; In the formula, ring D4 is R g is.

[0315] In certain embodiments of Formula (Ih), ring D4 is: oxo and R, respectively c C 3~10 Cycloalkyl or C 3~10 cycloalkenyl; and Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R cheterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0316] In certain such embodiments, ring D4 is heterocyclyl containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0317] In certain of the foregoing embodiments, ring D4 is selected from the group consisting of oxo and R c and wherein the nitrogen atom in the ring of the pyrrolidinyl or piperidinyl is selected from the group consisting of pyrrolidinyl, piperidinyl, oxentanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted by 1 to 2 substituents independently selected from the group consisting of R d As a non-limiting example of the above embodiment, ring D4 may be substituted with: It could be TIFF0007797513000247.tif37147.

[0318] In certain of the foregoing embodiments, ring D4 is selected from the group consisting of oxo and R c and wherein the nitrogen atom in the ring of said pyrrolidinyl or piperidinyl is selected from the group consisting of pyrrolidinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted by one or two substituents independently selected from the group consisting of R d As a non-limiting example of the above embodiment, ring D4 may be substituted with: It could be TIFF0007797513000248.tif19128.

[0319] In certain embodiments of Formula (Ih), ring D4 is a heteroaryl containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c For example, R 6 teeth It could be TIFF0007797513000249.tif19128.

[0320] In certain embodiments of Formula (Ih), n is 0.

[0321] In certain embodiments of formula (Ih), n is 1 or 2, for example, n is 1.

[0322] In certain embodiments of formula (Ih), TIFF0007797513000250.tif32128 The file is TIFF0007797513000251.tif32128.

[0323] In certain embodiments of Formula (Ih), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0324] In certain embodiments, the compound of formula (I) has the formula (Ii): TIFF0007797513000252.tif51128 or a pharmaceutically acceptable salt thereof; In the formula, ring D is a heterocyclylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c are independently selected from the group consisting of:

[0325] In certain embodiments of formula (Ii), R W Ga-L W -W;L W is C(=O).

[0326] In certain embodiments of formula (Ii), W is C 2~6 alkenyl, which is a group consisting of 1 to 3 R a and R g where W is sp 2 L through the hybridized carbon atom W As a non-limiting example of the foregoing embodiment, W can be CH=CH2.

[0327] In certain embodiments of formula (Ii), W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W As a non-limiting example of the foregoing embodiment, W is CH=CH2, CH=CHCH2NMe2 or It could be TIFF0007797513000253.tif7128.

[0328] In certain embodiments of Formula (Ii), -L W -W The file is TIFF0007797513000254.tif57159.

[0329] In certain embodiments of formula (Ii), ring D is selected from the group consisting of 1 to 2 R c may be substituted with TIFF0007797513000255.tif19128, where x1 and x2 are each independently 0, 1, or 2.

[0330] In certain of these embodiments, x1 is 0.

[0331] As a non-limiting example of the foregoing embodiment, ring D is: TIFF0007797513000256.tif40128.

[0332] As a further non-limiting example of the above embodiment, ring D is: TIFF0007797513000257.tif60159.

[0333] In certain embodiments of formula (Ii), TIFF0007797513000258.tif16128 contains 3 to 10 ring atoms and R W wherein 0 to 2 ring atoms (R W ) are heteroatoms, and each heteroatom is an N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclylene is optionally substituted with 1 to 3 substituents, each of which is selected from the group consisting of: oxo and -R c independently selected from the group consisting of: TIFF0007797513000259.tif16128 contains 3 to 10 ring atoms as defined above, R W a monocyclic heterocyclylene ring having a nitrogen atom bonded to TIFF0007797513000260.tif39137; optionally, TIFF0007797513000261.tif16128 contains 3 to 10 ring atoms as defined above, R W a bicyclic heterocyclylene ring having a nitrogen atom bonded to The file is TIFF0007797513000262.tif85160.

[0334] In certain embodiments of formula (Ii), n is 0.

[0335] In certain embodiments of formula (Ii), n is 1 or 2, for example, n is 1.

[0336] In certain embodiments of formula (Ii), TIFF0007797513000263.tif37128 The file is TIFF0007797513000264.tif37128.

[0337] In certain embodiments of formula (Ii), TIFF0007797513000265.tif37128 The file is TIFF0007797513000266.tif37128.

[0338] In certain embodiments of formula (Ii), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0339] In certain embodiments, the compound of formula (I) has the formula (Ij) TIFF0007797513000267.tif38128 or a pharmaceutically acceptable salt thereof; In the formula, L 2 is 1 to 6 R a C optionally substituted with 1~6 alkylene; R 6B Ha-R W is.

[0340] In certain embodiments of formula (Ij), R W Ga-L W -W;L WC(=O), NHC(=O) * or NHS(O) 1~2 * where the asterisk indicates the point of attachment to W.

[0341] In certain embodiments of formula (Ij), W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W As a non-limiting example of the foregoing embodiment, W is CH=CH2, CH=CHCH2NMe2, or It could be TIFF0007797513000268.tif7128.

[0342] In certain embodiments of Formula (Ij), -L W -W is -C(=O)CH=CH2, -C(=O)CH=CHCH2NMe2 or The file is TIFF0007797513000269.tif14128.

[0343] In certain embodiments of formula (Ij), L 2 However, 1 to 6 R a C optionally substituted with 1~3 alkylene, where R a Ha-NR e R f (eg, Nme2), halo (eg, fluoro), or alkoxyl (eg, methoxy).

[0344] Non-limiting examples of the aforementioned embodiments of formula (Ij) include L 2 teeth It could be TIFF0007797513000270.tif63166.

[0345] In certain embodiments of formula (Ij), n is 0.

[0346] In certain embodiments of formula (Ij), n is 1 or 2, for example, n is 1.

[0347] In certain embodiments of formula (Ij), TIFF0007797513000271.tif24128 The file is TIFF0007797513000272.tif24128.

