Indazoles as hematopoietic progenitor kinase 1 (HPK1) inhibitors and methods of use thereof

Abstract

The present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof, compositions containing the compounds, methods of using the compounds in the treatment of various conditions associated with HPK1, and methods of making these compounds. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to inhibitors of hematopoietic progenitor kinase 1 (HPK1), pharmaceutical compositions comprising the inhibitors, methods of using the inhibitors to treat various disorders associated with HPK1, and methods of preparing the compounds. Background Art

[0002] Immunotherapy is a treatment that uses the body's own immune system to help fight cancer and other conditions. In recent years, this relatively new approach has achieved remarkable clinical success in treating various tumor types, especially through treatment with immune checkpoint inhibitors and chimeric antigen T cell therapy. The most studied checkpoint inhibitors include CTLA4, PD-1, or PD-L1 inhibitors, which have shown significant anti-tumor activity by overcoming immunosuppressive mechanisms at the tumor site.

[0003] Hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1) is a serine / threonine kinase and a member of MAP4K. HPK1 is significantly expressed in subsets of the hematopoietic cell lineage. HPK1 is a newly discovered key negative regulator in the activation of T lymphocytes and dendritic cells. It has recently been demonstrated that the kinase activity of HPK1, as a new intracellular checkpoint molecule, plays an important role in anti-cancer immunity and has the potential advantage of combined therapy with existing checkpoint regimens. HPK1 inhibition is expected to have dual functions, 1. Prolonging T cell activation; 2. Enhancing APC function through dendritic cells. This dual targeting can work synergistically to achieve an effective immune response in the tumor microenvironment. Therefore, HPK1 has been confirmed as a new target for anti-cancer immunotherapy. Examples of cancers that may be treated using the compounds of the present disclosure include, but are not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas, and leukemias, including, but not limited to, bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, and thyroid cancer, acute lymphocytic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma, and Wilm's tumor.

[0004] Inhibition of HPK1 with small molecule inhibitors has the potential to treat cancer and other diseases [Hernandez, S., et.al., (2018) Cell Reports 25, 80-94]. Summary of the invention

[0005] The present disclosure provides novel indazole compounds and pharmaceutically acceptable salts that are potent HPK1 inhibitors and dual activators of T cells and dendritic cells.

[0006] One embodiment of the present disclosure is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof: Among them, A, R 2 , R 3 , R 4 , R 5 , R a , R c and M are as defined in the detailed description.

[0007] In another embodiment, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, a method of treating a subject suffering from a disease or condition associated with the regulation of HPK1 is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0009] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.

[0010] definition

[0011] For the sake of clarity, common terms used in this disclosure are defined herein.

[0012] The terms "substituent," "radical," "group," "moiety," and "fragment" are used interchangeably herein.

[0013] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon group having at least one unsaturated site (i.e., carbon-carbon, sp2 double bond). In embodiments, the alkenyl group has 2 to 12 carbon atoms. In some embodiments, the alkenyl group is C 2 -C 10 Alkenyl or C 2 -C 6 Examples of alkenyl groups include, but are not limited to, ethylene or vinyl (—CH═CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ) and 5-hexenyl (-CH 2 CH 2 CH2 CH 2 CH=CH 2 ).

[0014] As used herein, the term "alkoxy" is RO-, wherein R is an alkyl group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0015] As used herein, the term "alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl include methoxymethyl, methoxyethyl, methoxypropyl and ethoxyethyl.

[0016] As used herein, the term "alkoxycarbonyl" is ROC(O)-, wherein R is alkyl as defined herein. In various embodiments, R is C 1 -C 10 Alkyl or C 1 -C 6 alkyl.

[0017] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon group. In embodiments, the alkyl group has 1 to 12 carbon atoms. In some embodiments, the alkyl group is C 1 -C 10 Alkyl or C 1 -C 6 Alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" means an alkyl group having 1 to 4 carbon atoms.

[0018] As used herein, if the term "C 1 -C 6 ", it means the number of carbon atoms is 1 to 6. For example, C 1 -C 6 The alkyl group represents an alkyl group having any integer of 1 to 6 carbon atoms.

[0019] As used herein, the term "alkylamino" refers to an amino group substituted with one or more alkyl groups. "N-(alkyl)amino" is RNH-, and "N,N-(alkyl) 2 Amino group" is R 2 N-, wherein the R groups are alkyl groups as defined herein and are the same or different. In various embodiments, R is C 1 -C 10 Alkyl or C 1 -C 6 Examples of the alkylamino group include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and methylethylamino.

[0020] As used herein, the term "alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, wherein alkylamino is as defined herein. Examples of alkylaminoalkyl groups include methylaminomethyl and ethylaminomethyl.

[0021] As used herein, the term "alkynyl" refers to a straight or branched carbon chain group having at least one unsaturated site (i.e., carbon-carbon, sp triple bond). In embodiments, the alkynyl group has 2 to 12 carbon atoms. In some embodiments, the alkynyl group is C 2 -C 10 Alkynyl or C 2 -C 6 Examples of alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH 2 C≡CH).

[0022] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring with up to 7 atoms in each ring, wherein at least one ring is aromatic, or refers to an aromatic ring system with 5 to 14 carbon atoms, the aromatic ring system comprising a carbocyclic aromatic group fused to a 5- or 6-membered cycloalkyl. Representative examples of aryl include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl and indanyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0023] As used herein, the term "cycloalkyl" is a hydrocarbon group containing at least one saturated or partially unsaturated ring structure and connected via a ring carbon. In various embodiments, it refers to a saturated or partially unsaturated C 3 -C 12 The saturated or partially unsaturated C 3 -C 12 Examples of cyclic moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl."Cycloalkoxy" is RO-, where R is cycloalkyl.

[0024] As used herein, the terms "halogen" and "halo" refer to chlorine (-Cl), bromine (-Br), fluorine (-F) or iodine (-I). "Haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, and examples of haloalkoxy include, but are not limited to, -OCF 3 、-OCHF 2 and -OCH 2 F. "Haloalkoxyalkyl" refers to an alkyl moiety substituted with a haloalkoxy group, wherein haloalkoxy is as defined herein. Examples of haloalkoxyalkyl include trifluoromethoxymethyl, trifluoroethoxymethyl, and trifluoromethoxyethyl. "Haloalkyl" refers to an alkyl moiety substituted with one or more halogen groups. Examples of haloalkyl include -CF3 , -CHF 2 and -CH 2 F.

[0025] As used herein, the term "heteroalkyl" refers to a straight or branched chain alkyl group having 2 to 14 carbons (in some embodiments, 2 to 10 carbons) in the chain, one or more of which has been substituted with a heteroatom selected from S, O, P, and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.

[0026] As used herein, the term "heterocyclyl" includes heteroaryl as defined below, and refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic group having from 2 to 14 ring carbon atoms, and the monocyclic, bicyclic or tricyclic group has, in addition to the ring carbon atoms, from 1 to 4 heteroatoms selected from P, N, O and S. In various embodiments, the heterocyclic group is attached to another moiety through carbon or through a heteroatom, and is optionally substituted on carbon or heteroatoms. Examples of heterocyclic groups include azetidinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazole yl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepine "Heterocyclyloxy" is RO-, wherein R is a heterocyclyl. "Heterocyclic thio" is RS-, where R is a heterocyclic group.

[0027] As used herein, the term "3- or 4-membered heterocyclyl" refers to a monocyclic ring having 3 or 4 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O and S. Non-limiting examples of 3- or 4-membered heterocyclyl groups include aziridinyl, 2H-azirinyl, oxiranyl, thiirane, azetidinyl, 2,3-dihydroazetidinyl, azetidinyl, 1,3-diazetidinyl, oxetanyl, 2H-oxetyl, thietanyl and 2H-thietyl.

[0028] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms in the ring selected from the group consisting of N, O and S. Non-limiting examples of heteroaryl include pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzofuranyl, dibenzofuranyl, dibenzothienyl, benzothienyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thiaindenyl and pyrazinyl. Attachment of the heteroaryl group can occur through the aromatic ring, or, if the heteroaryl group is bicyclic or tricyclic and one of the rings is not aromatic or does not contain heteroatoms, through a non-aromatic ring or a ring that does not contain heteroatoms. "Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl group. "Heteroaryloxy" is RO-, where R is a heteroaryl group.

[0029] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxy group (-OH), wherein alkoxy is as defined herein. An example of a hydroxyalkoxy group is hydroxyethoxy.

[0030] As used herein, the term "hydroxyalkyl" refers to a straight or branched monovalent C 1 -C 10 The hydrocarbyl group, and examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0031] As used herein, the term "pharmaceutically acceptable" means suitable for use in pharmaceutical preparations, generally recognized as safe for such use, officially approved for such use by a national or state government regulatory agency, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0032] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle, or other ingredient that is pharmaceutically acceptable and is administered with the compounds of the present invention.

[0033] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts, and amine salts. Examples of acid addition salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of acid addition salts formed with organic acids are, for example, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4′-methylenebis(3-hydroxy-2-naphthoic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. Examples of metal salts include salts with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids.

[0034] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, aryl, heteroaryl, heterocycle or cycloalkyl), wherein at least one hydrogen atom of the substituted portion is replaced by a substituent. In one embodiment, each carbon atom of the substituted group is replaced by no more than two substituents. In another embodiment, each carbon atom of the substituted group is replaced by no more than one substituent. In the case of a ketone substituent, two hydrogen atoms are replaced by oxygen connected to the carbon by a double bond. Unless otherwise defined, substituents include halogen, hydroxyl, (low) alkyl, haloalkyl, mono or dialkylamino, aryl, heterocycle, -NO 2 、B(OH) 2 ,BPin,-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-NR a C(=O)OR b 、-NR a SO 2 R b 、-OR a 、-CN、-C(=O)R a 、-C(=O)OR a 、-C(=O)NR a R b 、-OC(=O)R a 、-OC(=O)OR a 、-OC(=O)NR a R b 、-NR a SO 2 R b ,-PO 3 R a 、-PO(OR a )(OR b ),-SO 2 R a 、-S(O)R a 、-SO(N)R a (e.g., sulfoximine), -(R a )S=NR b (e.g., sulfilimine) and -SR a , where R a and R b are the same or different and are independently -H, halogen, amino, alkyl, haloalkyl, aryl or heterocycle, or wherein R a and R bTogether with the nitrogen atom to which they are attached, they form a heterocyclic ring. a and R b Can be multiple.

