PARG inhibitors

Abstract

The present invention relates to sulfonamides and related compounds that are inhibitors of PARG and are useful in the treatment of cancer. [Formula 1] JPEG2025505882000217.jpg33164

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 309,753, filed February 14, 2022.

[0002] The present invention relates to sulfonamides and related compounds that are inhibitors of PARG and are useful in the treatment of cancer. [Background technology]

[0003] Cancer is a disease caused by abnormal and unregulated cell division.One of the characteristics of cancer is the upregulation or downregulation of cellular stress pathways, which cancer cells or tumors use to proliferative advantage.These cellular stress pathways often include, but are not limited to, oxidative stress, DNA damage stress, DNA replication stress, transcription stress, hypoxia, and others.

[0004] ADP-ribose, and the enzymes that produce ADP-ribose (poly(ADP-ribose) polymerase, or PARP) and hydrolyze ADP-ribose (poly(ADP-ribose) glycohydrolase, or PARG), play important roles in regulating cellular stress responses. There are two forms of ADP-ribose in cells: mono(ADP-ribose) (MAR) and poly(ADP-ribose) (PAR). Both forms of ADP-ribose are produced by a family of 17 PARP proteins, whose key role in cells is to regulate cellular stress responses (Cohen MS, Chang P. Nat Chem Biol. 2018).

[0005] In humans, PARG exists as a single gene with three splice isoforms. These isoforms function and localize in the nucleus, cytoplasm, and mitochondria. The best understood function of PARG is DNA damage repair. However, PARG also regulates gene splicing, transcription, and epigenetic pathways (Bock FJ, Todorova TT, Chang P. Mol Cell 2015), (Le May, Litis et al. Mol Cell. 2012), (Dahl, Maturi et al. Plos One, 2014), (Guastafierro, Catizone et al. Biochem J 2013), (Caiafa, Guastafierro et al. FASEB J 2009), cell division (Chang and Mitchison Nature 2004), cytoplasmic stress response (Leung, Chang et al. Mol Cell 2011), and other cellular stresses.

[0006] Modulation of both MAR and PAR levels has been shown to be an effective treatment for several cancers. Inhibiting ADP-ribose synthesis through the use of PARP inhibitors can be used for the treatment of several cancer types. PARG inhibitors act by modulating cellular stress responses, such as DNA damage response (DDR) and replication stress response. DDR and replication stress are very important cellular stress responses for cancer because they are the outcome of all cellular stress responses and therefore many cancers have them. Cancers accumulate DNA damage due to upregulation of cellular stress pathways and subsequent errors in DNA replication. In cancer, single-strand breaks (SSBs) are the most common type of DNA damage lesion, and PARG, together with PARP1, plays an important role in single-strand break repair (SSBR) and another repair mechanism called base excision repair (BER). PARP1 recognizes the break, binds to it, and rapidly synthesizes PAR on itself (automodification) and on histone proteins. Multiple DNA repair proteins, including the master regulator XRCC1, bind to newly synthesized PAR, are recruited to PAR, and then repair the break (Mortusewicz, Fouquerel et al. Nucleic Acid Res. 2011). Thus, the rapid increase of PAR acts as an important DNA repair signal. The signal initiated by PAR is transient, since PAR becomes rapidly degraded by PARG. If PARG is absent or nonfunctional, PAR rapidly accumulates and is toxic in cancer cells, leading to cell death. When PARP1 binds to PAR or is automodified by PAR, its catalytic ability is reduced, and thus PARG activity is an important regulator that supports the activation of PARP1 and keeps DNA damage repair signal "on" (Curtin and Szabo Mol Aspects Med. 2013).

[0007] PARG depletion by RNA interference (RNAi) has been shown to kill cancer cells and cause tumor regression in multiple mouse cancer models. Human and mouse cells with null or depleted PARG show increased sensitivity to DNA damaging agents, demonstrating a general defect in DNA damage-associated stress response upon inhibition or depletion of PARG. Other cancer-associated stress pathways have also been shown to be defective upon PARG knockdown, suggesting that PARG is an attractive target for the treatment of multiple cancer types. In humans, PARG depletion kills lung, ovarian, breast, cervical, and pancreatic cancer cells in vitro. Xenograft models of these human cancers implanted into mice show tumor regression when PARG protein expression is knocked down. Taken together, these results demonstrate that PARG is an effective target for the treatment of multiple stress-dependent cancers and cancers where cellular stress responses may not be evident. The present invention aims to provide a cell-permeable inhibitor of PARG. Summary of the Invention

[0008] The present invention relates to a compound of formula I: [ka] Compound or a pharma- ceutically acceptable salt thereof, wherein the constituent members are defined below.

[0009] The present invention further relates to a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0010] The present invention further relates to a method of inhibiting the activity of PARG, comprising contacting PARG with a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0011] The present invention further relates to a method for treating a disease or disorder in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the disease or disorder is characterized by overexpression or increased activity of PARG.

[0012] The present invention further relates to a method for treating cancer in a subject in need of cancer treatment, comprising administering to the subject a therapeutically effective amount of an agent that inhibits PARG activity, such as a compound of formula I or a pharma- ceutically acceptable salt thereof.The present disclosure also provides the use of the compounds described herein in the manufacture of a medicament for use in therapy.The present disclosure also provides the compounds described herein for use in therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention relates to a compound of formula I: [ka] Compound or a pharma- ceutically acceptable salt thereof, A is a group represented by the formula: [ka] is a group having the formula: B is a compound of formula (a), formula (b), or formula (c): [ka] is the basis of; X 1 is N or CR 1 and; X 2 is N or CR 2 and; X 3 is N or CR 3 and; X 4 is N or CR4 and; X 5 is N or CR 5 and; X 6 is N or CR 6 and; X 7 is N or CR 7 and; X 8 is N or CR 8 and; X 9 is N or CR 9 and; X 1 , X 2 , and X 3 Not more than two of are simultaneously N; X 4 , X 5 , and X 6 Not more than two of are simultaneously N; X 7 , X 8 , and X 9 Not more than two of are simultaneously N; R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are H, halo, and C, respectively. 1-4 independently selected from alkyl; R 3 , R 6 , and R 9 are H, halo, and NR, respectively. c R d , OR a , C 6-10 Aryl, C 3-7 R is independently selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 3 , R 6 , and R 9 The above C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 H, halo, C1-4 Alkyl, or C 1-4 is haloalkyl; R A and R B are H and C, respectively. 1-4 Alkyl, and C 2-6 alkenyl; R A and R B The above C 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O)2 NR c1 R d1 optionally substituted with 1, 2, or 3 substituents independently selected from R A and R B at least one of is other than H; R C1 and R C2 is C 1-6 Alkyl, C 2-6 alkenyl, and 5-membered heteroaryl; R C1 and R C2 The above C 1-6 Alkyl, C 2-6 alkenyl, and 5-membered heteroaryl are each selected from halo, C 1-6 C substituted with alkyl, R' 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)Rb2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R' is halo, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 are independently selected from; R D1 and R D2 H, halo, and C 1-4 independently selected from alkyl; R 11 H, CN, CCR”, CH 3 , C.H. 2 CN, CH 2 OH, CHF 2 , or C.H. 2 F; R” is H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , or N.R. c3 R d3 and; R 12 is H or F; R 13 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , or S(O) 2 NR c3 R d3 and R 13 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R.c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: [ka] If R is a group 13 H, CH 3 , and other than CN; Or, R 12 and R 13 are C groups containing, together with the C atom to which they are attached, one heteroatom selected from N and O. 3 cycloalkyl or 3-membered heterocycloalkyl group, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NRe3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 optionally substituted with 1, 2, or 3 substituents independently selected from Each Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R.c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 , H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl; Ra , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or, R c and R d together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O)2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Or, R c1 and R d1 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4optionally substituted with 1, 2, or 3 substituents independently selected from Or, R c2 and R d2 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Or, R c3 and R d3 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Each R a4 , R b4 , R c4 , and R d4 , H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , R e1 , R e2 , R e3 , and R e4 , H, C 1-4 alkyl, and CN.

[0014] The present invention relates to a compound of formula I: [ka] Compound or a pharma- ceutically acceptable salt thereof, A is a group represented by the formula: [ka] is a group having the formula: B is a compound of formula (a), formula (b), or formula (c): [ka] is the basis of; X 1 is N or CR 1 and; X 2 is N or CR 2 and; X 3 is N or CR 3 and; X 4 is N or CR 4 and; X 5 is N or CR 5 and; X 6 is N or CR 6 and; X 7 is N or CR 7 and; X 8 is N or CR 8 and; X 9 is N or CR 9 and; X 1 , X 2 , and X 3 Not more than two of are simultaneously N; X 4 , X 5 , and X 6 Not more than two of are simultaneously N; X 7 , X 8 , and X 9 Not more than two of are simultaneously N; R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are H, halo, and C, respectively. 1-4 independently selected from alkyl; R 3 , R 6 , and R 9 are H and C, respectively.6-10 Aryl, C 3-7 R is independently selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 3 , R 6 , and R 9 The above C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c Rd , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 H, halo, C 1-4 Alkyl, or C 1-4 is haloalkyl; R A and R B are H and C, respectively. 1-4 Alkyl, and C 2-6 alkenyl; R A and R B The above C 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)Rb1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, or 3 substituents independently selected from R A and R B at least one of is other than H; R C1 and R C2 is C 1-6 Alkyl, C 2-6 alkenyl, and 5-membered heteroaryl; R C1 and R C2 The above C 1-6 Alkyl, C 2-6 alkenyl, and 5-membered heteroaryl are each selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NRc2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R D1 and R D2 H, halo, and C 1-4 independently selected from alkyl; R 11 CN, CH 3 , CHF 2 , or C.H. 2 F; R 12 is H or F; R 13 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , or S(O) 2 NR c3 R d3 and R 13 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 Rb3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: [ka] If R is a group 13 H, CH 3 , and other than CN; Or, R 12 and R 13 are C groups containing, together with the C atom to which they are attached, one heteroatom selected from N and O. 3 cycloalkyl or 3-membered heterocycloalkyl group, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 Rd3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 optionally substituted with 1, 2, or 3 substituents independently selected from Each Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R.c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 , H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl; R a , R b , Rc , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or, R c and R d together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R.c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Or, R c1 and R d1 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Or, R c2 and R d2 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Or, R c3 and R d3 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)Rb4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 optionally substituted with 1, 2, or 3 substituents independently selected from Each R a4 , R b4 , R c4 , and R d4 , H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , R e1 , R e2 , R e3 , and R e4 , H, C 1-4 alkyl, and CN.

[0015] In some embodiments, A is [ka] It is.

[0016] In some embodiments, A is [ka] It is.

[0017] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0018] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0019] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0020] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0021] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0022] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0023] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0024] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0025] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0026] In some embodiments, A has the formula: [ka] It is a group having the formula:

[0027] In some embodiments, A is [ka] is selected from.

[0028] In some embodiments, A is [ka] [ka] is selected from.

[0029] In some embodiments, A is of the formula: [ka] If R is a group 13 H, CH 3 , fluoro, and CN.

[0030] In some embodiments, A is of the formula: [ka] If R is a group 13 H, CH 3 , and other than fluoro.

[0031] In some embodiments, B is represented by formula (a) or formula (b): [ka] is the basis.

[0032] In some embodiments, B has the formula (a): [ka] It is.

[0033] In some embodiments, B has the formula (b): [ka] It is.

[0034] In some embodiments, B is of formula (c): [ka] It is.

[0035] In some embodiments, A is [ka] and; B is a compound represented by the formula (a): [ka] It is.

[0036] In some embodiments, A is [ka] and; B is a compound represented by the formula (a): [ka] It is.

[0037] In some embodiments, A is [ka] and; B is a compound represented by the formula (b): [ka] It is.

[0038] In some embodiments, X 1 is N. In some embodiments, X 1 is CR 1 It is.

[0039] In some embodiments, X 2 is N. In some embodiments, X 2 is CR 2 It is.

[0040] In some embodiments, X 3 is N. In some embodiments, X 3 is CR 3 It is.

[0041] In some embodiments, X 4 is N. In some embodiments, X 4 is CR 4 It is.

[0042] In some embodiments, X 5 is N. In some embodiments, X 5 is CR 5 It is.

[0043] In some embodiments, X 6 is N. In some embodiments, X 6 is CR 6 It is.

[0044] In some embodiments, X 7 is N. In some embodiments, X 7 is CR 7 It is.

[0045] In some embodiments, X 8 is N. In some embodiments, X 8 is CR 8 It is.

[0046] In some embodiments, X 9 is N. In some embodiments, X 9 is CR 9 It is.

[0047] In some embodiments, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 It is.

[0048] In some embodiments, X 4 is CR 4 and X 5 is CR 5 and X 6 is CR 6 It is.

[0049] In some embodiments, X 7 is CR 7 and X8 is CR 8 and X 9 is CR 9 It is.

[0050] In some embodiments, R 1 is H. In some embodiments, R 1 is halo. In some embodiments, R 1 is C 1-4 It is an alkyl.

[0051] In some embodiments, R 2 is H. In some embodiments, R 2 is halo. In some embodiments, R 2 is C 1-4 It is an alkyl.

[0052] In some embodiments, R 3 is H. In some embodiments, R 3 is C 6-10 In some embodiments, R 3 is C 3-7 In some embodiments, R 3 is 5-10 membered heteroaryl. In some embodiments, R 3 is 4 to 10 membered heterocycloalkyl. In some embodiments, R 3 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and wherein the aryl group is substituted with 1, 2, 3, or 4 substituents independently selected from:

[0053] In some embodiments, R 3 is halo. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is bromo. In some embodiments, R 3 is iodo. In some embodiments, R 3is NR c R d In some embodiments, R 3 is N(CH 3 ) 2 In some embodiments, R 3 OR a In some embodiments, R 3 is OH. In some embodiments, R 3 OCH 3 In some embodiments, R 4 is H. In some embodiments, R 4 is halo. In some embodiments, R 4 is C 1-4 It is an alkyl.

[0054] In some embodiments, R 5 is H. In some embodiments, R 5 is halo. In some embodiments, R 5 is C 1-4 It is an alkyl.

[0055] In some embodiments, R 6 is H. In some embodiments, R 6 is C 6-10 In some embodiments, R 6 is C 3-7 In some embodiments, R 6 is 5-10 membered heteroaryl. In some embodiments, R 6 is 4 to 10 membered heterocycloalkyl. In some embodiments, R 6 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and wherein the aryl group is substituted with 1, 2, 3, or 4 substituents independently selected from:

[0056] In some embodiments, R 6 is C 6-10 Aryl, C 3-7cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are also included, including halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 Rb , and S(O) 2 NR c R d and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0057] In some embodiments, R 6 is halo. In some embodiments, R 6 is fluoro. In some embodiments, R 6 is chloro. In some embodiments, R 6 is bromo. In some embodiments, R 6 is iodo. In some embodiments, R 6 is NR c R d In some embodiments, R 6 is N(CH 3 ) 2 In some embodiments, R 6 OR a In some embodiments, R 6 is OH. In some embodiments, R 6 OCH 3 It is.

[0058] In some embodiments, R 6 is 4 to 10 membered heterocycloalkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d, C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0059] In some embodiments, R 6 is piperazinyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R.a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0060] In some embodiments, R 7 is H. In some embodiments, R 7 is halo. In some embodiments, R 7 is C 1-4 It is an alkyl.

[0061] In some embodiments, R 8 is H. In some embodiments, R 8 is halo. In some embodiments, R8 is C 1-4 It is an alkyl.

[0062] In some embodiments, R 9 is H. In some embodiments, R 9 is C 6-10 In some embodiments, R 9 is C 3-7 In some embodiments, R 9 is 5-10 membered heteroaryl. In some embodiments, R 9 is 4 to 10 membered heterocycloalkyl. In some embodiments, R 9 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b, N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and wherein the aryl group is substituted with 1, 2, 3, or 4 substituents independently selected from:

[0063] In some embodiments, R 9 is halo. In some embodiments, R 9 is fluoro. In some embodiments, R 9 is chloro. In some embodiments, R 9 is bromo. In some embodiments, R 9 is iodo. In some embodiments, R 9 is NR c R d In some embodiments, R 9 is N(CH 3 ) 2 In some embodiments, R 9 OR a In some embodiments, R 9 is OH. In some embodiments, R 9 OCH 3 It is.

[0064] In some embodiments, R 1 is H and R 2 is H and R 3 is H.

[0065] In some embodiments, R 4 is H and R 5 is H and R 6 is H.

[0066] In some embodiments, R 7 is H and R 8 is H and R 9 is H.

[0067] In some embodiments, R 10 is H. In some embodiments, R 10 is halo. In some embodiments, R 10 is C 1-4 In some embodiments, R 10 is C 1-4 It is haloalkyl.

[0068] In some embodiments, R A is H. In some embodiments, R A is C 1-4 In some embodiments, R A is ethyl. In some embodiments, R A is C 2-6 In some embodiments, R A is C 1-4 Alkyl and C 2-6 alkenyl; Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NRe1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0069] In some embodiments, R A is C 1-4 Alkyl, Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NRe1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0070] In some embodiments, R A is C 1-4 Cy is an alkyl and optionally substituted 1 It is.

[0071] In some embodiments, R A is C 2-6 alkenyl, Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NRe1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0072] In some embodiments, R A is C 2-6 alkenyl, C(O)R b1 , C(O)NR c1 R d1 , and C(O)OR a1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0073] In some embodiments, R A teeth, [ka] is selected from.

[0074] In some embodiments, R Bis H. In some embodiments, R B is C 1-4 In some embodiments, R B is C 2-6 In some embodiments, R B is C 1-4 Alkyl and C 2-6 alkenyl; Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0075] In some embodiments, R B H and C 1-4 alkyl, 1-4 Alkyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0076] In some embodiments, R B is C 1-4 Alkyl, Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0077] In some embodiments, R B is C 1-4 Alkyl, Cy 1 is optionally replaced by

[0078] In some embodiments, R B teeth, [ka] is selected from.

[0079] In some embodiments, R A is C 1-4 Alkyl and C 2-6 alkenyl, 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , C(O)R b1 , C(O)NR c1 R d1 , and C(O)OR a1 optionally substituted independently with 1, 2, or 3 substituents independently selected from R B H and C 1-4 alkyl, 1-4 Alkyl is Cy 1 is optionally replaced by

[0080] In some embodiments, R A and R B are respectively, C 1-4 It is an alkyl.

[0081] In some embodiments, R A and R B are each ethyl.

[0082] In some embodiments, R A teeth, [ka] Selected from; R B teeth, [ka] is selected from.

[0083] In some embodiments, R C1 is C 1-6 In some embodiments, R C1 is C 2-6 In some embodiments, R C1 is a 5-membered heteroaryl. In some embodiments, R C1 is C 1-6 Alkyl, C 2-6 alkenyl, and 5-membered heteroaryl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2, N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and wherein the aryl group is substituted with 1, 2, 3, or 4 substituents independently selected from:

[0084] In some embodiments, R C1 CH 3 It is.

[0085] In some embodiments, R C1 is a 5-membered heteroaryl; halo, C 1-6 C substituted with alkyl, R' 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R.a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0086] In some embodiments, R C1 is a 5-membered heteroaryl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0087] In some embodiments, R C1 is 1,3,4-thiadiazyl, halo, C 1-6 C substituted with alkyl, R' 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0088] In some embodiments, R C1 is 1,3,4-thiadiazyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 Rd2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0089] In some embodiments, R C1 is 1,3,4-thiadiazyl. In some embodiments, R C1 is 1,3,4-thiadiazyl, C 1-6 In some embodiments, R C1 is 1,3,4-thiadiazyl and is substituted with methyl. C1 is 1,3,4-thiadiazyl, C substituted by R' 1-6 In some embodiments, R C1 is 1,3,4-thiadiazyl, S(O) 2 R b2 C replaced by 1-6 In some embodiments, R C1 is 1,3,4-thiadiazyl, C 2-6 In some embodiments, R C1 is 1,3,4-thiadiazyl, C 3-7 Substituted by cycloalkyl.

[0090] In some embodiments, R C1 is 1,3,4-thiadiazyl, C 1-6 Substituted by haloalkyl.

[0091] In some embodiments, R C1 teeth, [ka] is selected from.

[0092] In some embodiments, R C1 teeth, [ka] In some embodiments, R C2 is C 1-6 In some embodiments, R C2 is C 2-6 In some embodiments, R C2 is a 5-membered heteroaryl. In some embodiments, R C2 is C 1-6 Alkyl, C 2-6 alkenyl, and 5-membered heteroaryl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R.c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 and wherein the aryl group is substituted with 1, 2, 3, or 4 substituents independently selected from:

[0093] In some embodiments, R D1 is H. In some embodiments, R D1 is halo. In some embodiments, R D1 is C 1-4 It is an alkyl.

[0094] In some embodiments, R D2 is H. In some embodiments, R D2 is halo. In some embodiments, R D2 is C 1-4 It is an alkyl.

[0095] In some embodiments, R 11 CN, CH 3 , CHF 2 , or C.H. 2 F. In some embodiments, R 11 CN, CH 3 , or C.H. 2 F. In some embodiments, R 11is CN. In some embodiments, R 11 CH 3 In some embodiments, R 11 is CHF 2 In some embodiments, R 11 CH 2 It's F.

[0096] In some embodiments, R 11 is H. In some embodiments, R 11 CH 2 In some embodiments, R 11 CH 2 CN. In some embodiments, R 11 is CCR”. In some embodiments, R 11 is CCH.

[0097] In some embodiments, R 12 is H. In some embodiments, R 12 is F.

[0098] In some embodiments, R 13 is H. In some embodiments, R 13 is halo. In some embodiments, R 13 is C 1-6 In some embodiments, R 13 is C 2-6 In some embodiments, R 13 is C 2-6 In some embodiments, R 13 is C 1-6 In some embodiments, R 13 is C 6-10 In some embodiments, R 13 is C 3-7 In some embodiments, R 13 is 5-10 membered heteroaryl. In some embodiments, R13 is 4 to 10 membered heterocycloalkyl. In some embodiments, R 13 is C 6-10 Aryl-C 1-4 In some embodiments, R 13 is C 3-7 Cycloalkyl-C 1-4 In some embodiments, R 13 is a 5- to 10-membered heteroaryl-C 1-4 In some embodiments, R 13 is 4-10 membered heterocycloalkyl-C 1-4 In some embodiments, R 13 is CN. In some embodiments, R 13 NO 2 In some embodiments, R 13 OR a3 In some embodiments, R 13 is SR a3 In some embodiments, R 13 is C(O)R b3 In some embodiments, R 13 is C(O)NR c3 R d3 In some embodiments, R 13 is C(O)OR a3 In some embodiments, R 13 is O.C.(O)R b3 In some embodiments, R 13 is OC(O)NR c3 R d3 In some embodiments, R 13 is C(=NR e3 )NR c3 R d3 In some embodiments, R 13 is NR c3 C(=NR e3 )NR c3 R d3 In some embodiments, R 13 is NRc3 R d3 In some embodiments, R 13 is NR c3 C(O)R b3 In some embodiments, R 13 is NR c3 C(O)OR a3 In some embodiments, R 13 is NR c3 C(O)NR c3 R d3 In some embodiments, R 13 is NR c3 S(O)R b3 In some embodiments, R 13 is NR c3 S(O) 2 R b3 In some embodiments, R 13 is NR c3 S(O) 2 NR c3 R d3 In some embodiments, R 13 is S(O)R b3 In some embodiments, R 13 is S(O)NR c3 R d3 In some embodiments, R 13 is S(O) 2 R b3 In some embodiments, R 13 is S(O) 2 NR c3 R d3 In some embodiments, R 13 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NRc3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and wherein the aryl group is substituted with 1, 2, 3, or 4 substituents independently selected from:

[0099] In some embodiments, R 13 is C 1-6 Alkyl, CN and OR a3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0100] In some embodiments, R 13 is H, ethyl, CH 2 CN and CH 2 CH 2 OH.

[0101] In some embodiments, R 13 is H, methyl, ethyl, ethenyl, CH 2 CN, CH 2 OH, CH 2 CH 2 OH and CH 2 CH 2 OCH 3 is selected from.

[0102] In some embodiments, R 12 and R 13 together with the C atom to which they are attached, 3 Forms a cycloalkyl group. In some embodiments, R 12 and R 13 together with the C atom to which they are attached, 3 Forming a cycloalkyl group, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3, C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0103] In some embodiments, R 12 and R 13 together with the C atom to which they are attached form a 3-membered heterocycloalkyl group containing one N atom. In some embodiments, R 12 and R 13 together with the C atom to which they are attached form a 3-membered heterocycloalkyl group containing one N atom, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)Rb3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 In some embodiments, R 12 and R 13 together with the C atom to which they are attached form a 3-membered heterocycloalkyl group containing one O atom. In some embodiments, R 12 and R 13 together with the C atom to which they are attached form a 3-membered heterocycloalkyl group containing one O atom, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 Rd3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0104] In some embodiments, R 12 and R 13 are each H.

[0105] In some embodiments, R 11 , R 12 and R 13 are each H.

[0106] In some embodiments, R 11 CN, CH 3 , or C.H. 2 F;R 12 is H;R 13 is H.