[0348] In certain embodiments of formula (Ij), TIFF0007797513000273.tif24128 The file is TIFF0007797513000274.tif24128.

[0349] In certain embodiments of formula (Ij), R 7 NR e R f , such as NH2, NH(C 1~3 alkyl) or N(C 1~3 alkyl)2, for example, R 7 is NH2.

[0350] In certain embodiments, the compound of formula (I) has the formula (Ik): TIFF0007797513000275.tif48128 or a pharmaceutically acceptable salt thereof; In the formula, ring D5 is R g2 is.

[0351] In certain embodiments of Formula (Ik), ring D5 is: oxo and R, respectively c C 3~10 Cycloalkylene or C 3~10 cycloalkenylene; and Heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0~2and the heterocyclylene or heterocycloalkenylene is independently selected from the group consisting of oxo and R c Heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0352] In certain embodiments of Formula (Ik), ring D5 is a heterocyclylene containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is independently selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0353] In certain embodiments of Formula (Ik), ring D5 is C3-C6 cycloalkylene (eg, cyclobutylene), oxetanylene, or tetrahydrofurylene.

[0354] In certain embodiments of formula (Ik), R W Ga-L W -W;L W is C(=O) or NHC(=O) * , N.R. d C(=O) * , NHS(O) 1~2 * where the asterisk indicates the point of attachment to W.

[0355] In certain embodiments of formula (Ik), W is C 2~6 Alkenyl or C 2~6 Alkynyl, which is one to three R a and R g where W is sp 2 or L through sp hybridized carbon atoms W As a non-limiting example, W can be CH=CH2, CH=CHCH2NMe2 or It could be TIFF0007797513000276.tif7128.

[0356] In certain embodiments of formula (Ik), -L W -W is -C(=O)CH=CH2, -C(=O)CH=CHCH2NMe2 or The file is TIFF0007797513000277.tif14128.

[0357] In certain embodiments of formula (Ik), n is 0.

[0358] In certain embodiments of formula (Ik), TIFF0007797513000278.tif37128 The file is TIFF0007797513000279.tif38128.

[0359] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 3a and R 3b are bonded to ring B and together form a saturated fused ring of 4 to 8 ring atoms; 0 to 2 of the ring atoms are each an independently selected heteroatom, and each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0~2 selected from the group consisting of: The saturated fused ring having 4 to 8 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0360] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 3a and R 3b are bonded to the ring atom of ring B to form oxo and R cand optionally substituted with 1 to 2 substituents independently selected from the group consisting of: This forms TIFF0007797513000280.tif21128, where: p1 and p2 are independently 0, 1, or 2; R Q is H, R d , C(=O)-W or S(O)W; cc is C(R 2a R 2b ) represents the point of attachment.

[0361] In certain of these embodiments, R Q is H. In certain embodiments, R Q R d In certain embodiments, R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 In certain embodiments, R Q is C(=O)-W or S(O)W. In certain of these embodiments, W is C 2~4 alkenyl. For example, R Q can be C(=O)-CH2=CH2.

[0362] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 3a and R 3b are bonded to the ring atoms of ring B, TIFF0007797513000281.tif23128 is formed, where R Q is H, R d , C(=O)-W or S(O)W; cc is C(R 2a R 2b ) represents the point of attachment to the aryl group. Q is H. In certain embodiments, R Q R d In certain embodiments, R Qis 1 to 3 independently selected R a C optionally substituted with 1~6 In certain embodiments, R Q is C(=O)-W or S(O)W. In certain of these embodiments, W is C 2~4 alkenyl. For example, R Q can be C(=O)-CH2=CH2.

[0363] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 3a and R 3b together with the ring atom of ring B to which each is attached: TIFF0007797513000282.tif121153, wherein R Q is H, R d , C(=O)-W or S(O)W; cc is C(R 2a R 2b ) represents the point of attachment to the aryl group. Q is H. In certain embodiments, R Q R d In certain embodiments, R Q is 1 to 3 independently selected R a C optionally substituted with 1~6 In certain embodiments, R Q is C(=O)-W or S(O)W. In certain of these embodiments, W is C 2~4 alkenyl. For example, R Q can be C(=O)-CH2=CH2.

[0364] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 1c is H.

[0365] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 2a and R 2b is H.

[0366] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 3a and R 3b is H.

[0367] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), ring A is TIFF0007797513000283.tif16128, where each R cB are independently selected R c and m is 1, 2, or 3. In certain such embodiments, m is 1 or 2, for example, 2.

[0368] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), ring A is TIFF0007797513000284.tif22128, where each R cB are: -halo, e.g. -Cl and -F; -CN; C 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~3 alkyl; and C substituted with 1 to 6 independently selected halo 1~3 alkyl.

[0369] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), ring A is TIFF0007797513000285.tif16128, where R cB1 is R c and;R cB2 is H or R c is.

[0370] In certain of these embodiments, R cB1 is halo, for example -F or -Cl, for example -F.

[0371] In certain embodiments, R cB2 C 1~4 Alkoxy or C 1~4 Haloalkoxy, e.g., C 1~4 Alkoxy, for example methoxy.

[0372] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), ring A is The file is TIFF0007797513000286.tif19128.

[0373] In certain embodiments of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), Ring A is a bicyclic heteroaryl containing 9-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c may be substituted with.

[0374] As a non-limiting example of the foregoing embodiment, ring A can be quinolinyl, indazolyl, pyrazolopyridyl, or isothiazolopyridyl, each of which is selected from the group consisting of 1 to 2 R c The ring nitrogen may be substituted with R d For example, ring A may be substituted with: TIFF0007797513000287.tif67153, which are R c It may be further substituted with.

[0375] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), n is 0.

[0376] In certain embodiments of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), R 4 is H.

[0377] Compound definition In some embodiments, the compound is other than a compound selected from the group consisting of the structures shown below. TIFF0007797513000288.tif84154

[0378] In some embodiments, the compound is other than one or more compounds disclosed in WO 2019 / 081486, WO 2016 / 120196, or U.S. Patent 10,428,063, each of which is incorporated by reference in its entirety.