[0035] As used herein, the term "therapeutically effective amount" means, when applied to the compounds of the invention, an amount of the compound sufficient to improve, alleviate, stabilize, reverse, slow or delay the development of a condition or disease state, or the development of a condition or disease symptom. In an embodiment, the methods of the invention provide for the administration of a combination of compounds. In this case, a "therapeutically effective amount" is an amount of the compound of the invention sufficient to elicit the desired biological effect in combination.

[0036] As used herein, the term "treatment" or "treating" means improving or reversing the progression or severity of a disease or condition, or improving or reversing one or more symptoms or side effects of such a disease or condition. As used herein, "treatment" or "treating" also means inhibiting or blocking, such as delaying, preventing, inhibiting, hindering or hindering the progression of a system, symptom or state of a disease or condition. For purposes of the present invention, "treatment" or "treating" further means a method for obtaining a beneficial or desired clinical outcome, wherein "beneficial or desired clinical outcome" includes, but is not limited to, relief of symptoms, alleviation of the degree of illness or disease, stabilization of the disease or condition state (i.e., no deterioration), delay or slowing of the disease or condition state, improvement or alleviation of the disease or condition state, and alleviation of the disease or condition, whether in part or in whole.

[0037] Compound

[0038] The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof: in: A is -NH-C(O)-LR 1 、-NH-R 1 or -R 1 ; L is a bond, -NH-, -O- or -CH 2 -; R 1 -H, -D, -CD 3 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, hydroxyl, -CD 2 OH, -CN, -NO 2 , haloalkyl, -C(O)R 9 、-C(O)OR9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O) 2 R 9 、-S(O)(=NH)R 10 、-S(O) 2 NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O) 2 R 9 、-N(R 6 )S(O) 2 NR 10 R 11 or -P(O)R 12 R 13 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally independently selected from R 7 is substituted with one or more substituents. R 2 -H, -D, -CD 3 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, hydroxyl, -CD 2 OH, -CN, -NO 2 , haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR10 R 11 、-SR 9 、-S(O)R 9 、-S(O) 2 R 9 、-S(O)(=NH)R 10 、-S(O) 2 NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O) 2 R 9 、-N(R 6 )S(O) 2 NR 10 R 11 or -P(O)R 12 R 13 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO 2 、-NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR10 R 11 ; R 3 -H, -D, -CD 3 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, halogen, cyano, hydroxyl, -CH 2 OH, -CD 2 OH, -OH, -CN, -NO 2 , haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O) 2 R 9 、-S(O)(=NH)R 10 、-S(O) 2 NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O) 2 R 9 、-N(R 6 )S(O) 2 NR 10 R 11 or -P(O)R 12 R 13 ; M is a bond, -O-, -S-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -C(O)R9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O) 2 R 9 、-S(O)(=NH)R 10 、-S(O) 2 NR 10 R 11 or -P(O)R 12 R 13 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD 3 、-NO 2 、-NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-NR 10 S(O) 2 R 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 ; R 5 -H, -D, -CD 3 , alkyl, alkenyl, alkynyl, cycloalkyl, halogen, hydroxyl, -CH 2 OH, -CD 2 OH, -CN or halogenated alkyl; R 6 -H, C 1-6 Alkyl or cycloalkyl; R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, oxo, cyano, hydroxyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O) 2 R 9 、-S(O)(=NH)R 10 、-S(O) 2 NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O) 2 R 9 、-N(R 6 )S(O) 2 NR 10 R 11 or -P(O)R 12 R 13 ; R 9 is -H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; Each R 10 and R 11 is independently -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, or R 10 and R 11 Together with the nitrogen atom to which they are attached, they form a 4- to 12-membered heterocyclic group, which is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO 2 、-NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R11 、-NR 10 C(=O)OR 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 ; Each R 12 and R 13 are independently alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic, or R 12 and R 13 Together with the phosphorus atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO 2 、-NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 ;and Each R a and R c are independently -H, -D, halogen, haloalkyl, -CN, -OR 9 or -NR 10 R 11 .

[0039] In various embodiments of formula (I) to formula (VI), the alkyl group is C 1-6 Alkyl; alkenyl is C 2-6 Alkenyl; alkynyl is C 2-6 The alkynyl and / or cycloalkyl groups are C3-8 Cycloalkyl.

[0040] In some embodiments, each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH 3 or -CN.

[0041] In some embodiments, R 2 Alkyl, haloalkyl, hydroxyalkyl, alkoxy, halogen, -COOH, -C(O)OCH 3 or -CN; and R 3 is halogen or alkyl.

[0042] In some embodiments, R 5 is -H, halogen or alkyl.

[0043] In some embodiments, each R a and R c is independently -H, halogen or alkyl.

[0044] In some embodiments, M is a bond, -O-, -CHR 6 -or-NR 6 -; and R 4 -H, -D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -C(O)R 9 、-NHC(O)R 9 、-C(O)NR 10 R 11 、-S(O) 2 R 9 、-S(O)(=NH)R 10 or -S(O) 2 NR 10 R 11 , where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -C(O)CH 3 、-CN、-CD 3 、-NR 10 R 11 、-NR 10 S(O) 2 R9 and-NR 10 C(=O)R 9 .

[0045] In some embodiments, MR 4 Selected from the group consisting of:

[0046] In another embodiment, a compound of formula (II) is provided:

[0047] Where R 2 , R 3 , R 4 , R 5 , R a , R c and M are as defined above for formula (I), and R 1 is a cyclopropyl group, which is optionally substituted by one or two R 7 replace.

[0048] In some embodiments, R 1 Selected from the group consisting of:

[0049] In some embodiments, each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH 3 or -CN; M is a bond, -O-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, halogen, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 、-NHC(O)R 9 or -C(O)NR 10 R 11 , wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally selected from hydroxy, amino, -COOH and -C(O)CH 3 One or more groups in the group consisting of 5 is -H, halogen or alkyl; each R a and R c is independently -H, halogen or alkyl.

[0050] Non-limiting exemplary compounds of formula (II) include compounds of Examples 1-42, 44-56, 59, 62, 63, 67-73, 75-78, 85-88, 94, 96-99, 104, 107, 115, 118, 127, 128, 132, 133, 136, 137, 141-143, 146, 154, 156, 160, 164, and 165 of Table 1.

[0051] In some embodiments, R 1 for And non-limiting exemplary compounds include the compounds of Example 1-Example 19, Example 21-Example 25, Example 27, Example 28, Example 30, Example 31, Example 33-Example 36, Example 40-Example 42, Example 44, Example 45, Example 48-Example 50, Example 53-Example 56, Example 59, Example 62, Example 63, Example 67-Example 73, Example 75-Example 77, Example 85-Example 87, Example 96-Example 99, Example 107, Example 115, Example 127-Example 128, Example 132, Example 133, Example 136, Example 137, Example 141-Example 143, Example 146 and Example 165 of Table 1.

[0052] In some embodiments, R 1 Selected from the group consisting of: , and non-limiting exemplary compounds include compounds of Example 20, Example 26, Example 29, Example 32, Example 37-Example 39, Example 46, Example 47, Example 51, Example 52, Example 78, Example 94, Example 104, Example 118 and Example 154 of Table 1.

[0053] In another embodiment, a compound of formula (III) is provided:

[0054] Where R 2 , R 3 , R 4 , R 5 , R a , R cand M are as defined above for formula (I), and R 1 Alkyl, alkenyl, alkynyl, halogen, hydroxyl, -CD 2 OH, -CN, -NO 2 , haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O) 2 R 9 、-S(O)(=NH)R 10 、-S(O) 2 NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O) 2 R 9 、-N(R 6 )S(O) 2 NR 10 R 11 or -P(O)R 12 R 13 , wherein alkyl, alkenyl or alkynyl is optionally independently selected from R 7 is substituted with one or more substituents.

[0055] In some embodiments, R 1Selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, methyl, ethyl, ethyl, butyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, dimethylaminomethyl, methylthiomethyl, methylamino, ethylamino, isopropylamino, methoxy, ethoxy, isopropoxy,

[0056] In some embodiments, each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH 3 or -CN; M is a bond, -O-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, halogen, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 、-NHC(O)R 9 or -C(O)NR 10 R 11 , wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally selected from hydroxy, amino, -COOH and -C(O)CH 3 One or more groups in the group consisting of 5 is -H, halogen or alkyl; and each R a and R c is independently -H, halogen or alkyl.

[0057] Non-limiting exemplary compounds of Formula (III) include compounds of Example 43, Example 61, Example 64, Example 66, Example 79-Example 83, Example 95, Example 100, Example 102, Example 103, Example 105, Example 106, Example 109, Example 110, Example 112-Example 114, Example 117, Example 119, Example 121, Example 122, Example 129, Example 130, Example 134, Example 135, Example 138-Example 140, Example 145, Example 147-Example 153, Example 155, Example 157-Example 159, and Example 161-Example 163 of Table 1.

[0058] In another embodiment, a compound of formula (IV) is provided:

[0059] Where R 2 , R 3 , R 4 , R 5 , R a , R c , L and M are as defined above for formula (I), and R 1 is cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally independently selected from R 7 is substituted with one or more substituents.

[0060] In some embodiments, R 1 Selected from the group consisting of:

[0061] In some embodiments, each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH 3 or -CN; M is a bond, -O-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, halogen, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 、-NHC(O)R 9 or -C(O)NR 10 R 11 , wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally selected from hydroxy, amino, -COOH and -C(O)CH 3 One or more groups in the group consisting of 5 is -H, halogen or alkyl; and each R a and R c is independently -H, halogen or alkyl.

[0062] Non-limiting exemplary compounds of Formula (IV) include compounds of Example 57, Example 58, Example 60, Example 74, Example 84, Example 89, Example 90, Example 92, Example 93, Example 108, Example 111, Example 116, Example 120, Examples 123-126, and Example 131 of Table 1.

[0063] In another embodiment, a compound of formula (V) is provided:

[0064] Where R1 , R 2 , R 3 , R 4 , R 5 , R a , R c and M are as defined above for formula (I).

[0065] In some embodiments, R 1 Selected from the group consisting of:

[0066] In some embodiments, each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH 3 or -CN; M is a bond, -O-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, halogen, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 、-NHC(O)R 9 or -C(O)NR 10 R 11 , wherein the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more groups selected from hydroxy, amino, -COOH and -C(O)CH 3 The group composed of 5 is -H, halogen or alkyl; and each R a and R c is independently -H, halogen or alkyl.

[0067] Non-limiting exemplary compounds of Formula (V) include compounds of Example 65 and Example 91 of Table 1.

