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

Abstract

The present disclosure provides compounds of formula (I) or pharma- ceutically acceptable salts thereof, compositions comprising the compounds, methods of using the compounds for the treatment of various disorders associated with HPK1, and methods of preparing these compounds. TIFF2025510271000109.tif44170

Description

[Technical field]

[0001] The present disclosure is directed to inhibitors of hematopoietic progenitor kinase 1 (HPK1), pharmaceutical compositions containing the inhibitors, methods of using the inhibitors for the treatment of various disorders associated with HPK1, and methods of preparing these compounds. [Background technology]

[0002] Immunotherapy is a treatment that uses the human body's own immune system to help fight cancer and other disorders. This relatively new approach has achieved notable clinical success in the treatment of various tumor types in recent years, especially with immune checkpoint inhibitors and chimeric antigen T cell therapy treatments. Most investigated checkpoint inhibitors, including CTLA4, PD-1, or PD-L1 inhibitors, have demonstrated significant antitumor activity by overcoming immune suppressive mechanisms at the tumor site.

[0003] Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a serine / threonine kinase and a member of MAP4K. HPK1 is prominently expressed in a subset of hematopoietic cell lineages. HPK1 has been newly identified as an essential negative regulator in the activation of T lymphocytes and dendritic cells. Besides the important role for the kinase activity of HPK1 in anti-cancer immunity as a new intracellular checkpoint molecule, the potential benefits of combination therapy with current checkpoint regimens have been recently demonstrated. HPK1 inhibition is expected to have dual functions: 1. Prolonged activation of T cells; 2. Enhancement of APC function by dendritic cells. This dual targeting may work synergistically for an efficient immune response in the tumor microenvironment. Therefore, HPK1 has been validated as a novel target for anti-cancer immunotherapy. Examples of cancers treatable using the compounds of the present disclosure include, but are not limited to, all forms of carcinoma, melanoma, blastoma, sarcoma, lymphoma and leukemia, including, but not limited to, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney and thyroid cancer, acute lymphocytic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma, and nephroblastoma (Wilm's tumor).

[0004] Inhibition of HPK1 using small molecule inhibitors has potential for the treatment of cancer and other disorders [Hernandez, S., et. al., (2018) Cell Reports 25, 80-94]. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure provides novel indazole compounds and pharma- ceutically acceptable salts as effective HPK1 inhibitors and dual activators of T cells and dendritic cells. [Means for solving the problem]

[0006] One embodiment of the present disclosure is a compound represented by formula (I):

[0007] [ka] or a pharma- ceutical acceptable salt, hydrate or solvate thereof, wherein A, R 2 , R 3 , R 4 , R 5 , R a , R c and M is as defined in the detailed description.

[0008] In another embodiment, there is provided a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or diluent and a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0009] In yet another embodiment, there is provided a method of treating a subject having a disease or disorder associated with modulation of HPK1, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.

[0011] definition

[0012] Common terms used in this disclosure are defined herein for the sake of clarity.

[0013] This specification uses the terms "substituents," "radicals," "groups," "moieties," and "fragments" interchangeably.

[0014] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbonyl group having at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond. In one embodiment, an alkenyl has 2 to 12 carbon atoms. In some embodiments, an alkenyl has C2 to C6. 10 alkenyl group or a C2-C6 alkenyl group. Examples of alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0015] As used herein, the term "alkoxy" is RO-, where R is alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy and propoxy.

[0016] As used herein, the term "alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, and ethoxyethyl.

[0017] As used herein, the term "alkoxycarbonyl" refers to ROC(O)-, where R is an alkyl group as defined herein. In various embodiments, R is a C1-C 10 It is an alkyl group or a C1 to C6 alkyl group.

[0018] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbonyl group. In one embodiment, an alkyl has 1 to 12 carbon atoms. In some embodiments, an alkyl has C1 to C6 10An alkyl group or a C1-C6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" means an alkyl group having 1 to 4 carbon atoms.

[0019] As used herein, when the term "C1-C6" is used, it means that the number of carbon atoms is 1 to 6. For example, C1-C6 alkyl means that the number of carbon atoms is any integer from 1 to 6 alkyl.

[0020] 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)2amino" is R2N-, where the R groups are alkyl as defined herein and may be the same or different. In various embodiments, R is a C1-C 10 It is an alkyl group or a C1-C6 alkyl group. Examples of the alkylamino group include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and methylethylamino.

[0021] As used herein, the term "alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, where alkylamino is as defined herein. Examples of alkylaminoalkyl groups include methylaminomethyl and ethylaminomethyl.