[0379] In some embodiments, R 2a , R 2b , R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 Ga-OL 1 -R 5 and;-L 1 If is CH2: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.

[0380] In some embodiments, R 5 is other than unsubstituted phenyl. In some embodiments, R 5 is other than unsubstituted cyclopropyl.

[0381] In some embodiments, ring A is other than phenyl optionally substituted with 1-2 F.

[0382] Non-limiting exemplary compounds In certain embodiments, the compound is selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt thereof.

[0383] (Table C1) For a particular compound, the symbol for the chiral center * indicates that this chiral center is resolved (i.e., a single epimer), but the absolute stereochemical configuration at that center has not been determined. TIFF0007797513000289.tif135170TIFF0007797513000290.tif169170TIFF0007797513000291.tif169170TIFF0007797513000292.tif176170TIFF0007797513000293.tif182170TIFF0007797513000294.tif182170TIFF0007797513000295.tif209170TIFF0007797513000296.tif170170TIFF0 007797513000297.tif203170TIFF0007797513000298.tif186170TIFF0007797513000299.tif191170TIFF0007797513000300.tif193170TIFF0007797513000301.tif178170TIFF0007797513000302.tif183170TIFF0007797513000303.tif175170TIFF0007797513000304.tif207170TIFF000779 7513000305.tif160170TIFF0007797513000306.tif166170TIFF0007797513000307.tif171170TIFF0007797513000308.tif182170TIFF00077975 13000309.tif165170TIFF0007797513000310.tif174170TIFF0007797513000311.tif170170TIFF0007797513000312.tif186170TIFF00077975130 00313.tif192170TIFF0007797513000314.tif166170TIFF0007797513000315.tif169170TIFF0007797513000316.tif182170TIFF00077975130003 17.tif183170TIFF0007797513000318.tif179170TIFF0007797513000319.tif164170TIFF0007797513000320.tif168170TIFF0007797513000321.tif166170TIFF0007797513000322.tif172170TIFF0007797513000323.tif172170TIFF0007797513000324.tif167170TIFF0007797513000325.tif175170TIFF0007797513000326.tif182170TIFF0007797513000327.tif177170TIFF0007797513000328.tif184170TIFF0007797513000329.tif1741 70TIFF0007797513000330.tif170170TIFF0007797513000331.tif180170TIFF0007797513000332.tif143170TIFF0007797513000333.tif138170TIFF0007797513000334.tif195170TIFF0007797513000335.tif182170TIFF0007797513000336.tif180170TIFF0007797513000337.tif187170TIFF00 07797513000338.tif187170TIFF0007797513000339.tif181170TIFF0007797513000340.tif192170TIFF0007797513000341.tif183170TIFF0007797513000342.tif179170TIFF0007797513000343.tif183170TIFF0007797513000344.tif186170TIFF0007797513000345.tif165170TIFF000779751 3000346.tif182170TIFF0007797513000347.tif176170TIFF0007797513000348.tif187170TIFF0007797513000349.tif182170TIFF0007797513000350.tif171170TIFF0007797513000351.tif170170TIFF0007797513000352.tif176170TIFF0007797513000353.tif172170TIFF0007797513000354.tif176170TIFF0007797513000355.tif176170TIFF0007797513000356.tif188170TIFF0007797513000357.tif175170TIFF000 7797513000358.tif174170TIFF0007797513000359.tif174170TIFF0007797513000360.tif183170TIFF0007797513000361.ti f187170TIFF0007797513000362.tif186170TIFF0007797513000363.tif185170TIFF0007797513000364.tif179170TIFF00077 97513000365.tif182170TIFF0007797513000366.tif192170TIFF0007797513000367.tif183170TIFF0007797513000368.tif17 6170TIFF0007797513000369.tif176170TIFF0007797513000370.tif165170TIFF0007797513000371.tif179170TIFF00077975 13000372.tif166170TIFF0007797513000373.tif171170TIFF0007797513000374.tif180170TIFF0007797513000375.tif1971 70TIFF0007797513000376.tif184170TIFF0007797513000377.tif195170TIFF0007797513000378.tif183170TIFF0007797513 000379.tif175170TIFF0007797513000380.tif182170TIFF0007797513000381.tif193170TIFF0007797513000382.tif179170.

[0384] Pharmaceutical Compositions and Administration Overview In some embodiments, the chemical entity (e.g., a compound that inhibits EGFR and / or HER2 or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal and / or combination thereof) is administered as a pharmaceutical composition comprising the chemical entity, one or more pharmaceutically acceptable excipients, and, optionally, one or more additional therapeutic agents described herein.

[0385] In some embodiments, the chemical substance can be administered in combination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer or other similar polymer-based delivery matrix, serum protein, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of vegetable saturated fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin or chemically modified derivatives, such as hydroxyalkylcyclodextrins, e.g., 2- and 3-hydroxypropyl-β-cyclodextrin or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions containing 0.005% to 100% of the chemical compounds described herein can be prepared, with the remainder made up of non-toxic excipients. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of the chemical compounds provided herein. Actual methods for preparing such dosage forms are known or readily apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22 nd See, e.g., Pharmaceutical Press, London, UK, 2012.

[0386] Route of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, transdermal, intracervical, intrasinus, intratracheal, enteral, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, superficial, transdermal, transmucosal, transtracheal, transureteral, transurethral, ​​and vaginal. In certain embodiments, one preferred route of administration is parenteral (eg, intratumoral).

[0387] Composition can be formulated for parenteral administration, for example, can be formulated for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal route.Typically, this composition can be prepared as an injectable agent as either a liquid solution or suspension;Also, solid form can be prepared that is suitable for preparing solution or suspension by adding liquid before injection;Also, preparation can be emulsified.The preparation of such preparation will be known to those skilled in the art in view of the present disclosure.