[0068] In another embodiment, a compound of formula (VI) is provided:

[0069] Where R 1 , R 2 , R 3 , R 4 , R 5 , R a , R c and M are as defined above for formula (I).

[0070] In some embodiments, R1 Selected from the group consisting of:

[0071] In some embodiments, each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH 3 or -CN; M is a bond, -O-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, halogen, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 、-NHC(O)R 9 or -C(O)NR 10 R 11 , wherein the cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more groups selected from hydroxy, amino, -COOH and -C(O)CH 3 The group composed of 5 is -H, halogen or alkyl; and each R a and R c is independently -H, halogen or alkyl.

[0072] Non-limiting exemplary compounds of Formula (VI) include the compound of Example 101 of Table 1.

[0073] In an embodiment, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable carrier or diluent and a compound of Formula (I) to Formula (VI) or a pharmaceutically acceptable salt thereof.

[0074] Medical uses and treatment methods using this compound

[0075] The present disclosure provides a method for treating a subject suffering from a disease or condition associated with the regulation of HPK1, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition associated with the regulation of HPK1 is cancer, metastasis, inflammation or autoimmune pathogenesis.

[0076] In some other embodiments, the disease is cancer, metastasis, inflammation or autoimmune disease. In a specific embodiment, the cancer is selected from the group consisting of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias, including but not limited to bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphocytic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma and Wilms' tumor (Wilm's tumor).

[0077] In another embodiment, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting HPK1 activity in a subject in need thereof. In some embodiments, the use comprises treating cancer.

[0078] Suitable subjects to be treated according to the present disclosure include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, humans, dogs, cats, cattle, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., and include mammals in utero. Subjects can be of any gender and can be at any stage of development. In one embodiment, a suitable subject to be treated according to the present disclosure is a human.

[0079] The compounds of the present disclosure are usually administered in a therapeutically effective amount. The compounds of the present disclosure can be administered by any suitable route in the form of a pharmaceutical composition suitable for the route and in a dose effective for the intended treatment. The effective dose is usually in the range of about 0.01 mg to about 1000 mg per kilogram of body weight per day, preferably about 0.01 mg / kg / day to about 500 mg / kg / day, in a single dose or divided dose. Depending on age, species and the disease or condition being treated, a dosage level below the lower limit of the range may be appropriate. In other cases, a larger dose can be used without harmful side effects. A larger dose can also be divided into several smaller doses for administration throughout the day. Methods for determining a suitable dose are well known in the art to which the present disclosure belongs. For example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th edition, 2000 can be used.

[0080] Pharmaceutical compositions, dosage forms and routes of administration

[0081] To treat the above-mentioned diseases or conditions, the compounds described herein or their pharmaceutically acceptable salts can be administered as follows:

[0082] Oral administration

[0083] Compounds of the present disclosure can be administered orally, including by swallowing, so that the compound enters the gastrointestinal tract, or is directly absorbed from the oral cavity into the bloodstream (e.g., buccal or sublingual administration). Compositions suitable for oral administration include solid, liquid, gel or powder preparations, and have dosage forms such as tablets, lozenges, capsules, granules or powders. Compositions for oral administration can be formulated to release immediately or regulate release, including delayed release or sustained release, optionally with enteric coating. Liquid preparations can include solutions, syrups and suspensoids, which can be used in soft capsules or hard capsules. Such preparations can include pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose or oil. The preparations can also include one or more emulsifiers and / or suspending agents.

[0084] In tablet dosage forms, the amount of drug present may be from about 0.05% to about 95% by weight of the dosage form, more typically from about 2% to about 50% by weight. In addition, the tablet may contain a disintegrant, which comprises from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25%. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, maltodextrin, or mixtures thereof.

[0085] Suitable lubricants for tablets may be present in amounts of about 0.1% to about 5% by weight and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

[0086] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starches, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose and starch.

[0087] Suitable solubilizers for tablets may be present in an amount of about 0.1% to about 3% by weight and include, but are not limited to, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic / caprylic mono / diglycerides, sorbitan fatty acid esters and Solutol HS TM .

[0088] Parenteral administration

[0089] The compounds of the present disclosure can be administered directly into the bloodstream, muscle or internal organs. Suitable modes of parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needles and needle-free syringes) and infusion methods.

[0090] Compositions for parenteral administration can be formulated to release immediately or to regulate release, including delayed release or sustained release. Most parenteral preparations are aqueous solutions containing excipients (including salts, buffers and isotonic agents). Parenteral preparations can also be prepared into dehydrated forms (e.g., by lyophilization) or sterile non-aqueous solutions. These preparations can be used together with suitable carriers (e.g., sterile water). Solubility enhancers can also be used to prepare parenteral solutions.

[0091] Transdermal administration

[0092] The compounds of the present disclosure can be administered topically to the skin or transdermally. Preparations for such topical administration may include lotions, solutions, emulsions, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration of preparations may include water, alcohol, mineral oil, glycerol, polyethylene glycol, etc. Topical or transdermal administration may also be performed by electroporation, iontophoresis, sonophoresis, etc. Compositions for topical administration may be formulated to release immediately or to regulate release, including delayed release or sustained release.

[0093] Combination therapy

[0094] The pharmaceutical composition according to the present disclosure may include one or more additional therapeutic agents, for example, to increase the efficacy or reduce side effects. Therefore, in some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from active ingredients, which can be used to treat or inhibit diseases mediated directly or indirectly by HPK1. Examples of such active ingredients include, but are not limited to, agents for treating cancer, metastasis, inflammation, or autoimmune pathogenesis. In some embodiments, the compound of formula (I) is administered together with an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA4 agent.

[0095] References for preparing pharmaceutical compositions

[0096] Methods for preparing pharmaceutical compositions for treating or preventing diseases or conditions are well known in the art to which the present disclosure belongs. For example, according to Handbook of Pharmaceutical Excipients (7th edition), Remington: The Science and Practice of Pharmacy (20th edition), Encyclopedia of Pharmaceutical Technology (3rd edition), or Sustained and Controlled Release Drug Delivery Systems (1978), pharmaceutically acceptable excipients, carriers, additives, etc. can be selected and then mixed with the compounds of the present disclosure to prepare pharmaceutical compositions.

[0097] The present disclosure provides a compound having various pharmacological effects by inhibiting HPK1 activity, a pharmaceutical composition having the compound as an effective agent, a medical use of the compound, especially for treating a disease or condition regulated by HPK1, and a method of treatment or prevention, the method comprising administering the compound to a subject in need of such treatment or prevention. The compounds of the present disclosure and their pharmaceutically acceptable salts have good safety and high selectivity for HPK1, and thus exhibit excellent performance as drugs.

[0098] Compound preparation

[0099] The following preparative examples illustrate the preparation of intermediate compounds useful in preparing compounds of formula (I).The novel intermediate compounds described herein and synthetic methods useful for preparing the intermediate compounds represent embodiments of the present invention.

[0100] Intermediate 1A. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0101] Step 1) 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole

[0102] To the solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (2g, 8.02mmol) in sulfuric acid (1.7mL) was added N-iodosuccinimide (2.7g, 12.03mmol) in batches. The mixture was stirred at 0°C for 3 hours. After the reaction was completed, the mixture was poured into ice water, quenched with solid NaOH, and then extracted with dichloromethane. The combined organic residue was concentrated in vacuo (2.99g, crude product).

[0103] 1H NMR (400 MHz, DMSO-d 6 )δ13.91(s, 1H), 8.27(d, J=1.6Hz, 1H).

[0104] Step 2) 4-bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0105] To a solution of 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole (2.99 g, 7.97 mmol, 1 eq) in THF (40 mL) was added 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq). The reaction mixture was stirred at 60 ° C for 16 hours. The reaction mixture was extracted with EtOAc and purified by MgSO 4 The organic residue was dried and purified by column chromatography (silica gel, hexane:EtOAc=1:0 to 4:1) to give 4-bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.64 g, 7.97 mmol, 60.7% yield).

[0106] 1 H NMR (400 MHz, DMSO-d 6 )δ8.84 (s, 1H), 5.80 (dd, J=9.9, 2.7Hz, 1H), 5.66 (s, 1H), 4.02 (t, J=6.6Hz, 1H ), 3.85-3.70(m, 1H), 2.33-2.21(m, 1H), 2.08-1.91(m, 2H), 1.79-1.45(m, 4H).

[0107] Step 3) 4-bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0108] To a solution of 4-bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (100 mg, 0.218 mmol, 1 eq) in 2-methyl-2-butanol (1.09 mL) was added Xantphos Pd G3 (21 mg, 21.8 μmol, 0.1 eq) and Cs 2 CO 3 (142 mg, 0.436 mmol, 2.0 eq). The mixture was degassed and heated to 40 ℃ with N 2 After purging 3 times, propan-2-amine (0.19 mL, 2.18 mmol, 10 eq) was added. The mixture was stirred at 90 °C for 3 h in a sealed tube.2 O (40 mL) to dilute the reaction mixture, and then extract the mixture with DCM (50 mL * 3). The combined organic layer was purified by Na 2 SO 4 Dry, filter and concentrate the filtrate in vacuo to give a residue. The residue was purified by silica gel chromatography (product was obtained in hexanes / EtOAc = 10 / 1) to give Intermediate 1A (47 mg, 0.120 mmol, 55% yield) as a beige solid.

[0109] 1 H NMR (400 MHz, DMSO-d 6 )δ8.43 (s, 1H), 5.74 (dd, J=9.6, 2.5Hz, 1H), 5.29 (dd, J=9.9, 3.3Hz, 1H), 4.63-4.57 (m, 1H), 3.99 (d, J=11 .0Hz, 1H), 3.74-3.68(m, 1H), 2.23-2.17(m, 1H), 2.05-1.95(m, 2H), 1.74-1.57(m, 3H), 1.23-1.18(m, 6H).

[0110] Intermediate 1B. 5-Chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-7-amine To a solution of intermediate 1A (210 mg, 537.53 μmol, 1 eq) and BPD (409.50 mg, 1.61 mmol, 3 eq) in To1. (5 mL) was added Pd(OAc) 2 (12.07 mg, 53.75 μmol, 0.1 eq), PPh 2 t-Bu (26.05 mg, 107.51 μmol, 0,2 eq) and KOAc (158.26 mg, 1.61 mmol, 3 eq). 2 The mixture was stirred at 110°C for 4 hours under a 2% CO atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine (30 mL*2) and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was purified by flash reverse phase chromatography (0.5% FA condition, 91% to 100% ACN) to obtain Intermediate 1B (115 mg, 262.71 μmol, 48.87% yield) as a yellow solid.