[0022] As used herein, the term "alkynyl" refers to a straight or branched carbon chain group having at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. In one embodiment, an alkynyl has 2 to 12 carbon atoms. In some embodiments, an alkynyl has C2 to C6. 10It is an alkynyl group or a C2-C6 alkynyl group. Examples of alkynyl groups include acetylene (-C≡CH) and propargyl (-CH2C≡CH).

[0023] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring of up to seven atoms in each ring, in which at least one ring is aromatic, or an aromatic ring system of 5 to 14 carbon atoms, including a carbocyclic aromatic group fused to a 5- or 6-membered cycloalkyl group. Representative examples of aryl groups include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and indanyl. Carbocyclic aromatic groups can be unsubstituted or optionally substituted.

[0024] As used herein, the term "cycloalkyl" refers to a hydrocarbyl group that contains at least one saturated or partially unsaturated ring structure and is bonded through a ring carbon. In various embodiments, it is a saturated or partially unsaturated C-C 12 It refers to a cyclic moiety, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. "Cycloalkyloxy" is RO-, where R is cycloalkyl.

[0025] As used herein, the terms "halogen" and "halo" refer to chloro (-Cl), bromo (-Br), fluoro (-F) or iodo (-I). "Haloalkoxy" refers to an alkoxy group substituted with one or more halo groups, and examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2 and -OCH2F. "Haloalkoxyalkyl" refers to an alkyl moiety substituted with a haloalkoxy group, where haloalkoxy is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl and trifluoromethoxyethyl. "Haloalkyl" refers to an alkyl moiety substituted with one or more halo groups. Examples of haloalkyl groups include -CF3, -CHF2, and -CH2F.

[0026] As used herein, the term "heteroalkyl" refers to a straight-chain or branched alkyl group having 2 to 14 carbons (in some embodiments, 2 to 10 carbons) in the chain, in which one or more of the carbons are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.

[0027] As used herein, the term "heterocyclyl" includes heteroaryl, as defined below, and refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic group of 2 to 14 ring carbon atoms and, in addition to the ring carbon atoms, 1 to 4 heteroatoms selected from P, N, O, and S. In various embodiments, a heterocyclic group is attached to another moiety through a carbon or through a heteroatom and may be substituted on the carbon or heteroatom.Examples of heterocyclyl are azetidinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthapyridinyl (naphthalene pyridinyl, naphthapyrid ... hthpyridinyl), oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiazolyl, thiazolyl, nyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof. "Heterocyclyloxy" is RO-, where R is heterocyclyl. "Heterocyclylthio" is RS-, where R is heterocyclyl.

[0028] As used herein, the term "3- or 4-membered heterocyclyl" refers to a monocyclic ring having 3 or 4 ring atoms, in which 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 heterocyclyls include aziridinyl, 2H-azirinyl, oxiranyl, thiiranyl, azetidinyl, 2,3-dihyroazetyl, azetyl, 1,2-dihydroazetyl, 1,3-dihydroazetyl, 1,4-dihydroazetyl, 1,5-dihydroazetyl, 1,6-dihydroazetyl, 1,7-dihydroazetyl, 1,8-dihydroazetyl, 1,9-dihydroazetyl, 1,1-dihydro ... , 3-diazetidinyl, oxetanyl, 2H-oxetyl, thietanyl, and 2H-thiethyl.

[0029] As used herein, the term "heteroaryl" refers to monocyclic, bicyclic, or tricyclic rings having up to seven atoms in each ring, where at least one ring is aromatic and contains from 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, pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazoyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl, and pyrazinyl. The binding of heteroaryl can occur through an aromatic ring, or, if heteroaryl is bicyclic or tricyclic and one of the rings is not aromatic or does not contain a heteroatom, it can occur through a non-aromatic ring or a ring that does not contain a heteroatom. "Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. "Heteroaryloxy" is RO-, where R is a heteroaryl.

[0030] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxyl group (-OH), where alkoxy is as defined herein. An example of a hydroxyalkoxy is hydroxyethoxy.

[0031] As used herein, the term "hydroxyalkyl" refers to a linear or branched monovalent C-C alkyl group substituted with at least one hydroxy group. 10 Refers to a hydrocarbon group; examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0032] As used herein, the term "pharmaceutical acceptable" means suitable for use in pharmaceutical preparations, generally considered safe for such use, officially approved by a national or state government regulatory agency for such use, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0033] As used herein, the term "pharmaceutical acceptable carrier" refers to a diluent, adjuvant, excipient, or carrier or other ingredient that is pharma- ceutically acceptable and with which a compound of the invention is administered.