[0388] The pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or propylene glycol aqueous solution; and sterile powder for the immediate preparation of sterile injectable solution or dispersion.In all cases, this form must be sterile and fluid enough to be easily syringable.It should also be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms, such as bacteria and fungi.

[0389] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use of absorption delaying agents in the composition, for example, aluminum monostearate and gelatin.

[0390] Sterile injection solution is prepared by incorporating the required amount of active compound into suitable solvent with various other components as listed above as necessary, and then sterilized by filtration.Generally, dispersion is prepared by incorporating various sterilized active components into a sterilized vehicle that contains basic dispersion medium and the other components as listed above that are required.For the sterile powder that is used to prepare sterile injection solution, the preferred preparation method is vacuum drying and freeze-drying, which obtains the powder of active component plus any additional desired components from the solution that has been previously sterilized and filtered.

[0391] Intratumoral injection is discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems," Neoplasia. 2006, 10, 788-795.

[0392] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (as well as PEG ointments), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide. SBN, vanilla essential oil, aerosol, paraben-containing phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0393] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[0394] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract by oral administration (eg, in solid or liquid dosage forms).

[0395] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage form, the chemical substance is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, iodopropanol, methylparaben ... The composition is mixed with starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.For capsules, tablets, and pills, dosage forms can also contain buffering agents.Similar solid compositions can also be used in filled soft gelatin capsules and filled hard gelatin capsules, where excipients such as lactose or milk sugar and high molecular weight polyethylene glycol are used as fillers.

[0396] In one embodiment, the composition is in the form of a unit dosage form, for example, a pill or tablet, and thus the composition can contain the chemical compound provided herein together with diluents such as lactose, sucrose, dicalcium phosphate, etc.; lubricants such as magnesium stearate, etc.; and binders such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powder, quince, solution or suspension (for example, in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) is enclosed in capsule (gelatin or cellulose-based capsule).Also contemplated are unit dosage forms in which one or more chemical compounds provided herein or additional active agents are physically separated; for example, capsules (or tablets in capsules) with granules of each drug; bilayer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0397] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful against the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0398] In certain embodiments, the excipient is sterile and generally does not contain any undesirable substances.The composition can be sterilized by conventional and well-known sterilization methods.For excipients of various oral dosage forms, such as tablets and capsules, sterility is not required.Usually, USP / NF standards are sufficient.

[0399] In certain embodiments, solid oral dosage form can further comprise one or more components that chemically and / or structurally direct the composition for delivery of said chemical substance to stomach or lower GI; for example, ascending colon and / or transverse colon and / or distal colon and / or small intestine.Exemplary formulation methods are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013,13,776-802, which is incorporated herein by reference in its entirety.

[0400] Examples include upper GI targeting approaches such as the Accordion Pill (Intec Pharma), float capsules and substances that can adhere to the mucosal wall.

[0401] Other examples include lower GI targeting approaches. Several enteric / pH-responsive coatings and excipients are available for targeting various regions of the intestinal tract. These materials are typically polymers designed to dissolve or erode in a specific pH range and are selected based on the GI region from which drug release is desired. These materials also function to protect acid-labile drugs from gastric fluids or limit exposure if the active ingredient may be irritating to the upper GI tract (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other approaches include dosage forms that respond to local intestinal flora in the GI tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0402] The ophthalmic compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0403] Topical compositions may include ointments and creams. Ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. Creams containing a selected active agent are typically viscous liquids or semi-solid, often either oil-in-water or water-in-oil emulsions. Cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl alcohol or stearyl alcohol; the aqueous phase usually, though not necessarily, exceeds the oil phase in volume and generally contains a humectant. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. As with other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0404] In any of the foregoing embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0405] Dosage Dosage amount can vary depending on the patient's requirements, the severity of the condition being treated and the specific compound being used.The determination of the appropriate dosage for a specific situation can be determined by those skilled in the medical field.The total daily dosage can be divided and administered in portions throughout the day, or can be provided by continuous delivery means.

[0406] In some embodiments, the compounds described herein are administered in a concentration of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 150 mg / Kg; from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0.1 mg / Kg to about 200 mg / Kg; from about 0.1 mg / Kg to about 150 mg / Kg). mg / Kg; about 0.1 mg / Kg to about 100 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg).

[0407] Regimen The aforementioned dosages may be administered daily (e.g., as a single dose or as two or more divided doses) or otherwise (e.g., every other day, every two days, every three days, weekly, twice weekly, biweekly, monthly).

[0408] In some embodiments, the administration period of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In a further embodiment, the period of suspension is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, a therapeutic compound is administered to an individual for a period of time, followed by a separate period of time. In another embodiment, the therapeutic compound is administered for a first period of time, a second period of time after the first period of time, a third period of time, and then a fourth period of time after the third period of time, with administration suspended during the second period, administration of the therapeutic compound initiated during the third period, and administration suspended during the fourth period of time. In one aspect of this embodiment, the period of administration of the therapeutic compound after the period of discontinued administration is repeated for a fixed or indefinite period of time. In a further embodiment, the period of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In a further embodiment, the period of time during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[0409] Treatment method Indications Provided herein are methods for inhibiting epidermal growth factor receptor tyrosine kinase (EGFR) and / or human epidermal growth factor receptor 2 (HER2). For example, provided herein are EGFR inhibitors useful for treating or preventing diseases or disorders associated with dysregulation of the expression, activity, or level of the EGFR gene, EGFR kinase, or any of them (i.e., EGFR-related diseases or disorders), such as central nervous system diseases, lung disorders, cardiovascular diseases, ischemia, liver diseases, gastrointestinal disorders, viral or bacterial infections, inflammatory diseases and / or autoimmune diseases, or cancers (e.g., EGFR-related cancers). In some embodiments, provided herein are HER2 inhibitors useful for treating or preventing diseases or disorders associated with dysregulation of the expression, activity, or level of the HER2 gene, HER2 kinase, or any of them, such as cancers (e.g., HER2-related cancers). In some embodiments, provided herein are EGFR and HER2 inhibitors.