[0112] 1 H NMR (400 MHz, DMSO-d 6 )δ8.36 (s, 1H), 5.76 (dd, J=2.5, 9.4Hz, 1H), 5.59 (dd, J=3.2, 9.5Hz, 1H), 4.84-4.69 (m, 1H), 4.05-3.92 (m, 1H), 3.79-3.66 (m , 1H), 2.21-2.10(m, 1H), 2.08-1.94(m, 2H), 1.78-1.68(m, 1H), 1.64-1.55(m, 2H), 1.32(s, 12H), 1.22(dd, J=2.1, 6.4Hz, 6H).

[0113] Intermediate 1C. 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazole

[0114] Step 1) 4-bromo-6-fluoro-1H-indazole

[0115] To AcOH (2371 mL) and H 2 To a solution of 3-bromo-5-fluoro-2-methylaniline (25 g, 123 mmol, 1.0 eq) in 2H2O (79 mL) was added NaNO 2 4- bromo -6- fluoro -1H- indazole (26.3 g, crude product) was obtained.

[0116] Step 2) 4-Bromo-6-fluoro-1-trityl-1H-indazole

[0117] To a solution of 4-bromo-6-fluoro-1H-indazole (26.3 g, 122 mmol, 1.0 eq) in THF (306 mL) was added NaH (6.36 g, 159 mmol, 1.3 eq) at 0°C. After 30 minutes, trityl chloride (37.5 g, 135 mmol, 1.1 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. Ice / EtOAc was added to the mixture and stirred at room temperature for 30 minutes. The mixture was extracted with EtOAc / water. The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate.The residue was solidified with DCM / hexanes to give 4-bromo-6-fluoro-1-trityl-1H-indazole (42.7 g, 93 mmol, 76% yield) as a yellow solid.

[0118] Step 3) 4-Bromo-6-fluoro-1-trityl-1H-indazole-5-carbaldehyde

[0119] To a solution of 4-bromo-6-fluoro-1-trityl-1H-indazole (500 mg, 1.093 mmol, 1.0 eq) in THF (5.5 mL) was added LDA (0.82 mL, 1.640 mmol, 1.5 eq) at -78°C. After 2 hours, methyl formate (0.101 mL, 1.640 mmol, 1.5 eq) was added at -78°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 hours. The mixture was washed with saturated NH 4 Cl was quenched, extracted with EtOAc (200 mL*3), and then 2 SO 4 Dry and concentrate. The crude 4-bromo-6-fluoro-1-trityl-1H-indazole-5-carbaldehyde was used in the next step.

[0120] Step 4) 4-Bromo-5-(difluoromethyl)-6-fluoro-1-trityl-1H-indazole

[0121] To a solution of 4-bromo-6-fluoro-1-trityl-1H-indazole-5-carbaldehyde (1062 mg, 2.188 mmol, 1,0 eq) in DCM (44 mL) was added DAST (1.445 mL, 17.63 mmol, 5.0 eq) at 0°C. The mixture was stirred at 25°C under nitrogen atmosphere for 16 hours. The reaction mixture was diluted with DCM and the resulting organic phase was washed with saturated NaHCO 3 and brine, and washed with Na 2 SO 4 Dry, filter and concentrate the filtrate in vacuo to give a residue. The crude 4-bromo-5-(difluoromethyl)-6-fluoro-1-trityl-1H-indazole was used directly in the next step.

[0122] Step 5) 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazole, Intermediate 1C

[0123] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1-trityl-1H-indazole (1110 mg, 2.188 mmol, 1.0 eq) in DCM (15 mL) was added TFA (5.1 mL, 65.6 mmol, 30 eq) at 0°C. The reaction mixture was stirred at room temperature for 5 hours. The mixture was washed with ice and saturated NaHCO 3 The reaction was quenched. The mixture was extracted with DCM and 2 SO 4Dry, filter and concentrate. The residue was purified by silica gel chromatography (product was obtained in EtOAc / hexane = 30 / 100) to give 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazole (418 mg, 1.577 mmol, 72%) as a yellow solid.

[0124] Intermediate 1D. 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine

[0125] Step 1) 4-bromo-5-(difluoromethyl)-6-fluoro-7-nitro-1H-indazole

[0126] 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazole, Intermediate 1C (133 mg, 0.502 mmol, 1.0 eq) was dissolved in H 2 SO 4 (0.627 mL). HNO was added dropwise at 0 °C. 3 (0.112mL, 2.509mmol, 5.0eq). The reaction mixture was stirred at 0°C for 2 hours. The reaction was checked by TLC. The mixture was poured into ice water and the precipitated solid was filtered. 4-bromo-5-(difluoromethyl)-6-fluoro-7-nitro-1H-indazole was obtained as an ivory solid.

[0127] Step 2) 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine, intermediate 1D

[0128] In EtOH / H 2 To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-7-nitro-1H-indazole (150 mg, 0.503 mmol, 1.0 eq) in 2H-2O (1.6 mL / 0.915 mL) were added iron (140 mg, 2.52 mmol, 5.0 eq) and NH 4 Cl (135 mg, 2.52 mmol, 5.0 eq). The reaction mixture was stirred at 80 °C for 3 h. The mixture was filtered through celite to remove iron. The filtrate was concentrated and washed with EtOAc / saturated NaHCO 3 The organic layer was extracted with Na 2 SO 4 Dry, filter and concentrate.The residue was purified by silica gel chromatography (product was obtained in EtOAc / hexane = 45 / 100) to give 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine (79 mg, 0.282 mmol, 56%) as a brown solid.

[0129] Intermediate 1E. 4-Bromo-5-(difluoromethyl)-6-fluoro-N,N-dimethyl-1H-indazol-7-amine

[0130] To the solution of intermediate 1D, i.e. 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazole-7-amine (79mg, 0.282mmol, 1.0eq) in MeOH (1.41mL), formaldehyde (0.105mL, 1.410mmol, 5.0eq), acetic acid (0.017mL, 0.282mmol, 1.0eq) and sodium cyanoborohydride (54mg, 0.846mmol, 3.0eq) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water and concentrated. Extracted with EtOAc, and filtered through Na 2 SO 4 Dry, filter and concentrate.The residue was purified by silica gel chromatography to give 4-bromo-5-(difluoromethyl)-6-fluoro-N,N-dimethyl-1H-indazol-7-amine (35 mg, 0.114 mmol, 40%) as a yellow solid.

[0131] Intermediate 1F. (4-bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)(cyclopropyl)methanol

[0132] Step 1) 4-bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0133] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazole (418 mg, 1.577 mmol, 1.0 eq) in THF (7.89 mL) was added DHP (0.433 mL, 4.73 mmol, 3.0 eq) and PPTS (79 mg, 0.315 mmol, 0.2 eq). The reaction mixture was stirred at 75 °C for 16 hours. The reaction mixture was extracted with EtOAc (50 mL*3). The combined organic layers were purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. The crude product was purified by silica gel chromatography to give 4-bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (437 mg, 1.252 mmol, 79%) as a white solid.

[0134] Step 2) (4-bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)(cyclopropyl)methanol, Intermediate 1F

[0135] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (437 mg, 1.252 mmol, 1.0 eq) in THF (25.0 mL) was added LDA (1.88 mL, 3.75 mmol, 3.0 eq) at -78 °C. The mixture was stirred at -78 °C for 2 hours, and cyclopropanecarboxaldehyde (0.187 mL, 2.503 mmol, 2.0 eq) was added at -78 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was washed with saturated NH at 0 °C. 4 Cl quenching and H 2 The mixture was extracted with EtOAc (150 mL*3) and washed with brine. The combined organic layers were purified by Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (product was obtained in EtOAc / hexane=30 / 100) to give (4-bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)(cyclopropyl)methanol (275 mg, 0.656 mmol, 52%) as a yellow solid.

[0136] Intermediate 1G. 4-Bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0137] Step 1) 4-bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-1H-indazol-7-amine

[0138] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazole-7-amine (164mg, 0.586mmol, 1.0eq) in DCM (2.93mL), acetone (0.43mL, 5.86mmol, 10.0eq) and acetic acid (0.335mL, 5.86mmol, 10.0eq) were added. The mixture was stirred at 25°C for 10 minutes. Sodium cyanoborohydride (74mg, 1.171mmol, 2.0eq) was added, and the mixture was then stirred at 25°C for 1 hour. The reaction was quenched with water and concentrated. Extracted with DCM, and filtered through Na 2 SO 4Dry, filter and concentrate. The residue was purified by silica gel chromatography (product was obtained in EtOAc / hexane = 20 / 100) to give 4-bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-1H-indazol-7-amine (154 mg, 0.478 mmol, 82%) as a yellow solid.

[0139] Step 2) 4-bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine, intermediate 1G

[0140] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-1H-indazole-7-amine (154 mg, 0.478 mmol, 1.0 eq) in THF (2.39 mL) was added DHP (0.131 mL, 1.434 mmol, 3.0 eq) and PPTS (24 mg, 0.096 mmol, 0.2 eq). The reaction mixture was stirred at 65 ° C for 16 hours. The reaction mixture was extracted with EtOAc (50 mL * 3). The combined organic layer was purified by Na 2 SO 4 The mixture was dried, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (product was obtained under EtOAc / hexane=10 / 100) to give 4-bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine (137 mg, 0.337 mmol, 71%) as a yellow oil.

[0141] Intermediate 1H. (1S,2S)-2-Fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide

[0142] Step 1) (1S,2S)-N-(6-bromoimidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0143] MsCl (4.57 mL, 58.7 mmol, 2.5 eq) and 3-methylpyridine (11.38 mL, 117 mmol, 5.0 eq) were added to a solution of 6-bromoimidazo [1,2-a] pyrazine-2-amine (5 g, 23.47 mmol, 1.0 eq) and (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (2.93 g, 28.2 mmol, 1.2 eq) in ACN (117 mL) at 0 ° C. The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was poured into ice water and a yellow solid was precipitated. The mixture was filtered, and the filter cake was washed with a small amount of water and dried in vacuo to give (1S, 2S) -N- (6-bromoimidazo [1,2-a] pyrazine-2-yl) -2-fluorocyclopropane-1-carboxamide (5.81 g, 19.42 mmol, 83%) as a yellow solid.