[0107] In some embodiments, at least one Cy 1 is C 6-10 In some embodiments, at least one Cy is aryl.1 is C 3-7 In some embodiments, at least one Cy is cycloalkyl. 1 is 5-10 membered heteroaryl. In some embodiments, at least one Cy 1 is 4-10 membered heterocycloalkyl. In some embodiments, at least one Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and wherein the aryl group is substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0108] In some embodiments, at least one Cy 1 is a 4-membered heterocycloalkyl. In some embodiments, at least one Cy 1 is oxetanyl. In some embodiments, at least one Cy 1 teeth, [ka] It is.

[0109] In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , Rc2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 1-6 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 1-6 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 2-6 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 2-6In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 6-10 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 3-7 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of R is a 5-10 membered heteroaryl. a , R b , R c , R d , R a1 , R b1 , R c1 , Rd1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of R is 4-10 membered heterocycloalkyl. a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 6-10 Aryl-C 1-4 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 3-7 Cycloalkyl-C 1-4 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , Rb3 , R c3 , and R d3 At least one of the 5- to 10-membered heteroaryl-C 1-4 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of the 4- to 10-membered heterocycloalkyl-C 1-4 In some embodiments, R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 At least one of them is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 and wherein the aryl group is substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0110] In some embodiments, R c and R d together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group. c and R d together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0111] In some embodiments, R c1 and R d1 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group. c1 and R d1 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R.a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0112] In some embodiments, R c2 and R d2 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group. c2 and R d2 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NRc4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0113] In some embodiments, R c3 and R d3 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group. c3 and R d3 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4, O.C.(O)R b4 , O-C(O)NR c4 R d4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)NR c4 R d4 , N.R. c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 and wherein the aryl group is substituted with 1, 2, or 3 substituents independently selected from:

[0114] In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of R a4 , R b4 , R c4 , and R d4 At least one of them is C 1-6 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of them is C 1-6 In some embodiments, R a4 , R b4 , Rc4 , and R d4 At least one of them is C 2-6 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of them is C 2-6 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of them is C 6-10 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of them is C 3-7 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of R is a 5-10 membered heteroaryl. a4 , R b4 , R c4 , and R d4 At least one of R is 4-10 membered heterocycloalkyl. a4 , R b4 , R c4 , and R d4 At least one of them is C 6-10 Aryl-C 1-4 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of them is C 3-7 Cycloalkyl-C 1-4 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of the 5- to 10-membered heteroaryl-C 1-4In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of the 4- to 10-membered heterocycloalkyl-C 1-4 In some embodiments, R a4 , R b4 , R c4 , and R d4 At least one of them is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substituted with 1, 2, or 3 substituents independently selected from haloalkoxy.

[0115] In some embodiments, R e , R e1 , R e2 , R e3 , and R e4 At least one of R e , R e1 , R e2 , R e3 , and R e4 At least one of them is C 1-4 In some embodiments, R e , R e1 , R e2 , R e3, and R e4 At least one of the is CN.

[0116] In some embodiments, the compound of formula IIA: [ka] Provided herein are compounds of formula (I) having the formula:

[0117] In some embodiments, the compound of formula IIB: [ka] Provided herein are compounds of formula (I) having the formula:

[0118] In some embodiments, the compound of formula IIC: [ka] Provided herein are compounds of formula (I) having the formula:

[0119] In some embodiments, the compound of formula IIA-1: [ka] Provided herein are compounds of formula (I) having the formula:

[0120] In some embodiments, the compound of formula IIA-2: [ka] Provided herein are compounds of formula (I) having the formula:

[0121] In some embodiments, the compound of formula IIA-3: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R f is R b1 , N.R. c1 R d1 OR a1 is] is provided herein.

[0122] In some embodiments, R f is R b1 It is.

[0123] In some embodiments, R f is NR c1 R d1 It is.

[0124] In some embodiments, R f OR a1 It is.

[0125] In some embodiments, the compound of formula IIA-4: [ka] Provided herein are compounds of formula (I) having the formula:

[0126] In some embodiments, the compound of formula IIB-1: [ka] Provided herein are compounds of formula (I) having the formula:

[0127] In some embodiments, the compound of formula IIB-2: [ka] Provided herein are compounds of formula (I) having the formula:

[0128] In some embodiments, the compound of formula IIB-2: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R C’ Halo, C 1-6 C substituted with alkyl, R' 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2, N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 Select from is provided herein.

[0129] In some embodiments, the compound of formula IIC-1: [ka] Provided herein are compounds of formula (I) having the formula:

[0130] In some embodiments, the compound of formula IIC-2: [ka] Provided herein are compounds of formula (I) having the formula:

[0131] In some embodiments, the compound of formula IIIA: [ka] Provided herein are compounds of formula (I) having the formula:

[0132] In some embodiments, the compound of formula IIIB: [ka] Provided herein are compounds of formula (I) having the formula:

[0133] In some embodiments, the compound of formula IIIC: [ka] Provided herein are compounds of formula (I) having the formula:

[0134] In some embodiments, the compound of formula IIID: [ka] Provided herein are compounds of formula (I) having the formula:

[0135] In some embodiments, the compound of formula IIIE: [ka] Provided herein are compounds of formula (I) having the formula:

[0136] In some embodiments, the compound of formula IIIF: [ka] Provided herein are compounds of formula (I) having the formula:

[0137] In some embodiments, the compound of formula IIIG: [ka] Provided herein are compounds of formula (I) having the formula:

[0138] In some embodiments, the compound of formula IVA: [ka] Provided herein are compounds of formula (I) having the formula:

[0139] In some embodiments, the compound of formula IVB: [ka] or a pharma- ceutically acceptable salt thereof. [Wherein Z is CH 2 , O, or S] is provided herein.

[0140] In some embodiments, the compound of formula IVB': [ka] or a pharma- ceutically acceptable salt thereof. [Wherein Z is CH 2 , N, O, or S] is provided herein.

[0141] In some embodiments, the compound of formula IVB-1: [ka] Provided herein are compounds of formula (I) having the formula:

[0142] In some embodiments, the compound of formula IVB-2: [ka] or a pharma- ceutically acceptable salt thereof. [Wherein Z is CH 2 , O, or S] is provided herein.

[0143] In some embodiments, the compound of formula IVB-2': [ka] or a pharma- ceutically acceptable salt thereof. [Wherein Z is CH 2 , N, O, or S] is provided herein.

[0144] In some embodiments, Z is CH 2 It is.

[0145] In some embodiments, Z is N.

[0146] In some embodiments, Z is O.

[0147] In some embodiments, Z is S.

[0148] In some embodiments, a compound of formula (I) or a pharma- ceutically acceptable salt thereof is provided, A is a group represented by the formula: [ka] is a group having the formula: B is a compound of formula (a), formula (b), or formula (c): [ka] is the basis of; X 1 is CR 1 and; X 2 is CR 2 and; X 3 is CR 3 and; X 4 is CR 4 and; X 5 is CR 5 and; X 6 is CR 6 and; X 7 is CR 7 and; X 8 is CR 8 and; X 9 is CR 9 and; R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are H, halo, and C, respectively. 1-4 independently selected from alkyl; R 3 , R 6 , and R 9 are H, halo, and NR, respectively. c R d , OR a , C 6-10 Aryl, C 3-7 R is independently selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 3 , R 6 , and R 9 The above C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 is H; R A and R B are H and C, respectively. 1-4 Alkyl, and C 2-6 alkenyl; R A and R B The above C1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, or 3 substituents independently selected from R A and R B at least one of is other than H; R C1 and R C2is a 5-membered heteroaryl; R C1 and R C2 wherein each of said 5-membered heteroaryls is halo, C 1-6 C substituted with alkyl, R' 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NRc2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R' is halo, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 are independently selected from; R D1 and R D2 is H; R 11 are H, CN, and CH 3 , C.H.2 OH, CHF 2 , or C.H. 2 F; R 12 is H; R 13 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3, S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , or S(O) 2 NR c3 R d3 and R 13 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: [ka] If R is a group 13 H, CH 3 , and other than CN; Or, R 12 and R 13 are C groups containing, together with the C atom to which they are attached, one heteroatom selected from N and O. 3 cycloalkyl or 3-membered heterocycloalkyl group, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 Rd3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 each is a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocycloalkyl; each is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1, O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 are H and C, respectively. 1-6 independently selected from alkyl; R e , R e1 , R e2 , R e3 , and R e4 are H and C, respectively.1-4 alkyl, independently selected from is provided herein.

[0149] In some embodiments, a compound of formula (I) or a pharma- ceutically acceptable salt thereof is provided, A is a group represented by the formula: [ka] is a group having the formula: B is a compound of formula (a), formula (b), or formula (c): [ka] is the basis of; X 1 is CR 1 and; X 2 is CR 2 and; X 3 is CR 3 and; X 4 is CR 4 and; X 5 is CR 5 and; X 6 is CR 6 and; X 7 is CR 7 and; X 8 is CR 8 and; X 9 is CR 9 and; R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are H, halo, and C, respectively. 1-4 independently selected from alkyl; R 3 , R 6 , and R 9 are H and C, respectively.6-10 Aryl, C 3-7 R is independently selected from cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 3 , R 6 , and R 9 The above C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c Rd , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 is H; R A and R B are H and C, respectively. 1-4 Alkyl, and C 2-6 alkenyl; R A and R B The above C 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 Rb1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, or 3 substituents independently selected from R A and R B at least one of is other than H; R C1 and R C2 is a 5-membered heteroaryl; R C1 and R C2 wherein each of said 5-membered heteroaryls is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R.c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R D1 and R D2 is H; R 11 CN, CH 3 , CHF 2 , or C.H. 2 F; R 12 is H; R 13 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R.a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , or S(O) 2 NR c3 R d3 and R 13 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NRc3 R d3 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: [ka] If R is a group 13 H, CH 3 , and other than CN; Or, R 12 and R 13 are C groups containing, together with the C atom to which they are attached, one heteroatom selected from N and O. 3 cycloalkyl or 3-membered heterocycloalkyl group, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NRc3 R d3 , and S(O) 2 NR c3 R d3 optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 each is a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocycloalkyl; each is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)Rb1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , and R d3 are H and C, respectively. 1-6 independently selected from alkyl; R e , R e1 , R e2 , R e3 , and R e4 are H and C, respectively. 1-4 alkyl, independently selected from is provided herein.

[0150] In some embodiments, a compound of formula (I) or a pharma- ceutically acceptable salt thereof is provided, A is a group represented by the formula: [ka] is a group having the formula: B is a compound represented by formula (a) or (b): [ka] Based on X 1 is CR 1 and; X 2 is CR2 and; X 3 is CR 3 and; X 4 is CR 4 and; X 5 is CR 5 and; X 6 is CR 6 and; R 1 , R 2 , R 4 , and R 5 are each H; R 3 and R 6 are H, halo, and NR, respectively. c R d , OR a and 4 to 10 membered heterocycloalkyl; R 3 and R 6 Each of the 4-10 membered heterocycloalkyl groups is C(O)R b is optionally replaced by; R A and R B are H and C, respectively. 1-4 Alkyl, and C 2-6 alkenyl; R A and R B The above C 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 and C(O)NR c1 R d1 (C(O)OR a1 Optionally substituted with 1, 2, or 3 substituents independently selected from R A and R B at least one of is other than H; R C1 is C 1-6 alkyl or 5-membered heteroaryl, the 5-membered heteroaryl being C 1-6 C substituted with alkyl, R' 1-6 Alkyl, C 2-6 Alkenyl, C 3-7Cycloalkyl, or C 1-6 optionally substituted with haloalkyl; R' is S(O) 2 R b2 and; R D1 is H; R 11 CN, CH 3 , or C.H. 2 F; R 12 is H; R 13 is H or C 1-6 alkyl, 1-6 Alkyl is CN and OR a3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 1 are each 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, C 1-6 optionally substituted with alkyl; R b , R a1 , R c1 , and R d1 are H and C, respectively. 1-6 alkyl, independently selected from is provided herein.

[0151] In some embodiments, a compound of formula (I) or a pharma- ceutically acceptable salt thereof is provided, A is a group represented by the formula: [ka] is a group having the formula: B is a compound represented by formula (a) or (b): [ka] Based on X 1 is CR 1 and; X 2 is CR 2and; X 3 is CR 3 and; X 4 is CR 4 and; X 5 is CR 5 and; X 6 is CR 6 and; R 1 , R 2 , R 4 , and R 5 are each H; R 3 and R 6 are each independently selected from H and 4-10 membered heterocycloalkyl; R 3 and R 6 Each of the 4-10 membered heterocycloalkyl groups is C(O)R b is optionally replaced by; R A and R B are H and C, respectively. 1-4 Alkyl, and C 2-6 alkenyl; R A and R B The above C 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 and C(O)NR c1 R d1 (C(O)OR a1 Optionally substituted with 1, 2, or 3 substituents independently selected from R A and R B at least one of is other than H; R C1 is a 5-membered heteroaryl, C 1-6 optionally substituted with haloalkyl; R D1 is H; R 11 CN, CH 3 , or C.H. 2 F; R 12 is H; R 13 is H or C 1-6 alkyl, 1-6 Alkyl is CN and OR a3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 1 are each 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, C 1-6 optionally substituted with alkyl; R b , R a1 , R c1 , and R d1 are H and C, respectively. 1-6 alkyl, independently selected from is provided herein.

[0152] In some embodiments, Ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate; (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid; (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enamide; 1,3-Diethyl-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; 1,3-Diethyl-N-(3-methylthietan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide; 1,3-Diethyl-N-(1-methylcyclobutyl)-2,4-dioxoquinazoline-6-sulfonamide; 1,3-Diethyl-N-(3-methyloxolan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate; N-(3-cyanooxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide; Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazolin-3-yl}but-2-enoate; Methyl (E)-5-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)pent-2-enoate; 1,3-Diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-methyloxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-2-(cyanomethyl)-1-methylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(3-(difluoromethyl)oxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-N-methyl-4-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)but-2-enamide; 1,3-Diethyl-N-(3-(fluoromethyl)oxetan-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1R,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1R,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2R,3R)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2R,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclobutyl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-Chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-1-((2,4-dimethylthiazol-5-yl)methyl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(3-cyanooxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(dimethylamino)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2S,3S)-2,3-dimethyloxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(oxetan-3-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-((methylsulfonyl)methyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyano-2-methyloxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(isopropylsulfonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-(6-(N-(3-cyanooxetan-3-yl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-vinyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-methylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1,3-Diethyl-N-(3-methylazetidin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-(1-methylcyclopentyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-vinylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2S)-1-cyano-2-vinylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2R)-1-cyano-2-ethylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2S)-1-cyano-2-ethylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-1-methyl-2-vinylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-(2-methoxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2R)-1-cyano-2-(2-methoxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; N-((2R,3S)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3R)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 4-Chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-Chloro-N-(1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2-(2-hydroxyethyl)-1-methylcyclopropyl)-1H-indazole-6-sulfonamide; 1,3-Diethyl-N-((1R,2S)-1-(hydroxymethyl)-2-vinylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-((1R,2R)-1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 4-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,3-dimethyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-Methyl-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-methoxy-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1,3-Diethyl-N-((1R,2R)-2-(hydroxymethyl)cyclobutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-2-(hydroxymethyl)cyclobutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-(fluoromethyl)oxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; N-((1S,2S)-1-cyano-2-(hydroxymethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (S)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-vinyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; and 1-(5-bromo-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide Provided herein is a compound of formula (I), selected from:

[0153] In some embodiments, Ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate; (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid; (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enamide; 1,3-Diethyl-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; 1,3-Diethyl-N-(3-methylthietan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide; 1,3-Diethyl-N-(1-methylcyclobutyl)-2,4-dioxoquinazoline-6-sulfonamide; 1,3-Diethyl-N-(3-methyloxolan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate; N-(3-cyanooxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide; Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazolin-3-yl}but-2-enoate; Methyl (E)-5-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)pent-2-enoate; 1,3-Diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-methyloxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-2-(cyanomethyl)-1-methylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(3-(difluoromethyl)oxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-N-methyl-4-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)but-2-enamide; and 1,3-Diethyl-N-(3-(fluoromethyl)oxetan-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide Provided herein is a compound of formula (I), selected from:

[0154] In some embodiments, 1,3-Diethyl-N-((1S,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1R,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1R,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2R,3R)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2R,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclobutyl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-Chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-1-((2,4-dimethylthiazol-5-yl)methyl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(3-cyanooxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(dimethylamino)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2S,3S)-2,3-dimethyloxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(oxetan-3-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-((methylsulfonyl)methyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyano-2-methyloxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(isopropylsulfonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-(6-(N-(3-cyanooxetan-3-yl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-vinyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-methylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1,3-Diethyl-N-(3-methylazetidin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-(1-methylcyclopentyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-vinylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2S)-1-cyano-2-vinylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2R)-1-cyano-2-ethylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2S)-1-cyano-2-ethylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-1-methyl-2-vinylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-(2-methoxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2R)-1-cyano-2-(2-methoxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; N-((2R,3S)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3R)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 4-Chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-Chloro-N-(1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2-(2-hydroxyethyl)-1-methylcyclopropyl)-1H-indazole-6-sulfonamide; 1,3-Diethyl-N-((1R,2S)-1-(hydroxymethyl)-2-vinylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-((1R,2R)-1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 4-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,3-dimethyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-Methyl-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-methoxy-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1,3-Diethyl-N-((1R,2R)-2-(hydroxymethyl)cyclobutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-Diethyl-N-((1S,2S)-2-(hydroxymethyl)cyclobutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-(fluoromethyl)oxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; N-((1S,2S)-1-cyano-2-(hydroxymethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (S)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-vinyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; and 1-(5-bromo-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide Provided herein is a compound of formula (I), selected from:

[0155] It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0156] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" includes methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, and C 6 It is specifically intended to disclose alkyl individually.

[0157] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places herein.Unless otherwise specified, these rings can be attached to the remainder of the molecule at any ring member allowed by valence.For example, the term "pyridinyl ring", "pyridyl ring", or "pyridine ring" can refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0158] The term "n-membered," where "n" is an integer, typically describes the number of atoms forming the ring in the moiety where "n" is the number of atoms forming the ring. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0159] For compounds of the invention in which a variable occurs more than once, each variable may be a different moiety independently selected from the group defining the variable. For example, when a structure is drawn with two R groups present simultaneously on the same compound, the two R groups may represent different moieties independently selected from the groups defined for R.

[0160] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0161] As used herein, the term "substituted" means that a hydrogen atom has been replaced with a non-hydrogen group. It is understood that substitution at a given atom is limited by valency.

[0162] As used herein, "C i-j The term " is used in conjunction with a chemical group to specify a range of the number of carbon atoms in the chemical group, with ij defining the range. For example, C 1-6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0163] As used herein, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. In some embodiments, the alkyl group contains 1-7, 1-6, 1-4, or 1-3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0164] As used herein, "alkenyl," employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2-6 or 2-4 carbon atoms. Exemplary alkenyl groups include (but are not limited to) ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0165] As used herein, "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0166] As used herein, "halo" or "halogen," employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0167] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having up to the full valence of halogen atom substituents, which may be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.

[0168] As used herein, the term "alkoxy," employed alone or in combination with other terms, refers to a group of formula -Oalkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy groups), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0169] As used herein, "haloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkoxy groups include -OCF 3 It is.

[0170] As used herein, "amino" used alone or in combination with other terms means NH 2 Refers to...

[0171] As used herein, the term "cycloalkyl", used alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included within the definition of cycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to the cycloalkyl ring (i.e., having a common bond with the cycloalkyl ring), such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of the cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also encompasses bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like). In some embodiments, cycloalkyl groups have 3-10 ring members or 3-7 ring members. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are C 3-7Monocyclic cycloalkyl groups. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0172] As used herein, the term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system that optionally contains one or more alkenylene or alkynylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Also included within the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to a non-aromatic heterocycloalkyl ring (i.e., having a bond in common with the non-aromatic heterocycloalkyl ring), such as 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl] and the like). In some embodiments, heterocycloalkyl groups have 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or 2 to 8 carbon atoms. In some embodiments, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Carbon atoms or heteroatoms in the ring(s) of a heterocycloalkyl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized.In some embodiments, the heterocycloalkyl moiety is C. 2-7 Monocyclic heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahyropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0173] As used herein, the term "aryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, an aryl group has 6-10 carbon atoms or 6 carbon atoms. In some embodiments, an aryl group is a monocyclic or bicyclic group. In some embodiments, an aryl group is phenyl or naphthyl.

[0174] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, or the like. Carbon atoms or heteroatoms in the ring(s) of a heteroaryl group may be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms may be quaternized, provided that the aromatic nature of the ring is preserved. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0175] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereomers) are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms.

[0176] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked to one form by appropriate substitution. Examples of tautomeric forms (pyridazin-3(2H)-one and pyridazin-3-ol) are illustrated below. [ka]

[0177] The compounds of the present invention also include isotopes of all atoms occurring in intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium.

[0178] The term "compound," as used herein, unless otherwise specified, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0179] All compounds and their pharma- ceutically acceptable salts may be found in or isolated together with other substances such as water and solvents (eg, in the form of hydrates and solvates).

[0180] In some embodiments, the compound of the present invention or its salt is substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched with the compound of the present invention. Substantial separation can include a composition that contains at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present invention or its salt. Methods for isolating compounds and their salts are routine in the art.

[0181] As used herein, and unless otherwise specified, the term "about" refers to a numerical value or range of values ​​provided to describe a particular solid form, (e.g., a specific temperature or temperature range (such as those describing melting, dehydration, or glass transition); mass change (such as mass change as a function of temperature or humidity); solvent or water content (e.g., in terms of mass or percentage); or peak location (e.g., 13It indicates that the values ​​or ranges of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art, while still describing the particular solid form when used in connection with analysis by C NMR, DSC, TGA, and XRPD, etc.

[0182] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0183] The present invention also encompasses pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (such as amines); alkali or organic salts of acidic residues (such as carboxylic acids); and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of the two. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0184] synthesis The compounds of the present invention (including their salts) may be prepared using known organic synthesis techniques, and may be synthesized according to any of a number of possible synthetic routes.

[0185] The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0186] Preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical nature of protecting groups can be found, for example, in TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0187] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible) or mass spectrometry), or by chromatography (such as high performance liquid chromatography (HPLC) or thin layer chromatography).

[0188] The expressions "ambient temperature," "room temperature," and "RT," as used herein, are understood in the art and generally refer to a temperature that is about the same as the temperature of the room in which a reaction is carried out (e.g., the reaction temperature), for example, a temperature of about 20° C. to about 30° C.

[0189] Compounds of formula I can be prepared according to a number of preparation routes known in the literature.The exemplary synthetic method for preparing the compounds of the present invention is provided in the following scheme.Unless otherwise stated, all substituents are as defined herein.

[0190] In the process illustrated in Scheme 1, a suitably substituted sulfonic acid chloride containing compound of formula (1-1) is displaced with an amine compound (1-2) in the presence of a base (e.g., DIEA) to form a sulfonamide compound of formula (1-3). The compound of formula (1-3) is displaced with a compound of formula (1-4) in the presence of a base (e.g., potassium carbonate) to form an ester compound of formula (1-5). The ester compound of formula (1-5) is hydrolyzed in the presence of lithium hydroxide to form a carboxylic acid compound of formula (1-6). The carboxylic acid compound of formula (1-6) is aminated in the presence of thionyl chloride and ammonia to form an amide compound of formula (1-7). [ka] In the formula, Z1 is represented by the formula: [ka] is a group having the formula: m1 is an integer selected from 1, 2, 3, and 4.

[0191] In the process illustrated in Scheme 1', a suitably substituted sulfonic acid chloride containing compound of formula (1-1) is displaced with an amine compound (1-2) in the presence of a base (e.g., DIEA) to form a sulfonamide compound of formula (1-3). The compound of formula (1-3) is displaced with a compound of formula (1-4) in the presence of a base (e.g., potassium carbonate) to form an ester compound of formula (1-5). The ester compound of formula (1-5) is hydrolyzed in the presence of lithium hydroxide to form a carboxylic acid compound of formula (1-6). The carboxylic acid compound of formula (1-6) is aminated in the presence of thionyl chloride and ammonia to form an amide compound of formula (1-7). [ka] In the formula, Z1 is represented by the formula: [ka] is a group having the formula: m1 is an integer selected from 1, 2, 3, and 4.