[0410] As used herein, "EGFR inhibitor" encompasses any compound that exhibits (e.g., inhibits or reduces) EGFR inactivation activity. In some embodiments, the EGFR inhibitor may be selective for EGFR kinases with one or more mutations. For example, the EGFR inhibitor may bind to the adenosine triphosphate (ATP) binding site within the tyrosine kinase domain. In some embodiments, the EGFR inhibitor is an allosteric inhibitor.

[0411] The compounds provided herein can inhibit EGFR. In some embodiments, the compounds can bind to the EGFR adenosine triphosphate (ATP) binding site within the tyrosine kinase domain.

[0412] The ability of test compound to act as an EGFR inhibitor can be demonstrated by assays known in the art.The activity of compounds and compositions provided herein as EGFR inhibitors can be assayed in vitro, in vivo, or in cell lines.In vitro assays include assays that examine the inhibition of kinase and / or ATPase activity.Another in vitro assay quantifies the ability of inhibitors to bind to protein kinase, which can be measured by radiolabeling the compound before binding, isolating the compound / kinase complex, and measuring the amount of bound radiolabel, or by carrying out a competition experiment in which new compounds are incubated with kinases bound to known radioligands.In some cases, EGFR inhibitors can be evaluated by their effect on the initial rate of EGFR tyrosine kinase catalytic peptide phosphorylation (e.g., Yun et al.Cancer Cell.2007;11(3):217-227). In some embodiments, the binding constant of an EGFR inhibitor can be measured using fluorescence kinetics (e.g., Yun et al. Cancer Cell. 2007; 11(3): 217-227). Examples of surface plasmon resonance (SPR) binding assays include those disclosed in Li, Shiqing, et al. Cancer cell 7.4(2005): 301-311. Additional EGFR inhibitor assays can be found, for example, in WO 2019 / 246541 and WO 2019 / 165358, both of which are incorporated by reference in their entireties).

[0413] Assays can include, for example, growth inhibition assays, such as those measuring cell growth inhibition, for example, MTS assays or Cell Titer Glo Luminescent Cell Viability Assays (Promega®). To perform such assays, cells are seeded and grown in cell culture plates and then exposed to test compounds for various periods of time. Cell viability after this exposure is then assessed. Data can be normalized to untreated cells and displayed graphically. Growth curves can be fitted using a nonlinear regression model with a sigmoidal dose-response. As another example, Western blot analysis can be used. In such assays, cells are seeded and grown in culture plates, and then the next day are treated with test compounds for various periods of time. The cells are washed with PBS and lysed. Lysates were separated using SDS-PAGE gels, transferred to nitrocellulose membranes, and probed with appropriate antibodies (e.g., phospho-EGFR (Tyr068) (3777), total EGFR (2232), p-Akt (Ser473) (4060), total Akt (9272), p-ERK (Thr202 / Tyr204) (4370), total ERK (9102), and HSP90 (SC-7947)).

[0414] Additional assays may include, for example, ALPHALISA TECHNOLOGY®-based assays (see, e.g., Promega's ALPHALISA® EGF / EGFR Binding Kit). Such assays use luminescent oxygen channeling chemistry to detect molecules of interest in, for example, buffers, cell culture media, serum, and plasma. For example, biotinylated EGF is bound to streptavidin-coated AlphaLISA donor beads, and EGFR-Fc is captured by anti-human IgG Fc-specific AlphaLISA acceptor beads. When EGF binds to EGFR, the donor and acceptor beads come into close proximity, and excitation of the donor bead causes the release of singlet oxygen molecules, which triggers an energy transfer cascade within the acceptor bead. This results in a sharp emission peak at 615 nm. Such assays may be used, for example, in competitive binding experiments.

[0415] Further examples of assays may include Sox technology-based assays (see, e.g., PHOSPHOSENS® Sox-based Homogeneous, ASSAYQUANT® Kinetic or Endpoint / Red Fluorescence-based Assays). Such assays utilize chelation-enhanced fluorescence (CHEF) and use sulfonamide-oxine (Sox) chromophores in peptide or protein substrates to create real-time sensors of phosphorylation. See, e.g., U.S. Patent Nos. 8,586,570 and 6,906,194.

[0416] The efficacy of the EGFR inhibitors provided herein is 50 When measured under substantially similar conditions, a low EC 50 Compounds with high EC 50In some embodiments, the substantially similar conditions include measuring EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells, A431 cells, Ba / F3 cells, or 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0417] Additionally, the efficacy of the EGFR inhibitors provided herein is measured by IC 50 It can also be measured by a low IC value when measured under substantially similar conditions. 50 Compounds with high IC 50 In some embodiments, the substantially similar conditions include measuring EGFR-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells, A431 cells, Ba / F3 cells, or 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof).

[0418] Additionally, selectivity between wild-type EGFR and EGFR containing one or more of the mutations described herein can be measured using cell proliferation assays in which cell proliferation is dependent on kinase activity. For example, mouse Ba / F3 cells transfected to have an appropriate form of wild-type EGFR (e.g., VIII; containing the wild-type EGFR kinase domain), or an exon 19 deletion / T790M, Del / T790M / L718Q, L858R / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, exon 19 deletion / T790M, or exon 20 insertion, e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, or H773_V774insX (e.g., A767_V775insX). Ba / F3 cells transfected with the vector V769_D770insASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH or P772_H773insPNP may be used. Proliferation assays were performed over a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and EC 50 is calculated.

[0419] An alternative method for measuring the effect on EGFR activity is to assay the phosphorylation of EGFR. Wild-type or mutant (L858R / T790M, Del / T790M, Del / T790M / L718Q, L858R / T790M / C797S, Del / T790M / C797S, L858R / T790M / I941R, or L858R / T790M / L718Q) EGFR can be transfected into cells that do not normally express endogenous EGFR, and the ability of inhibitors (e.g., used at concentrations as described above) to inhibit EGFR phosphorylation can be assayed. Cells are exposed to increasing concentrations of the inhibitor and stimulated with EGF. The effect on EGFR phosphorylation is assayed by Western blotting using a phospho-specific EGFR antibody.