[0034] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutical 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 with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Examples of acid addition salts formed with organic acids are e.g. 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, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic) acid, 3-hydroxy-4-methyl-2-naphthoic acid, 4-methyl-5-methyl-1 ... 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.

[0035] As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, aryl, heteroaryl, heterocycle, or cycloalkyl) in which at least one hydrogen atom of the substituted moiety is replaced with a substituent. In one embodiment, each carbon atom of the substituted group is substituted with no more than two substituents. In another embodiment, each carbon atom of the substituted group is substituted with no more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced with oxygen attached to the carbon through a double bond. Unless otherwise defined, the substituents are halo, hydroxyl, (lower) alkyl, haloalkyl, mono- or di-alkylamino, aryl, heterocycle, -NO2, 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 SO2R 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 SO2R b , -PO3R a , -PO(OR a )(OR b ), -SO2R a , -S(O)R a , -SO(N)R a (e.g., sulfoximine), -(R a )S=NR b (e.g., sulfilimine) and -SR a Including R a and R bare the same or different and independently -H, halo, amino, alkyl, haloalkyl, aryl or heterocycle, or R a and R b R together with the nitrogen atom to which they are attached form a heterocyclic ring. a and R b may be plural based on the atom to which they are attached.

[0036] As used herein, the term "therapeutically effective amount" means, when applied to a compound of the present invention, an amount of the compound sufficient to ameliorate, alleviate, stabilize, reverse, slow or delay the progression of a disorder or disease state, or a symptom of a disorder or disease.In one embodiment, the method of the present invention provides for the administration of a combination of compounds.In such a case, the "therapeutically effective amount" is the amount of the compound of the present invention in combination sufficient to cause the intended biological effect.

[0037] As used herein, the term "treatment" or "treating" refers to the amelioration or reversal of the progression or severity of a disease or disorder, or the amelioration or reversal of one or more symptoms or side effects of such a disease or disorder. "Treatment" or "treating" also refers to the inhibition or blocking, such as delaying, stopping, restricting, impeding or hindering the progression of a disease or disorder system, condition or state. For the purposes of the present invention, "treatment" or "treating" further refers to an approach to obtain beneficial or desired clinical results, which include, but are not limited to, the alleviation, whether partial or total, of the symptoms of a disorder or disease, the reduction in severity, the stabilization (i.e., not worsening) of the disease or disorder state, the delay or slowing of the disease or disorder state, the remission or palliation of the disease or disorder state, and the remission of the disease or disorder.

[0038] compound

[0039] The present disclosure provides a compound of formula (I):

[0040] [ka] or a pharma- ceutical acceptable salt, hydrate, or solvate thereof, wherein A is -NH-C(O)-LR 1 , -NH-R 1 , or -R 1 and; L is a bond, -NH-, -O-, or -CH2-; R 1 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, 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)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)2R 9 , -N(R6 )S(O)NR 10 R 11 , or -P(O)R 12 R 13 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 7 and optionally substituted with one or more substituents independently selected from: R 2 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, 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)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)2R 9 , -N(R 6 )S(O)NR 10 R 11 , or -P(O)R 12 R 13wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is halo, hydroxyl, 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 may be substituted with one or more groups selected from the group consisting of: R 3 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxy, -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)NR 10 R 11 , -NR 10 R 11 , -N(R 6 )NR 10 R 11 , -N(R 6 ) OR 9 , -N(R6 )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)2 NR 10 R 11 , or -P(O)R 12 R 13 and; M is a bond, -O-, -S-, -CHR 6 -, or -NR 6 - and; R 4 is -H, -D, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxy, -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)NR 10 R 11 , or -P(O)R 12 R 13 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is halo, hydroxyl, 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)NR10 R 11 , -OC(=O)R 9 , -OC(=O)OR 9 , and -OC(=O)NR 10 R 11 may be substituted with one or more groups selected from the group consisting of: R 5 is -H, -D, -CD3, alkyl, alkenyl, alkynyl, cycloalkyl, halo, hydroxyl, -CH2OH, -CD2OH, -CN, or haloalkyl; R 6 -H, C 1~6 alkyl, or cycloalkyl; R 7 is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, oxo, cyano, hydroxy, -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)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)2R 9 , -N(R 6 )S(O)NR 10 R 11, or -P(O)R 12 R 13 and; 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 taken together with the nitrogen atom to which they are attached, are halo, hydroxyl, 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 forming a 4-12 membered heterocyclyl optionally substituted with one or more groups selected from the group consisting of: Each R 12 and R 13 is independently alkyl, alkoxyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, or R 12 and R 13 together with the phosphorus atom to which they are attached, they are halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO2, -NR 10 R 11 , -NR 10 C(=O)R9 , -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 forming a 4-8 membered heterocyclyl optionally substituted with one or more groups selected from the group consisting of: R a and R c each independently is -H, -D, halo, haloalkyl, -CN, -OR 9 or -NR 10 R 11 (It is.)