[0192] In the process illustrated in Scheme 2, a compound of formula (2-1) is displaced by a compound of formula (2-2) in the presence of a base (e.g., potassium carbonate) to form a compound of formula (2-3). The compound of formula (2-3) is sulfonated in the presence of a sulfonic acid chloride (2-4) to form a sulfonic acid compound of formula (2-5). The sulfonic acid compound of formula (2-5) is displaced by an amine compound (2-6) in the presence of a base (e.g., triethylamine) to form a sulfonamide compound of formula (2-7). [ka] In the formula, Z1 is represented by the formula: [ka] is a group having the formula: RZ1 , H, C 1-4 Alkyl and C 2-6 alkenyl, 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0193] In the process illustrated in Scheme 2', a compound of formula (2-1) is displaced by a compound of formula (2-2) in the presence of a base (e.g., potassium carbonate) to form a compound of formula (2-3). The compound of formula (2-3) is sulfonated in the presence of a sulfonic acid chloride (2-4) to form a sulfonic acid compound of formula (2-5). The sulfonic acid compound of formula (2-5) is displaced by an amine compound (2-6) in the presence of a base (e.g., triethylamine) to form a sulfonamide compound of formula (2-7). [ka] In the formula, Z1 is represented by the formula: [ka] is a group having the formula: R Z1 , H, C 1-4 Alkyl and C 2-6 alkenyl, 1-4 Alkyl and C 2-6 Each alkenyl is Cy 1 , Haro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R.c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0194] In the process illustrated in Scheme 3, an appropriately substituted bromide compound of formula (3-1) is reacted with XantPhos, Pd 2 (dba) 3 -CHCl 3 and is displaced by a thiol compound of formula (3-2) in the presence of a base (e.g., DIEA) to form a compound of formula (3-3). The compound of formula (3-3) is displaced by a compound of formula (3-4) in the presence of a base (e.g., cesium carbonate) to form a compound of formula (3-5). The thiol compound of formula (3-5) is reacted with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in the presence of an acid (e.g., acetic acid) to form a sulfonic acid compound of formula (3-6). The sulfonic acid compound of formula (3-6) is displaced by an amine compound of formula (3-7) in the presence of a base (e.g., pyridine) to form a sulfonamide compound of formula (3-8). A sulfonamide compound of formula (3-8) is displaced with an amine compound of formula (3-9) in the presence of RuPhos, RuPhos Pd G3, and a base (eg, cesium carbonate) to form a compound of formula (3-10). [ka] In the formula, Z1 is represented by the formula: [ka] is a group having the formula: Z2 is a heterocycloalkyl containing 3 to 9 ring members in addition to the N atom; R Z2 Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c Rd , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d Selected from; m2 is an integer selected from 1, 2, 3, and 4.

[0195] In the process illustrated in Scheme 3', an appropriately substituted bromide compound of formula (3-1) is reacted with XantPhos, Pd 2 (dba) 3 -CHCl 3 and is displaced by a thiol compound of formula (3-2) in the presence of a base (e.g., DIEA) to form a compound of formula (3-3). The compound of formula (3-3) is displaced by a compound of formula (3-4) in the presence of a base (e.g., cesium carbonate) to form a compound of formula (3-5). The thiol compound of formula (3-5) is reacted with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in the presence of an acid (e.g., acetic acid) to form a sulfonic acid compound of formula (3-6). The sulfonic acid compound of formula (3-6) is displaced by an amine compound of formula (3-7) in the presence of a base (e.g., pyridine) to form a sulfonamide compound of formula (3-8). A sulfonamide compound of formula (3-8) is displaced with an amine compound of formula (3-9) in the presence of RuPhos, RuPhos Pd G3, and a base (eg, cesium carbonate) to form a compound of formula (3-10). [ka] In the formula, Z1 is represented by the formula: [ka] is a group having the formula: Z2 is a heterocycloalkyl containing 3 to 9 ring members in addition to the N atom; R Z2 Halo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d Selected from; m2 is an integer selected from 1, 2, 3, and 4.

[0196] In the process illustrated in Scheme 4, an appropriately substituted fluorinated aldehyde-containing compound of formula (4-1) is displaced with an amine compound (4-2) in the presence of a base to form an aldehyde compound of formula (4-3). The compound of formula (4-3) is reacted with a hydrazine compound of formula (4-4) to form an indazole compound of formula (4-5). The indazole compound of formula (4-5) is displaced with a thiadiazole-bromide compound of formula (4-6) in the presence of a base to form a 1-indazole compound of formula (4-7). The indazole compound of formula (4-7) is displaced with an amine compound of formula (4-8) in the presence of potassium metabisulfite and a base to form a sulfonamide compound of formula (4-9). [ka] In the formula, Z1 is represented by the formula: [ka] each R 6’ Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , C(=NR e )NR c Rd , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d and q is an integer selected from 0, 1, 2, and 3.

[0197] Methods for Use The compound of the present invention can inhibit the activity of PARG.For example, the compound of the present invention can be used to inhibit the activity of PARG in cells or in individuals or patients who need enzyme inhibition by administering an inhibitory amount of the compound of the present invention to cells, individuals or patients.In some embodiments, PARG is PARG1.

[0198] As PARG inhibitors, the compounds of the present invention are useful in treating various diseases or disorders associated with abnormal expression or activity of PARG. For example, the compounds of the present invention are useful in treating cancer.

[0199] In some embodiments, the cancer is a stress-dependent cancer.

[0200] In some embodiments, the cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, mantle cell lymphoma, and renal cell carcinoma.

[0201] As used herein, the term "cell" is meant to refer to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism (such as a mammal). In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism (such as a mammal).

[0202] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or in an in vivo system. For example, "contacting" PARG with a compound of the invention or "contacting" a cell with a compound of the invention includes administering a compound of the invention to an individual or patient (such as a human) having PARG, and introducing a compound of the invention into a sample containing, for example, a cell preparation or purified preparation containing PARG.

[0203] As used herein, the terms "individual" or "patient", used interchangeably, refer to mammals, and particularly humans.

[0204] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician.

[0205] As used herein, the term "treating" or "treatment" refers to 1) inhibiting a disease (i.e., halting further development of pathology and / or symptoms) in an individual experiencing or exhibiting pathology or symptoms of the disease, or 2) ameliorating a disease (i.e., reversing pathology and / or symptoms) in an individual experiencing or exhibiting pathology or symptoms of the disease.

[0206] As used herein, the term "preventing" or "prevention" refers to preventing disease in an individual who may be predisposed to the disease, but who has not yet experienced or exhibited the pathology or symptoms of the disease.

[0207] Combination therapy One or more additional pharmaceutical agents or therapeutic methods (e.g., chemotherapy or other anti-cancer agents, immune stimulants, immune suppressants, immunotherapy, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic, or signal transduction inhibitors, etc.) may be used in combination with the compounds of the invention. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0208] Suitable drugs for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapy, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds of the present invention may be effective in combination with antihormonal drugs for the treatment of breast cancer and other tumors.Suitable examples are antiestrogens (including but not limited to tamoxifen and toremifene), aromatase inhibitors (including but not limited to letrozole, anastrozole, and exemestane), corticosteroids (e.g. prednisone), progestins (e.g. megastrol acetate), and estrogen receptor antagonists (e.g. fulvestrant).Suitable antihormonal drugs used for the treatment of prostate cancer and other cancers may also be combined with the compounds of the present invention. These include antiandrogens (including, but not limited to, flutamide, bicalutamide, and nilutamide), luteinizing hormone releasing hormone (LHRH) analogs (including leuprolide, goserelin, triptorelin, and histrelin), LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0209] Angiogenesis inhibitors can be effective in some tumors in combination with the compounds of the present invention.These include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR.Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept.VEGF kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0210] Chemotherapeutic agents or other anti-cancer agents suitable for use in combination with the compounds of the invention include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, as well as triethylenemelamine, triethylenethio-phosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0211] Other anti-cancer agent(s) for use in combination with the compounds of the invention include antibody therapeutics directed to checkpoint or costimulatory molecules (such as CTLA-4, PD-1, PD-L1, or 4-1BB), or antibodies directed to cytokines (such as IL-10, TGF-β), respectively. Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab, and durvalumab. Additional anti-cancer agent(s) for use in combination with the compounds of the invention include antibody therapeutics directed to surface molecules of hematological cancers (such as ofatumumab, rituximab, and alemtuzumab).

[0212] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those of skill in the art. In addition, their administration is described in the standard literature. For example, the administration of some chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0213] Pharmaceutical Formulations and Dosage Forms When used as a pharmaceutical, the compound of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a combination of the compound of the present invention or its pharma- ceutically acceptable salt and at least one pharma-ceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be oral, topical (including delivery to the eye and mucous membranes, including intranasal, vaginal, and rectal), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including nebulizers; intratracheal, intranasal, epidermal, and transdermal), ocular, or parenteral.

[0214] The present invention also includes pharmaceutical compositions that contain one or more of the compounds of the present invention as active ingredients in combination with one or more pharma-ceutically acceptable carriers.In preparing the compositions of the present invention, active ingredients are typically mixed with excipients, diluted by excipients, or enclosed in such carriers, for example, in the form of capsules, sachets, paper, or other containers.When excipients are used as diluents, they can be solid, semi-solid, or liquid materials, and act as vehicles, carriers, or media for active ingredients.Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% active compound by weight, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0215] The composition can be formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0216] Active compound can be effective over a wide dosage range and is generally administered in a pharmacologic effective amount.However, it will be understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the pathology being treated, the selected administration route, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0217] For the preparation of solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms (such as tablets, pills, and capsules). This solid preformulation is then subdivided into unit dosage forms of the type described above.

[0218] The tablet or pill containing the compound of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of extended action.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or be released after a delay.A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0219] For oral or injection administration, liquid forms into which the compounds and compositions of the present invention may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0220] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect.

[0221] Compositions can be nebulized by use of inert gases. Nebulized solutions can be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0222] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration (such as prophylaxis or treatment), the condition of the patient, the mode of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or partially arrest the symptoms of the disease and its complications. The effective dose will depend on the pathology of the disease being treated, and in addition, as determined by the attending clinician, on factors such as the severity of the disease, the age, weight, and overall condition of the patient, and the like.

[0223] The composition administered to patient can be in the form of pharmaceutical composition described above.These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.Aqueous solutions can be packaged for immediate use or can be lyophilized, and lyophilized preparations are combined with sterile aqueous carriers before administration.

[0224] The therapeutic dosage of the compound of the present invention may vary, for example, according to the particular use for which the treatment is performed, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. The dosage is likely to depend on variables such as the type and degree of progression of the disease or disorder, the general health status of the particular patient, the relative biological effectiveness of the selected compound, the formulation of excipients, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0225] The compounds of the present invention may be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as antiviral agents, anticancer agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, and the like. EXAMPLES

[0226] Definition: ACN (acetonitrile); AcOH (acetic acid); BPO (benzoyl peroxide); CH 3 CN(acetonitrile);CDCl 3 (deuterated chloroform); CD 3 OD (deuterated methanol); CH 2 Cl 2 (Dichloromethane);Cs 2 CO 3 (Cesium carbonate);DCM(Dichloromethane);DEA(Diethylamine);DEAD(Diethyl azodicarboxylate);DIEA(N,N-Diisopropylethylamine);DMF(N,N-Dimethylformamide);DMAP(4-Dimethylaminopyridine);DMSO(Dimethylsulfoxide);DMSO-d 6 (deuterated dimethylsulfoxide); EA (ethyl acetate); ESI (electrospray ionization); EtOAc (ethyl acetate); EtOH (ethanol); g (grams); h (hours); 1H NMR(Proton Nuclear Magnetic Resonance);HCl(Hydrogen Acid);Hz(Hertz);IPA(Isopropyl Alcohol);K 2 CO 3 (potassium carbonate); L (liter); LiCl (lithium chloride); LiOH (lithium hydroxide); LCMS (liquid chromatography-mass spectrometry); M (molar); MeMgBr (methylmagnesium bromide); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimolar); MTBE (methyl tert-butyl ether); m / z (mass-to-charge ratio); N 2 (nitrogen);NaCl(sodium chloride);NH 4 Cl(ammonium chloride);NaN 3 (Sodium azide);NH 3 (Ammonia);NH 4 HCO 3 (Ammonium Bicarbonate); nm(Nanometer); PE(Petroleum Ether); PPh 3 (triphenylphosphine); prep-HPLC (preparative high performance liquid chromatography); ppm (parts per million); RT (room temperature); RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl); RuPhos-3rd generation-Palladacycle ((2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)] palladium(II) methanesulfonate); TEA (triethylamine); TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl); THF (tetrahydrofuran); TsCl (tosyl chloride); Rt (retention time); TLC (thin layer chromatography); TMSCN (trimethylsilyl cyanide); UV (ultraviolet); v / v (volume / volume); Xantphos ((9,9-dimethyl-9H-xanthene-4,5-diyl) bis(diphenylphosphane)).

[0227] Example 1: Ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate [ka] Step 1: Synthesis of N-{bicyclo[1.1.1]pentan-1-yl}-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide Bicyclo[1.1.1]pentan-1-amine hydrochloride (917.63 mg, 7.673 mmol, 1.0 equiv.) and 2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (2 g, 7.673 mmol, 1 equiv.) were dissolved in THF (20 mL). DIEA (2479.32 mg, 19.183 mmol, 2.5 equiv.) was added. The mixture was stirred at room temperature overnight. The mixture was analyzed by TLC (DCM / MeOH 1:1). The mixture was poured into water and the precipitated solid was collected by filtration and washed with water (2×10 mL). This gave N-{bicyclo[1.1.1]pentan-1-yl}-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (2 g, 76.33%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.56 (s, 2H), 8.66 (s, 1H), 8.28 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 2.28 (s, 1H), 1.71 (s, 6H).

[0228] Step 2: Synthesis of ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate To a mixture of N-{bicyclo[1.1.1]pentan-1-yl}-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (1.2 g, 3.905 mmol, 1 equiv.) and ethyl (2E)-4-bromobut-2-enoate (0.75 g, 3.905 mmol, 1.0 equiv.) in DMF (12 mL) was added K 2 CO 3(589.68 mg, 4.267 mmol, 1.05 equiv) was added and stirred at room temperature overnight. The desired product could be detected by LCMS. The mixture was diluted with EA (50 mL) and washed with water (3×20 mL). The resulting mixture was diluted with Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under pressure. The crude product (1.5 g) was purified by reversed-phase flash chromatography with the following conditions: column, C18 gel; mobile phase, MeCN in water, gradient 10%-80% in 40 min; detector, UV 254 nm. The desired compound was collected and purified for Prep-HPLC with the following conditions (XBridge Shield RP 18OBD column 30*150 mm, 5 um; mobile phase A: water-NH 4 HCO 3 , mobile phase B: ACN; flow rate 60 mL / min; gradient 25% B to 51% B in 7 min; 254 / 220 nm; Rt 6.32 min (detected by LCMS and collectEd)) and concentrated in vacuo to give ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate (222.9 mg) as a white solid. LCMS (ESI, m / z): 420.05 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.71 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 8.6, 2.2 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.92 (dt, J = 15.9, 4.7 Hz, 1H), 5.94 (dt, J = 15.7, 1.8 Hz, 1H), 4.82 - 4.60 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.28 (s, 1H), 1.72 (s, 7H), 1.19 (t, J = 7.1 Hz, 3H).

[0229] Example 2: (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid [ka] Step 1: Synthesis of (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid To ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate (220 mg, 0.524 mmol, 1 equiv.) in THF (3 mL), 2 LiOHH ​​in HO (3 mL) 2 220.08 mg, 5.240 mmol, 10 equiv. was added. The mixture was stirred at room temperature overnight. The mixture was acidified to pH 1-2 with HCl (1 M). The aqueous layer was extracted with EA (2×10 mL). This layer was washed with water (1×10 mL) and diluted with Na 2 SO 4 The resulting mixture was dried over hexane and concentrated under vacuum. The resulting mixture was directly lyophilized to give the desired product (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid (200 mg, 87.68%) as a white solid. LCMS (ESI, m / z): 392 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6) δ 11.95 (s, 2H), 8.74 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 8.7, 2.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.82 (dt, J = 15.8, 4.9 Hz, 1H), 5.83 (dt, J = 15.8, 1.8 Hz, 1H), 4.65 (dd, J = 4.9, 1.9 Hz, 2H), 2.29 (s, 1H), 1.72 (s, 6H).

[0230] Example 3: (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enamide [ka] Step 1: Synthesis of (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enamide SOCl 2 A mixture of (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid (120 mg, 0.307 mmol, 1 equiv.) in (1 mL, 13.786 mmol, 44.97 equiv.) was stirred at 60° C. for 2 h. The resulting mixture was concentrated under reduced pressure. NH 3 (g) was added. The mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with DMF (2 mL) for Pre-HPLC (Column: YMC-Actus Triart C18, 30×150 nm, 5 um; Mobile phase A: Water (10 mmol / L NH 4 HCO 3, mobile phase B: ACN; flow rate: 60 ml / min; gradient: 20% B to 42% B in 7 min, wavelength: 254 nm; RT 4.98). This gave (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enamide (23.9 mg, 19.87%) as a white solid. LCMS (ESI, m / z): 391 [M+H] + ; 1 H NMR (300 MHz, methanol-d 4 ) δ 8.50 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 8.6, 2.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.80 (dt, J = 15.6, 5.2 Hz, 1H), 6.05 (dt, J = 15.6, 1.7 Hz, 1H), 4.77 (dd, J = 5.3, 1.8 Hz, 2H), 2.28 (s, 1H), 1.81 (s, 6H).

[0231] Example 4: 1,3-Diethyl-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide [ka] Step 1: Synthesis of 1,3-diethyl-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide To a solution of 3-methyloxetan-3-amine (27.50 mg, 0.316 mmol, 1 equiv.) in pyridine (2 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (100 mg, 0.316 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The solid was purified by HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (NH 4 HCO 3 +0.1% NH 3 -H2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B, 40% B in 7 min; wavelength: 254 nm; RT1 (min): 6.43) to give 1,3-diethyl-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide (36.9 mg, 31.75%) as a white solid. LCMS (ES. m / z): 368 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.44 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 8.09 (dd, J = 8.9, 2.4 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.16 (m, 4H), 3.99 (q, J = 7.0 Hz, 2H), 1.42 (s, 3H), 1.21 (dt, J = 17.0, 7.0 Hz, 6H).

[0232] Example 5: 1,3-Diethyl-N-(3-methylthietan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide [ka] Step 1: Synthesis of 1,3-diethyl-N-(3-methylthietan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide To a solution of 3-methylthietan-3-amine hydrochloride (44.08 mg, 0.316 mmol, 1 equiv.) in pyridine (2 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (100 mg, 0.316 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1). The crude product was purified by HPLC using the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (NH4 HCO 3 +0.1% NH 3 -H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 63% B in 7 min, 63% B; wavelength: 254 nm; RT1 (min): 6) to give 1,3-diethyl-N-(3-methylthietan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide (8.1 mg, 6.62%) as a white solid. LCMS (ES. m / z): 384 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.45 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 8.9, 2.4 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.53 (d, J = 9.2 Hz, 2H), 2.74 - 2.64 (m, 2H), 1.57 (s, 3H), 1.21 (dt, J = 16.4, 7.0 Hz, 6H).

[0233] Example 6: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide [ka] Step 1: Synthesis of 6-(benzylsulfanyl)-4-chloro-1H-indazole To a stirred solution of 6-bromo-4-chloro-1H-indazole (5 g, 21.600 mmol, 1 eq.) and benzyl mercaptan (5.37 g, 43.200 mmol, 2 eq.) in 1,4-dioxane (50 ml) was added Xantphos (2.50 g, 4.320 mmol, 0.2 eq.) and Pd 2 (dba) 3 CHCl3 (2.24 g, 2.160 mmol, 0.1 equiv.) was dissolved in N 2 The mixture was added in portions at room temperature under atmospheric pressure. To the above mixture, DIEA (8.38 g, 64.800 mmol, 3 equiv.) was added dropwise at room temperature over 2 min. The resulting mixture was stirred at 100° C. for an additional 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to give 6-(benzylsulfanyl)-4-chloro-1H-indazole (5.6 g, 93.41%) as a yellow solid. LCMS (ESI, m / z): 275 [M+H] + .

[0234] Step 2: Synthesis of 6-(benzylsulfanyl)-4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole To a stirred solution of 6-(benzylsulfanyl)-4-chloro-1H-indazole (2.6 g, 9.368 mmol, 1 equiv., 99%) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (2.01 g, 9.368 mmol, 1 equiv.) in DMF (25 mL) was added Cs 2 CO 3 (3.05 g, 9.368 mmol, 1 equiv.) was added in small portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 3 h under nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2×100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified with CH 2 Cl 2 / MeOH (12:1) to give 6-(benzylsulfanyl)-4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (3 g, 72.06%) as a yellow solid. LCMS (ESI, m / z): 409 [M+H] + .

[0235] Step 3: Synthesis of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride To a stirred solution of 6-(benzylsulfanyl)-4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (2.8 g, 6.300 mmol, 1 equiv, 92%) and AcOH (0.5 mL) in acetonitrile (50 mL) was added H 2 2H2O (50 mL) was added dropwise at room temperature under air atmosphere. To the above mixture, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.86 g, 9.450 mmol, 1.5 equiv) was added in portions over 5 min at 0° C. The resulting mixture was stirred at 0° C. for an additional 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified with HCl. 2 Cl 2 / MeOH (9:1) to give 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride (2.5 g, 97.87%) as a yellow solid. LCMS (ESI, m / z): 365 [MH] - .

[0236] Step 4: Synthesis of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)indazole-6-sulfonamide To a stirred solution of 3-methyloxetan-3-amine (54.28 mg, 0.623 mmol, 1.2 equiv.) in pyridine (2 mL), 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride (200 mg, 0.519 mmol, 1 equiv.) was added in small portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for another night. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by HCl. 2 Cl 2 / MeOH (12:1) to give 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)indazole-6-sulfonamide (220 mg, 92.35%) as an off-white solid. LCMS: (ES, m / z): [M+H] + =436.

[0237] Step 5: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide To a stirred solution of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)indazole-6-sulfonamide (160 mg, 0.367 mmol, 1 equiv.) and 2-methyl-1-(piperazin-1-yl)propan-1-one (86.03 mg, 0.550 mmol, 1.5 equiv.) in 1,4-dioxane (2 mL), RuPhos (68.52 mg, 0.147 mmol, 0.4 equiv.) and RuPhos palladacycle 3rd generation (61.41 mg, 0.073 mmol, 0.2 equiv.) were added dropwise at room temperature under nitrogen atmosphere. 2 CO 3 (239.22 mg, 0.734 mmol, 2 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 100° C. for an additional 16 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution under the following conditions (Column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 47% B to 67% B in 7 min, 67% B; wavelength: 254 nm; RT1 (min): 5.38) to give 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (65 mg, 31.84%) as a white solid. LCMS (ESI, m / z): 556 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 7.60 (t, J = 53.0 Hz, 1H), 7.15 (d, J = 1.4 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.17 - 4.09 (d, J = 6.1 Hz, 2H), 3.83 - 3.72 (m, 4H), 3.47 (m, 4H), 2.95 (p, J = 6.8 Hz, 1H), 1.44 (s, 3H), 1.05 (d, J = 6.7 Hz, 6H).

[0238] Example 7: 1,3-Diethyl-N-(1-methylcyclobutyl)-2,4-dioxoquinazoline-6-sulfonamide [ka] Step 1: 1,3-Diethylquinazoline-2,4-dione 1,3-Dihydroquinazoline-2,4-dione (6 g, 37.003 mmol, 1 equiv.), bromoethane (12.10 g, 111.009 mmol, 3 equiv.), K 2 CO 3 (15.34 g, 111.009 mmol, 3 equiv) was stirred at room temperature for 16 h. The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give 1,3-diethylquinazoline-2,4-dione (8 g, 89.15%) as a white solid. LCMS (ES. m / z): 219 [M+H] + .

[0239] Step 2: 1,3-Diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride A solution of 1,3-diethylquinazoline-2,4-dione (3 g, 13.745 mmol, 1 equiv) in chlorosulfonic acid (10 mL) was stirred at 60° C. for 5 h. The mixture was allowed to cool to room temperature. The reaction mixture was poured dropwise into crushed ice and the isolated solid was collected. The solid was washed with diethyl ether. The precipitated solid was collected by filtration. This gave 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (4 g, 78.09%) as a light brown solid. LCMS (ESI, m / z): 317 [M+H] + .

[0240] Step 3: 1,3-Diethyl-N-(1-methylcyclobutyl)-2,4-dioxoquinazoline-6-sulfonamide To a solution of 1-methylcyclobutan-1-amine hydrochloride (42.23 mg, 0.348 mmol, 1.1 equiv), TEA (95.84 mg, 0.948 mmol, 3 equiv) in DCM (3 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (100 mg, 0.316 mmol, 1 equiv). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by HCl. 2 Cl 2 The mixture was eluted with 1,2-dichlorophenyl ether (1:1) / EA (3:1). The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution under the following conditions (column: XBridge Shield RP18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO3 +0.1% NH 3 -H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 55% B in 7 min, 55% B; wavelength: 254 nm; RT1 (min): 5.45) to give 1,3-diethyl-N-(1-methylcyclobutyl)-2,4-dioxoquinazoline-6-sulfonamide (55.2 mg, 47.80%) as a white solid. LCMS (ES. m / z): 366 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.44 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 8.9, 2.3 Hz, 1H), 8.00 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 2.19 - 2.02 (m, 2H), 1.74-1.51 (m, 4H), 1.31-1.17 (m, 9H).

[0241] Example 8: 1,3-Diethyl-N-(3-methyloxolan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide [ka] Step 1: Synthesis of 1,3-diethyl-N-(3-methyloxolan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide To a solution of 3-methyloxolane-3-amine hydrochloride (65.16 mg, 0.474 mmol, 1 equiv.), TEA (143.76 mg, 1.422 mmol, 3 equiv.) in DCM (3 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (150 mg, 0.474 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 / EA 1:1). The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution with the following conditions (Column: XBridge Shield RP18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B, 45% B in 7 min; wavelength: 254 nm; RT1 (min): 5.18) to give 1,3-diethyl-N-(3-methyloxolan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide (56.1 mg, 31.03%) as a white solid. LCMS (ES. m / z): 382 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.46 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 8.9, 2.4 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.70 (dt, J = 8.3, 6.3 Hz, 3H), 3.34 (d, J = 8.8 Hz, 1H), 2.13 (dt, J = 13.3, 6.8 Hz, 1H), 1.72 (dt, J = 12.7, 7.6 Hz, 1H), 1.29 - 1.12 (m, 9H).