[0420] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of EGFR. For example, the compounds provided herein can bind to the EGFR adenosine triphosphate (ATP) binding site in the tyrosine kinase domain. In some embodiments, the compounds provided herein can exhibit nanomolar-level efficacy against EGFR kinases containing activating mutations or EGFR inhibitor-resistant mutations, such as the resistance mutations in Table 2a and Table 2b (e.g., L747S, D761Y, T790M, and T854A), and have minimal activity against related kinases (e.g., wild-type EGFR). Inhibition of wild-type EGFR can cause undesirable side effects (e.g., diarrhea and skin rash), which can affect quality of life and compliance. In some cases, inhibition of wild-type EGFR can result in dose-limiting toxicity. See, for example, Morphy. J. Med. Chem. 2010, 53, 4, 1413-1437 and Peters. J. Med. Chem. 2013, 56, 22, 8955-8971.

[0421] In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)) or a pharmaceutically acceptable salt thereof may selectively target EGFR kinase. For example, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)) or a pharmaceutically acceptable salt thereof may selectively target EGFR kinase over another kinase or non-kinase target.

[0422] In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of EGFR comprising one or more mutations described herein (e.g., one or more mutations described in Table 1a and Table 1b) compared to inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of EGFR comprising one or more mutations described herein compared to inhibition of wild-type EGFR by at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)) or a pharmaceutically acceptable salt thereof may exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)) or a pharmaceutically acceptable salt thereof may exhibit up to 10,000-fold greater inhibition of EGFR having a combination of mutations described herein compared to the inhibition of wild-type EGFR.

[0423] In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, can exhibit about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, can exhibit about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, can exhibit about 100- to about 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, can exhibit about 1000- to about 10,000-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR.

[0424] In other embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, may exhibit greater inhibition of an EGFR containing one or more mutations described herein (e.g., one or more mutations described in Table 1a and Table 1b) compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)) or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, can exhibit up to 10,000-fold greater inhibition of EGFR having a combination of mutations described herein compared to inhibition of wild-type EGFR.

[0425] In other embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, exhibits about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, exhibits about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, can exhibit about 100- to about 1000-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor, can exhibit about 1000- to about 10,000-fold greater inhibition of EGFR containing one or more mutations described herein compared to the inhibition of wild-type EGFR.

[0426] The compounds of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik)), or pharmaceutically acceptable salts or solvates thereof, are useful for treating diseases and disorders that can be treated with EGFR inhibitors, such as EGFR-associated diseases and disorders, such as diseases of the central nervous system (e.g., neurodegenerative diseases), pulmonary disorders, cardiovascular diseases, ischemia, liver diseases, gastrointestinal disorders, viral or bacterial infections, inflammatory diseases and / or autoimmune diseases (e.g., psoriasis and atopic dermatitis), and proliferative disorders, such as cancer, e.g., hematopoietic cancers and solid tumors (e.g., advanced-stage solid tumors).

[0427] As used herein, "HER2 inhibitor" encompasses any compound that exhibits (e.g., inhibits or reduces) HER2 inactivation activity. In some embodiments, the HER2 inhibitor may be selective for HER2 kinases with one or more mutations. In some embodiments, the HER2 inhibitor may bind to the HER2 adenosine triphosphate (ATP) binding site within the tyrosine kinase domain.

[0428] Provided herein is a compound that can inhibit HER2.For example, the compound can bind to the HER2 adenosine triphosphate (ATP) binding site in tyrosine kinase domain.In some embodiments, provided herein is a compound that can inhibit wild-type HER2.In some embodiments, provided herein is a compound that can inhibit the HER2 that has one or more mutations described herein.

[0429] The ability of test compound to act as HER2 inhibitor can be demonstrated by assays known in the art.The activity of compounds or compositions provided herein as HER2 inhibitors can be assayed in vitro, in vivo, or in cell lines.In vitro assays include assays that examine the inhibition of kinase and / or ATPase activity.Another in vitro assay quantifies the ability of inhibitors to bind to protein kinase, which can be measured by radiolabeling the compound before binding, isolating the compound / kinase complex, and measuring the amount of bound radiolabel, or by carrying out a competition experiment in which new compounds are incubated with kinases bound to known radioligands.In some cases, HER2 inhibitors can be evaluated by their effect on the initial rate of HER2 tyrosine kinase catalytic peptide phosphorylation (for example, Yun et al.Cancer Cell.2007;11(3):217-227). For example, an assay that indirectly measures the ADP formed by the HER2 kinase reaction can be used (see, for example, ATP / NADH-coupled assay systems and luminescent kinase assays, such as Promega's ADP-GLO™ Kinase Assay). See, for example, Hanker et al. Cancer Discov. 2017 Jun; 7(6): 575-585; Robichaux et al. Nat Med. 2018 May; 24(5): 638-646; and Yun et al. Proc Natl Acad Sci US A. 2008 Feb 12; 105(6): 2070-5. In some embodiments, an assay that detects the phosphorylation of a substrate using a labeled anti-phospho-tyrosine antibody can be used (see, for example, Rabindran et al. Cancer Res. 2004 Jun 1; 64(11): 3958-65). In some embodiments, the binding constant of a HER2 inhibitor can be measured using fluorescence kinetics (eg, Yun et al. Cancer Cell. 2007;11(3):217-227).Examples of SPR binding assays include those disclosed in Li, Shiqing, et al. Cancer cell 7.4(2005):301-311. In some embodiments, covalent binding of HER2 inhibitors to HER2 can be detected using mass spectrometry, see, for example, Irie et al. Mol Cancer Ther. 2019 Apr;18(4):733-742. Additional HER2 inhibitor assays can be found, for example, in U.S. Patent No. 9,920,060, WO 2019 / 241715, and U.S. Patent Application Publication No. 2017 / 0166598, each of which is incorporated by reference in its entirety.