[0041] In various embodiments of formulae (I)-(VI), alkyl is C 1~6 Alkyl is C 2~6 alkenyl; akylnyl is C 2~6 Al quinyl and / or cycloalkyl is C 3~8 It is cycloalkyl.

[0042] In some embodiments, R 2 and R 3 Each of is independently -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3, or -CN.

[0043] In some embodiments, R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo, -COOH, -C(O)OCH3, or -CN; and R 3 is halo or alkyl.

[0044] In some embodiments, R 5 is -H, halo, or alkyl.

[0045] In some embodiments, R a and R c Each of is independently -H, halo, or alkyl.

[0046] 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, halo, cyano, hydroxy, -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)NR 10 R 11 and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl can be any of the following: halo, 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 and optionally substituted with one or more groups selected from the group consisting of:

[0047] In some embodiments, MR 4 teeth,

[0048] [ka] is selected from the group consisting of:

[0049] In another embodiment, the compound of formula (II):

[0050] [ka] A compound of the formula:

[0051] In the formula, R 2 , R 3 , R 4 , R 5 , R a , R c and M are as defined above for formula (I), and R 1 1 or 2 R 7 and optionally substituted cyclopropyl.

[0052] In some embodiments, R 1 teeth,

[0053] [ka] is selected from the group consisting of:

[0054] In some embodiments, R 2 and R 3 each is independently -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3, or -CN; M is a bond, -O-, -CHR 6 -, or -NR 6 - and;R 4 is -H, -D, alkyl, halo, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 , -NHC(O)R 9 or -C(O)NR 10 R11 wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, -COOH, and -C(O)CH3; R 5 is -H, halo, or alkyl; and R a and R c Each of is independently -H, halo, or alkyl.

[0055] Non-limiting exemplary compounds of Formula (II) include the 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 in Table 1.

[0056] In some embodiments, R 1 teeth,

[0057] [ka] and non-limiting exemplary compounds are Examples 1-19, 21-25, 2 Includes compounds 7, 28, 30, 31, 33–36, 40–42, 44, 45, 48–50, 53–56, 59, 62, 63, 67–73, 75–77, 85–87, 96–99, 107, 115, 127–128, 132, 133, 136, 137, 141–143, 146, and 165.

[0058] In some embodiments, R 1 teeth,

[0059] [ka] and non-limiting exemplary compounds include compounds of Examples 20, 26, 29, 32, 37-39, 46, 47, 51, 52, 78, 94, 104, 118, and 154 in Table 1.

[0060] In another embodiment, the compound of formula (III):

[0061] [ka] A compound of the formula:

[0062] In the formula, 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 alkyl, alkenyl, alkynyl, halo, 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)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(R6 )C(O)NR 10 R 11 , -N(R 6 )S(O)2R 9 , -N(R 6 )S(O)NR 10 R 11 , or -P(O)R 12 R 13 and the alkyl, alkenyl, or alkynyl is R 7 One or more substituents independently selected from may be substituted with.

[0063] In some embodiments, R 1 is fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, methyl, ethyl, ethyl, butyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, dimethylaminomethyl, methiomethyl, methylamino, ethylamino, isopropylamino, methoxy, ethoxy, isopropyloxy,

[0064] [ka] is selected from the group consisting of:

[0065] In some embodiments, R 2 and R 3 each is independently -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3, or -CN; M is a bond, -O-, -CHR 6 -, or -NR 6 - and;R 4 is -H, -D, alkyl, halo, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 , -NHC(O)R 9 or -C(O)NR10 R 11 wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, -COOH, and -C(O)CH3; R 5 is -H, halo, or alkyl; and R a and R c Each of is independently -H, halo, or alkyl.

[0066] Non-limiting exemplary compounds of formula (III) include the compounds of Examples 43, 61, 64, 66, 79-83, 95, 100, 102, 103, 105, 106, 109, 110, 112-114, 117, 119, 121, 122, 129, 130, 134, 135, 138-140, 145, 147-153, 155, 157-159, and 161-163 in Table 1.