[0144] Step 2) (1S,2S)-2-Fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide

[0145] To a solution of (1S,2S)-N-(6-bromoimidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide (5.81 g, 19.42 mmol, 1.0 eq) in 1,4-dioxane (97 mL) were added bis(tributyltin) (24.5 mL, 48.6 mmol, 2.5 eq), Pd 2 (dba) 3 (1779 mg, 1.942 mmol, 0.1 eq), tricyclohexylphosphine (1089 mg, 3.88 mmol, 0.2 eq) and LiCl (4.94 g, 117 mmol, 6.0 eq). The reaction mixture was degassed and heated to 40 ℃ with N 2 The mixture was purged 3 times and then stirred at 110°C for 16 hours. The mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate the filtrate to give the crude product. The residue was purified by silica gel chromatography to give Intermediate 1H, (1S,2S)-2-fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide (2.81 g, 5.52 mmol, 28%) as an ivory solid.

[0146] Synthesis of compounds of formula (I) The following compounds were prepared using Synthetic Methods A to J. Illustrative synthetic examples of some compounds of the present disclosure are described below, and other compounds can be prepared by methods analogous to those described below, using different starting materials or reaction materials.

[0147] Synthesis Method A

[0148] Example 14. 6-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1, 2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; Example 18. 2-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazine-6- (Isopropyl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0149] Step 1) (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0150] To a solution of Intermediate 1H (644 mg, 1.26 mmol, 1.3 eq) and Intermediate 1A (380 mg, 0.973 mmol, 1.0 eq) in EtOH (4.86 mL) was added Ad 2 nBuP-Pd-G3 (71 mg, 0.097 mmol, 0.1 eq). The mixture was degassed and heated to 40 ℃ with N 2 Purge 3 times, then 2 The mixture was stirred at 90° C. under atmosphere for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography to give Compound 1 (400 mg, 0.754 mmol, 77.5% yield) as a yellow solid.

[0151] Step 2) (2R,3R,4S,5S,6S)-2-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0152] To a solution of compound 1 (0.4 g, 754.76 μmol, 1 eq) in DCM (40 mL) were added compound 2 (541.91 mg, 1.13 mmol, 1.5 eq) and BF 3 ·Et 2 O (214.25 mg, 1.51 mmol, 186.30 μL, 2 eq). The mixture was stirred at 20 °C for 2 h. LC-MS found the desired MS. The mixture was poured into saturated NaHCO 3 (30 mL) and extracted with DCM (30 mL). The organic layer was concentrated. 2The residue was purified by HPLC-MS / MS (5% CO, DCM: MeOH = 20: 1) to obtain Example 18 (200 mg, 244.06 μmol, 10.78% yield, 93% purity) as a white solid.

[0153] 1 H NMR (400 MHz, CDCl 3 -d) δ12.21(br s, 1H), 9.11(br s, 1H), 8.97(br s, 1H), 8.51(s, 1H1, 8.34(br s, 1H), 8.04 (s, 1H), 5.43-5.30 (m, 1H), 5.10 (d, J=9.5Hz, 1H), 5.00-4.77 (m, 2H), 4.57 (br t, J = 9.4 Hz, 1H), 4.25 (d, J = 9.9 Hz, 1H), 3.90 (s, 3H), 3.62 (td, J = 6.6, 13.2 Hz, 1H), 2.09 (s, 3H), 2.04 (s, 3H), 2.01-1.94 (m, 2H), 1.92 (s, 3H), 1.40-1.26 (m, 7H); LCMS (electrospray) m / z 762.6 (M+H) + .

[0154] Step 3) (2S,3S,4S,5R,6R)-6-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0155] To a solution of Example 18 (150 mg, 196.82 μmol, 1 eq) in THF (2 mL) was added MeOH (2 mL) / H 2 O (1 mL) and LiOH-H 2 O (104.91 mg, 2.5 mmol, 12.70 eq). The mixture was stirred at 0°C for 5 minutes. The mixture was neutralized to pH 7.0 with 1 M HCl and concentrated. The mixture was purified by prep-HPLC (column: Phenomenex C 18150*25 mm*10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 5%-35%, 8 min) to purify the mixture. After freeze drying, we obtained the desired product. Example 14 (50 mg, 79.59 μmol, 40.44% yield, 99% purity) was obtained as a white solid.

[0156] 1H NMR (400 MHz, DMSO-d 6 )δ13.62 (br s, 1H), 11.61-11.16 (m, 1H), 9.07 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 7.96 (br s, 1H), 5.05 (br s, 1H), 4.94-4.74 (m, 1H), 4.62 (br d, J=8.6Hz, 1H), 4.49 (br s, 1H), 3.69-3.63 (m, 1H), 3.61-3.54 (m, 1H), 3.24 (br d, J=9.0Hz, 2H), 2.90 (br t, J=8.8Hz, 1H), 2.62 (br s, 1H), 2.20 (br s, 1H), 1.77-1.64 (m, 1H), 1.29-1.10 (m, 8H); LCMS (electrospray) m / z 622.2 (M+H) + .

[0157] Synthesis Method B

[0158] Example 20. (1S, R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid

[0159] Step 1) Methyl (1S,2R)-2-((6-bromoimidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylate

[0160] To a solution of compound 3 (430 mg, 2.02 mmol, 1 eq) and (1R, 2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (436.36 mg, 3.03 mmol, 1.5 eq) in DCM (5 mL) was added EDCI (580.41 mg, 3.03 mmol, 1.5 eq). The mixture was stirred at 15 ° C for 16 hours. The mixture was then warmed to 30 ° C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash reverse phase chromatography (0.5% FA conditions, 25% to 33% ACN). Compound 4 (50 mg, 147.43 μmol, 7.30% yield) was obtained as a white solid.

[0161] 1 H NMR (400 MHz, DMSO-d 6)δ11.40 (s, 1H), 8.90 (d, J=1.3Hz, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 3.53 (s, 3H), 2.34 (dt, J=6 .4, 8.6Hz, 1H), 2.21 (dt, J=6.9, 8.7Hz, 1H), 1.45 (dt, J=4.3, 6.5Hz, 1H), 1.28-1.20 (m, 1H).

[0162] Step 2) (1S,2R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid

[0163] To a solution of compound 4 (50 mg, 147.43 μmol, 1 eq) and intermediate 1B (70.99 mg, 162.17 μmol, 1.1 eq) in dioxane (2 mL) was added Pd(dppf)Cl 2 (10.79 mg, 14.74 μmol, 0.1 eq) and K 2 CO 3 (61.13 mg, 442.29 μmol, 3 eq). The mixture was degassed and heated with N 2 Purge 3 times, then 2 The mixture was stirred at 90 ° C for 16 hours under atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase chromatography (0.5% FA conditions, 53% to 59% ACN). Compound 5 (20 mg, 35.97 μmol, 24.40% yield) was obtained as a yellow solid.

[0164] Step 3) (1S,2R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid

[0165] To a solution of compound 5 (20 mg, 35.97 μmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 1 mL). The mixture was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 11 min) purification and lyophilization to obtain the product. Example 20 (5 mg, 10.60 μmol, 29.46% yield, 100% purity) was obtained as a white solid.

[0166] 1 H NMR (400 MHz, DMSO-d 6 )δ13.22-13.11(m, 1H), 12.21-12.07(m, 1H), 11.49-11.33(m, 1H), 9.01(s, 1H), 8.88(s, 1H), 8.31(s, 1H), 7.94(br s, 1H), 5.19(br d, J=8.3Hz, 1H), 4.12-3.95(m, 1H), 2.31-2.24(m, 1H), 2.12-2.02(m, 1H), 1.50-1.41 (m, 1H), 1.23 (d, J=6.2Hz, 6H), 1.21-1.17 (m, 1H); LCMS (electrospray) m / z 472.2(M+H) + .

[0167] Synthesis Method C

[0168] Example 32. (1S, 2R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo [1,2-a]Pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid methyl ester

[0169] Step 1) N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)acetamide

[0170] To a solution of compound 6 (18.9 g, 74.10 mmol, 1 eq) in dioxane (200 mL) was added Pd 2 (dba) 3 (1.36g, 1.48mmol, 0.02eq), PCy 3 (831.15 mg, 2.96 mmol, 960.87 μL, 0.04 eq) and LiCl (18.85 g, 444.58 mmol, 9.11 mL, 6 eq). The mixture was degassed and heated with N 2 The mixture was heated to 110°C and then (SnBu 3 ) 2 (92.54 g, 159.53 mmol, 79.78 mL, 2.15 eq) was added dropwise to the mixture. 2The mixture was stirred at 110° C. for 48 hours under a 2% CO atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc). c =10 / 1 to 1 / 2) to obtain compound 7 (7.9 g, 16.98 mmol, 22.92% yield) as a yellow solid.

[0171] 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s, 1H), 8.97(s, 1H), 8.53-8.45(m, 1H), 8.20(s, 1H), 2.09(s, 3H), 1.65-1.49(m, 6H), 1.38-1.24(m, 6H), 1.15-1.06(m, 6H), 0.93-0.80(m, 9H).

[0172] Step 2) N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide

[0173] To a solution of compound 7 (1 g, 2.15 mmol, 1 eq) and intermediate 1A (839.77 mg, 2.15 mmol, 1 eq) in EtOH (10 mL) was added Ad 2 n-BuP-Pd-G3 (156.54 mg, 214.95 μmol, 0.1 eq). 2 The mixture was stirred at 90°C for 16 hours under a C atmosphere. The reaction mixture was quenched by adding saturated aqueous KF solution (20 mL), and the mixture was stirred at 15°C for 1 hour. EtOAc was added to the mixture. c (50 mL), then filtered. The filtrate was extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine (80 mL*2) and washed with anhydrous Na 2 SO 4 The mixture was dried, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=10 / 1 to 1 / 5). Compound 8 (250 mg, 622.16 μmol, 28.94% yield) was obtained as a yellow solid.

[0174] Step 3) 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-amine

[0175] To a solution of compound 8 (250 mg, 622.16 μmol, 1 eq) in MeOH (10 mL) was added LiOH-H2 O (130.54 mg, 3.11 mmol, 5 eq). The mixture was stirred at 70 ° C for 16 hours. The mixture was then stirred at 70 ° C for another 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash reverse phase chromatography (at H 2 The residue was purified under O / ACN conditions (0.5% FA, 21%-27% ACN) to obtain compound 9 (90 mg, 250.15 μmol, 40.21% yield) as a yellow solid.

[0176] Step 4) (1S,2R)-methyl 2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylate

[0177] To a solution of compound 9 (20 mg, 55.59 μmol, 1 eq) and (1R,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (9.61 mg, 66.71 μmol, 1.2 eq) in THF (2 mL) was added THF. 3 P (53.06 mg, 83.38 μmol, 49.59 μL, 50% purity, 1.5 eq) and Py (21.99 mg, 277.94 μmol, 22.43 μL, 5 eq). The mixture was stirred at 15 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 31%-61%, 8 min) and lyophilized to give the product. Example 32 (5.7 mg, 11.44 μmol, 20.58% yield, 97.5% purity) was obtained as a yellow solid.