[0430] The efficacy of the HER2 inhibitors provided herein is measured by EC 50 A lower EC value can be measured under substantially similar conditions. 50 Compounds with high EC 50 In some embodiments, the substantially similar conditions include measuring HER2-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells or Ba / F3 cells expressing wild-type HER2, mutant HER2, or any fragment thereof).

[0431] The efficacy of HER2 inhibitors provided herein is also shown in IC 50 It can also be measured by a low IC value when measured under substantially similar conditions. 50 Compounds with high IC 50 In some embodiments, the substantially similar conditions include measuring HER2-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells or Ba / F3 cells expressing wild-type HER2, mutant HER2, or any fragment thereof).

[0432] Assays can include, for example, growth inhibition assays, suc...

Claims

1. Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 is: (a)-OL 1 -R 5 ; and selected from the group consisting of: L 1 and L 2 are independently: a bond and 1 to 6 R a C optionally substituted with 1～10 alkylene; R 5 teeth: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are each independently N, N(H), N(R d ), O and S(O) 0～2 and the heteroaryl is selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with ・1 to 4 R c C optionally substituted with 6～10 aryl; ・C 3～10 Cycloalkyl or C 3～10 cycloalkenyl, each optionally substituted with 1 to 4 substituents, each substituent being: oxo and R c C is independently selected from the group consisting of 3～10 Cycloalkyl or C 3～10 cycloalkenyl; ・ wherein Ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X In addition to the nitrogen atom in the ring bonded to d ), O and S(O) 0～2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is an oxo or -R c (independently selected from the group consisting of: ・1 to 6 R a may be substituted with -S(O) 0～2 (C 1～6 alkyl); ・-R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y selected from the group consisting of: However, L 1 If is a bond, R 5 is the following: 1 to 6 R a may be substituted with -S(O) 0～2 (C 1～6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; and -L 5 -R g2 -R Y , other than; R 6 teeth: ・H; · Halo; ·-OH; ・-NR e R f ; ・-R g ; ・-R w ・-L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and ・Each contains 1 to 6 R a optionally substituted with -C 1～6 Alkoxy or -S(O) 0～2 (C 1～6 alkyl) selected from the group consisting of: L 5 and L 6 are independently -O-, -S(O) 0～2 , -NH or -N(R d ) - and; R W Ha-L W -W, where L W is C(=O), S(O) 1～2 , OC(=O) ＊ , NHC(=O) ＊ , N.R. d C(=O) ＊ , NHS(O) 1～2 ＊ or NR d S (O) 1～2 ＊ where the asterisk represents the point of attachment to W, W is C 2～6 Alkenyl; C 2～6 alkynyl; or C 3～10 arenyl, each of which is 1 to 3 R a and R g where W is sp 2 or L through sp hybridized carbon atoms W coupled to, thereby resulting in an α,β-unsaturated system; R X is C(=O)(C 1～6 alkyl) or S(O) 2 (C 1～6 alkyl), each of which is selected from 1 to 6 R a may be substituted with; R Y is:-R g and -(L g ) g -R g selected from the group consisting of: R 1c , R 2a , R 2b , R 3a and R 3b each independently represents: H; halo; -OH; -C(O)OH or -C(O)NH 2 ;-CN;-R b ;-L b -R b ; each contains 1 to 6 R a may be substituted with -C 1～6 Alkoxy or -C 1～6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g wherein R is selected from the group consisting of 1c is other than the following: halo, -CN and -C(O)OH; or Variable section R 1c , R 2a , R 2b , R 3a and R 3b two of which, together with the ring atoms of ring B to which they are attached, form a saturated or unsaturated fused ring of 3 to 12 ring atoms; 0 to 2 of the ring atoms are each independently selected heteroatoms (-N(R 1c When —N(R )— forms part of the saturated or unsaturated fused ring, 1c )—), each of the independently selected heteroatoms is selected from N, NH, N(R d ), O and S(O) 0～2 selected from the group consisting of: The saturated or unsaturated fused ring of 3 to 12 ring atoms is oxo, R c and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 are: H and R d selected from the group consisting of: Each R 7 are independently selected R c and n is 0, 1, 2, or 3; R a Each occurrence of is independently: -OH; -halo; -NR e R f ;C 1～4 Alkoxy;C 1～4 Haloalkoxy; -C(=O)O(C 1～4 alkyl); -C(=O)(C 1～4 alkyl); -C(=O)OH; -CONR'R"; -S(O) 1～2 NR'R”;-S(O) 1～2 (C 1～4 alkyl); and cyano; R b Each occurrence of independently 1～6 Alkyl, C 2～6 Alkenyl or C 2～6 alkynyl, each of which is selected from 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O); C(=O)O; S(O) 1～2 ;C(=O)NH ＊ ;C(=O)NR d＊ ;S(O) 1～2 NH ＊ ; or S(O) 1～2 N (R d ) ＊ where the asterisk is R b represents the point of attachment to; R c each occurrence independently represents: halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1～10 Alkyl; C 3～5 Cycloalkyl; C 2～6 Alkenyl; C 2～6 Alkynyl; C 1～4 Alkoxy or C 1～4 C optionally substituted with haloalkoxy 1～4 Alkoxy;C 1～4 Haloalkoxy; -S(O) 1～2 (C 1～4 alkyl); -S(O)(=NH)(C 1～4 alkyl); -NR e R f ;-OH;-S(O) 1～2 NR'R”;-C 1～4 Thioalkoxy;-NO 2 ;-C(=O)(C 1～10 alkyl); -C(=O)O(C 1～4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF 5 selected from the group consisting of: R d Each occurrence of is independently: 1 to 3 independently selected R a C optionally substituted with 1～6 Alkyl; -C(O)(C 1～4 alkyl); -C(O)O(C 1～4 alkyl);-CONR'R";-S(O) 1～2 NR'R”;-S(O) 1～2 (C 1～4 alkyl); -OH; and C 1～4 selected from the group consisting of alkoxy; R e and R f Each occurrence of is independently: H; 1 to 3 C 1～3 C optionally substituted with alkyl group 3～5 Cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0～2 and the heterocyclyl is independently selected from the group consisting of oxo and R c heterocyclyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: 1～6 alkyl, where each substituent is NR'R", -OH, C 1～6 Alkoxy, C 1～6 C independently selected from the group consisting of haloalkoxy and halo; 1～6 Alkyl; -C(O)(C 1～4 alkyl); -C(O)O(C 1～4 alkyl);-CONR'R";-S(O) 1～2 NR'R”;-S(O) 1～2 (C 1～4 alkyl); -OH; and C 1～4 selected from the group consisting of alkoxy; R g Each occurrence of independently: - oxo and R respectively c C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3～10 Cycloalkyl or C 3～10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0～2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryls containing 5 to 10 ring atoms, of which 1 to 4 are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O and S(O) 0～2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c heteroaryl, optionally substituted with ・1 to 4 R c C optionally substituted with 6～10 Aryl selected from the group consisting of: L g Each occurrence of is independently: -O-, -NH-, -NR d , -S(O) 0～2 , C(O), and 1 to 3 R a C optionally substituted with 1～3 alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is a base; Each occurrence of R' and R" is independently: H; -OH; and C 1～4 selected from the group consisting of alkyl; However, R 2a , R 2b , R 3a and R 3b are H and R 1c is H or methyl; ring A is phenyl optionally substituted with 1 to 2 F; X 1 Ga-OL 1 -R 5 and;-L 1 is CH 2 If: R 5 is other than unsubstituted phenyl and unsubstituted cyclopropyl; Additionally: the compound is other than 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((1-phenylpropan-2-yl)oxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one; A compound or a pharmaceutically acceptable salt thereof.