[0242] Example 9: Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate [ka] Step 1: Synthesis of N-(3-methyloxetan-3-yl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide To a mixture of 3-methyloxetan-3-amine (0.33 g, 3.837 mmol, 1.0 equiv.) and DIEA (1.49 g, 11.511 mmol, 3.0 equiv.) in THF (15 mL) was added 2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (1 g, 3.837 mmol, 1 equiv.) in small portions at 0° C. The mixture was stirred at room temperature overnight. The desired product could be detected by LCMS. The mixture was poured into water. The precipitated solid was collected by filtration and purified by HCl. 2 The resulting mixture was concentrated under reduced pressure to give N-(3-methyloxetan-3-yl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (1 g, 75.35%) as a white solid. LCMS (ESI, m / z): 312[M+H] + .

[0243] Step 2: Synthesis of methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate N-(3-methyloxetan-3-yl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (1 g, 3.212 mmol, 1 equiv.) and methyl (2E)-4-bromobut-2-enoate (0.52 g, 2.891 mmol, 0.9 equiv.) in DMF (12 mL), K 2 CO 3 (0.47 g, 3.373 mmol, 1.05 equiv) was stirred at room temperature overnight. The resulting mixture was diluted with EA (30 mL). The resulting mixture was diluted with H 2 The resulting solution was washed with NaO (5×15 mL). 2 SO 4The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (100:0 to 95:5) to give methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate (400 mg, 90% purity). The mixture was diluted with DMF (2 mL) for Pre-HPLC (Column: XBridge Prep OBD column, 19*250 nm, 5 um; Mobile phase A: water (NH at 10 mmol / L) 4 HCO 3 , mobile phase B: ACN; flow rate: 25 ml / min; gradient: 24% B to 52% B in 7 min, wavelength: 254 nm; RT 5.25). The resultant was directly lyophilized to give the desired product methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate (300 mg, 22.47%) as a white solid. LCMS (ESI, m / z): 410 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 8.45 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 8.6, 2.3 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.93 (dt, J = 15.9, 4.8 Hz, 1H), 5.97 (dt, J = 15.9, 1.8 Hz, 1H), 4.67 (dd, J = 4.9, 1.9 Hz, 2H), 4.53 (d, J = 6.1 Hz, 2H), 4.13 - 4.11 (m, 2H), 3.64 (s, 3H), 1.42 (s, 3H).

[0244] Example 10: N-(3-cyanooxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide [ka] Step 1: Synthesis of N-(3-cyanooxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide To a solution of 3-aminooxetane-3-carbonitrile hydrochloride (63.72 mg, 0.474 mmol, 1 equiv.) in pyridine (3 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (150 mg, 0.474 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 / EA, 1:1). The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution with the following conditions (column: XBridge Shield RP18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 25% B, 25% B in 7 min; wavelength: 254 nm; RT1 (min): 6.1;) to give N-(3-cyanooxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (37.7 mg, 20.77%) as a white solid. LCMS (ESI, m / z): 379 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 8.9, 2.4 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 4.87 - 4.80 (m, 2H), 4.73 - 4.67 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.20 (dt, J = 19.7, 7.0 Hz, 6H).

[0245] Example 11: Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazolin-3-yl}but-2-enoate [ka] Step 1: Synthesis of methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazolin-3-yl}but-2-enoate To a solution of methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate (100 mg, 0.244 mmol, 1 equiv.) and oxetan-3-ylmethanol (21.52 mg, 0.244 mmol, 1 equiv.) in THF was added Ph 3 P (96.10 mg, 0.366 mmol, 1.5 equiv.) and DEAD (63.81 mg, 0.366 mmol, 1.5 equiv.) were added. After stirring at room temperature under nitrogen atmosphere for 16 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography with the following conditions: column, silica gel; mobile phase, EA in PE, gradient 0% to 50% in 40 min; detector, UV 254 nm. The residue was purified by Prep-HPLC (column: XSelect CSH OBD C18 column, 19*150 mm, 5 μm; mobile phase A: water (NH 4 HCO 3 +0.1% NH 3 -H 2 0), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 24% B to 54% B in 7 min, 54% B; wavelength: 254 nm; RT1 (min): 5) to give methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazolin-3-yl}but-2-enoate (34.4 mg, 29.34%) as a white solid. LCMS (ESI, m / z): 478[MH] - ;1 H NMR (300 MHz, DMSO-d 6 ) δ 8.54 (m, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.9, 2.4 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 6.93 (dt, J = 15.9, 4.6 Hz, 1H), 6.00 (dt, J = 15.8, 1.8 Hz, 1H), 4.71 (dd, J = 4.6, 2.0 Hz, 2H), 4.61 (dd, J = 7.8, 6.1 Hz, 2H), 4.54 (d, J = 6.1 Hz, 2H), 4.49 - 4.43 (m, 4H), 4.14 (d, J = 6.0 Hz, 2H), 3.64 (s, 3H), 3.40 (d, J = 7.2 Hz, 1H), 1.42 (s, 3H).

[0246] Example 12: Methyl (E)-5-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)pent-2-enoate [ka] Step 1: Synthesis of 3-allyl-N-(3-methyloxetan-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide N-(3-methyloxetan-3-yl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (1 g, 3.212 mmol, 1 equiv.) and 4-bromo-1-butene (0.41 g, 3.051 mmol, 0.95 equiv.) in DMF (15 mL), K 2 CO 3 (0.47 g, 3.373 mmol, 1.05 equiv) was stirred at room temperature overnight. The desired product could be detected by LCMS. The resulting mixture was diluted with EA (50 mL). The resulting mixture was diluted with H 2 The resulting solution was washed with NaO (3×20 mL).2 SO 4 The mixture was dried over 1000 ml and concentrated. The residue was purified by silica gel column chromatography, eluted with EA / PE (0:100 to 55:45) to give 3-(but-3-en-1-yl)-N-(3-methyloxetan-3-yl)-2,4-dioxo-1H-quinazoline-6-sulfonamide (400 mg crude). The mixture was purified under the following conditions: column: YMC-Actus Triart C18.30*150 nm, 5 μm; mobile phase a: water (10 mmol / L NH 4 HCO 3 ), mobile phase b: ACN; flow rate: 65 mL / min; gradient: 22% b to 42% b in 7 min, wavelength: 254 nm; RT: 4.87 / 6.18. This gave 3-(but-3-en-1-yl)-N-(3-methyloxetan-3-yl)-2,4-dioxo-1H-quinazoline-6-sulfonamide (170 mg, 13.76%) as a white solid. LCMS (ESI, m / z): 352[M+H] +

[0247] Step 2: Synthesis of methyl (E)-5-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)pent-2-enoate A mixture of 3-(but-3-en-1-yl)-N-(3-methyloxetan-3-yl)-2,4-dioxo-1H-quinazoline-6-sulfonamide (130 mg, 0.356 mmol, 1 eq.) and methyl acrylate (30.63 mg, 0.356 mmol, 1.0 eq.), Grubbs catalyst 2nd generation (90.61 mg, 0.107 mmol, 0.3 eq.) in DCM (35 mL) was stirred at room temperature overnight. The desired product could be detected by LCMS (approximately 20% by LCMS). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (100:0 to 90:10) to give methyl (2E)-5-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}pent-2-enoate (35 mg crude). The crude product was purified by elution with the following conditions (Column: XBridge Shield rp18 OBD column, 19*250nm, 10um; Mobile phase A: water (10mmol / L NH 4 HCO 3 , mobile phase B: ACN; flow rate: 25 ml / min; gradient: 10% B to 25% B in 10 min, wavelength: 254 nm; RT 8.3) to give methyl (2E)-5-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}pent-2-enoate (25.1 mg, 16.58%) as a white solid. LCMS (ESI, m / z): 424[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 ) δ 8.51 (d, J = 2Hz, 1H), 8.09 - 8.07 (m, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.02 - 6.99 (m, 1H), 5.90 (d, J = 15.6Hz, 1H), 4.72 (d, J = 6Hz, 2H), 4.26 (d, J = 6.4Hz, 2H), 4.27 - 4.17 (m, 2H), 3.71 (s, 3H), 2.67-2.62 (m, 2H), 1.55 (s, 3H).

[0248] Example 13A: 1,3-Diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry predicted) [ka] Step 1: Synthesis of 2-ethyl-1-methylcyclopropan-1-amine Titanium isopropoxide (4.15 g, 14.615 mmol, 0.60 equiv) in THF (15 mL), CH 3 To a solution of CN (1.00 g, 24.359 mmol, 1.00 equiv) was added butyl(chloro)magnesium (12.06 mL, 24.115 mmol, 0.99 equiv) at 0° C. The mixture was stirred at 0° C. for 1 h. 3 -Et 2 2H2O (6.57 mL, 24.367 mmol, 1.00 equiv, 47%) was added and stirred at 0° C. for 1 h. The resulting mixture was extracted with EtOEt (2×50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES. m / z): 100 [M+H] + .

[0249] Step 2: Synthesis of 1,3-diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (speculated) To a solution of 2-ethyl-1-methylcyclopropan-1-amine (313.1 mg, 3.155 mmol, 5 equiv), TEA (191.68 mg, 1.893 mmol, 3 equiv) in DCM (8 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (200 mg, 0.631 mmol, 1.00 equiv). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 / EA 10:1). The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution with the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH 3 -H 2 The mixture was concentrated under reduced pressure. The product was purified by Prep-HPLC under the following conditions (column: CHIRALPAK IE, 2×25 cm, 5 μm; mobile phase A: Hex:DCM=3:1 (0.5% 2M NH 3 -MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 20 min; Wavelength: 220 / 254 nm; RT1 (min): 11.997; RT2 (min): 13.686; Sample solvent: EtOH--HPLC; Injection volume: 0.6 mL; Number of runs: 10. / / Column: CHIRALPAK IF, 25 × cm, 5 μm; Mobile phase A: EtOH--HPLC, Mobile phase B: Hex (0.5% 2 M NH 3-MeOH)-HPLC; flow rate: 18 mL / min; gradient: 60% B to 60% B in 30 min; wavelength: 220 / 254 nm; RT1 (min): 18.07; RT2 (min): 22.72; sample solvent: EtOH:DCM=1:1; injection volume: 0.5 mL; number of runs: 4) to obtain rel-1,3-diethyl-N-((1S,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (5.4 mg, 2.24%), rel-1,3-diethyl-N-((1R,2R ... Methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (34.1 mg, 14.19%), rel-1,3-diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (5.6 mg, 2.32%), and rel-1,3-diethyl-N-((1R,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (30.1 mg, 12.51%) were obtained as off-white solids.

[0250] Example 13A: 1,3-diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.46 (d, J = 2.3 Hz, 1H), 8.14-8.04 (m, 2H), 7.71 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.45-1.36 (m, 1H), 1.25-1.09 (m, 7H), 0.94-0.89 (m, 6H), 0.61 (d, J = 10.7 Hz, 1H), 0.53 (s, 2H).

[0251] Example 13B: 1,3-diethyl-N-((1S,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.46 (d, J = 2.3 Hz, 1H), 8.14-8.05 (m, 2H), 7.72 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.45-1.34 (m, 1H), 1.25-1.09 (m, 7H), 0.98-0.87 (m, 6H), 0.63 (s, 1H), 0.53 (s, 2H).

[0252] Example 13C: 1,3-diethyl-N-((1R,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.43 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.05 (dd, J = 8.9, 2.3 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.20-1.04 (m, 11H), 0.83-0.73 (m, 5H), 0.10-0.02 (m, 1H).

[0253] Example 13D: 1,3-diethyl-N-((1R,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (300 MHz, DMSO-d 6) δ 8.43 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 8.05 (dd, J = 8.9, 2.3 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.25-1.04 (m, 11H), 0.83-0.69 (m, 5H), 0.1-0.02 (m, 1H).

[0254] Example 14: 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-methyloxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] Step 1: Synthesis of 5-(bromomethyl)-2-methyl-1,3-thiazole A solution of 2,5-dimethyl-1,3-thiazole (2.4 g, 21.205 mmol, 1 equiv.), NBS (4.53 g, 25.446 mmol, 1.2 equiv.), and BPO (6.52 g, 25.446 mmol, 1.2 equiv.) in benzene (50 mL) was heated with N 2 Stirred at 120° C. under atmosphere for 2 h. The resulting mixture was stirred at room temperature for 16 h. The residue was purified by the following conditions: column, silica gel; mobile phase, EA in PE, gradient 0% to 50% in 40 min; detector, UV 254 nm. This gave 5-(bromomethyl)-2-methyl-1,3-thiazole (300 mg, 7.37%) as an off-white solid. LCMS (ESI, m / z): 193.95 [M+H] + .

[0255] Step 2: Synthesis of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-N-(3-methyloxetan-3-yl)-2,4-dioxo-1H-quinazoline-6-sulfonamide N-(3-methyloxetan-3-yl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (500 mg, 1.606 mmol, 1.00 equiv.) in DMF (10 mL, 129.215 mmol), Cs 2 CO 3 A solution of 5-(bromomethyl)-2-methyl-1,3-thiazole (784.95 mg, 2.409 mmol, 1.5 equiv.) and 5-(bromomethyl)-2-methyl-1,3-thiazole (246.79 mg, 1.285 mmol, 0.8 equiv.) was stirred at room temperature for 3 h. The aqueous layer was extracted with EA (3×50 mL). The residue was purified under the following conditions: column, silica gel; mobile phase, EA in PE, gradient 0% to 50% in 40 min; detector, UV 254 nm. This gave 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-N-(3-methyloxetan-3-yl)-2,4-dioxo-1H-quinazoline-6-sulfonamide (100 mg, 14.74%) as a white solid. LCMS (ESI, m / z): 422.95[M+H] + .

[0256] Step 3: Synthesis of 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-methyloxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide To a solution of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-N-(3-methyloxetan-3-yl)-2,4-dioxo-1H-quinazoline-6-sulfonamide (80 mg, 0.189 mmol, 1 equiv.) and (2,4-dimethyl-1,3-thiazol-5-yl)methanol (27.12 mg, 0.189 mmol, 1 equiv.) in THF (2 mL, 24.686 mmol), DIAD (49.47 mg, 0.283 mmol, 1.5 equiv.) and PPh 3 (74.50 mg, 0.283 mmol, 1.5 equiv.) was added. After stirring at room temperature under nitrogen atmosphere for 16 h, the residue was purified by silica gel column chromatography and eluted with DCM:MeOH (10:1). The residue was purified by silica gel column chromatography under the following conditions: column, C18 silica gel; mobile phase, H2 Purification by reversed-phase flash chromatography using ACN in O, 10% to 50% gradient in 40 min; detector, UV 254 nm. This gave 1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide (42.5 mg, 37.74%) as an off-white solid. LCMS (ESI, m / z): 548.05[M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.18-8.14 (m, 1H), 7.66 (d, J = 8.7 Hz, 2H), 5.46 (s, 2H), 5.27 (s, 2H), 4.53 (d, J = 6.0 Hz, 2H), 4.14 (d, J = 6.3 Hz, 2H), 2.58 (s, 3H), 2.51-2.47 (m, 6H), 1.40 (s, 3H).

[0257] Example 15A: 1,3-Diethyl-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed) [ka] Step 1: Synthesis of 2-(2-amino-2-methylcyclopropyl)ethanol A solution of 3-buten-1-ol (4 g, 55.473 mmol, 1.2 equiv.), ACN (1.90 g, 46.227 mmol, 1 equiv.), and titanium isopropylate (15.77 g, 55.473 mmol, 1.2 equiv.) in THF (464 mL, 5727.045 mmol) was added to N 2The mixture was stirred at room temperature under atmospheric pressure for 30 minutes. To the stirred mixture was added bromo(cyclohexyl)magnesium (110.95 mL, 110.946 mmol, 2.4 equiv.) in a N 2 The reaction was stirred at room temperature for 3 h under atmospheric pressure for 3 h. 2 The resulting mixture was quenched with O. The resulting mixture was filtered and the filter cake was washed with EA (100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EA (3×150 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. LCMS (ESI, m / z): 116 [M+H] + .

[0258] Step 2: Synthesis of 1,3-diethyl-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide To a stirred solution of 2-[(1R,2R)-2-amino-2-methylcyclopropyl]ethanol (2 g, 5 eq., crude) and 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (1 g, 3.157 mmol, 1 eq.) in DCM (20 mL, 314.612 mmol), TEA (1.1 g, 10.870 mmol) was added dropwise at room temperature and stirred for 16 h. The residue was purified by the following conditions: column, silica gel; mobile phase, EA in PE, gradient 0%-80% in 60 min; detector, UV 254 nm. The resulting mixture was purified by chiral_HPLC with the following conditions (Column: CHIRALPAK IE-3, 4.6*50mm 3um; Mobile phase A (Hex:DCM=3:1)(0.1% DEA):EtOH=50:50; Flow rate: 1mL / min; Gradient: 0% B to 0% B; Injection volume: 5ul mL) to give 1,3-diethyl-N-[(1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl]-2,4-dioxoquinazoline-6-sulfonamide (23.4mg) as a white solid and 1,3-diethyl-N-[(1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl]-2,4-dioxoquinazoline-6-sulfonamide (22.5mg) as a white solid.

[0259] Example 15A: 1,3-diethyl-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): LCMS (ESI, m / z): 396.15 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6) δ 8.45 (d, J = 2.1 Hz, 1H), 8.11-8.07 (m, 1H), 7.71 (d, J = 9.0 Hz, 1H), 5.10 (brs,1H),4.18 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.44 (t, J = 6.7 Hz, 2H), 1.61-1.54 (m, 1H), 1.35-1.20 (m, 7H), 0.93 (s, 3H), 0.70 - 0.52 (m, 3H).

[0260] Example 15B: 1,3-diethyl-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): LCMS (ESI, m / z): 396.10 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.45 (d, J = 2.4 Hz, 1H), 8.11-8.04 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 4.49 (s,1H),4.18 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.44 (q, J = 6.4 Hz, 2H), 1.60-1.52 (m, 1H), 1.37-1.28 (m,1H),1.26 - 1.16 (m, 6H), 0.93 (s, 3H), 0.67-0.52 (m, 3H).

[0261] Example 16: N-((1SR,2SR)-2-(cyanomethyl)-1-methylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry predicted) [ka] ACN (4.5 mL, 85.609 mmol) and H 21,3-Diethyl-N-[2-(2-hydroxyethyl)-1-methylcyclopropyl]-2,4-dioxoquinazoline-6-sulfonamide (70 mg, 0.177 mmol, 1 equiv.) and NH 4 To a stirred solution of OAc (54.58 mg, 0.708 mmol, 4 equiv.), (acetyloxy)(phenyl)-lambda3-iodanyl acetate (125.43 mg, 0.389 mmol, 2.2 equiv.) and TEMPO (14.11 mg, 0.090 mmol, 0.51 equiv.) were added in portions at room temperature and stirred for 16 h. The resulting mixture was quenched, extracted, dried and concentrated under reduced pressure. The residue was purified by Prep-TLC (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (NH 4 HCO 3 +0.1% NH 3 -H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 57% B in 8 min, 57% B; wavelength: 254 nm; RT1 (min): 7) to give N-((1SR,2SR)-2-(cyanomethyl)-1-methylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (23.7 mg, 34.19%) as a white solid. LCMS (ESI, m / z): 391.05[M+H] + ; 1 H NMR (400 MHz, DMSO-d 6) δ 8.47 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 8.13-8.11 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 4.18 (q, J = 6.9 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 2.65-2.59 (m, 1H), 2.45-2.39 (m, 1H), 1.24-1.17 (m, 6H), 1.10 - 1.00 (m, 1H), 0.90 (s, 4H), 0.79-0.75 (m, 1H).

[0262] Example 17A: N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed) [ka] Step 1: Synthesis of 3-(dibenzylamino)-2-methyloxetane-3-carbonitrile A solution of 2-methyloxetan-3-one (250 mg, 2.904 mmol, 1 eq.) in DCE was treated with AcOH (261.58 mg, 4.356 mmol, 1.5 eq.) at room temperature for 2 min under nitrogen atmosphere, followed by dropwise addition of dibenzylamine (859.34 mg, 4.356 mmol, 1.5 eq.) at room temperature. The resulting mixture was stirred at room temperature for 10 min under nitrogen atmosphere. To the above mixture, TMSCN (432.14 mg, 4.356 mmol, 1.5 eq.) was added dropwise at room temperature over 3 min. The resulting mixture was stirred at 60° C. for an additional 18 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give 3-(dibenzylamino)-2-methyloxetane-3-carbonitrile (250 mg, 23.70%) as an off-white oil. LCMS (ES. m / z): 293 [M+H] + .

[0263] Step 2: Synthesis of dibenzyl-2,3-dimethyloxetan-3-amine To a stirred mixture of 3-(dibenzylamino)-2-methyloxetane-3-carbonitrile (250 mg, 0.855 mmol, 1 equiv.) in THF, MeMgBr (509.80 mg, 4.275 mmol, 5 equiv.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 5 h under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched at room temperature by the addition of water (20 mL). The resulting mixture was diluted with CH 2 Cl 2 (3×20 mL). The combined organic layers were washed with water (3×10 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (10:1) to give N,N-dibenzyl-2,3-dimethyloxetan-3-amine (120 mg, 45.48%) as an off-white oil. LCMS (ES. m / z): 282 [M+H] + .

[0264] Step 3: Synthesis of 2,3-dimethyloxetan-3-amine Pd(OH) in MeOH 2 A mixture of / C (299.43 mg, 2.130 mmol, 5 equiv.) and N,N-dibenzyl-2,3-dimethyloxetan-3-amine (120 mg, 0.426 mmol, 1 equiv.) was stirred overnight at room temperature under a hydrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was purified by CH 2 Cl 2 (5×10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES. m / z): 102 [M+H] + .

[0265] Step 4: Synthesis of N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide To a stirred mixture of 2,3-dimethyloxetan-3-amine (20 mg, 0.198 mmol, 1 eq.) and pyridine (5 mL, 0.063 mmol, 0.32 eq.) in DCM, 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (62.63 mg, 0.198 mmol, 1 eq.) was added dropwise at room temperature under air atmosphere. The resulting mixture was stirred at room temperature under air atmosphere for 2 hours. The desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to give N-(2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide as an off-white solid. The crude product was purified by chiral HPLC with the following conditions (column: CHIRALPAK IC-3, 4.6*50mm 3μm; mobile phase A: MTBE:(0.1% DEA):IPA=60:40; flow rate: 1mL / min; gradient: 0% B to 0% B; injection volume: 5μl mL) to give rel-N-[(2S,3S)-2,3-dimethyloxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (7.5mg, 9.70%), rel-N-[(2R,3R)-2,3-dimethyloxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (7.1mg, 9.20%), rel-N-[(2R,3R)-2,3-dimethyloxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (7.2mg, 9.20%), rel-N-[(2S,3S)-2,3-dimethyloxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (7.2mg, 9.20%), rel-N-[(2R,3R ... ), rel-N-[(2R,3S)-2,3-dimethyloxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (10.1 mg, 13.08%), and rel-N-[(2R,3S)-2,3-dimethyloxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (11.8 mg, 15.50%) were obtained as off-white solids.

[0266] Example 17A: N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (400 MHz, chloroform-d) δ 8.76 (s, 1H), 8.17-8.14 (m, 1H), 7.46 - 7.29 (m, 2H), 5.67 (s, 1H), 4.61-4.58 (m, 2H), 4.32-4.15 (m, 5H), 1.48-1.15 (m, 11H).

[0267] Example 17B: N-((2R,3R)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (400 MHz, chloroform-d) δ 8.76-8.74 (m, 1H), 8.17-8.15 (m, 1H), 7.35 - 7.26 (m, 2H), 5.67 (s, 1H), 4.61-4.56 (m, 2H), 4.32 - 4.14 (m, 5H), 1.65-1.31 (m, 11H).

[0268] Example 17C: N-((2R,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (400 MHz, chloroform-d) δ 8.74 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.47 - 7.27 (m, 1H), 5.95 (d, J = 8.7 Hz, 1H), 4.92-4.88 (m, 1H), 4.60-4.58 (m, 1H), 4.26-4.01 (m, 5H), 1.43 - 1.25 (m, 14H).

[0269] Example 17D: N-((2S,3R)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (stereochemistry assumed): 1 H NMR (400 MHz, chloroform-d) δ 8.74 (s, 1H), 8.17-8.14 (m, 1H), 7.35 - 7.26 (m, 1H), 6.03 (d, J = 6.6 Hz, 1H), 4.93-4.89 (m, 1H), 4.60-4.57 (m, 1H), 4.28 - 4.08 (m, 5H), 1.43-1.28 (m, 14H).