[0178] 1 H NMR (400 MHz, DMSO-d 6)δ13.28-13.07(m, 1H), 11.36(s, 1H), 9.01(s, 1H), 8.87(s, 1H), 8.31(s, 1H), 7.97(br s, 1H), 5.20(br dd, J=1.9, 9.3Hz, 1H), 4.19-3.99(m, 1H), 3.54(s, 3H), 2.40-2.33(m, 1H), 2.26-2.17(m, 1H), 1.51-1.44(m, 1H), 1.27(br d, J=4.3Hz, 1H), 1.23 (d, J=6.3Hz, 6H); LCMS (electrospray) m / z 486.1 (M+H) + .

[0179] Synthesis Method D

[0180] Example 17. (1S,2S)-N-(6-(5-(difluoromethyl)-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl) Imidazolo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0181] To a solution of Intermediate 1E (35 mg, 0.114 mmol, 1.0 eq) and Intermediate 1H (70 mg, 0.136 mmol, 1.2 eq) in EtOH (0.568 mL) was added Ad 2 nBuP-Pd-G3 (9 mg, 0.011 mmol, 0.1 eq). The mixture was degassed and heated to 40 ℃ with N 2 Purge 3 times, then 2 Stir at 90° C. under atmosphere for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by prep-TLC (DCM / MeOH=10 / 1, DCM / MeOH=15 / 1) to give Example 17 (0.87 mg, 0.001945 mmol, 2%) as a yellow solid.

[0182] 1 H NMR (400 MHz, DMSO-d 6 )δ 13.58 (s, 1H), 11.38 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.08 (t, J = 52.5 Hz, 1H), 5.09-4.86 (m, 1H), 3.00-2.91 (m, 6H), 2.22-2.17 (m, 1H), 1.72-1.64 (m, 2H), 1.20-1.20 (m, 1H); LCMS (electrospray) m / z 448.10 (M+H) + .

[0183] Synthesis Method E

[0184] Example 19. (1S, 2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-5-(difluoromethyl)-6-fluoro-1H-indole oxazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0185] To a solution of Intermediate 1F (275 mg, 0.656 mmol, 1.0 eq) and Intermediate 1H (401 mg, 0.787 mmol, 1.2 eq) in EtOH (3.28 mL) was added Ad 2 nBuP-Pd-G3 (48 mg, 0.066 mmol, 0.1 eq). The mixture was degassed and heated to 40 ℃ with N 2 Purge 3 times, then 2 The mixture was stirred at 90 °C for 16 hours under atmosphere. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (product was obtained under MeOH / DCM=10 / 100) to give Example 19 (47.7 mg, 0.101 mmol, 15%) and Compound 10 (25 mg, 0.045 mmol, 7%) as yellow solids.

[0186] 1 H NMR (400 MHz, DMSO-d 6 )δ13.33(s, 1H), 11.39(s, 1H), 9.04(s, 1H), 8.97(d, J=1.6Hz, 1H), 8.39(s, 1H ), 8.15 (s, 1H), 7.10 (t, J = 52.5Hz, 1H), 5.83 (d, J = 3.8Hz, 1H), 5.07-4.86 (m, 1 H), 4.65 (q, J = 3.8 Hz, 1H), 2.23-2.16 (m, 1H), 1.75-1.65 (m, 1H), 1.46-1.41 (m, 1H), 1.22-1.19 (m, 1H), 0.62-0.54 (m, 2H), 0.44-0.31 (m, 2H); LCMS (electrospray) m / z 475.10 (M+H) + .

[0187] Synthesis Method F

[0188] Example 28. (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl) Imidazolo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0189] Step 1) (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0190] To a solution of intermediate 1G (137 mg, 0.337 mmol, 1.0 eq) and intermediate 1H (189 mg, 0.371 mmol, 1.1 eq) in EtOH (1.69 mL) was added Ad2nBuP-Pd-G3 (25 mg, 0.034 mmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times and then heated under N2. 2 The mixture was stirred at 90° C. under atmosphere for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography to give compound 11 (19 mg, 0.035 mmol, 10%) as a yellow solid.

[0191] Step 2) (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0192] To a solution of compound 11 (19 mg, 0.035 mmol, 1.0 eq) in EtOAc (0.17 mL) was added 1N HCl in EtOAc solution (0.871 mL, 0.871 mmol, 25.0 eq). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was washed with saturated NaHCO 3 Quenched with EtOAc c (20 mL). Use saturated NaHCO 3 The combined organic layers were washed with N a2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. The crude product was purified twice by prep-TLC (MC:MeOH=20:1, 10:1) to give Example 28 as a yellow solid.

[0193] 1 H NMR (400 MHz, DMSO-d 6 )δ13.54-13.09 (s, 1H), 11.52-11.23 (s, 1H), 9.07-8.91 (s, 1H), 8.91-8.80 (s, 1H), 8.49-8.29 (s, 1H), 7.38-6.84 (t, 1H), 5.19-4.74 (m, 2H), 4.26-3.87 (m, 1H), 2.28-2.10 (m, 1H), 1.80-1.59 (m, 1H), 1.29-1.20 (m, 7H); LCMS (electrospray) m / z 462.10 (M+H) +

[0194] Synthesis Method G

[0195] Example 146. (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0196] Step 1) (S,E)-N-ethylidene-2-methylpropane-2-sulfenamide

[0197] To a solution of (S)-2-methylpropane-2-sulfenamide (3.00 g, 24.75 mmol, 1 eq) and acetaldehyde (9.81 g, 222.77 mmol, 12.50 mL, 9 eq) in DCM (30 mL) were added PPTS (622.03 mg, 2.48 mmol, 0.1 eq) and MgSO 4 (8.94 g, 74.26 mmol, 3 eq). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 1: 0 to 10: 1). Compound 13 (2.9 g, 19.70 mmol, 79.57% yield) was obtained as a colorless liquid.

[0198] Step 2) (S)-N-((1S)-1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)ethyl)-2-methylpropane-2-sulfenamide

[0199] To a solution of compound 14 (1 g, 3.00 mmol, 1 eq) in THF (20 mL) was added LDA (2 M, 2.25 mL, 1.5 eq) at -78 °C under argon atmosphere. The reaction was stirred at -78 °C for 30 minutes, then compound 13 (662.57 mg, 4.50 mmol, 62.60 μL, 1.5 eq) in THF (3 mL) was added. The reaction was warmed to 20 °C and maintained for 2 hours. NH 4 Cl (50 mL) aqueous solution was added dropwise to the reaction mixture. The aqueous phase was extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine (20 mL*2) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Chromatography on silica gel (petroleum ether: EtOAc c =100:1 to 10:1) to purify the residue to obtain the product. TLC (petroleum ether: EtOAc c=2:1). Compound 15 (1.1 g, 2.29 mmol, 76.26% yield) was obtained as a yellow oil.

[0200] Step 3) (1S,2S)-N-(6-(7-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0201] To a solution of compound 15 (550.00 mg, 1.14 mmol, 1 eq) in EtOH (20 mL) were added intermediate 1H (582.51 mg, 1.14 mmol, 1 eq) and Ad 2 nBuP-Pd-G3 (83.31 mg, 114.39 μmol, 0.1 eq). The suspension was degassed and heated to 40 ℃ with N 2 The reaction mixture was then purged for 1 min under N 2 The mixture was stirred at 90°C for 15 hours. 5 mL of saturated aqueous KF solution was added to quench the reaction mixture. The mixture was quenched by water (20 mL) and extracted with EtOAc (20 mL*2). The combined organic layers were washed with 20 mL of brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a residue. 2 The residue was purified by HPLC-MS / MS (0.05% FA, 55%-60%) to give the product. A mixture of Compound 16 and Example 132 (350 mg, 564.42 μmol, 49.34% yield) was obtained as a yellow solid.

[0202] 150 mg of the mixture was taken and purified by prep-HPLC (column: Unisil 3-100C18 Ultra150*50mm*3um; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 7 min) to give the product. Example 132 (10.6 mg, 19.46 μmol, 8.04% yield, 98.4% purity) was obtained as a light yellow solid. Compound 16 (60 mg, 96.76 μmol, 40.00% yield) was obtained as a light yellow solid.

[0203] 1 H NMR (400 MHz, DMSO-d 6)δ13.40(br s, 1H), 11.47-11.35(m, 1H), 9.07(br s, 1H), 9.02 (s, 1H), 8.44-8.36 (m, 1H), 8.12-8.02 (m, 1H), 5.62-5.47 (m, 1H), 5.24-5.12 (m, 1H), 5.10-4.85 (m, 1H), 2.21 (br d, J=4.3Hz, 1H), 1.78-1.74 (m, 1H), 1.71 (br d, J=6.7Hz, 3H), 1.24-1.20 (m, 1H), 1.06 (br s, 9H); LCMS (electrospray) m / z 536.1 (M+H) + .

[0204] Step 4) (1S,2S)-N-(6-(7-((S)-1-aminoethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0205] To a solution of compound 16 and Example 132 (130 mg, 209.64 μmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 52.41 μL, 1 eq). The reaction was stirred at 20 °C for 1 hour. The reaction mixture was concentrated. The residue was purified by reverse flash chromatography (MeCN / H 2 The residue was purified by HPLC-MS / MS (HPLC-MS / MS), and the product was obtained by HPLC-MS / MS (HPLC-MS / MS). Compound 17 (83 mg, 152.06 μmol, 72.53% yield, TFA) was obtained as a light yellow solid.

[0206] Step 5) (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0207] To a solution of compound 17 (83 mg, 177.24 μmol, 1 eq, HCl) and TEA (53.81 mg, 531.73 μmol, 74.01 μL, 3 eq) in DCM (1 mL) was added TFAA (55.84 mg, 265.86 μmol, 36.98 μL, 1.5 eq). The reaction mixture was stirred at 20 ° C for 10 minutes. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex lunaC18150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 10 min) to give the product. Example 146 (50.2 mg, 95.11 μmol, 53.66% yield, 100% purity) was obtained as a white solid.