2. X 1 Ga-OL 1 -R 5 2. The compound of claim 1, wherein:

3. R 5 is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0～2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R cA where each R cA are independently selected R c 2. The compound of claim 1, wherein:

4. R 5 but wherein Ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, of which 0 to 2 ring atoms (R X ) are heteroatoms, and each heteroatom is N, N(H), N(R d ), O and S(O) 0～2 and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents, each of which is selected from the group consisting of: oxo and -R c 2. The compound of claim 1, independently selected from the group consisting of:

5. R 5 Ga-R g2 -R W 2. The compound of claim 1, wherein:

6. R 5 R W 2. The compound of claim 1, wherein:

7. R 5 Ga-R g2 -R Y 2. The compound of claim 1, wherein:

8. R 5 C, each of which is optionally substituted with 1 to 4 substituents 3～10 Cycloalkyl or C 3～10 cycloalkenyl, each substituent being: oxo and R c 2. The compound of claim 1, independently selected from the group consisting of:

9. R 5 However, 1 to 6 R a may be substituted with -S(O) 0～2 (C 1～6 2. The compound of claim 1, wherein the aryl group is aryl, ...

10. R 5 But -L 5 -R g , -L 5 -R g2 -R Y and -L 5 -R g2 -R W 2. The compound of claim 1, selected from:

11. L 1 However, 1 to 6 R a C optionally substituted with 1～10 2. The compound of claim 1, which is an alkylene.

12. L 1 2. The compound of claim 1, wherein is a bond.

13. X 1 but 2. The compound of claim 1, wherein:

14. R 6 R g 2. The compound of claim 1, wherein:

15. R 6 Ga-R g2 -R W or -R g2 -R Y 2. The compound of claim 1, wherein:

16. R 6 Ga-R W 2. The compound of claim 1, wherein:

17. R 6 However, each has 1 to 6 R a optionally substituted with -C 1～6 Alkoxy or -S(O) 0～2 (C 1～6 2. The compound of claim 1, wherein the aryl group is aryl, ...

18. 2. The compound of claim 1, wherein n is 0.

19. R 1c 2. The compound of claim 1, wherein

20. R 2a and R 2b 2. The compound of claim 1, wherein

21. R 3a and R 3b 2. The compound of claim 1, wherein

22. Ring A where each R cB are independently selected R c 2. The compound of claim 1, wherein:

23. 23. The compound of claim 22, wherein m is 1 or 2.

24. Ring A where R cB1 is R c and;R cB2 is H or R c 2. The compound of claim 1, wherein:

25. Ring A 2. The compound of claim 1, wherein:

26. Ring A is a heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O and S(O) 0～2 and the heteroaryl is independently selected from the group consisting of 1 to 4 R c 2. The compound of claim 1, optionally substituted with:

27. R 4 2. The compound of claim 1, wherein

28. The following table:

2. The compound of claim 1, selected from the group consisting of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

29. The compound or a pharmaceutically acceptable salt thereof.

30. 30. A pharmaceutical composition comprising the compound of claim 1 or 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

31. 30. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of claim 1 or 29 or a pharmaceutically acceptable salt thereof.

32. 30. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of claim 1 or 29 or a pharmaceutically acceptable salt thereof, (a) determining that the cancer is associated with dysregulation of the expression or activity or levels of the EGFR gene, EGFR kinase, or any of them; and (b) administering the pharmaceutical composition to the subject. A pharmaceutical composition for use in a method comprising:

33. 30. A pharmaceutical composition for treating EGFR-associated cancer in a subject, comprising a therapeutically effective amount of a compound of claim 1 or 29 or a pharmaceutically acceptable salt thereof, A pharmaceutical composition administered to a subject identified or diagnosed as having an EGFR-associated cancer.

34. 33. The pharmaceutical composition of claim 32, wherein the dysregulation of the expression or activity or level of the EGFR gene, the EGFR kinase protein, or any thereof is one or more point mutations in the EGFR gene.

35. The one or more point mutations in the EGFR gene are selected from the following: and 35. The pharmaceutical composition of claim 34, which results in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the amino acid positions set forth in

36. The one or more point mutations are those listed in the table below: and 36. The pharmaceutical composition of claim 35, wherein the mutation is selected from the following:

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