[0270] Example 18: N-(3-(difluoromethyl)oxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] To a solution of 3-(difluoromethyl)oxetan-3-amine (58.29 mg, 0.474 mmol, 1 equiv.), TEA (143.76 mg, 1.422 mmol, 3 equiv.) in DCM (3 mL) was added 1,3-diethyl-2,4-dioxoquinazoline-6-sulfonyl chloride (150 mg, 0.474 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 / EA 1:1). The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution with the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 47% B in 7 min, 47% B; wavelength: 254 nm; RT1 (min): 6.03) to give N-[3-(difluoromethyl)oxetan-3-yl]-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide (29.0 mg, 15.14%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.11 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.13 (dd, J = 8.9, 2.4 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 6.31 (t, J = 55.2 Hz, 1H), 4.55 (s, 4H), 4.18 (q, J = 7.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 1.21 (t*2, J = 7.0 Hz, 6H). LCMS (ES. m / z): 404 [M+H] + .

[0271] Example 19: (E)-N-methyl-4-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)but-2-enamide [ka] Step 1: Synthesis of (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoic acid Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate (150 mg, 0.366 mmol, 1 equiv.) in THF (2 mL) and H 2 LiOHH ​​in 2HO (2 mL) 2A mixture of 2H2O (76.87 mg, 1.830 mmol, 5.0 equiv) and 2H2O (76.87 mg, 1.830 mmol, 5.0 equiv) was stirred at room temperature overnight. The desired product could be detected by LCMS. The mixture was acidified to pH 1-2 with HCl (2 M). The aqueous layer was extracted with EA (2 x 5 mL) and washed with anhydrous Na 2 SO 4 The filtrate was concentrated under reduced pressure to give the desired product (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoic acid (130 mg, 80.77%) as a white solid. LCMS (ESI, m / z): 396[M+H] +

[0272] Step 2: Synthesis of (E)-N-methyl-4-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)but-2-enamide A mixture of (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoic acid (40 mg, 0.101 mmol, 1 eq.) and methylamine (3.14 mg, 0.101 mmol, 1.0 eq.), EDCI (23.27 mg, 0.121 mmol, 1.2 eq.), HOBT (16.40 mg, 0.121 mmol, 1.2 eq.), DIEA (32.69 mg, 0.253 mmol, 2.5 eq.) in THF (4 mL) was stirred at room temperature overnight. The desired product could be detected by LCMS. The resulting mixture was diluted with EA (25 mL) and diluted with H 2 The resulting solution was washed with 10 mL of NaO (3×10 mL). 2 SO 4 The mixture was dried at 40° C. and concentrated under vacuum. The mixture was diluted with DMF (2 mL) for Pre-HPLC (Column: XBridge Shield rp18 OBD column, 19*250 nm, 10 um; Mobile phase A: water (10 mmol / L NH 4 HCO 3, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10% B to 25% B in 10 min, wavelength: 254 nm; RT 8.3). This gave (2E)-N-methyl-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enamide (14.1 mg, 34.09%) as a white solid. LCMS (ESI, m / z): 409 [M+H] + ; 1 H NMR (300 MHz, methanol-d 4 ) δ 8.51 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 8.7, 2.2 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 6.79 (dt, J = 15.5, 5.3 Hz, 1H), 6.16 - 5.80 (m, 1H), 4.84 - 4.60 (m, 4H), 4.41 - 4.18 (m, 2H), 2.77 (s, 3H), 1.55 (s, 3H).

[0273] Example 20: 1,3-Diethyl-N-(3-(fluoromethyl)oxetan-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka]

[0274] Intermediate 1: 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carboxylate [ka] Step 1: Synthesis of tert-butyl 4-(5-bromo-3-fluoro-2-formylphenyl)piperazine-1-carboxylate 4-Bromo-2,6-difluorobenzaldehyde (5 g, 22.624 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (5.06 g, 27.149 mmol, 1.2 equiv.), and K 2 CO 3 (6.25 g, 45.248 mmol, 2 equiv) was stirred at 80° C. for 12 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (150 mL) was added. The mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (150 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-(5-bromo-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (5 g, 51.36%) as a yellow solid. LCMS (ESI, m / z): 387, 389 [M+H] +.

[0275] Step 2: Synthesis of tert-butyl 4-(6-bromo-1H-indazol-4-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(5-bromo-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (5 g, 12.912 mmol, 1 eq.) and hydrazine hydrate (80%, 2.59 g, 51.648 mmol, 4 eq.) in DMSO (40 mL) was stirred at 100° C. for 30 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (150 mL) was added. The mixture was extracted with EA (3×100 mL) and the combined organic layers were washed with brine (150 mL) and washed with anhydrous Na 2 SO 4The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-(6-bromo-1H-indazol-4-yl)piperazine-1-carboxylate (4 g, 73.13%) as a yellow solid. LCMS (ESI, m / z): 381, 383[M+H] + .

[0276] Step 3: Synthesis of tert-butyl 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carboxylate tert-Butyl 4-(6-bromo-1H-indazol-4-yl)piperazine-1-carboxylate (4 g, 10.491 mmol, 1 equiv.), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (2.71 g, 12.589 mmol, 1.2 equiv.), and Cs in DMF (40 mL). 2 CO 3 (6.84 g, 20.982 mmol, 2 equiv) was stirred at 70° C. for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (100 mL) was added. The mixture was extracted with EA (3×80 mL) and the combined organic layers were washed with brine (100 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give tert-butyl 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carboxylate (3.0 g, 55%) as a yellow solid and tert-butyl 4-{6-bromo-2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carboxylate (0.5 g, 9.2%) as a yellow solid. LCMS (ESI, m / z): 515, 517 [M+H] + .

[0277] Step 4: Synthesis of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(piperazin-1-yl)indazole To a stirred solution of tert-butyl 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carboxylate (2.5 g, 4.851 mmol, 1 equiv.) in 1,4-dioxane (20 mL) was added dropwise HCl (4 M in 1,4-dioxane, 5 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The mixture was concentrated. The residue was purified by silica gel column chromatography (eluted with 3:1 EA / PE) to give 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(piperazin-1-yl)indazole (1.8 g, 80.42%) as a yellow solid. LCMS (ESI, m / z): 415, 417 [M+H] + .

[0278] Example 21: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclobutyl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclobutyl)indazole-6-sulfonamide To a stirred solution of 1-methylcyclobutan-1-amine hydrochloride (189.43 mg, 1.558 mmol, 2 equiv.) in DMF was added DIEA (301.99 mg, 2.337 mmol, 3 equiv.) in small portions at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. Water (20 mL) was then added. The resulting mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclobutyl)indazole-6-sulfonamide (60 mg, crude) as a yellow oil. LCMS (ESI, m / z): 434, 436[M+H] + .

[0279] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclobutyl)-1H-indazole-6-sulfonamide To a stirred mixture of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclobutyl)indazole-6-sulfonamide (60 mg, 0.138 mmol, 1 equiv.) and 2-methyl-1-(piperazin-1-yl)propan-1-one (25.93 mg, 0.166 mmol, 1.2 equiv.) in 1,4-dioxane (2 mL), RuPhos palladacycle 3rd generation (11.57 mg, 0.014 mmol, 0.1 equiv.), RuPhos (12.91 mg, 0.028 mmol, 0.2 equiv.), and Cs 2 CO 3(135.17 mg, 0.414 mmol, 3 equiv.) was added. The mixture was stirred at 70° C. under nitrogen atmosphere for 4 h. The resulting mixture was filtered and the filter cake was washed with DCM (3×5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by HPLC using the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (NH 4 HCO 3 +0.1% NH 3 H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 75% B in 7 min, 75% B; wavelength: 254 nm; RT1 (min): 6; number of runs: 0) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclobutyl)-1H-indazole-6-sulfonamide (21.3 mg, 27.74%) as a white solid. LCMS (ESI, m / z): 554.15 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ=8.77 (s, 1H), 8.31 (s, 1H), 7.26 (s, 1H), 7.15-6.87 (m, 1H), 4.83 (s, 1H), 3.95-3.78 (m, 4H), 3.48-3.39 (m, 4H), 2.92-2.81 (m, 1H), 2.34-2.22 (m, 2H), 1.98-1.87 (m, 2H), 1.83-1.66 (m, 2H), 1.45 (s, 3H), 1.19 (d, J = 6.8 Hz, 6H).

[0280] Example 22: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide [ka] 1-(4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one (1 g, 2.060 mmol, 1 equiv.), dipotassium sulfinosulfonate (0.92 g, 4.120 mmol, 2 equiv.), triphenylphosphane (0.16 g, 0.618 mmol, 0.3 equiv.), tetraethylazanium bromide (0.48 g, 2.266 mmol, 1.1 equiv.), sodium formate (0.42 g, 6.180 mmol, 3 equiv.), Pd(AcO) in DMSO (10 mL). 2 A mixture of 3-(fluoromethyl)oxetan-3-amine hydrochloride (0.88 g, 6.180 mmol, 3 eq.) in DIEA (5 mL) was added at 0° C. to the above mixture. Then, NCS (1.38 g, 10.335 mmol, 5.02 eq.) in THF (10 mL) was added at 0° C. The resulting mixture was stirred for an additional hour at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 30% to 70% in 10 min; detector, UV 254 nm. This gave 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (155.2 mg, 13.03%) as an off-white solid. LCMS (ESI, m / z): 574[M+H] + . 1H NMR (400 MHz, chloroform-d) δ=8.77 (s, 1H), 8.33 (s, 1H), 7.19 (s, 1H), 7.17-6.87 (m, 1H), 5.80 (s, 1H), 4.88-4.78 (m, 3H), 4.71 (s, 1H), 4.46 (d, J=7.2 Hz, 2H), 3.99-3.76 (m, 4H), 3.55-3.39 (m, 4H), 2.96-2.81 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H)

[0281] Example 23: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 6-(benzylsulfanyl)-1H-indazole 6-Bromo-1H-indazole (1 g, 5.075 mmol, 1 equiv.), benzyl mercaptan (1.26 g, 10.150 mmol, 2 equiv.), DIEA (1.97 g, 15.225 mmol, 3 equiv.), Pd 2 (dba) 3 A mixture of XantPhos (464.75 mg, 0.508 mmol, 0.1 equiv.) and XantPhos (587.34 mg, 1.015 mmol, 0.2 equiv.) was added to N 2 Stirred at 100° C. under atmosphere for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (100 mL) was added. The mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 6-(benzylsulfanyl)-1H-indazole (800 mg, 59.03%) as a yellow solid. LCMS (ESI, m / z): 241 [M+H] + .

[0282] Step 2: Synthesis of 6-(benzylsulfanyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole and 2-(6-(benzylthio)-2H-indazol-2-yl)-5-(difluoromethyl)-1,3,4-thiadiazole 6-(benzylsulfanyl)-1H-indazole (800 mg, 3.329 mmol, 1 equiv.), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (1.07 g, 4.994 mmol, 1.5 equiv.), and Cs in DMF (10 mL). 2 CO 3 (2.17 g, 6.658 mmol, 2 equiv) was stirred at 100° C. for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (100 mL) was added. The mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give a mixture of 6-(benzylsulfanyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole and 2-(6-(benzylthio)-2H-indazol-2-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (800 mg, 58%) as a yellow solid. LCMS (ESI, m / z): 375 [M+H] + .

[0283] Step 3: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride DCM (4 mL), AcOH (0.3 mL, 5.235 mmol, 9.80 eq.), and H 2 To a stirred solution of 6-(benzylsulfanyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole and 2-(6-(benzylthio)-2H-indazol-2-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (200 mg, 0.534 mmol, 1 equiv) in 2H2O (0.6 mL, 33.306 mmol, 62.35 equiv) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (315.71 mg, 1.602 mmol, 3 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with anhydrous Na 2 After filtration, the filtrate was concentrated under reduced pressure to give a mixture of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride and 2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride (100 mg, crude) as a white solid. LCMS (ESI, m / z): 351, 353 [M+H] + .

[0284] Step 4: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide To a stirred solution of a mixture of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride in DCM (3 mL) and TEA (57.70 mg, 0.570 mmol, 2 equiv.) was added 3-methyloxetan-3-amine (37.26 mg, 0.427 mmol, 1.5 equiv.) in DCM dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated. The residue was purified by reverse phase chromatography (column: C18; mobile phase, A: water (NH 4 HCO 3 A: ACN (5% to 60% over 30 min; detector, UV 254 nm), affording 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide (18.8 mg, 32.42%) as a white solid. LCMS (ESI, m / z): 401.95 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.97 (s, 1H), 8.85 (s, 1H), 8.78 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.76-7.50 (m, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.15 (d, J=6.8 Hz, 2H), 1.44 (s, 3H).

[0285] Example 24: Synthesis of 4-chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] To a stirred solution of 3-methyloxetan-3-amine (67.86 mg, 0.778 mmol, 2 equiv) in DCM (2 mL) was added TEA (157.63 mg, 1.556 mmol, 4 equiv) and 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride (150 mg, 0.389 mmol, 1 equiv) at 0° C. The resulting mixture was stirred at 25° C. for 2 h. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 34% B to 64% B in 7 min, 64% B; Wavelength: 254nm; RT1(min): 6.2; Number of runs: 0) to give 4-chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (10.6mg, 6.20%) as a white solid. LCMS (ESI, m / z): 436.00 [M+H] + . 1 H NMR (300 MHz, chloroform-d) δ=9.10(s, 1H), 8.46 (s, 1H), 7.89 (s, 1H), 7.19-6.84 (m, 1H), 5.37 (s, 1H), 4.76 (d, J=6.6 Hz, 2H), 4.38 (d, J=6.9 Hz, 2H), 1.65 (s, 3H).

[0286] Example 25A: N-(3-cyanooxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] Step 1: Synthesis of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonyl chloride ClSO 3 A mixture of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-1H-quinazoline-2,4-dione (400 mg, 1.464 mmol, 1 equiv) in H (1 mL) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was quenched at 0° C. by the addition of water (50 mL). The mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over hexane and concentrated to give 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonyl chloride (400 mg, crude) as a yellow solid. LCMS (ESI, m / z): 372, 374[M+H] +

[0287] Step 2: Synthesis of N-(3-cyanooxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide A mixture of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonyl chloride (100 mg, 0.269 mmol, 1 eq.) and 3-aminooxetane-3-carbonitrile (31.66 mg, 0.323 mmol, 1.2 eq.) in pyridine (2 mL, 0.025 mmol, 0.09 eq.) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was diluted with ethyl acetate (20 mL). The resulting mixture was washed with brine (3×20 mL) and purified by elution with anhydrous Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by elution with 100 ml of ethyl acetate under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 25% B in 7 min, 25% B; wavelength: 254 nm; RT1 (min): 6; number of runs: 0) to give N-(3-cyanooxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (19.3 mg, 16.43%) as a white solid. LCMS (ESI, m / z): 434.05 [M+H] + 1 H NMR (400 MHz, chloroform-d) δ=11.96 (br, 1H), 8.34 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.61 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 5.20 (s, 2H), 4.81 (d, J=7.5 Hz, 2H), 4.69 (d, J=7.2 Hz, 2H), 2.67 (s, 3H).

[0288] Example 25B: N-(3-cyanooxetan-3-yl)-1-((2,4-dimethylthiazol-5-yl)methyl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] N-(3-cyanooxetan-3-yl)-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonamide (100 mg, 0.231 mmol, 1 equiv.), (2,4-dimethyl-1,3-thiazol-5-yl)methanol (49.55 mg, 0.347 mmol, 1.5 equiv.), and PPh in THF (2 mL).3 (E)-N-[[(propan-2-yloxy)carbonyl]imino](propan-2-yloxy)formamide (93.30 mg, 0.462 mmol, 2 equiv.) was added dropwise at 0° C. to a mixture of (121.02 mg, 0.462 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (20 mL). The resulting mixture was washed with brine (3×20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of hexane. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 23% B to 53% B, 53% B in 7 min; Wavelength: 254nm; RT1(min): 6.88; Number of runs: 0) to give N-(3-cyanooxetan-3-yl)-1-((2,4-dimethylthiazol-5-yl)methyl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (7.9mg, 6.08%) as a white solid. LCMS (ESI, m / z): 559.05[M+H] + 1 H NMR (400 MHz, chloroform-d) δ=12.03 (br, 1H), 8.18 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 5.26 (s, 2H), 4.91 (d, J=7.5 Hz, 2H), 4.75 (d, J=7.8 Hz, 2H), 4.50 (s, 2H), 2.63 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H).

[0289] Example 26: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(dimethylamino)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde 4-Bromo-2,6-difluorobenzaldehyde (500 mg, 2.262 mmol, 1 equiv.), dimethylamine (102.00 mg, 2.262 mmol, 1 equiv.), and K 2 CO 3 (625.36 mg, 4.524 mmol, 2 equiv.) was stirred at 80° C. for 16 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EA (40 mL). The resulting mixture was washed with 4×10 water and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to give 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde (500 mg, 90%) as a yellow solid. LCMS (ESI, m / z): 246, 248[M+H] + .

[0290] Step 2: Synthesis of 6-bromo-N,N-dimethyl-1H-indazol-4-amine Into a stirred solution of 4-bromo-2-(dimethylamino)-6-fluorobenzaldehyde (1 g, 4.064 mmol, 1 equiv) in DMSO (10 mL) was placed hydrazine hydrate (797.35 mg, 16.256 mmol, 4 equiv). The mixture was stirred at 100° C. for 16 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was diluted with EA (100 mL). The resulting mixture was washed with brine (3×80 mL) and diluted with anhydrous Na 2SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to give 6-bromo-N,N-dimethyl-1H-indazol-4-amine (800 mg, 81.99%) as a yellow solid. LCMS (ESI, m / z): 240, 242[M+H] +

[0291] Step 3: Synthesis of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N,N-dimethylindazol-4-amine 6-Bromo-N,N-dimethyl-1H-indazol-4-amine (800 mg, 3.332 mmol, 1 equiv.) in DMF (10 mL) and Cs 2 CO 3 To a stirred mixture of (2.17 g, 6.664 mmol, 2 equiv) was added 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (859.71 mg, 3.998 mmol, 1.2 equiv). The mixture was stirred at 70° C. for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Then water (60 mL) was added. The mixture was washed with EA (3×80 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 3:1 EA / PE) to give 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N,N-dimethylindazol-4-amine (750 mg, 60.15%) as a white solid. LCMS (ESI, m / z): 374, 376[M+H] + .

[0292] Step 4: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(dimethylamino)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide A mixture of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N,N-dimethylindazol-4-amine (200 mg, 0.534 mmol, 1 equiv), potassium metabisulfite (237.65 mg, 1.068 mmol, 2 equiv), TEAB (151.23 mg, 1.043 mmol, 1.1 equiv), sodium formate (72.70 mg, 1.068 mmol, 2 equiv), PPh3 (42.06 mg, 0.160 mmol, 0.3 equiv), phen (28.89 mg, 0.160 mmol, 0.3 equiv), and palladium acetate (12.00 mg, 0.053 mmol, 0.1 equiv) in DMSO (3 mL) was stirred at 70 °C for 4 h under nitrogen atmosphere. The reaction was then cooled to room temperature. A solution of 3-methyloxetan-3-amine (93.13 mg, 1.068 mmol, 2 equiv) in THF (3 mL) and a solution of NBS (285.38 mg, 1.602 mmol, 3 equiv) in THF (2 mL) were added. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. Water (50 mL) was then added. The mixture was washed with EA (3×50 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 15% B to 45% B, 45% B in 7 min; Wavelength: 254nm; RT1(min): 6; Number of runs: 0) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(dimethylamino)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide (22.5mg, 9.45%) as a white solid. LCMS (ESI, m / z): :445.05 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ=8.91 (s, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.76-7.41 (m, 1H), 6.87 (s, 1H), 4.58 (d, J=6.0 Hz, 2H), 4.13 (d, J=6.6 Hz, 2H), 3.31 (s, 6H), 1.58 (s, 3H)

[0293] Example 27: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2S,3S)-2,3-dimethyloxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (stereochemistry predicted) [ka] Step 1: Synthesis of 3-(dibenzylamino)-2-methyloxetane-3-carbonitrile A solution of 2-methyloxetan-3-one (700 mg, 8.131 mmol, 1 eq.) and dibenzylamine (3208.19 mg, 16.262 mmol, 2 eq.) in AcOH (8 mL) was treated with TMSCN (1613.33 mg, 16.262 mmol, 2 eq.) at 0° C. The resulting mixture was stirred at 25° C. under nitrogen atmosphere for 14 h. The desired product could be detected by LCMS. The reaction was quenched with water (50 mL). The resulting mixture was washed with EA (3×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 3-(dibenzylamino)-2-methyloxetane-3-carbonitrile (500 mg, crude). LCMS (ESI, m / z): 293[M+H] +

[0294] Step 2: Synthesis of N,N-dibenzyl-2,3-dimethyloxetan-3-amine To a solution of 3-(dibenzylamino)-2-methyloxetane-3-carbonitrile (500 mg, 1.710 mmol, 1 equiv.) in THF (10 mL) was added MeMgBr (1019.59 mg, 8.550 mmol, 5 equiv.) dropwise at 0° C. The resulting mixture was stirred at 60° C. for 5 h under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was diluted with saturated NH 4 The mixture was quenched with EA (3×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give N,N-dibenzyl-2,3-dimethyloxetan-3-amine (300 mg, crude). LCMS (ESI, m / z): 282[M+H] +

[0295] Step 3: Synthesis of 2,3-dimethyloxetan-3-amine To a stirred solution of N,N-dibenzyl-2,3-dimethyloxetan-3-amine (300 mg, 1.066 mmol, 1 equiv) in MeOH (8 mL) was added Pd(OH) 2 / C (149.71 mg, 1.066 mmol, 1 equiv.) was dissolved in N 2 The resulting mixture was diluted with H 2 Stirred at 25° C. under atmosphere for 14 hours. The desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure to give 2,3-dimethyloxetan-3-amine (80 mg, crude). LCMS (ESI, m / z): 102[M+H] +

[0296] Step 4: Synthesis of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(2,3-dimethyloxetan-3-yl)indazole-6-sulfonamide To a solution of 2,3-dimethyloxetan-3-amine (13.13 mg, 0.130 mmol, 1 equiv.) and pyridine (102.68 mg, 1.300 mmol, 10 equiv.) in DCM (2 mL) was added 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride (50 mg, 0.130 mmol, 1 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The solid was filtered off and washed with DCM (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 41% B to 71% B in 10min, 71% B; Wavelength: 254nm; RT1(min): 8.7; Number of runs: 0) to give 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(2,3-dimethyloxetan-3-yl)indazole-6-sulfonamide (4.6mg, 7.61%) as a white solid. LCMS (ESI, m / z): 450, 452[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.12 (s, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 7.88 (s, 1H), 7.15-6.88 (m, 1H), 5.30-5.20 (m, 1H), 4.65-4.61 (m, 1H), 4.36-4.14 (m, 1H), 1.55 (s, 3H), 1.31-1.25 (m, 3H).

[0297] Step 5: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2S,3S)-2,3-dimethyloxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide To a stirred mixture of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(2,3-dimethyloxetan-3-yl)indazole-6-sulfonamide (15 mg, 0.033 mmol, 1 eq.), RuPhos Pd G3 (5.58 mg, 0.007 mmol, 0.2 eq.), RuPhos (6.30 mg, 0.013 mmol, 0.4 eq.), and cesium carbonate (32.59 mg, 0.099 mmol, 3 eq.) in dioxane, 2-methyl-1-(piperazin-1-yl)propan-1-one (6.25 mg, 0.040 mmol, 1.2 eq.) was added in portions at room temperature. The resulting mixture was stirred at 100° C. under N2 for 24 hours. The desired product could be detected by LCMS. The solid was taken out and washed with EA (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 33% B to 63% B, 63% B in 7 min; Wavelength: 254nm; RT1(min): 6; Number of runs: 0) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2S,3S)-2,3-dimethyloxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (stereochemistry predicted) (4.1mg, 21.56%) as a white solid. LCMS (ESI, m / z): 570.10[M+H] + , 1 H NMR (300 MHz, DMSO-d 6) δ 8.93 (s, 1H), 8.51-8.44 (m, 2H), 7.77-7.42 (m, 1H), 7.15 (s, 1H), 4.78-4.71 (m, 1H), 4.42 (d, J = 5.7 Hz, 1H), 3.87 (d, J = 5.7 Hz, 1H), 3.78-3.74 (m, 4H), 3.44-3.32 (m, 4H), 2.99-2.90 (m, 1H), 1.25 (s, 3H), 1.06-1.02 (m, 9H).

[0298] Example 28A: N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] Step 1: Synthesis of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonyl chloride A solution of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-1H-quinazoline-2,4-dione (200.00 mg, 0.73 mmol, 1.00 equiv) in chlorosulfonic acid (0.50 mL) was stirred at 60° C. for 1.5 h. After the reaction, the reaction mixture was poured into EA (5 mL) and then added to ice water (5 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×5 mL) and extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonyl chloride (200.00 mg, crude) as a light yellow solid. The crude product was used directly for the next step without further purification. LCMS (ESI, m / z): 372, 374 [M+H] +

[0299] Step 2: Synthesis of N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide To a stirred solution of 3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonyl chloride (165.07 mg, 0.44 mmol, 1.00 equiv) in pyridine (3.00 mL) was added 3-(fluoromethyl)oxetan-3-amine (70.00 mg, 0.67 mmol, 1.50 equiv) in small portions at 0° C. The resulting mixture was stirred at room temperature for 1.0 h. The resulting mixture was diluted with CH 2 Cl 2 (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give N-[3-(fluoromethyl)oxetan-3-yl]-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonamide (80.00 mg, 40.88%) as a light yellow solid. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD column 30*150mm 5μm, n; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 16% B to 46% B, 46% B in 7 min; Wavelength: 254nm; RT1(min): 6.00 (detected and collected by lcms)). This gave N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; formic acid (13.0 mg, 65.00%) as a white solid. LCMS (ESI, m / z): 441.00 [M+H] + , 1 H NMR (300 MHz, DMSO-d 6) δ=12.01 (s, 1H), 8.80 (s, 1H), 8.34 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.61 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 5.19 (s, 2H), 4.68 (s, 1H), 4.52-4.50 (m, 3H), 4.32 (d, J=6.6 Hz, 2H), 2.57 (s, 3H).