[0067] In another embodiment, the compound of formula (IV):

[0068] [ka] A compound of the formula:

[0069] In the formula, 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, and the cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 7 may be substituted with one or more substituents independently selected from:

[0070] In some embodiments, R 1 teeth,

[0071] [ka] is selected from the group consisting of:

[0072] In some embodiments, R 2 and R 3 each is independently -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3, or -CN; M is a bond, -O-, -CHR 6 -, or -NR 6 - and;R 4 is -H, -D, alkyl, halo, 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 with one or more groups selected from the group consisting of hydroxy, amino, -COOH, and -C(O)CH3; R 5 is -H, halo, or alkyl; and R a and R c Each of is independently -H, halo, or alkyl.

[0073] Non-limiting exemplary compounds of formula (IV) include the compounds of Examples 57, 58, 60, 74, 84, 89, 90, 92, 93, 108, 111, 116, 120, 123-126, and 131 in Table 1.

[0074] In another embodiment, the compound of formula (V):

[0075] [ka] A compound of the formula:

[0076] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R c and M is as defined above for formula (I).

[0077] In some embodiments, R 1 teeth,

[0078] [ka] is selected from the group consisting of:

[0079] In some embodiments, R 2 and R 3 each is independently -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3, or -CN; M is a bond, -O-, -CHR 6 -, or -NR 6 - and;R 4 is -H, -D, alkyl, halo, 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 with one or more groups selected from the group consisting of hydroxy, amino, -COOH, and -C(O)CH3; R 5 is -H, halo, or alkyl; and R a and R c Each of is independently -H, halo, or alkyl.

[0080] Non-limiting exemplary compounds of formula (V) include the compounds of Examples 65 and 91 in Table 1.

[0081] In another embodiment, the compound of formula (VI):

[0082] [ka] A compound of the formula:

[0083] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R c and M is as defined above for formula (I).

[0084] In some embodiments, R 1 teeth,

[0085] [ka] is selected from the group consisting of:

[0086] In some embodiments, R 2 and R 3 each is independently -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, -C(O)OCH3, or -CN; M is a bond, -O-, -CHR 6 -, or -NR 6 - and;R 4 is -H, -D, alkyl, halo, cyano, hydroxy, dialkylamino, haloalkyl, hydroxyalkyl, amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(O)R 9 , -NHC(O)R 9 or -C(O)NR 10 R 11wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, -COOH, and -C(O)CH3; R 5 is -H, halo, or alkyl; and R a and R c Each of is independently -H, halo, or alkyl.

[0087] Non-limiting exemplary compounds of formula (VI) include the compound of Example 101 in Table 1.

[0088] In one embodiment, there is provided a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or diluent and a compound of Formulae (I)-(VI) or a pharma- ceutical acceptable salt thereof.

[0089] Medical Uses and Methods of Treatment Using the Compounds

[0090] The present disclosure provides a method of treating a subject having a disease or disorder associated with the regulation of HPK1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with the regulation of HPK1 is cancer, metastasis, inflammation, or auto-immune pathogenesis.

[0091] 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 carcinoma, melanoma, blastoma, sarcoma, lymphoma and leukemia, including but not limited to bladder cancer, brain cancer, 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 nephroblastoma (Wilms' tumor).

[0092] In another embodiment, there is provided a use of a compound of formula (I) or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for inhibiting HPK1 activity in a subject in need of such inhibition. In some embodiments, the use comprises the treatment of cancer.

[0093] 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, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, and primates, including mammals in utero. Subjects may be of any gender and at any stage of development. In one embodiment, suitable subjects to be treated according to the present disclosure are humans.

[0094] The compounds of the present disclosure are generally administered in a therapeutically effective amount. The compounds of the present disclosure may be administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. An effective dosage is typically within the range of about 0.01 to about 1000 mg per kg of body weight per day, preferably about 0.01 to about 500 mg / kg / day, in single or divided doses. Depending on the age, species, and disease or condition being treated, dosage levels below the lower end of this range may be suitable. In other cases, even larger doses may be used without adverse side effects. The larger dose may also be divided into several smaller doses for administration throughout the day. Methods for determining suitable dosages are well known in the art to which the present disclosure pertains. For example, see Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20 th ed., 2000 may be used.

[0095] Pharmaceutical compositions, dosage forms and routes of administration

[0096] For the treatment of the above-mentioned diseases or conditions, the compounds described herein or pharma- ceutically acceptable salts thereof can be administered as follows.

[0097] Oral route

[0098] The compounds of the present disclosure may be administered orally, including by swallowing, so that the compound enters the gastrointestinal tract or is absorbed directly into the bloodstream from the mouth (e.g., buccal or sublingual administration). Suitable compositions for oral administration include solid, liquid, gel or powder formulations, and have dosage forms such as tablets, lozenges, capsules, granules or powders. Compositions for oral administration may be formulated as immediate or modified release, including delayed or sustained release, optionally with enteric coating. Liquid formulations may include solutions, syrups and suspensions, which may be used in soft or hard capsules. Such formulations may include pharma-ceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oils. The formulation may also include one or more emulsifying agents and / or suspending agents.