[0208] 1 H NMR (400 MHz, DMSO-d 6 )δ13.52(s, 1H), 11.41(s, 1H), 9.98(br d, J=6.2Hz, 1H), 908 (d, J=0.6Hz, 1H), 9.02 (d, J=1.3Hz, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 5.64-5.52 (m, 1H), 5.0 9-4.86 (m, 1H), 2.25-2.15 (m, 1H), 1.70 (d, J=7.2Hz, 3H), 1.69-1.64 (m, 1H), 1.26-1.16 (m, 1H); LCMS (electrospray) m / z 528.2(M+H) + .

[0209] Synthesis Method H

[0210] Example 91. 5-Chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazolo[1,2-a]pyrazin-6-yl)-1H-indazol-7-amine

[0211] Step 1) N-[6-[5-chloro-6-fluoro-7-(isopropylamino)-2-tetrahydropyran-2-yl-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2,2,2-trifluoro-acetamide

[0212] In dioxane (50 mL) and H 2 To a solution of intermediate 1B (3.5 g, 8.00 mmol, 1 eq) and compound 18 (2.72 g, 8.80 mmol, 1.1 eq) in 2% O (5 mL) was added Pd(dppf)Cl 2(585.04 mg, 799.56 μmol, 0.1 eq) and K 3 PO 4 (5.09 g, 23.99 mmol, 3 eq). 2 The mixture was stirred at 80°C for 6 hours under a 2% atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (80 mL) and extracted with EtOAc (100 mL*2). The combined organic layers were washed with brine (100 mL*2) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=10 / 1 to 1 / 1). Compound 19 (2 g, 3.70 mmol, 46.33% yield) was obtained as a red solid.

[0213] Step 2) 6-[5-chloro-6-fluoro-7-(isopropylamino)-2-tetrahydropyran-2-yl-indazol-4-yl]imidazo[1,2-a]pyrazin-2-amine

[0214] To MeOH (20 mL) and H 2 To a solution of compound 19 (2.1 g, 3.89 mmol, 1 eq) in 20 (6 mL) was added K 2 CO 3 (2.69 g, 19.45 mmol, 5 eq). The mixture was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase chromatography [water (0.5% FA) / ACN conditions, 51% to 57% ACN]. Compound 20 (1.2 g, 2.70 mmol, 69.50% yield) was obtained as a yellow solid.

[0215] Step 3) 5-Chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazolo[1,2-a]pyrazin-6-yl)-2-tetrahydropyran-2-yl-indazol-7-amine

[0216] DIPEA (58.23 mg, 450.55 μmol, 78.48 μL, 2eq) and compound 21 (78.37 mg, 337.91 μmol, 42.36 μL, 1.5eq) were added to a solution of compound 20 (100.00 mg, 225.27 μmol, 1 eq) in DMA (1 mL). The reaction mixture was stirred at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse flash chromatography (ACN, water (FA0.05%)) to give compound 22 (30 mg, 58.37 μmol, 25.91% yield) as a yellow solid.

[0217] LCMS (electrospray) m / z 514.1 (M+H) + .

[0218] Step 4) 5-chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazolo[1,2-a]pyrazin-6-yl)-1H-indazol-7-amine

[0219] Compound 22 (30 mg, 58.37 μmol, 1 eq) was dissolved in HCl / dioxane (4 M, 2 mL, 137.06 eq). The reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Unisil 3-100C18Ultra 150*50mm*3um; mobile phase: [water (FA)-ACN]; B%: 33%-63%, 7 min) and lyophilized to give Example 91 (11.2 mg, 25.98 μmol, 44.52% yield) as a yellow solid.

[0220] 1 H NMR (400 MHz, DMSO-d 6 )δ13.15(s, 1H), 8.85(s, 1H), 8.72(s, 1H), 7.92(s, 1H), 7.57(s, 1H), 5.21-5.10(m, 1H), 4. 10-3.98 (m, 1H), 3.80-3.72 (m, 4H), 3.31-3.24 (m, 4H), 1.23 (d, J=6.3Hz, 6H); LCMS (electrospray) m / z 430.1(M+H) + .

[0221] Synthesis Method I

[0222] Example 101. 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyrazin-2-amine

[0223] Step 1) 6-[5-chloro-6-fluoro-7-(isopropylamino)-2-tetrahydropyran-2-yl-indazol-4-yl]-N-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-2-amine

[0224] Compound 23 (38.79 mg, 450.55 μmol, 2 eq) and compound 20 (100 mg, 225.27 μmol, 1 eq) and AcOH (1.35 mg, 22.53 μmol, 1.29 μL, 0.1 eq) were dissolved in MeOH (2 mL). After 0.5 h, NaBH 3 CN (28.31 mg, 450.55 μmol, 2 eq) was added to the mixture. The reaction mixture was stirred at 25 °C for 15.5 hours. The reaction mixture was quenched with 5 mL of water and extracted with EtOAc (10 mL*3). The combined organic phase was washed with saturated brine (10 mL*2) and purified by Na 2 SO 4 Drying, filtration and concentration of the filtrate under reduced pressure gave compound 24 (100 mg, 194.55 μmol, 86.36% yield) as a yellow solid.

[0225] Step 2) 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyrazin-2-amine

[0226] Compound 24 (100 mg, 194.55 μmol, 1 eq) was dissolved in HCl / dioxane (4 M, 2 mL, 41.12 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [water (FA)-ACN]; B%: 27%-57%, 7 min) to give Example 101 (23.0 mg, 53.26 μmol, 27.38% yield) as a light yellow solid.

[0227] 1 H NMR (400 MHz, DMSO-d 6 )δ13.29-12.99 (m, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 7.93 (brd, J = 1.9Hz, 1H), 7.33 (s, 1H), 6.47 (d, J = 6.6Hz, 1H), 5.15 (br d, J=9.0Hz, 1H), 4.21-4.13 (m, 1H), 3.93-3.81 (m, 2H), 3.78-3.70 (m, 1H), 3.60 (dd, J=3. 8, 8.7Hz, 1H), 2.24-2.14 (m, 1H), 1.91-1.80 (m, 1H), 1.23 (d, J=6.3Hz, 6H); LCMS (electrospray) m / z 430.2(M+H)+ .

[0228] Synthesis Method J

[0229] Step 1) HCl / MeOH (4.00M, 86.8mL, 1.00eq) was added to a solution of compound 1 (184g, 347mmol, 1.00eq) in MeOH (1.00L). The mixture was stirred at 15°C for 6 hours. The reactants were concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 (250*80mm*15um); mobile phase: [water (0.05% HCl)-CAN]; B%: 35%-60%, 35min). The residue was purified by saturated NaHHCO 3 The eluent was basified with aqueous solution and the mixture was concentrated in vacuo. c The combined organic layer was separated, washed with brine (5.00 L), and purified by N a2 SO 4 The product (160 g, 358 mmol, 1.00 eq) was dried. HCl / MeOH (4.00 M, 800 mL, 8.92 eq) was added to a solution of the product (160 g, 358 mmol, 1.00 eq) in MeOH (1000 mL). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give compound 25 (152 g, 311 mmol, 86.6% yield, 98.7% purity, HCl) as a yellow solid.

[0230] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.58 (s, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 8.50 (s, 1H), 8.00 (s, 2H), 4.98 (dtd, J = 3.7, 6.8, 66.0 Hz, 1H), 4.14 (dq, J = 4.0, 6.4 Hz, 1H), 2.23-2.20 (m, 1H), 1.72-1.68 (m, 1H), 1.26 (d, J = 6.4 Hz, 6H), 1.23-1.21 (m, 1H); LCMS (electrospray) m / z = 446.1 (M+H) + .

[0231] To a solution of compound 25 (120 mg, 0.269 mmol, 1.0 eq) in 1,4-dioxane (1.35 mL) was added Pd(dpPf)Cl at 25 °C. 2(98 mg, 0.135 mmol, 0.5 eq) and sodium tert-butoxide (38.8 mg, 0.404 mmol, 1.5 eq). The reaction mixture was degassed under N2 conditions and heated to 160 ° C in a microwave reactor for 3 hours. After cooling, the reaction mixture was diluted with saturated NH4C1, extracted with EtOAc (20 mL * 3), and then filtered through MgSO 4 Dried and concentrated. The residue was purified by silica gel chromatography (DCM / methanol=20 / 1) to give Example 165 (4.8 mg, 0.012 mmol, 4.33%) as a yellow solid.

[0232] 1 H NMR (500 MHz, DMSO-d 6 )δ13.07 (s, 1H), 11.33 (s, 1H), 9.17 (s, 1H), 9.01 (s, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.55 (d, J = 14.2 Hz, 2H), 5.11-4.76 (m, 2H), 4.00 (d, J = 11.3 Hz, 1H), 2.19 (t, J = 7.2 Hz, 1H), 1.70 (dd, J = 23.2, 3.8 Hz, 1H), 1.22 (d, J = 6.3 Hz, 7H); LCMS (electrospray) m / z 412.15 (M+H) + .

[0233] Table 1 below shows the compounds of the Examples as well as the general synthetic methods used to prepare the compounds and characterization data.

[0234] Table 1. Compounds of Examples

[0235] Evaluation of compounds

[0236] HPK1 kinase assay

[0237] ADP-Glo ​​by Promega TM Kinase assay was used to measure HPK1 kinase activity. In this assay, 5 ng of recombinant human HPK1 (signalchem) was mixed with 5 μL of compound (0.5% DMSO), 5 μL of MBP (0.5 μg / μl) and 5 μL of ATP (25 μM) in buffer (40 mM Tris, 7.5; 20 mM MgCl 2; 0.1mg / ml BSA; 50μM DTT. ). The analysis was started by incubating the reaction mixture in a 96-well plate at 30°C for 40 minutes. After incubation, 25μL ADP-Glo ​​reagent was added and the reaction was incubated at room temperature for 40 minutes to stop the reaction and degrade residual ATP. The ADP product was then converted to ATP by adding 50μL of detection reagent to each well. After 30 minutes of room temperature incubation, luminescence was detected using a Molecular device I3X plate reader. IC was calculated from a series of inhibition percentage values ​​determined over a range of inhibitor concentrations using GraphPad Prism 7 software and the software program implemented in SigmaPlot 13.0. 50 value.

[0238] Table 2 shows the IC values ​​of the compounds of the present invention. 50 Values, where + represents >1000 nM, ++ represents 501 nM-1000 nM, +++ represents 101 nM-500 nM, and ++++ represents <100 nM.