[0300] Example 28B: 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] To a stirred solution of N-[3-(fluoromethyl)oxetan-3-yl]-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-1H-quinazoline-6-sulfonamide (55.00 mg, 0.13 mmol, 1.00 equiv.) and (2,4-dimethyl-1,3-thiazol-5-yl)methanol (17.88 mg, 0.13 mmol, 1.00 equiv.) in THF (8.00 mL), PPh 3 (65.50 mg, 0.25 mmol, 2.00 equiv) was added in small portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 min. Then DIEA (32.28 mg, 0.25 mmol, 2.00 equiv) was added at 0° C. The resulting mixture was stirred at 0° C. for an additional 1.5 h. The reaction was diluted with H 2 The resulting mixture was extracted with EA (3×10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by elution with 100 ml of ethyl acetate under the following conditions (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO3 +0.1% NH 3 H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 53% B in 7 min, 53% B; wavelength: 254 nm; RT1 (min): 6; (detected and collected by LCMS). This gave 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (8.2 mg, 11.38%) as a white solid. LCMS (ESI, m / z): 566.05 [M+H] + , 1 H NMR (300 MHz, DMSO-d 6 ) δ= 8.47 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.67-7.63 (m, 2H), 5.46 (s, 2H), 5.26 (s, 2H), 4.69 (s, 1H), 4.53-4.51 (m, 3H), 4.34 (d, J=6.9 Hz, 2H), 2.58 (s, 3H), 2.49 (s, 3H), 2.47(s, 3H).

[0301] Example 29: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(oxetan-3-yl)-1H-indazole-6-sulfonamide [ka] 1-(4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one (100 mg, 0.206 mmol, 1 equiv.), potassium metabisulfite (91.61 mg, 0.412 mmol, 2 equiv.), sodium formate (42.06 mg, 0.618 mmol, 3 equiv.), PPh in DMSO (3 mL). 3(59.45 mg, 0.227 mmol, 1.1 equiv.), phen (9.28 mg, 0.051 mmol, 0.25 equiv.), and Pd(OAc) 2 To a stirred mixture of (4.63 mg, 0.021 mmol, 0.1 equiv) was added tetraethylazanium boranide (32.88 mg, 0.227 mmol, 1.1 equiv). The mixture was stirred at 70° C. for 4 h under N2. To the above was added dropwise oxetan-3-amine (30.12 mg, 0.412 mmol, 2 equiv) and NBS (110.01 mg, 0.618 mmol, 3 equiv) in THF (1 mL). The mixture was stirred at 25° C. for another hour. The desired product could be detected by LCMS. The solid was removed by filtration and washed with (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by HPLC under the following conditions: (Column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH 4 HCO 3 +0.1% NH 3 H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(oxetan-3-yl)-1H-indazole-6-sulfonamide (17.8 mg, 14.97%) as a yellow solid. LCMS (ESI, m / z): 542.10[M+H] + , 1 H NMR (300 MHz, DMSO-d 6 ) δ= 8.94 (s, 1H), 8.79 (br, 1H), 8.39 (s, 1H), 7.78-7.43 (m, 1H), 7.08 (s, 1H), 4.52-4.40 (m, 3H), 4.35-4.26 (m, 2H), 3.78-3.75 (m, 4H), 3.47-3.35 (m, 4H), 2.99-2.90 (m, 1H), 1.06 (d, J=6.9 Hz, 6H).

[0302] Example 30: N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide A solution of 1-(4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one (500 mg, 1.030 mmol, 1 equiv.) in DMSO (5 mL) was treated with dipotassium sulfinosulfonate (458.07 mg, 2.060 mmol, 2 equiv.), tetraethylazanium boronide (164.42 mg, 1.133 mmol, 1.1 equiv.), sodium formate (210.18 mg, 3.090 mmol, 3 equiv.), triphenylphosphine (81.06 mg, 0.309 mmol, 0.3 equiv.), phen (55.69 mg, 0.309 mmol, 0.3 equiv.), and Pd(OAc) 2(23.13 mg, 0.103 mmol, 0.1 equiv) was added. The mixture was stirred at 70° C. for 4 h under nitrogen atmosphere. To the above, ammonium hydroxide (108.31 mg, 3.090 mmol, 3 equiv) in THF (1 mL) and NBS (550.07 mg, 3.090 mmol, 3 equiv) in THF (3 mL) were added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 1 h under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with brine (30 mL). The aqueous layer was extracted with EA (3×30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:3) to give 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (340 mg, 54.38%) as a yellow solid. LCMS (ESI, m / z): 486[M+H] + , Rt 0.769 minutes.

[0303] Step 2: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide To a stirred mixture of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (800 mg, 1.648 mmol, 1 equiv.) in THF (12 mL), titanium isopropylate (2.34 g, 8.240 mmol, 5 equiv.) and 3-oxetanone (1.19 g, 16.480 mmol, 10 equiv.) were added dropwise at room temperature. The mixture was stirred at 60° C. for 2 hours. To the above mixture, another batch of titanium isopropylate (2.34 g, 8.240 mmol, 5 equiv.) and 3-oxetanone (1.19 g, 16.480 mmol, 10 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 60° C. for another 2 hours. The resulting mixture was concentrated to give 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide (crude), which was used directly in the next step without further purification. LCMS (ES, m / z): 540[M+H] + , Rt 1.096 minutes.

[0304] Step 3: Synthesis of N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide To a stirred mixture of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide (2.3 g, 4.263 mmol, 1 equiv.) in THF (10 mL) was added trimethylsilanecarbonitrile (2.11 g, 21.315 mmol, 5 equiv.) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with brine (50 mL). After filtration, the filtrate was extracted with EA (3×50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by elution with the following conditions: (column, C18 silica gel; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH 3 .H 2 Purification by reverse-phase flash chromatography with 10 mL / min 2H2O, mobile phase B: ACN (30% to 30% in 20 min; flow rate: 100 mL / min; UV 254 nm) gave N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (152.6 mg, 6.14%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ=9.67 (br, 1H), 8.95 (s, 1H), 8.45 (s, 1H), 7.78-7.43 (m, 1H), 7.14 (s, 1H), 4.81 (d, J=6.9 Hz, 2H), 4.70 (d, J=7.2 Hz, 2H), 3.82-3.74 (m, 4H), 3.47-3.42 (m, 4H), 2.99-2.90 (m, 1H), 1.05 (d, J=6.9 Hz, 6H). LCMS (ES, m / z): 567[M+H] + , Rt 0.910 minutes.

[0305] Example 31: 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-((methylsulfonyl)methyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 2-bromo-5-(methanesulfonylmethyl)-1,3,4-thiadiazole A mixture of 2-bromo-5-[(methylsulfanyl)methyl]-1,3,4-thiadiazole (300 mg, 0.044 mmol, 1 equiv.) and m-CPBA (15.33 mg, 0.088 mmol, 2 equiv.) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (30 mL). The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-5-(methanesulfonylmethyl)-1,3,4-thiadiazole (150 mg, crude) as a yellow oil. LCMS (ESI, m / z): 257, 259 [M+H] + .

[0306] Step 2: Synthesis of 1-(4-{6-bromo-1-[5-(methanesulfonylmethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (300 mg, 0.854 mmol, 1 equiv.), 2-bromo-5-(methanesulfonylmethyl)-1,3,4-thiadiazole (329.41 mg, 1.281 mmol, 1.5 equiv.), and Cs in DMF (3 mL). 2 CO 3 (695.70 mg, 2.135 mmol, 2.5 equiv) was stirred at 70° C. for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was quenched with water (50 mL). The aqueous layer was extracted with EA (3×50 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 1-(4-{6-bromo-1-[5-(methanesulfonylmethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one (87 mg, 19.31%) as a yellow solid. LCMS (ESI, m / z): 527, 529 [M+H] + .

[0307] Step 3: Synthesis of 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-((methylsulfonyl)methyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide 1-(4-{6-bromo-1-[5-(methanesulfonylmethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one (87 mg, 0.165 mmol, 1 equiv.), potassium metabisulfite (73.34 mg, 0.330 mmol, 2 equiv.), TEAB (27.44 mg, 0.182 mmol, 1.1 equiv.), sodium formate (33.65 mg, 0.495 mmol, 3 equiv.), PPh3 (12.98 mg, 0.050 mmol, 0.3 equiv.), phen (8.92 mg, 0.050 mmol, 0.3 equiv.), and Pd(OAc) in DMSO (1 mL). 2 (3.70 mg, 0.017 mmol, 0.1 equiv) was stirred at 70° C. for 4 h under nitrogen atmosphere. The reaction was then cooled to room temperature. A solution of 3-methyloxetan-3-amine (28.74 mg, 0.330 mmol, 2 equiv) in THF (1 mL) and a solution of NBS (88.07 mg, 0.495 mmol, 3 equiv) in DMF (1 mL) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (30 mL). The aqueous layer was extracted with EA (3×30 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20% B to 50% B, 50% B in 7 min; Wavelength: 254nm; RT1(min): 5.87; Number of runs: 0) to give 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-((methylsulfonyl)methyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (11.2mg, 11.01%) as a yellow solid. LCMS (ESI, m / z): 598.10[M+H] + . 1HNMR (300 MHz, DMSO-d 6 ) δ=8.95 (s, 1H), 8.71 (br, 1H), 8.57(s, 1H), 7.13 (s, 1H), 5.27 (s, 2H), 4.57 (d, J=6.0 Hz, 2H), 4.12 (d, J=6.0 Hz, 2H), 4.83-4.67 (m, 4H), 3.54-3.33 (m, 4H), 3.18 (s, 3H), 3.02-2.91 (m, 1H), 1.43 (s, 3H), 1.05 (d, J=6.6 Hz, 6H).

[0308] Example 32: N-(3-cyano-2-methyloxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide Into a 20 mL vial, add 1-(4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1-yl)-2-methylpropan-1-one (300.00 mg, 0.62 mmol, 1.00 equiv.), dipotassium sulfinosulfonate (274.44 mg, 1.24 mmol, 2.00 equiv.), tetraethylazanium boronide (98.65 mg, 0.68 mmol, 1.10 equiv.), sodium formate (92.47 mg, 1.36 mmol, 2.20 equiv.), PPh 3 (48.64mg, 0.19mmol, 0.30eq), phen(33.42mg, 0.19mmol, 0.30eq), Pd(OAc) 2 (13.88 mg, 0.06 mmol, 0.10 equiv.) and DMSO (5.00 mL) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70° C. under nitrogen atmosphere for 4.0 h. The reaction mixture was then cooled to 0° C. and NH 3 .H 2 2H2O (216.62 mg, 6.18 mmol, 10.00 equiv.) and NBS (220.03 mg, 1.24 mmol, 2.00 equiv.) in THF (1.00 mL) were added dropwise at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1.0 h. After the reaction, the desired product could be detected by LCMS. The reaction was poured into 10 mL of ice / water. The precipitated solid was collected by filtration and washed with water (3×5 mL). The resulting solid was analyzed by TLC plate (CH 2 Cl 2 / MeOH=15:1) to give 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (90.00 mg, 29.99%) as a tan solid. LCMS (ESI, m / z): 485.95 [M+H] + .

[0309] Step 2: Synthesis of N-(3-cyano-2-methyloxetan-3-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide To a stirred solution of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (50.00 mg, 0.10 mmol, 1.00 equiv) in THF (2.00 mL) was added Ti(Oi-Pr) 4 (292.69 mg, 1.03 mmol, 10.00 equiv) and 2-methyloxetan-3-one (88.66 mg, 1.03 mmol, 10.00 equiv) were added dropwise at room temperature. The resulting mixture was stirred at 70° C. for 17.0 h. To the above mixture, trimethylsilyl cyanide (102.16 mg, 1.03 mmol, 10.00 equiv) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 1.0 h. The desired product was detected by LCMS. The reaction was quenched with water (10 mL) at 0° C. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×5 mL). The filtrate was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×15 mL) and anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by TLC (100% EA) to give N-(3-cyano-2-methyloxetan-3-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (20 mg). The crude product (20 mg) was purified using the following conditions (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3+0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 20% B to 50% B, 50% B in 7 min; wavelength: 254nm; RT1(min): 5.87; (detected and collected by LCMS)) and purified by Prep-HPLC to give N-(3-cyano-2-methyloxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (3.00mg, 4.81%) as a light yellow solid. LCMS (ESI, m / z): 581.15 [M+H] + NMR: 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.90 (s, 1H), 8.44 (s, 1H), 7.56 (t, J=56.0 Hz, 1H), 7.15 (s, 1H), 5.05-4.82 (m, 1H), 4.67-4.52 (m, 2H) 3.82-3.76 (m, 4H), 3.50-3.40 (m, 4H), 2.97-2.90 (m, 1H), 1.42-1.35 (m, 3H), 1.03 (d, J=6.8 Hz, 6H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -109.76.

[0310] Example 33: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(isopropylsulfonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 4-chloro-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide To a mixture of 6-bromo-4-chloro-1H-indazole (500 mg, 2.160 mmol, 1 equiv), tetraethylazanium bromide (499.33 mg, 2.376 mmol, 1.1 equiv), sodium formate (323.14 mg, 4.752 mmol, 2.2 equiv), PPh3 (169.97 mg, 0.648 mmol, 0.3 equiv), phen (116.78 mg, 0.648 mmol, 0.3 equiv), and dipotassium sulfinosulfonate (960.45 mg, 4.320 mmol, 2 equiv) in DMSO (8 mL) was added Pd(OAc)2 (48.49 mg, 0.216 mmol, 0.1 equiv). The mixture was cooled to 5° C. for 2 h and cooled to 10° C. for 2 h. 2 The mixture was degassed by bubbling with hexane and stirred for 10 min. The mixture was stirred for 4 h. To the mixture was added 3-methyloxetan-3-amine (376.37 mg, 4.320 mmol, 2 equiv) in THF (5.00 mL) at room temperature, followed by a solution of NBS (768.90 mg, 4.320 mmol, 2 equiv) in THF (5.00 mL) at 0° C. The mixture was stirred at room temperature for 30 min. The desired product could be detected by LCMS. The mixture was added with brine (10 mL) and H2O (10 mL) and extracted with EtOAc (10 mL×3). The organic layers were combined and washed with Na 2 SO 4The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient 10% to 50% in 20 min; detector, UV 254 nm to give 4-chloro-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide (80 mg, 12.27%) as a yellow oil. LCMS (ESI, m / z): 302.00 [M+H] + .

[0311] Step 2: Synthesis of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)indazole-6-sulfonamide To a mixture of 4-chloro-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide (80 mg, 0.265 mmol, 1 eq.) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (68.41 mg, 0.318 mmol, 1.2 eq.) in DMF (2 mL), Cs2CO3 (215.95 mg, 0.663 mmol, 2.5 eq.) was added. The mixture was stirred at room temperature for 16 h. The desired product could be detected by LCMS. The mixture was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient 20% to 80% in 30 min; detector, UV 254 nm to give 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)indazole-6-sulfonamide (30 mg, 25.96%) as a yellow oil. LCMS (ESI, m / z): 435.95 [M+H] +

[0312] Step 3: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(propane-2-sulfonyl)piperazin-1-yl]indazole-6-sulfonamide To a mixture of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)indazole-6-sulfonamide (60 mg, 0.138 mmol, 1 equiv.) and piperazine (13.04 mg, 0.152 mmol, 1.1 equiv.) in dioxane (3 mL), Ruphos (6.42 mg, 0.014 mmol, 0.1 equiv.) and Cs 2 CO 3 (7.48 mg, 0.022 mmol, 2 equiv.) was added. The mixture was stirred at 100° C. under N2 for 16 h. The desired product could be detected by LCMS. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient 30% to 100% in 20 min; detector, UV 254 nm to give 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(propane-2-sulfonyl)piperazin-1-yl]indazole-6-sulfonamide (30 mg, 36.83%) as a yellow oil. LCMS (ESI, m / z): 486.05[M+H] +

[0313] Step 4: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(isopropylsulfonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide To a mixture of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-(piperazin-1-yl)indazole-6-sulfonamide (20 mg, 0.041 mmol, 1 eq.) in DCM (2 mL), propane-2-sulfonyl chloride (7.05 mg, 0.049 mmol, 1.2 eq.) and TEA (8.34 mg, 0.082 mmol, 2 eq.) were added at −78° C. The mixture was stirred at −78° C. for 30 min and at 0° C. for 2 h. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 45% B to 65% B, 65% B in 7 min; Wavelength: 254nm; RT1(min): 6.23; Number of runs: 0) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(isopropylsulfonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide (2.3mg, 9.43%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.94 (d, J = 1.0 Hz, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 7.42 - 7.80 (m, 1H), 7.20 (d, J = 3.0 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.18 - 4.10 (m, 2H), 3.59 - 3.41 (m, 9H), 1.44 (s, 3H), 1.29 (d, J = 6.0 Hz, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -109.83. LCMS (ESI, m / z): 592.15[M+H] + .

[0314] Example 34: 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide 6-Bromo-4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (150 mg, 0.293 mmol, 1 equiv.), potassium metabisulfite (130.42 mg, 0.586 mmol, 2 equiv.), tetraethylazanium boronide (46.81 mg, 0.322 mmol, 1.1 equiv.), sodium formate (59.84 mg, 0.879 mmol, 3 equiv.), PPh in DMSO (2 mL). 3 (23.08 mg, 0.088 mmol, 0.3 equiv.), phen (15.86 mg, 0.088 mmol, 0.3 equiv.), and Pd(OAc) 2 (6.59 mg, 0.029 mmol, 0.1 equiv) was stirred at 70° C. for 4 h under nitrogen atmosphere. The reaction was then cooled to room temperature. A solution of 3-(fluoromethyl)oxetan-3-amine (61.66 mg, 0.586 mmol, 2 equiv) in pyridine (2 mL) and a solution of NBS (208.82 mg, 1.172 mmol, 4 equiv) in THF (2 mL) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (30 mL). The aqueous layer was extracted with EA (3×30 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried over 1000 ml of hexane. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 35% B to 65% B, 65% B in 7 min; Wavelength: 254nm; RT1(min): 6.73; Number of runs: 0) to give 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide (9.3mg, 5.28%) as a white solid. LCMS (ESI, m / z): 600.05[M+H] + , 1HNMR (300 MHz, DMSO-d 6 ) δ=9.03 (br, 1H), 8.95 (s, 1H), 8.46 (s, 1H), 7.78-7.43 (m, 1H), 7.18 (s, 1H), 4.68 (s, 1H), 4.59-4.52 (m, 3H), 4.34 (d, J=6.6 Hz, 2H), 3.85-3.71 (m, 4H), 3.52-3.41 (m, 4H), 3.11-3.00 (m, 1H), 1.88-1.51 (m, 8H).

[0315] Example 35: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of (4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)piperazin-1-yl)(pyrrolidin-1-yl)methanone To a stirred mixture of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(piperazin-1-yl)indazole (1 g, 2.408 mmol, 1 eq.) and TEA (970 mg, 7.224 mmol, 3 eq.) in DCM (10 mL) was added pyrrolidine-1-carbonyl chloride (390 mg, 2.890 mmol, 1.2 eq.) in portions at 0° C. The resulting mixture was stirred at 25° C. for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:2) to give (4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (400 mg, 32.42%) as a yellow solid. LCMS (ES, m / z): 512, 514 [M+H] + .

[0316] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide To a stirred mixture of (4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (100 mg, 0.195 mmol, 1 equiv.) in DMSO (2 mL), potassium metabisulfite (87 mg, 0.390 mmol, 2 equiv.), PPh 3 (15 mg, 0.058 mmol, 0.3 equiv), sodium formate (40 mg, 0.585 mmol, 3 equiv), phen (11 mg, 0.058 mmol, 0.3 equiv), palladium acetate (4 mg, 0.020 mmol, 0.1 equiv), and TEAB (31 mg, 0.215 mmol, 1.1 equiv) were added. The resulting mixture was cooled to 5° C. for 2 hours and then cooled to 5° C. for 2 hours. 2The mixture was stirred at 70° C. for 4 h under reduced pressure. Then, NBS (122 mg, 0.682 mmol, 3.5 eq.) and 3-methyloxetan-3-amine (34 mg, 0.390 mmol, 2 eq.) in THF (2 mL) were added dropwise at 0° C. The resulting mixture was stirred at room temperature for another hour. The desired product could be detected by LCMS. The reaction was quenched with water (20 mL). The mixture was washed with EA (3×15 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 31% B to 61% B in 7 min, 61% B; Wavelength: 254nm; RT1(min): 6.35; Number of runs: 0) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide (13.1mg, 11.47%) as a yellow solid. LCMS (ES, m / z): 583.20 [M+H] + , 1 H NMR (300 MHz, chloroform-d) δ=8.71 (s, 1H), 8.32 (s, 1H), 7.20 (s, 1H), 7.18-6.82 (m, 1H), 5.42 (s, 1H), 4.76 (d, J = 6.6 Hz, 2H), 4.35 (d, J = 6.9 Hz, 2H), 3.58-3.53 (m, 4H), 3.49-3.41 (m, 8H), 1.90-1.85 (m, 4H), 1.66 (s, 3H).

[0317] Example 36: 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide To a stirred mixture of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(pyrrolidine-1-carbonyl)piperazin-1-yl]indazole (200 mg, 0.390 mmol, 1 equiv.) in DMSO (2 mL), potassium metabisulfite (174 mg, 0.780 mmol, 2 equiv.), PPh 3 (31 mg, 0.117 mmol, 0.3 equiv), sodium formate (80 mg, 1.170 mmol, 3 equiv), palladium acetate (9 mg, 0.039 mmol, 0.1 equiv), and phen (21 mg, 0.117 mmol, 0.3 equiv) were added. The resulting mixture was cooled to 5° C. for 2 hours and then cooled to 5° C. for 2 hours. 2 The mixture was stirred at 70° C. for 4 h under reduced pressure. Then, 3-(fluoromethyl)oxetan-3-amine (82 mg, 0.780 mmol, 2 equiv.), DIEA (1 mL), and NCS (182 mg, 1.365 mmol, 3.5 equiv.) in THF (2 mL) were added dropwise. The mixture was stirred at 0° C. for another 1 h. The desired product could be detected by LCMS. The reaction was quenched with water (20 mL). The mixture was washed with EA (3×15 mL) and diluted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254nm; RT1(min): 6.8; Number of runs: 0) to obtain 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide (16.6mg, 6.84%) as a yellow solid. LCMS (ESI, m / z): 601.15 [M+H] + , 1 H NMR (300 MHz, DMSO-d 6 ) δ=9.03-8.94 (m, 2H), 8.45 (s, 1H), 7.77-7.42 (m, 1H), 7.18 (s, 1H), 4.69 (s, 1H), 4.58-4.54 (m, 3H), 4.35 (d, J=6.6 Hz, 2H), 3.52-3.46 (m, 5H), 3.45-3.33 (m, 7H), 1.82-1.78 (m, 4H).

[0318] Example 37: N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide [ka] Step 1: Synthesis of 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carbonyl chloride A solution of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(piperazin-1-yl)indazole (500 mg, 1.204 mmol, 1 eq.), TEA (365.53 mg, 3.612 mmol, 3 eq.) in DCM (3 mL) was treated with triphosgene (117.90 mg, 0.397 mmol, 0.33 eq.) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 1.5 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure to give 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carbonyl chloride (600 mg, crude) as a yellow solid. LCMS (ESI, m / z): 477, 479 [M+H] +

[0319] Step 2: Synthesis of 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide A solution of (2,2-difluoroethyl)(methyl)amine (358.31 mg, 3.768 mmol, 3 equiv.) in THF (5 mL) was treated with TEA (381.29 mg, 3.768 mmol, 3 equiv.) at 10° C. for 10 min, followed by dropwise addition of 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1-carbonyl chloride (600 mg, 1.256 mmol, 1 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with DCM (3×30 mL) and purified with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EA (3:1) to give 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide (300 mg, 44.53%) as a white solid. LCMS (ESI, m / z): 536, 538 [M+H] +

[0320] Step 3: Synthesis of N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide Mixture of 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide (70 mg, 0.131 mmol, 1 equiv.), potassium metabisulfite (58.03 mg, 0.261 mmol, 2.00 equiv.), TEAB (20.83 mg, 0.144 mmol, 1.1 equiv.), sodium formate (26.63 mg, 0.393 mmol, 3 equiv.), PPh in DMSO (2 mL). 3 (10.27 mg, 0.039 mmol, 0.3 equiv.), phen (7.06 mg, 0.039 mmol, 0.3 equiv.), and Pd(OAc) 2(2.93 mg, 0.013 mmol, 0.1 equiv) was stirred at 70° C. for 4 h under nitrogen atmosphere. The mixture was then cooled to room temperature. A solution of 3-methyloxetan-3-amine (22.74 mg, 0.262 mmol, 2 equiv) in THF (2 mL) and a solution of NBS (92.92 mg, 0.524 mmol, 4 equiv) in THF (2 mL) were added dropwise. The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (30 mL). The resulting mixture was washed with brine (4×20 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 33% B to 63% B in 7 min, 63% B; Wavelength: 254nm; RT1(min): 6.45; Number of runs: 0) to give N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide (20.3mg, 25.51%) as a yellow solid. LCMS (ESI, m / z): 607.05[M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ=8.94 (s, 1H), 8.61 (br, 1H), 8.46 (s, 1H), 7.78-7.43 (m, 1H), 7.17 (s, 1H), 6.41-6.01 (m, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.13 (d, J=6.3 Hz, 2H), 3.69-3.61 (m, 2H), 3.58-3.49 (m, 8H), 2.99 (s, 3H), 1.43 (s, 3H).