[0099] The amount of drug present in a tablet dosage form 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. The tablet may also contain a disintegrant, comprising from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0100] Suitable lubricants for use in tablets may be present in an amount 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.

[0101] Suitable binders for use in tablets include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, etc. Suitable diluents for use in tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0102] Suitable solubilizers for use in 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, castor oil (natural or hydrogenated), HCOR™ (Nikkol), oleyl esters, Gelucire™, caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, and Solutol HS™.

[0103] Parenteral Administration

[0104] The compounds of the present disclosure may be administered directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, and intracranial, etc. Suitable devices for parenteral administration include syringes (including needles and needle-free syringes) and infusion methods.

[0105] Compositions for parenteral administration may be formulated as immediate or modified release, including delayed or sustained release. Most parenteral formulations are aqueous solutions containing excipients, buffers and isotonic agents, including salts. Parenteral formulations may also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle, e.g., sterile water. Solubility enhancers may also be used to improve the stability of parenteral solutions. It may be used in the preparation.

[0106] Transdermal Administration

[0107] The compounds of the present disclosure may be administered topically to the skin or transdermally. The formulations for topical administration may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, and patches. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, and polyethylene glycol. Topical or transdermal administration may also be performed by electroporation, iontophoresis, and phonophoresis. The compositions for topical administration may be formulated as immediate or modified release, including delayed or sustained release.

[0108] Combination therapy

[0109] The pharmaceutical composition according to the present disclosure may contain one or more additional therapeutic agents, for example, to increase efficacy or reduce side effects.In some embodiments, the pharmaceutical composition thus further contains one or more additional therapeutic agents selected from active ingredients useful for treating or inhibiting diseases directly or indirectly mediated 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.

[0110] References for preparing pharmaceutical compositions

[0111] Methods for preparing pharmaceutical compositions for treating or preventing a disease or condition are well known in the art to which this disclosure pertains. th ed.), Remington: The Science and Practice of Pharmacy (20 thed.), Encyclopedia of Pharmaceutical Technology (3 rd Pharmaceutically acceptable excipients, carriers, additives, and the like can be selected based on the principles of the present invention, such as those described in US Pat. No. 6,399,411, entitled "Pharmaceutical Delivery Systems," in The Journal of Pharmaceutical Sciences, Vol. 13, No. 1, ed., or Sustained and Controlled Release Drug Delivery Systems (1978), and then mixed with the compounds of the present disclosure to form a pharmaceutical composition.

[0112] The present disclosure provides compounds that have various pharmacological effects by inhibiting HPK1 activity, pharmaceutical compositions that have the compounds as effective drugs, medical uses of the compounds, particularly for treating diseases or disorders regulated by HPK1, and treatment or prevention methods that include administering the compounds to subjects that require such treatment or prevention.The compounds of the present disclosure and their pharmacologic acceptable salts have good safety and high selectivity for HPK1, and therefore exhibit excellent properties as drugs.

[0113] Preparation of compounds

[0114] The following preparation examples illustrate the preparation of intermediate compounds useful for preparing compounds of formula (I). In addition to the novel intermediate compounds described herein, synthetic processes useful for preparing the intermediate compounds represent embodiments of the invention.

[0115] Intermediate 1A. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0116] [ka]

[0117] Step 1) 4-Bromo-5-chloro-6-fluoro-7-iodo-1H-indazole

[0118] To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (2 g, 8.02 mmol) in sulfuric acid (1.7 mL) was added N-iodosuccinimide (2.7 g, 12.03 mmol) in small portions. The mixture was stirred at 0° C. for 3 h. After the reaction was complete, the mixture was poured into ice water, quenched with solid NaOH, and then extracted with dichloromethane. The combined organic residues were concentrated in vacuo (2.99 g, crude product).

[0119] 1 H NMR (400MHz, DMSO-d6) δ 13.91 (s, 1H), 8.27 (d, J=1.6Hz, 1H).

[0120] Step 2) 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0121] To a solution of 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole (2.99 g, 7.97 mmol, 1 equiv.) in THF (40 mL) was added 3,4-dihydro-2H-pyran (2.18 ml, 23.9 mmol, 3 equiv.) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 equiv.). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was extracted with EtOAc and dried over MgSO4. The organic residue was purified by column chromatography (silica gel, hexane:EtOAc=1:0 to 4:1). 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) was obtained.

[0122] 1 H NMR(400MHz, DMSO-d6) δ 8.84(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).