[0239] Table 2. In vitro activity data against HPK1

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof: in: A is -NH-C(O)-L-R 1 、-NH-R 1 or -R 1 ; L is a bond, -NH-, -O- or -CH2-; R 1 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, hydroxyl, -CD2OH, -CN, -NO2, haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O)2R 9 、-S(O)(=NH)R 10 、-S(O)2NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O)2R 9 、-N(R 6 )S(O)2NR 10 R 11 or -P(O)R 12 R 13 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally independently selected from R 7 substituted with one or more substituents; R 2 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, hydroxyl, -CD2OH, -CN, -NO2, haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O)2R 9 、-S(O)(=NH)R 10 、-S(O)2NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O)2R 9 、-N(R 6 )S(O)2NR 10 R 11 or -P(O)R 12 R 13 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO2, -NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 the groups formed; R 3 -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -CH2OH, -CD2OH, -OH, -CN, -NO2, haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O)2R 9 、-S(O)(=NH)R 10 、-S(O)2NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O)2R 9 、-N(R 6 )S(O)2NR 10 R 11 or -P(O)R 12 R 13 ; M is a bond, -O-, -S-, -CHR 6 -or-NR 6 -; R 4 is -H, -D, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-S(O)2R 9 、-S(O)(=NH)R 10 、-S(O)2NR 10 R 11 or -P(O)R 12 R 13 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD3, -NO2, -NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-NR 10 S(O)2R 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 the groups formed; R 5 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, hydroxyl, -CH2OH, -CD2OH, -CN or haloalkyl; R 6 -H, C 1-6 Alkyl or cycloalkyl; R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, oxo, cyano, hydroxyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O)2R 9 、-S(O)(=NH)R 10 、-S(O)2NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O)2R 9 、-N(R 6 )S(O)2NR 10 R 11 or -P(O)R 12 R 13 ; R 9 is -H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; Each R 10 and R 11 is independently -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, or R 10 and R 11 Together with the nitrogen atom to which they are attached, they form a 4- to 12-membered heterocyclic group, which is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO2, -NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 the groups formed; Each R 12 and R 13 are independently alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic, or R 12 and R 13 Together with the phosphorus atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO2, -NR 10 R 11 、-NR 10 C(=O)R 9 、-NR 10 C(=O)NR 10 R 11 、-NR 10 C(=O)OR 9 、-OR 9 、-C(=O)R 9 、-C(=O)OR 9 、-C(=O)NR 10 R 11 、-OC(=O)R 9 、-OC(=O)OR 9 and -OC(=O)NR 10 R 11 the group formed; and Each R a and R c are independently -H, -D, halogen, haloalkyl, -CN, -OR 9 or -NR 10 R 11 .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R 2 and R 3 are independently -H, -D, halogen, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3 or -CN; R 5 is -H, halogen or alkyl; Each R a and R c are independently -H, halogen or alkyl; M is a bond, -O-, -CHR 6 -or-NR 6 -;and R 4 -H, -D, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -C(O)R 9 、-NHC(O)R 9 、-C(O)NR 10 R 11 、-S(O)2R 9 、-S(O)(=NH)R 10 or -S(O)2NR 10 R 11 , where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -C(O)CH3, -CN, -CD3, -NR 10 R 11 、-NR 10 S(O)2R 9 and-NR 10 C(=O)R 9 The group composed of.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxy, halogen, -COOH, -C(O)OCH3 or -CN; R 3 is halogen or alkyl; and MR 4 Selected from the group consisting of:

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II): in, R 1 is a cyclopropyl group, which is optionally substituted by one or two R 7 replace.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 for 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(methoxy)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-ethoxyethyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(1-methoxypropan-2-yl)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1,1-difluoropropan-2-yl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-7-(tetrahydrofuran-3-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-7-(3-oxocyclopent-1-en-1-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(1-hydroxypropan-2-yl)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(2-hydroxycyclopentyl)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-7-(1-(methylamino)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopent-1-en-1-yl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(dimethylamino)ethyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(dimethylamino)propan-2-yl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; 6-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(3-hydroxycyclopent-1-en-1-yl)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(2-methoxycyclopentyl)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate; (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(amino(cyclopropyl)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminopropan-2-yl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminoethyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-2-Fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2R)-2-Fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1R,2S)-2-Fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-(hydroxymethyl)-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(amino(cyclopropyl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyclopropyl)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(amino(cyclopropyl)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminoethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(1-hydroxyethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-7-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyclopropyl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminoethyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyclopropyl)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide formate; 6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-7-(isopropylamino)-1H-indazole-5-carboxylic acid methyl ester; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropanecarboxamide formate; (1S,2S)-N-(6-(7-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropanecarboxamide formate; (1S,2S)-N-(6-(7-(cyclopropanecarboxamido(cyclopropyl)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(cyclopropanecarboxamido)ethyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-7-(1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-cyano-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; 6-Fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-7-(isopropylamino)-1H-indazole-5-carboxylic acid; (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(1-formamidoethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(cyclopropanecarboxamido)ethyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropanecarboxamido(cyclopropyl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(1-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-((tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-((tert-butylsulfinyl)amino)ethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(1-formamidoethyl)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(((tert-butylsulfinyl)amino)(cyclopropyl)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminopropan-2-yl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide formate; (1S,2S)-N-(6-(7-(1-acetamidopropan-2-yl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(2,2,2-trifluoroacetamido)methyl)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(formamido)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(1-hydroxyethyl)-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((R)-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1-acetylazetidin-3-yl)oxy)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(azetidin-3-yloxy)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide formate; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; and (1S,2S)-2-Fluoro-N-(6-(6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide.

7. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (1S,2R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylic acid; (1R,2S)-N1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-N2,N2-diethylcyclopropane-1,2-dicarboxamide; (1R,2S)-N1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-N2-ethylcyclopropane-1,2-dicarboxamide; (1S,2R)-methyl 2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylate; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(chloromethyl)cyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; (1R,2S)-N1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1,2-dicarboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide; Methyl (1-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropyl)carbamate; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-cyanocyclopropane-1-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-1-fluorocyclopropane-1-carboxamide; 1-amino-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(fluoromethyl)cyclopropane-1-carboxamide; (1R,2S)-N-(6-(6-fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; (1R,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; (1R,2S)-2-cyano-N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide; N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide; and (1R,2S)-2-Cyano-N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide.

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (III): in, R 1 Alkyl, alkenyl, alkynyl, halogen, hydroxyl, -CD2OH, -CN, -NO2, haloalkyl, -C(O)R 9 、-C(O)OR 9 、-C(O)NR 10 R 11 、-OR 9 、-OC(O)R 9 、-OC(O)NR 10 R 11 、-SR 9 、-S(O)R 9 、-S(O)2R 9 、-S(O)(=NH)R 10 、-S(O)2NR 10 R 11 、-NR 10 R 11 、-N(R 6 )NR 10 R 11 、-N(R 6 )OR 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)R 9 、-N(R 6 )C(O)OR 9 、-N(R 6 )C(O)NR 10 R 11 、-N(R 6 )S(O)2R 9 、-N(R 6 )S(O)2NR 10 R 11 or -P(O)R 12 R 13 , wherein alkyl, alkenyl or alkynyl is optionally independently selected from R 7 is substituted with one or more substituents.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, methyl, ethyl, ethyl, butyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, dimethylaminomethyl, methylthiomethyl, methylamino, ethylamino, isopropylamino, methoxy, ethoxy, isopropoxy, 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)propanamide; N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-(trifluoromethyl)-2H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2,2,2-trifluoroacetamide; (S)-2-amino-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acrylamide; 2-amino-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)isobutyramide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)pivalamide; N-(6-(6-fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; Isopropyl (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamate; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(methylthio)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-N-methylacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(dimethylamino)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(methylthio)acrylamide; (R)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(dimethylamino)acrylamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-methoxyacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)butanamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carboxamide; Methyl (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamate; Ethyl (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamate; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)pentanamide; 1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-3-ethylurea; 1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-3-methylurea; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2,2-difluoroacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-hydroxyacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-3-hydroxypropanamide; N-(6-(7-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(7-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; (S)-N-(1-(4-(2-acetamidoimidazo[1,2-a]pyrazin-6-yl)-5-chloro-6-fluoro-1H-indazol-7-yl)ethyl)-2,2,2-trifluoroacetamide; (R)-N-(1-(4-(2-acetamidoimidazo[1,2-a]pyrazin-6-yl)-5-chloro-6-fluoro-1H-indazol-7-yl)ethyl)-2,2,2-trifluoroacetamide; (S)-N-(6-(5-chloro-6-fluoro-7-(1-formamidoethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(7-((1-acetylazetidin-3-yl)oxy)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(7-(azetidin-3-yloxy)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide formate; N-(6-(5-chloro-6-fluoro-7-((1-(2-hydroxyacetyl)azetidin-3-yl)oxy)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((1-propionylazetidin-3-yl)oxy)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxyazetidin-1-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxypyrrolidin-1-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-7-(cyclopropyl(hydroxy)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)propanamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(1-(3-hydroxyazetidin-1-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide; N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)propanamide; and N-(6-(5-chloro-6-fluoro-7-(1-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide.

12. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IV): in, R 1 is a cycloalkyl, aryl, heteroaryl or heterocyclic group, wherein the cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally independently selected from R 7 is substituted with one or more substituents.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)benzamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)picolinamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclobutanecarboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)pyrrolidine-3-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)morpholine-4-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(pyridin-3-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-morpholineacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-4-methylpiperazine-1-carboxamide formate; N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(pyridin-3-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)azetidine-2-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)tetrahydrofuran-2-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-(oxetan-3-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)piperazine-1-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-1-methylpiperidine-4-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)pyrrolidine-1-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)tetrahydrofuran-3-carboxamide; (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamic acid cyclobutyl ester formate; and N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)oxetane-3-carboxamide.

15. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (V):

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-1,5-dihydro-2H-pyrrol-2-one; and 5-Chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazolo[1,2-a]pyrazin-6-yl)-1H-indazol-7-amine.

18. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (VI):

19. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from the group consisting of:

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein the compound is 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyrazin-2-amine.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

22. A method of treating a subject having a disease or condition associated with modulation of HPK1, the method comprising: A therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

23. The method according to claim 22, wherein: The disease is cancer, and wherein the compound according to any one of claims 1-20 is administered together with an anti-PD-1 agent, an anti-PD-L1 agent or an anti-CTLA4 agent.

24. The method according to claim 22, wherein: The disease is cancer, metastasis, inflammation or an autoimmune disease.

25. The method according to claim 24, wherein: The cancer is selected from the group consisting of carcinoma, melanoma, blastoma, sarcoma, lymphoma and leukemia, including but not limited to bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma and Wilms' tumor (Wilm's tumor).

Images