[0321] Example 38: N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(pyrrolidine-1-carbonyl)piperazin-1-yl]indazole-6-sulfonamide 6-Bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(pyrrolidine-1-carbonyl)piperazin-1-yl]indazole (150 mg, 0.293 mmol, 1 equiv.), potassium metabisulfite (130 mg, 0.586 mmol, 2 equiv.), PPh 3 A stirred mixture of (23 mg, 0.088 mmol, 0.3 equiv), sodium formate (60 mg, 0.879 mmol, 3 equiv), palladium acetate (7 mg, 0.029 mmol, 0.1 equiv), and TEAB (47 mg, 0.322 mmol, 1.1 equiv) was added to N 2 Stirred at 70° C. under atmosphere for 4 h. To the above was added dropwise ammonium hydroxide (103 mg, 2.930 mmol, 10 eq) and NBS (182 mg, 1.025 mmol, 3.5 eq) in THF (1 mL). The mixture was stirred at 0° C. for another 1 h. The desired product could be detected by LCMS. The reaction was quenched with water (20 mL). The mixture was washed with EA (2×20 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to give 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(pyrrolidine-1-carbonyl)piperazin-1-yl]indazole-6-sulfonamide (80 mg, 53.33%) as a yellow solid. LCMS (ES, m / z): 513[M+H]+ ,

[0322] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(oxetan-3-ylidene)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide To a stirred mixture of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (80 mg, 0.165 mmol, 1 eq.) in tetrahydrofuran (6 mL), titanium isopropylate (230 mg, 0.825 mmol, 5 eq.) and 3-oxetanone (120 mg, 1.650 mmol, 10 eq.) were added dropwise. The resulting mixture was stirred at 60° C. for 12 hours. To the above mixture, another batch of titanium isopropylate (230 mg, 0.825 mmol, 5 eq.) and 3-oxetanone (120 mg, 1.650 mmol, 10 eq.) was added dropwise. The resulting mixture was stirred at 60° C. for another 5 hours. The resulting mixture was concentrated to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(oxetan-3-ylidene)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide (150 mg, crude). LCMS (ES, m / z): 567[M+H] + .

[0323] Step 3: Synthesis of N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide A solution of 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)-4-[4-(pyrrolidine-1-carbonyl)piperazin-1-yl]indazole-6-sulfonamide (100 mg, 0.176 mmol, 1 equiv.) in THF (2 mL) was treated dropwise with TMSCN (87.55 mg, 0.880 mmol, 5 equiv.). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered and the filter cake was washed with EA (3×10 mL). The solids were filtered off and washed with (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 19% B to 49% B in 7 min; Wavelength: 254nm; RT1(min):6) to give N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide (4.8mg, 4.43%) as a yellow solid. LCMS (ESI, m / z): 594.05[M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ= 9.61 (br, 1H), 8.95 (s, 1H), 8.45 (s, 1H), 7.73-7.47 (m, 1H), 7.14 (s, 1H), 4.82 (d, J = 7.2 Hz, 2H), 4.71 (d, J = 7.2 Hz, 2H), 3.52-3.45 (m, 8H), 3.33-3.31 (m, 4H), 1.79-1.76 (m, 4H).

[0324] Example 39: N-(3-cyanooxetan-3-yl)-4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 6-bromo-4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole To a stirred solution of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(piperazin-1-yl)indazole (380 mg, 0.915 mmol, 1 eq.) and cyclopropanecarboxylic acid (94 mg, 1.098 mmol, 1.2 eq.) in DMF (5 mL) was added DIEA (591.36 mg, 4.575 mmol, 5 eq.) and HATU (695.90 mg, 1.830 mmol, 2 eq.) in small portions at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. Then water (50 mL) was added. The mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with 1:1 EA / PE) to give 6-bromo-4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (300 mg, 64%) as a yellow solid. LCMS (ES, m / z): 483, 485[M+H] + .

[0325] Step 2: Synthesis of 4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide A mixture of 6-bromo-4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (100 mg, 0.207 mmol, 1 equiv.), dipotassium sulfinosulfonate (91.99 mg, 0.414 mmol, 2 equiv.), triphenylphosphine (16.28 mg, 0.062 mmol, 0.3 equiv.), sodium formate (42.21 mg, 0.621 mmol, 3 equiv.), TEAB (33.02 mg, 0.228 mmol, 1.1 equiv.), phen (11.19 mg, 0.062 mmol, 0.3 equiv.), and Pd(OAC) in DMSO (2 mL). 2 (4.64 mg, 0.021 mmol, 0.1 equiv) was stirred at 70° C. for 4 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. To the above mixture, ammonium hydroxide (21.75 mg, 0.621 mmol, 3 equiv) and NBS (110.47 mg, 0.621 mmol, 3 equiv) in THF (1 mL) were added at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:2) to give 4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (60 mg, 53.98%) as a yellow solid. LCMS (ES, m / z): 484[M+H] + .

[0326] Step 3: Synthesis of 4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide To a stirred mixture of 4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (50 mg, 0.103 mmol, 1 equiv.) in tetrahydrofuran (3 mL), titanium isopropylate (146.96 mg, 0.515 mmol, 5 equiv.) and 3-oxetanone (74.52 mg, 1.030 mmol, 10 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at 60° C. for 16 hours. The resulting mixture was concentrated to give 4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide (100 mg, crude). LCMS (ES, m / z): 538[M+H] + .

[0327] Step 4: Synthesis of N-(3-cyanooxetan-3-yl)-4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide To a stirred mixture of 4-(4-cyclopropanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide (50 mg, 0.093 mmol, 1 equiv.) in DCM (2 mL) was added trimethylsilanecarbonitrile (46.14 mg, 0.465 mmol, 5 equiv.). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL). The mixture was washed with EA (3×15 mL) and purified with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by elution with 100 ml of ethyl acetate under the following conditions: (Column: XBridge Prep Phenyl OBD C18 column, 19*100mm, 5μm; Mobile phase A: water (10mmol / L NH 4 HCO 3 +0.1% NH 3 H2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min, 60% B; wavelength: 254 nm; RT1 (min): 6; number of runs: 0) to give N-(3-cyanooxetan-3-yl)-4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (2.0 mg, 3.77%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ=9.59 (br, 1H), 8.96 (s, 1H), 8.45 (s, 1H), 7.77-7.42 (m, 1H), 7.14 (s, 1H), 4.82 (d, J = 6.9 Hz, 2H), 4.71 (d, J = 6.9 Hz, 2H), 4.02-3.95 (m, 2H), 3.81-3.66 (m, 2H), 3.55-3.42 (m, 4H), 2.09-2.01 (m, 1H), 0.79-0.72 (m, 4H). LCMS (ES, m / z): 565 [M+H] + .

[0328] Example 40: N-(3-cyanooxetan-3-yl)-4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 6-bromo-4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole To a mixture of 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(piperazin-1-yl)indazole hydrochloride (500 mg, 1.107 mmol, 1 equiv.), cyclopentanecarboxylic acid (252.69 mg, 2.214 mmol, 2 equiv.), and DIEA (715.30 mg, 5.535 mmol, 5 equiv.) in DMF (20 mL) was added HATU (841.75 mg, 2.214 mmol, 2 equiv.) in portions at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (100 mL). The aqueous layer was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give 6-bromo-4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (400 mg, 70.67%) as a yellow solid. LCMS (ESI, m / z): 511, 513 [M+H] + .

[0329] Step 2: Synthesis of 4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide 6-Bromo-4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole (140 mg, 0.274 mmol, 1 equiv.), potassium metabisulfite (121.73 mg, 0.548 mmol, 2 equiv.), tetraethylazanium bromide (58.63 mg, 0.279 mmol, 1.1 equiv.), tetraethylazanium bromide (63.29 mg, 0.301 mmol, 1.1 equiv.), PPh in DMSO (2 mL). 3(21.54 mg, 0.082 mmol, 0.3 equiv.), phen (14.80 mg, 0.082 mmol, 0.3 equiv.), and Pd(OAc) 2 (6.15 mg, 0.027 mmol, 0.1 equiv) was stirred at 70° C. for 4 h under nitrogen atmosphere. The reaction was then cooled to room temperature. NH 3 H 2 A solution of 2H2O (19.19 mg, 0.548 mmol, 2 equiv.) and NBS (146.18 mg, 0.822 mmol, 3 equiv.) in THF (1 mL) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (30 mL). The aqueous layer was extracted with EA (3×30 mL). The combined organic layers were washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (80 mg, 57.12%) as a yellow solid. LCMS (ESI, m / z): 512 [M+H] + .

[0330] Step 3: Synthesis of 4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide To a stirred mixture of 4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (80 mg, 0.156 mmol, 1 equiv.) in THF (2 mL), Ti(Oi-Pr) 4(177.79 mg, 0.624 mmol, 4 eq.) and 3-oxetanone (112.69 mg, 1.560 mmol, 10 eq.) were added dropwise at room temperature. The resulting mixture was stirred at 60° C. for 16 h. The reaction was monitored by LCMS. The resulting mixture was concentrated to give 4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide (100 mg, crude). LCMS (ESI, m / z): 566 [M+H] + .

[0331] Step 4: Synthesis of N-(3-cyanooxetan-3-yl)-4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide A mixture of 4-(4-cyclopentanecarbonylpiperazin-1-yl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(oxetan-3-ylidene)indazole-6-sulfonamide (80 mg, 0.141 mmol, 1 eq.) and trimethylsilyl cyanide (70.16 mg, 0.705 mmol, 5 eq.) in THF (2 mL) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 53% B in 7 min, 53% B; Wavelength: 254nm; RT1(min): 6.8; Number of runs: 0) to give N-(3-cyanooxetan-3-yl)-4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (10.4mg, 11.18%) as a yellow solid. LCMS (ESI, m / z): 593.10 [M+H]+ . 1 H NMR (300 MHz, DMSO-d 6 ) δ=9.65 (br, 1H), 8.96 (s, 1H), 8.46 (s, 1H), 7.78-7.43 (m, 1H), 7.14 (s, 1H), 4.83 (d, J=7.2 Hz, 2H), 4.71 (d, J=7.2 Hz, 2H), 3.75-3.46 (m, 4H), 3.46-3.33 (m,4H), 3.09-3.01 (m, 1H), 1.82-1.72 (m, 4H), 1.71-1.59 (m, 4H).

[0332] Example 41: 4-(6-(N-(3-cyanooxetan-3-yl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide [ka] Step 1: Synthesis of N-(2,2-difluoroethyl)-4-{1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-sulfamoylindazol-4-yl}-N-methylpiperazine-1-carboxamide 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}-N-methyl-N-(2-methylpropyl)piperazine-1-carboxamide (150 mg, 0.284 mmol, 1 equiv.), potassium metabisulfite (126.22 mg, 0.568 mmol, 2 equiv.), tetraethylazanium bromide (65.62 mg, 0.312 mmol, 1.1 equiv.), sodium formate (57.91 mg, 0.852 mmol, 3.00 equiv.), phen (15.35 mg, 0.085 mmol, 0.3 equiv.), PPh in DMSO (2 mL). 3 (22.34 mg, 0.085 mmol, 0.3 equiv.), and Pd(OAc) 2(6.37 mg, 0.028 mmol, 0.1 equiv) was stirred at 70 °C for 4 h under nitrogen atmosphere. To the above mixture, NH3·H2O (19.90 mg, 0.568 mmol, 2 equiv) and NBS (50.52 mg, 0.285 mmol, 3 equiv) in THF (1 mL) were added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (30 mL). The aqueous layer was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give N-(2,2-difluoroethyl)-4-{1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-sulfamoylindazol-4-yl}-N-methylpiperazine-1-carboxamide (100 mg, 65.66%) as a yellow solid. LCMS (ESI, m / z): 537[M+H] +

[0333] Step 2: Synthesis of N-(2,2-difluoroethyl)-4-{1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-[(oxetan-3-ylidene)sulfamoyl]indazol-4-yl}-N-methylpiperazine-1-carboxamide To a stirred mixture of 4-{1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-sulfamoylindazol-4-yl}-N-(2-fluoroethyl)-N-methylpiperazine-1-carboxamide (100 mg, 0.193 mmol, 1 equiv.) in THF (3 mL), Ti(Oi-Pr) 4(219.25 mg, 0.772 mmol, 4 eq.) and 3-oxetanone (138.98 mg, 1.930 mmol, 10 eq.) were added dropwise at room temperature. The resulting mixture was stirred at 60° C. for 16 h. The reaction was monitored by LCMS. The resulting mixture was concentrated to give N-(2,2-difluoroethyl)-4-{1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-[(oxetan-3-ylidene)sulfamoyl]indazol-4-yl}-N-methylpiperazine-1-carboxamide (120 mg, crude). LCMS (ESI, m / z): 591[M+H] + .

[0334] Step 3: Synthesis of 4-(6-(N-(3-cyanooxetan-3-yl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide A mixture of N-(2,2-difluoroethyl)-4-{1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-[(oxetan-3-ylidene)sulfamoyl]indazol-4-yl}-N-methylpiperazine-1-carboxamide (100 mg, 0.169 mmol, 1 eq.) in THF (3 mL) was added dropwise with trimethylsilyl cyanide (83.99 mg, 0.845 mmol, 5 eq.). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified using the following conditions (column: XBridge Prep Phenyl OBD II). Purification by Prep-HPLC with C18 column, 19*100mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3+0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 19% B to 49% B, 49% B in 7 min; wavelength: 254nm; RT1(min): 6; number of runs: 0) to give 4-(6-(N-(3-cyanooxetan-3-yl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide (6.1mg, 5.73%) as a yellow solid. LCMS (ESI, m / z): 618.05[M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ=9.63 (br, 1H), 8.95(s, 1H), 8.46 (s, 1H), 7.96-7.34 (m, 1H), 7.16 (s, 1H), 6.57-5.91 (m, 1H), 4.83 (d, J=7.2 Hz, 2H), 4.70 (d, J=7.2 Hz, 2H), 3.68-3.61 (m, 2H), 3.45-3.33 (m, 8H), 2.99 (s, 3H).

[0335] Example 42: N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 1-(4-(6-bromo-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazol-4-ylpiperazin-1-yl)-2-methylpropan-1-one 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (1 g, 2.847 mmol, 1 equiv.) and Cs in DMF (10 mL). 2 CO 3 (2.78 g, 8.541 mmol, 3 eq.) was added in portions to a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (1.02 g, 5.694 mmol, 2 eq.). The resulting mixture was stirred at 70° C. for 2 h. The desired product could be detected by LCMS. The reaction was quenched with brine (100 mL). The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give 1-(4-(6-bromo-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1-one (400 mg, 31.27%) as a yellow solid. LCMS (ES, m / z): 449, 451[M+H] + ,

[0336] Step 2: Synthesis of N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide To a stirred mixture of 1-{4-[6-bromo-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one (200 mg, 0.445 mmol, 1 equiv.) in DMSO (3 mL), dipotassium sulfinosulfonate (198 mg, 0.890 mmol, 2 equiv.), PPh 3 (35 mg, 0.134 mmol, 0.3 equiv), sodium formate (91 mg, 1.335 mmol, 3 equiv), Pd(OAc) 2(10 mg, 0.045 mmol, 0.1 eq), TEAB (71.03 mg, 0.490 mmol, 1.1 eq), and phen (24 mg, 0.134 mmol, 0.3 eq) were added. The resulting mixture was stirred at 70° C. for 4 h under N2. Then, 3-(fluoromethyl)oxetan-3-amine hydrochloride (189 mg, 1.335 mmol, 3 eq) in pyridine (1.5 mL) and NBS (316 mg, 1.780 mmol, 4 eq) in THF (2 mL) were added dropwise at 0° C. The resulting mixture was stirred at room temperature for another hour. The desired product could be detected by LCMS. The reaction was quenched with water (20 mL). The mixture was washed with EA (3×15 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 26% B to 56% B in 7 min, 56% B; Wavelength: 254nm; RT1(min): 5.55; Injection volume: 1.7mL; Number of runs: 1) to give N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (10.2mg, 4.24%) as a white solid. LCMS (ES, m / z): 538.05 [M+H] + , 1 H NMR (300 MHz, DMSO-d 6 ) δ=8.85-8.84 (m, 2H), 8.46 (s, 1H), 7.12 (s, 1H), 4.69 (s, 1H), 4.57-4.53 (m, 3H), 4.34 (d, J = 6.9 Hz, 2H), 3.81-3.74 (m, 4H), 3.50-3.40 (m, 4H), 3.02-2.91 (m, 1H), 2.74 (s, 3H), 1.05 (d, J = 6.6 Hz, 6H).

[0337] Example 43: 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide [ka] Step 1: Synthesis of 2-bromo-5-cyclopropyl-1,3,4-thiadiazole 2-Methyl-2-propylnitrit (1.68 g, 16.291 mmol, 2.3 equiv.) and CuBr in ACN (20 mL). 2 (3.64 g, 16.291 mmol, 2.3 equiv) was stirred at room temperature for 10 min. To the above mixture, 5-cyclopropyl-1,3,4-thiadiazol-2-amine (1 g, 7.083 mmol, 1 equiv) was added in small portions. The mixture was stirred at room temperature for an additional 3 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give 2-bromo-5-cyclopropyl-1,3,4-thiadiazole (700 mg, 48.19%) as a yellow oil. LCMS (ESI, m / z): 205, 207[M+H] +

[0338] Step 2: Synthesis of 1-{4-[6-bromo-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one and 1-{4-[6-bromo-2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (1 g, 2.85 mmol, 1 equiv.), 2-bromo-5-cyclopropyl-1,3,4-thiadiazole (701 mg, 3.42 mmol, 1.2 equiv.), and Cs in DMF (10 mL).2 CO 3 (2.31 g, 7.12 mmol, 2.5 equiv) was stirred at 70° C. for 3 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (100 mL). The aqueous layer was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give a mixture of 1-{4-[6-bromo-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one and 1-{4-[6-bromo-2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one (600 mg, 44%) as a yellow solid. LCMS (ESI, m / z): 475, 477[M+H] +

[0339] Step 3: Synthesis of 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide A mixture of 1-{4-[6-bromo-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one and 1-{4-[6-bromo-2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one (300 mg, 0.631 mL) in DMSO (2 mL) (mmol, 1 equiv.), potassium metabisulfite (280.59 mg, 1.262 mmol, 2 equiv.), tetraethylazanium bromide (145.88 mg, 0.694 mmol, 1.1 equiv.), sodium formate (128.74 mg, 1.893 mmol, 3 equiv.), PPh3 (49.65 mg, 0.189 mmol, 0.3 equiv.), phen (34.12 mg, 0.189 mmol, 0.3 equiv.), and Pd(AcO). 2 (14.17 mg, 0.063 mmol, 0.1 equiv) was stirred at 70° C. for 4 h under nitrogen atmosphere. To the above mixture, 3-(fluoromethyl)oxetan-3-amine (265.32 mg, 2.524 mmol, 4 equiv), pyridine (0.5 mL, 0.006 mmol, 0.01 equiv), and NBS (449.26 mg, 2.524 mmol, 4 equiv) in THF (2 mL) were added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with water (50 mL). The aqueous layer was extracted with EA (3×50 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by elution with 100 ml of ethyl acetate under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min, 60% B; wavelength: 254 nm; RT1 (min): 6.17; injection volume: 0.8 mL; number of runs: 2) and purified by Prep-HPLC to give 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyryl) 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (24.6 mg, 6.85%) and 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide (13.6 mg, 3.79%) were obtained as white solids. 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide: LCMS (ESI, m / z): 564.25[M+H] + . 1HNMR (300 MHz, DMSO-d 6 ) δ=8.89 (br, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 7.12 (s, 1H), 4.68 (s, 1H), 4.61-4.48 (m, 3H), 4.33 (d, J=6.9 Hz, 2H), 3.77-3.74 (m, 4H), 3.43-3.32 (m, 4H), 2.97-2.89 (m, 1H), 2.59-2.51 (m, 1H), 1.28-1.25 (m, 2H), 1.24-1.21 (m, 2H), 1.06 (d, J=6.6 Hz, 6H).2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide: 1 H NMR (300 MHz, DMSO-d 6) δ 9.52 (s, 1H), 8.69 (br, 1H), 7.65 (s, 1H), 6.72 (s, 1H), 4.68 (s, 1H), 4.59-4.50 (m, 3H), 4.33 (d, J=6.6 Hz, 2H), 3.76-3.71 (m, 4H), 3.38-3.29 (m, 4H), 2.99-2.90 (m, 1H), 2.73-2.50 (m, 1H), 1.35-1.28 (m, 2H), 1.21-1.11 (m, 2H), 1.06 (d, J=6.6 Hz, 6H).

[0340] Example 44: N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] A solution of 1-{4-[6-bromo-1-(1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one (200 mg, 0.459 mmol, 1.00 equiv) in DMSO (5 mL) was dissolved in potassium metabisulfite (204.28 mg, 0.918 mmol, 2.00 equiv), tetraethylazanium boronide (106.20 mg, 0.505 mmol, 1.10 equiv), sodium formate (93.73 mg, 1.377 mmol, 3.00 equiv), triphenylphosphine (32.42 mg, 0.124 mmol, 0.30 equiv), PPh 3(36.15 mg, 0.138 mmol, 0.30 equiv), 1,10-phenanthroline (24.84 g, 0.138 mmol, 0.30 equiv), and palladium acetate (10.31 mg, 0.046 mmol, 0.10 equiv). The mixture was stirred at 70° C. for 4 hours under nitrogen atmosphere. To the above was added 3-(fluoromethyl)oxetan-3-amine (144.87 mg, 1.377 mmol, 3.00 equiv) and pyridine (2 mL) in small portions. Then NBS (245.30 mg, 1.377 mmol, 3.00 equiv) in THF (5 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate. The resulting mixture was concentrated under reduced pressure. The crude product was purified by elution with hexane under the following conditions (Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH 4 HCO 3 +0.1% NH 3 H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 54% B in 7 min, 54% B; wavelength: 220 nm; RT1 (min): 5.23; injection volume: 1 mL; number of runs: 3) to give N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (22.1 g, 9.15%) as a white solid. LCMS (ESI, m / z): 524.05. 1HNMR (300 MHz, DMSO-d 6) δ=9.45 (s, 1H), 8.94-8.88 (m, 2H), 8.53 (s, 1H), 7.15 (s, 1H), 4.70 (s, 1H), 4.58-4.54 (m, 3H), 4.35 (d, J=6.9 Hz, 2H), 3.85-3.76 (m, 4H), 3.48-3.41 (s, 4H), 2.97-2.93 (m, 1H), 1.05 (d, J=6.6 Hz, 6H).

[0341] Example 45: 4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide [ka] 1-{4-[6-bromo-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one (120 mg, 0.267 mmol, 1 equiv.), potassium metabisulfite (118.74 mg, 0.534 mmol, 2 equiv.), tetraethylazanium bromide (61.73 mg, 0.294 mmol, 1.1 equiv.), sodium formate (54.48 mg, 0.801 mmol, 3 equiv...