[0123] Step 3) 4-Bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0124] 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 equiv.) in 2-methyl-2-butanol (1.09 mL) was added Xantphos Pd G3 (21 mg, 21.8 μmol, 0.1 equiv.) and Cs2CO3 (142 mg, 0.436 mmol, 2.0 equiv.). The mixture was degassed and purged with N2 three times, then propan-2-amine (0.19 mL, 2.18 mmol, 10 equiv.) was added. The mixture was stirred in a sealed tube at 90 °C for 3 h. The reaction mixture was diluted with H2O (40 mL). The mixture was then extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (product came out in hexane / EtOAc=10 / 1) to give intermediate 1A (47 mg, 0.120 mmol, 55% yield) as a beige solid.

[0125] 1 H NMR (400MHz, DMSO-d6) δ 8.43(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).

[0126] 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

[0127] [ka]

[0128] To a solution of intermediate 1A (210 mg, 537.53 μmol, 1 equiv.) and BPD (409.50 mg, 1.61 mmol, 3 equiv.) in Tol. (5 mL) was added Pd(OAc)2 (12.07 mg, 53.75 μmol, 0.1 equiv.), PPh2t-Bu (26.05 mg, 107.51 μmol, 0.2 equiv.) and KOAc (158.26 mg, 1.61 mmol, 3 equiv.). The mixture was stirred at 110° C. for 4 h under N2 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), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (0.5% FA condition, 91% to 100% ACN) to give Intermediate 1B (115 mg, 262.71 μmol, 48.87% yield) as a yellow solid.

[0129] 1 H NMR (400MHz, DMSO-d6) δ 8.36(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).

[0130] Intermediate 1C. 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazole

[0131] [ka]

[0132] Step 1) 4-Bromo-6-fluoro-1H-indazole

[0133] To a solution of 3-bromo-5-fluoro-2-methylaniline (25 g, 123 mmol, 1.0 equiv.) in AcOH (2371 mL) and H2O (79 mL) was added NaNo2 (10.14 g, 147 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 16 h. Checked by LCMS, the reaction mixture was concentrated and the residue was solidified with ice water. The reaction mixture was filtered, then washed with water and dried in vacuum to give 4-bromo-6-fluoro-1H-indazole (26.3 g, crude product) as an orange solid.

[0134] Step 2) 4-Bromo-6-fluoro-1-trityl-1H-indazole

[0135] To a solution of 4-bromo-6-fluoro-1H-indazole (26.3 g, 122 mmol, 1.0 equiv) in THF (306 mL) was added NaH (6.36 g, 159 mmol, 1.3 equiv) at 0° C. After 30 min, trityl chloride (37.5 g, 135 mmol, 1.1 equiv) was added at 0° C. The reaction mixture was stirred at room temperature for 16 h. The mixture was added to ice / EtOAc and stirred at room temperature for 30 min. The mixture was extracted with EtOAc / water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was solidified with DCM / hexane to give 4-bromo-6-fluoro-1-trityl-1H-indazole (42.7 g, 93 mmol, 76% yield) as a yellow solid.

[0136] Step 3) 4-Bromo-6-fluoro-1-trityl-1H-indazole-5-carbaldehyde

[0137] To a solution of 4-bromo-6-fluoro-1-trityl-1H-indazole (500 mg, 1.093 mmol, 1.0 equiv) in THF (5.5 mL) was added LDA (0.82 mL, 1.640 mmol, 1.5 equiv) at -78 °C. After 2 h, methyl formate (0.101 mL, 1.640 mmol, 1.5 equiv) was added at -78 °C. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (200 mL x 3), then dried over Na2SO4 and concentrated. The crude 4-bromo-6-fluoro-1-trityl-1H-indazole-5-carbaldehyde was used in the next step.

[0138] Step 4) 4-Bromo-5-(difluoromethyl)-6-fluoro-1-trityl-1H-indazole

[0139] To a solution of 4-bromo-6-fluoro-1-trityl-1H-indazole-5-carbaldehyde (1062 mg, 2.188 mmol, 1.0 equiv.) in DCM (44 mL) was added DAST (1.445 mL, 17.63 mmol, 5.0 equiv.) at 0° C. The mixture was stirred at 25° C. for 16 h under nitrogen atmosphere. The reaction mixture was diluted with DCM, then the resulting organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and the filtrate was concentrated 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.

[0140] Step 5) 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazole, Intermediate 1C

[0141] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1-trityl-1H-indazole (1110 mg, 2.188 mmol, 1.0 equiv) in DCM (15 mL) was added TFA (5.1 mL, 65.6 mmol, 30 equiv) at 0° C. The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with ice and saturated NaHCO3. The mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (product came out 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.