Claims

1. Formula I: 【Chemistry 1】 Compound or a pharma- ceutically acceptable salt thereof, A is of the formula: 【Chemistry 2】 is a group having the formula: B is a compound represented by formula (a), formula (b), or formula (c): 【Chemistry 3】 is a group represented by the formula: X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is N or CR ５ and X ６ is N or CR ６ and X ７ is N or CR ７ and X ８ is N or CR ８ and X ９ is N or CR ９ and X １ , X ２ , and X ３ no more than two of are simultaneously N; X ４ , X ５ , and X ６ no more than two of are simultaneously N; X ７ , X ８ , and X ９ no more than two of are simultaneously N; R １ , R ２ , R ４ , R ５ , R ７ , and R ８ are H, halo, and C, respectively. １－４ independently selected from alkyl; R ３ , R ６ , and R ９ are H, halo, and NR, respectively. ｃ R ｄ , OR ａ , C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; R ３ , R ６ , and R ９ The above C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R １０ H, halo, C １－４ Alkyl, or C １－４ haloalkyl; R Ａ and R Ｂ are H, C, １－４ Alkyl, and C ２－６ alkenyl; R Ａ and R Ｂ The above C １－４ Alkyl and C ２－６ Each alkenyl is Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ is other than H; R Ｃ１ and R Ｃ２ is C １－６ Alkyl, C ２－６ alkenyl, and 5-membered heteroaryl; R Ｃ１ and R Ｃ２ The above C １－６ alkyl, C substituted by R′ １－６ Alkyl, C ２－６ alkenyl, and 5-membered heteroaryl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R' is halo, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ are independently selected from; R Ｄ１ and R Ｄ２ H, halo, and C １－４ independently selected from alkyl; R １１ H, CN, CCR”, CH ３ , C.H. ２ C.N., C.H. ２ OH, CHF ２ , or C.H. ２ F; R" is H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , or N.R. ｃ３ R ｄ３ and R １２ is H or F; R １３ H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , or S(O) ２ N.R. ｃ３ R ｄ３ and R １３ The above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: 【Chemistry 4】 If R is a group １３ is H, CH ３ , and other than CN; Or, R １２ and R １３ are, together with the C atom to which they are attached, a C group containing one heteroatom selected from N and O. ３ forming a cycloalkyl or 3-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, or 3 substituents independently selected from Each Cy １ is C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl; R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ The above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or, R ｃ and R ｄ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ｃ１ and R ｄ１ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ｃ２ and R ｄ２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ｃ３ and R ｄ３ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Each R ａ４ , R ｂ４ , R ｃ４ , and R ｄ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is OH, CN, amino, halo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ , R ｅ１ , R ｅ２ , R ｅ３ , and R ｅ４ is H, C １－４ alkyl, and CN.

2. Formula I: 【Chemistry 5】 Compound or a pharma- ceutically acceptable salt thereof, A is of the formula: 【Chemistry 6】 is a group having the formula: B is a compound represented by formula (a), formula (b), or formula (c): 【Chemistry 7】 is a group represented by the formula: X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is N or CR ５ and X ６ is N or CR ６ and X ７ is N or CR ７ and X ８ is N or CR ８ and X ９ is N or CR ９ and X １ , X ２ , and X ３ no more than two of are simultaneously N; X ４ , X ５ , and X ６ no more than two of are simultaneously N; X ７ , X ８ , and X ９ no more than two of are simultaneously N; R １ , R ２ , R ４ , R ５ , R ７ , and R ８ are H, halo, and C, respectively. １－４ independently selected from alkyl; R ３ , R ６ , and R ９ are H, C, ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; R ３ , R ６ , and R ９ The above C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R １０ H, halo, C １－４ Alkyl, or C １－４ haloalkyl; R Ａ and R Ｂ are H, C, １－４ Alkyl, and C ２－６ alkenyl; R Ａ and R Ｂ The above C １－４ Alkyl and C ２－６ Each alkenyl is Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ is other than H; R Ｃ１ and R Ｃ２ is C １－６ Alkyl, C ２－６ alkenyl, and 5-membered heteroaryl; R Ｃ１ and R Ｃ２ The above C １－６ Alkyl, C ２－６ alkenyl, and 5-membered heteroaryl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Ｄ１ and R Ｄ２ H, halo, and C １－４ independently selected from alkyl; R １１ CN, CH ３ , C.H.F. ２ , or C.H. ２ F; R １２ is H or F; R １３ H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , or S(O) ２ N.R. ｃ３ R ｄ３ and R １３ The above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: 【Chemistry 8】 If R is a group １３ is H, CH ３ , and other than CN; Or, R １２ and R １３ are, together with the C atom to which they are attached, a C group containing one heteroatom selected from N and O. ３ forming a cycloalkyl or 3-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, or 3 substituents independently selected from Each Cy １ is C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl; R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ The above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or, R ｃ and R ｄ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ｃ１ and R ｄ１ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ｃ２ and R ｄ２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Or, R ｃ３ and R ｄ３ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , O.C.(O)R ｂ４ , O.C.(O)NR ｃ４ R ｄ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)NR ｃ４ R ｄ４ , N.R. ｃ４ C(O)OR ａ４ , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , and S(O) ２ N.R. ｃ４ R ｄ４ optionally substituted with 1, 2, or 3 substituents independently selected from Each R ａ４ , R ｂ４ , R ｃ４ , and R ｄ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ alkyl, １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is OH, CN, amino, halo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ , R ｅ１ , R ｅ２ , R ｅ３ , and R ｅ４ is H, C １－４ alkyl, and CN.

3. A, 【Chemistry 9】 2. The compound of claim 1, wherein:

4. A, 【Chemistry 10】 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

5. A, 【Chemistry 11】 The compound according to any one of claims 1 to 4, wherein:

6. A, 【Chemistry 12】 The compound according to any one of claims 1 to 4, wherein:

7. A, 【Chemistry 13-1】 【Chemistry 13-2】 4. The compound of claim 1 or 3, or a pharma- ceutically acceptable salt thereof, selected from:

8. A, 【Chemistry 14】 The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, selected from:

9. B is a compound of formula (a): 【Chemistry 15】 9. The compound according to any one of claims 1 to 8, which is: or a pharma- ceutically acceptable salt thereof.

10. B is a compound of formula (b): 【Chemistry 16】 9. The compound according to any one of claims 1 to 8, which is: or a pharma- ceutically acceptable salt thereof.

11. B is a compound of formula (c): 【Chemistry 17】 9. The compound according to any one of claims 1 to 8, which is: or a pharma- ceutically acceptable salt thereof.

12. A, 【Chemistry 18】 and B is a compound of formula (a): 【Chemistry 19】 2. The compound of claim 1, wherein:

13. A, 【Chemistry 20】 and B is of formula (a): 【Chemistry 21】 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

14. A, 【Chemical 22】 and B is a compound of formula (b): 【Chemistry 23】 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

15. X １ is CR １ And X ２ is CR ２ And X ３ is CR ３ 10. The compound according to any one of claims 1 to 9, which is: or a pharma- ceutically acceptable salt thereof.

16. R １ is H, and R ２ is H, and R ３ is H, or a pharma- ceutically acceptable salt thereof.

17. X ４ is CR ４ And X ５ is CR ５ And X ６ is CR ６ 15. The compound according to any one of claims 1 to 8, 10 and 14, which is: or a pharma- ceutically acceptable salt thereof.

18. R ４ is H, and R ５ is H, and R ６ is H, or a pharma- ceutically acceptable salt thereof.

19. R ６ But, H, Halo, NR ｃ R ｄ , OR ａ , C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; R ３ , R ６ , and R ９ The above C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ 19. The compound of any one of claims 1, 3-8, 10, 14, and 17-18, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

20. R ６ But, C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ 20. The compound of any one of claims 1 to 8, 10, 14, and 17 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

21. R ６ is 4-10 membered heterocycloalkyl; halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ 21. The compound of claim 19 or 20, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

22. R ６ is piperazinyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ 22. The compound of any one of claims 19 to 21, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

23. X ７ is CR ７ And X ８ is CR ８ And X ９ is CR ９ 12. The compound according to any one of claims 1 to 8 and 11, which is: or a pharma- ceutically acceptable salt thereof.

24. R ７ is H, and R ８ is H, and R ９ is H, or a pharma- ceutically acceptable salt thereof.

25. R Ａ But, C １－４ Alkyl and C ２－６ alkenyl; Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ 17. The compound of any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

26. R Ａ But, C １－４ is alkyl, and Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ 17. The compound of any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

27. R Ａ But, C １－４ Cy is an alkyl and is optionally substituted １ 17. The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof.

28. R Ａ The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, wherein is ethyl.

29. R Ａ But, C ２－６ alkenyl, and Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ 17. The compound of any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

30. R Ａ But, C ２－６ alkenyl, C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , and C(O)OR ａ１ 17. The compound of any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

31. R Ａ but, 【Chemistry 24】 17. The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, selected from:

32. R Ｂ But H and C １－４ alkyl, １－４ The alkyl is Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ 32. The compound of any one of claims 1 to 9, 12 to 13, 15 to 16, and 25 to 31, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

33. R Ｂ is H, or a pharma- ceutically acceptable salt thereof.

34. R Ｂ But, C １－４ is alkyl, and Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ 32. The compound of any one of claims 1 to 9, 12 to 13, 15 to 16, and 25 to 31, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

35. R Ｂ But, C １－４ is alkyl, and Cy １ 32. The compound of any one of claims 1 to 9, 12 to 13, 15 to 16, and 25 to 31, or a pharma- ceutically acceptable salt thereof, optionally substituted by:

36. R Ｂ but, 【Chemistry 25】 32. The compound according to any one of claims 1 to 9, 12 to 13, 15 to 16, and 25 to 31, or a pharma- ceutically acceptable salt thereof, selected from:

37. R Ａ But, C １－４ Alkyl and C ２－６ alkenyl, １－４ Alkyl and C ２－６ Each alkenyl is Cy １ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , and C(O)OR ａ１ optionally substituted independently with 1, 2, or 3 substituents independently selected from R Ｂ But H and C １－４ alkyl, １－４ The alkyl is Cy １ optionally replaced by The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof.

38. R Ａ and R Ｂ are respectively C １－４ 17. The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, which is alkyl.

39. R Ａ and R Ｂ The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof, wherein each is ethyl.

40. R Ａ but, 【Chemistry 26】 Selected from: R Ｂ but, 【Chemical 27】 Selected from: The compound according to any one of claims 1 to 9, 12 to 13, and 15 to 16, or a pharma- ceutically acceptable salt thereof.

41. R Ｃ１ is a 5-membered heteroaryl; halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ 23. The compound of any one of claims 1 to 8, 14, and 17 to 22, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

42. R Ｃ１ is 1,3,4-thiadiazyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ 23. The compound of any one of claims 1 to 8, 14, and 17 to 22, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

43. R Ｃ１ is 1,3,4-thiadiazyl, C １－６ 23. The compound of any one of claims 1 to 8, 14, and 17 to 22, or a pharma- ceutically acceptable salt thereof, which is substituted by haloalkyl.

44. R Ｃ１ but, 【Chemistry 28】 23. The compound according to any one of claims 1 to 8, 14, and 17 to 22, or a pharma- ceutically acceptable salt thereof, selected from:

45. R Ｃ１ but, ​ 23. The compound according to any one of claims 1 to 8, 14, and 17 to 22, which is: or a pharma- ceutically acceptable salt thereof.

46. R Ｄ is H, or a pharma- ceutically acceptable salt thereof.

47. R １１ But CN, CH ３ , C.H.F. ２ , or C.H. ２ F, or a pharma- ceutically acceptable salt thereof.

48. R １１ The compound according to any one of claims 1 to 5 and 7 to 46, or a pharma- ceutically acceptable salt thereof, wherein is CN.

49. R １１ CH ３ 47. The compound according to any one of claims 1 to 5 and 7 to 46, which is: or a pharma- ceutically acceptable salt thereof.

50. R １１ CH ２ F, or a pharma- ceutically acceptable salt thereof.

51. R １１ is H, or a pharma- ceutically acceptable salt thereof.

52. R １１ CH ２ 47. The compound according to any one of claims 1 to 5 and 7 to 46, or a pharma- ceutically acceptable salt thereof, wherein R is 0, R is 1 or R is 2;

53. R １２ is H, or a pharma- ceutically acceptable salt thereof.

54. R １３ But H and C １－６ alkyl, １－６ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 54. The compound of any one of claims 1 to 5 and 7 to 53, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

55. R １３ is H, or a pharma- ceutically acceptable salt thereof.

56. R １３ But, C １－６ alkyl, CN and OR ａ３ 55. The compound of any one of claims 1 to 5 and 7 to 54, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

57. R １３ is H, methyl, ethyl, ethenyl, CH ２ C.N., C.H. ２ O.H., C.H. ２ CH ２ OH and CH ２ CH ２ OCH ３ 55. The compound according to any one of claims 1 to 5 and 7 to 54, or a pharma- ceutically acceptable salt thereof, selected from:

58. R １３ is H, ethyl, CH ２ CN and CH ２ CH ２ 55. The compound of any one of claims 1 to 5 and 7 to 54, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of: OH.

59. R １２ and R １３ 53. The compound of any one of claims 1 to 5 and 7 to 52, or a pharma- ceutically acceptable salt thereof, wherein each is H.

60. R １１ , R １２ and R １３ 47. The compound of any one of claims 1 to 5 and 7 to 46, or a pharma- ceutically acceptable salt thereof, wherein each is H.

61. R １１ But CN, CH ３ , or C.H. ２ F; R １２ is H; R １３ is H, ethyl, CH ２ CN and CH ２ CH ２ OH, 47. The compound according to any one of claims 1 to 5 and 7 to 46, or a pharma- ceutically acceptable salt thereof.

62. Formula IIA, IIB, or IIC: 【Chemistry 30】 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

63. Formula IIA-1, IIA-2, IIA-3, or IIA-4: 【Chemistry 31】 63. The compound of claim 62 having the formula: or a pharma- ceutically acceptable salt thereof, ｆ is R ｂ１ , N.R. ｃ１ R ｄ１ OR ａ１ is.]

64. Formula IIB-1 or IIB-2: 【Chemistry 32】 63. The compound of claim 62 having the formula: or a pharma- ceutically acceptable salt thereof.

65. Formula IIB-3: 【Chemical Formula 33】 63. The compound of claim 62 having the formula: or a pharma- ceutically acceptable salt thereof, Ｃ’ Ha, Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ are selected independently.

66. Formula IIC-1 or IIC-2: 【Chemical 34】 63. The compound of claim 62 having the formula: or a pharma- ceutically acceptable salt thereof.

67. Formula IIIA, IIIB, IIIC, IIID, or IIIE: 【Chemistry 35】 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

68. Formula IIIF or IIIG: 【Chemical 36】 The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof.

69. Formula IVA or IVB: 【Chemical 37】 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, ２ , O, or S.

70. Formula IVB': 【Chemical Formula 38】 The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof, ２ , N, O, or S.

71. Formula IVB-1 or IVB-2: 【Chemical Formula 39】 70. The compound of claim 69, having the formula: or a pharma- ceutically acceptable salt thereof, ２ , O, or S.

72. Formula IVB-2': 【Chemistry 40】 The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof, ２ , N, O, or S.

73. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, A is of the formula: 【Chemistry 41】 is a group having the formula: B is a compound represented by formula (a), formula (b), or formula (c): 【Chemistry 42】 is a group represented by the formula: X １ is CR １ and X ２ is CR ２ and X ３ is CR ３ and X ４ is CR ４ and X ５ is CR ５ and X ６ is CR ６ and X ７ is CR ７ and X ８ is CR ８ and X ９ is CR ９ and R １ , R ２ , R ４ , R ５ , R ７ , and R ８ are H, halo, and C, respectively. １－４ independently selected from alkyl; R ３ , R ６ , and R ９ are H, halo, and NR, respectively. ｃ R ｄ , OR ａ , C ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; R ３ , R ６ , and R ９ The above C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R １０ is H; R Ａ and R Ｂ are H, C, １－４ Alkyl, and C ２－６ alkenyl; R Ａ and R Ｂ The above C １－４ Alkyl and C ２－６ Each alkenyl is Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ is other than H; R Ｃ１ and R Ｃ２ is a 5-membered heteroaryl; R Ｃ１ and R Ｃ２ Each of said 5-membered heteroaryls is selected from halo, C １－６ alkyl, C substituted by R′ １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R' is S(O) ２ R ｂ２ and R Ｄ１ and R Ｄ２ is H; R １１ is H, CN, CH ３ , C.H. ２ OH, CHF ２ , or C.H. ２ F; R １２ is H; R １３ H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , or S(O) ２ N.R. ｃ３ R ｄ３ and R １３ The above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: 【Chemistry 43】 If R is a group １３ is H, CH ３ , and other than CN; Or, R １２ and R １３ are, together with the C atom to which they are attached, a C group containing one heteroatom selected from N and O. ３ forming a cycloalkyl or 3-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, or 3 substituents independently selected from Cy １ each is a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocycloalkyl; each is halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ are H and C, respectively. １－６ independently selected from alkyl; R ｅ , R ｅ１ , R ｅ２ , R ｅ３ , and R ｅ４ are H and C, respectively. １－４ alkyl.

74. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, A is of the formula: 【Chemistry 44】 is a group having the formula: B is a compound represented by formula (a), formula (b), or formula (c): 【Chemistry 45】 is a group represented by the formula: X １ is CR １ and X ２ is CR ２ and X ３ is CR ３ and X ４ is CR ４ and X ５ is CR ５ and X ６ is CR ６ and X ７ is CR ７ and X ８ is CR ８ and X ９ is CR ９ and R １ , R ２ , R ４ , R ５ , R ７ , and R ８ are H, halo, and C, respectively. １－４ independently selected from alkyl; R ３ , R ６ , and R ９ are H, C, ６－１０ Aryl, C ３－７ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; R ３ , R ６ , and R ９ The above C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , C(=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ C (=NR ｅ ) N.R. ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ N.R. ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ N.R. ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R １０ is H; R Ａ and R Ｂ are H, C, １－４ Alkyl, and C ２－６ alkenyl; R Ａ and R Ｂ The above C １－４ Alkyl and C ２－６ Each alkenyl is Cy １ , Haro, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ is other than H; R Ｃ１ and R Ｃ２ is a 5-membered heteroaryl; R Ｃ１ and R Ｃ２ Each of said 5-membered heteroaryls is selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Ｄ１ and R Ｄ２ is H; R １１ CN, CH ３ , C.H.F. ２ , or C.H. ２ F; R １２ is H; R １３ H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , or S(O) ２ N.R. ｃ３ R ｄ３ and R １３ The above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl and 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is of the formula: 【Chemistry 46】 If R is a group １３ is H, CH ３ , and other than CN; Or, R １２ and R １３ are, together with the C atom to which they are attached, a C group containing one heteroatom selected from N and O. ３ forming a cycloalkyl or 3-membered heterocycloalkyl group; halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O)R ｂ３ , O.C.(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ optionally substituted with 1, 2, or 3 substituents independently selected from Cy １ each is a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocycloalkyl; each is halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ are H and C, respectively. １－６ independently selected from alkyl; R ｅ , R ｅ１ , R ｅ２ , R ｅ３ , and R ｅ４ are H and C, respectively. １－４ alkyl.

75. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, A is of the formula: 【Chemistry 47】 is a group having the formula: B is a compound represented by formula (a) or (b): 【Chemistry 48】 Based on X １ is CR １ and X ２ is CR ２ and X ３ is CR ３ and X ４ is CR ４ and X ５ is CR ５ and X ６ is CR ６ and R １ , R ２ , R ４ , and R ５ are each H; R ３ and R ６ are H, halo, and NR, respectively. ｃ R ｄ , OR ａ and 4- to 10-membered heterocycloalkyl; R ３ and R ６ Each of said 4- to 10-membered heterocycloalkyl is C(O)R ｂ optionally replaced by; R Ａ and R Ｂ are H, C, １－４ Alkyl, and C ２－６ alkenyl; R Ａ and R Ｂ The above C １－４ Alkyl and C ２－６ Each alkenyl is Cy １ and C(O)NR ｃ１ R ｄ１ (C(O)OR ａ１ Optionally substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ is other than H; R Ｃ１ is C １－６ alkyl or 5-membered heteroaryl, the 5-membered heteroaryl being C １－６ alkyl, C substituted by R′ １－６ Alkyl, C ２－６ Alkenyl, C ３－７ Cycloalkyl, or C １－６ optionally substituted with haloalkyl; R' is S(O) ２ R ｂ２ and R Ｄ１ is H; R １１ CN, CH ３ , or C.H. ２ F; R １２ is H; R １３ is H or C １－６ alkyl, １－６ Alkyl is CN and OR ａ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy １ are each 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl; C １－６ optionally substituted with alkyl; R ｂ , R ａ１ , R ｃ１ , and R ｄ１ are H and C, respectively. １－６ alkyl.

76. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, A is of the formula: 【Chemistry 49】 is a group having the formula: B is a compound represented by formula (a) or (b): 【Chemistry 50】 Based on X １ is CR １ and X ２ is CR ２ and X ３ is CR ３ and X ４ is CR ４ and X ５ is CR ５ and X ６ is CR ６ and R １ , R ２ , R ４ , and R ５ are each H; R ３ and R ６ are each independently selected from H and 4-10 membered heterocycloalkyl; R ３ and R ６ Each of said 4- to 10-membered heterocycloalkyl is C(O)R ｂ optionally replaced by; R Ａ and R Ｂ are H, C, １－４ Alkyl, and C ２－６ alkenyl; R Ａ and R Ｂ The above C １－４ Alkyl and C ２－６ Each alkenyl is Cy １ and C(O)NR ｃ１ R ｄ１ , (C(O)OR ａ１ Optionally substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ is other than H; R Ｃ１ is a 5-membered heteroaryl; １－６ optionally substituted with haloalkyl; R Ｄ１ is H; R １１ CN, CH ３ , or C.H. ２ F; R １２ is H; R １３ is H or C １－６ alkyl, １－６ Alkyl is CN and OR ａ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy １ are each 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl; C １－６ optionally substituted with alkyl; R ｂ , R ａ１ , R ｃ１ , and R ｄ１ are H and C, respectively. １－６ alkyl.

77. Ethyl (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoate; (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enoic acid; (2E)-4-[6-({bicyclo[1.1.1]pentan-1-yl}sulfamoyl)-2,4-dioxo-1H-quinazolin-3-yl]but-2-enamide; 1,3-diethyl-N-(3-methyloxetan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; 1,3-diethyl-N-(3-methylthietan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide; 1,3-diethyl-N-(1-methylcyclobutyl)-2,4-dioxoquinazoline-6-sulfonamide; 1,3-diethyl-N-(3-methyloxolan-3-yl)-2,4-dioxoquinazoline-6-sulfonamide; Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-2,4-dioxo-1H-quinazolin-3-yl}but-2-enoate; N-(3-cyanooxetan-3-yl)-1,3-diethyl-2,4-dioxoquinazoline-6-sulfonamide; Methyl (2E)-4-{6-[(3-methyloxetan-3-yl)sulfamoyl]-1-(oxetan-3-ylmethyl)-2,4-dioxoquinazolin-3-yl}but-2-enoate; Methyl (E)-5-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)pent-2-enoate; 1,3-diethyl-N-((1S,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-methyloxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-2-(cyanomethyl)-1-methylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(3-(difluoromethyl)oxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-N-methyl-4-(6-(N-(3-methyloxetan-3-yl)sulfamoyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)but-2-enamide; and 1,3-Diethyl-N-(3-(fluoromethyl)oxetan-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide 2. The compound of claim 1, selected from:

78. 1,3-diethyl-N-((1S,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-((1R,2R)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-((1R,2S)-2-ethyl-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2R,3R)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2R,3S)-2,3-dimethyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclobutyl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-1-((2,4-dimethylthiazol-5-yl)methyl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(3-cyanooxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(dimethylamino)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((2S,3S)-2,3-dimethyloxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-((2,4-dimethylthiazol-5-yl)methyl)-N-(3-(fluoromethyl)oxetan-3-yl)-3-((2-methylthiazol-5-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(oxetan-3-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-((methylsulfonyl)methyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyano-2-methyloxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(isopropylsulfonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-cyanooxetan-3-yl)-4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-(6-(N-(3-cyanooxetan-3-yl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-vinyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-4-(4-methylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1,3-diethyl-N-(3-methylazetidin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-(1-methylcyclopentyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-vinylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2S)-1-cyano-2-vinylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2R)-1-cyano-2-ethylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2S)-1-cyano-2-ethylcyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-((1S,2S)-1-methyl-2-vinylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-(1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-(2-methoxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1R,2R)-1-cyano-2-(2-methoxyethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; N-((2R,3S)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3R)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((2S,3S)-3-cyano-2-methyloxetan-3-yl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 4-chloro-N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-chloro-N-(1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2-(2-hydroxyethyl)-1-methylcyclopropyl)-1H-indazole-6-sulfonamide; 1,3-diethyl-N-((1R,2S)-1-(hydroxymethyl)-2-vinylcyclopropyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; N-((1S,2S)-1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; N-((1R,2R)-1-cyano-2-(2-hydroxyethyl)cyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((1S,2S)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-((1R,2R)-2-(2-hydroxyethyl)-1-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-1H-indazole-6-sulfonamide; 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(2,3-dimethyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-Methyl-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-methoxy-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 1,3-diethyl-N-((1R,2R)-2-(hydroxymethyl)cyclobutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 1,3-diethyl-N-((1S,2S)-2-(hydroxymethyl)cyclobutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; 4-(4-(cyclopentanecarbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; N-(2,2-difluoroethyl)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-(fluoromethyl)oxetan-3-yl)sulfamoyl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; N-((1S,2S)-1-cyano-2-(hydroxymethyl)cyclopropyl)-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (S)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyryl-3-methylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1-(5-vinyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide; and 1-(5-bromo-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide 2. The compound of claim 1, selected from:

79. 79. A pharmaceutical composition comprising a compound according to any one of claims 1 to 78, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

80. 80. A method of inhibiting the activity of PARG, comprising contacting said PARG with a compound according to any one of claims 1 to 78, or a pharma- ceutically acceptable salt thereof.

81. 81. The method of claim 80, wherein said contacting is in vitro.

82. 11. A method of treating a disease or disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 78, or a pharma- ceutically acceptable salt thereof.

83. 83. The method of claim 82, wherein the disease or disorder is cancer.

84. 84. The method of claim 83, wherein the cancer is a stress-dependent cancer.

85. 84. The method of claim 83, wherein the cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, mantle cell lymphoma, and renal cell carcinoma.

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