[0142] Intermediate 1D. 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine

[0143] [ka]

[0144] Step 1) 4-Bromo-5-(difluoromethyl)-6-fluoro-7-nitro-1H-indazole

[0145] 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazole, intermediate 1C (133 mg, 0.502 mmol, 1.0 equiv) was dissolved in H2SO4 (0.627 mL) at 0 °C. HNO3 (0.112 mL, 2.509 mmol, 5.0 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. 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.

[0146] Step 2) 4-Bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine, Intermediate 1D

[0147] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-7-nitro-1H-indazole (150 mg, 0.503 mmol, 1.0 equiv) in EtOH / H2O (1.6 mL / 0.915 mL) was added iron (140 mg, 2.52 mmol, 5.0 equiv) and NH4Cl (135 mg, 2.52 mmol, 5.0 equiv). 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 extracted with EtOAc / saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (product came out 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.

[0148] Intermediate 1E. 4-Bromo-5-(difluoromethyl)-6-fluoro-N,N-dimethyl-1H-indazol-7-amine

[0149] [ka]

[0150] To a solution of intermediate 1D, 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine (79 mg, 0.282 mmol, 1.0 equiv) in MeOH (1.41 mL) was added formaldehyde (0.105 mL, 1.410 mmol, 5.0 equiv), acetic acid (0.017 mL, 0.282 mmol, 1.0 equiv) and sodium cyanoborohydride (54 mg, 0.846 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water and concentrated. Extracted with EtOAc, dried over Na2SO4, filtered and concentrated. 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.

[0151] Intermediate 1F. (4-Bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)(cyclopropyl)methanol

[0152] [ka]

[0153] Step 1) 4-Bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0154] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazole (418 mg, 1.577 mmol, 1.0 equiv) in THF (7.89 mL) was added DHP (0.433 mL, 4.73 mmol, 3.0 equiv) and PPTS (79 mg, 0.315 mmol, 0.2 equiv). The reaction mixture was stirred at 75° C. for 16 h. The reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated 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.

[0155] Step 2) (4-Bromo-5-(difluoromethyl)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)(cyclopropyl)methanol, Intermediate 1F

[0156] 4-Bromo-5-(difluoromethyl)-6-fluoro- in THF (25.0 mL) To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (437 mg, 1.252 mmol, 1.0 equiv) was added LDA (1.88 mL, 3.75 mmol, 3.0 equiv) at -78 °C. The mixture was stirred at -78 °C for 2 h, and cyclopropanecarbaldehyde (0.187 mL, 2.503 mmol, 2.0 equiv) was added at -78 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl at 0 °C and diluted with H2O. The mixture was extracted with EtOAc (150 mL x 3) and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (the product came out 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.

[0157] Intermediate 1G. 4-Bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0158] [ka]

[0159] Step 1) 4-Bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-1H-indazol-7-amine

[0160] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-1H-indazol-7-amine (164 mg, 0.586 mmol, 1.0 equiv) in DCM (2.93 mL) was added acetone (0.43 mL, 5.86 mmol, 10.0 equiv) and acetic acid (0.335 mL, 5.86 mmol, 10.0 equiv). The mixture was stirred at 25° C. for 10 min. Sodium cyanoborohydride (74 mg, 1.171 mmol, 2.0 equiv) was added and then the mixture was stirred at 25° C. for 1 h. The reaction was quenched with water and concentrated. Extracted with DCM, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (the product came out 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.

[0161] Step 2) 4-Bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine, intermediate 1G

[0162] To a solution of 4-bromo-5-(difluoromethyl)-6-fluoro-N-isopropyl-1H-indazol-7-amine (154 mg, 0.478 mmol, 1.0 equiv) in THF (2.39 mL) was added DHP (0.131 mL, 1.434 mmol, 3.0 equiv) and PPTS (24 mg, 0.096 mmol, 0.2 equiv). The reaction mixture was stirred at 65° C. for 16 h. The reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by HPLC using HPLC. Purification by silica gel chromatography (product came out in EtOAc / hexane=10 / 100) gave 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.

[0163] Intermediate 1H. (1S,2S)-2-Fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide

[0164] [ka]

[0165] Step 1) (1S,2S)-N-(6-bromoimidazo[1,2-a]pyrazine-2-yl (fluoro)-2-fluorocyclopropane-1-carboxamide

[0166] To a solution of 6-bromoimidazo[1,2-a]pyrazin-2-amine (5 g, 23.47 mmol, 1.0 equiv.) and (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (2.93 g, 28.2 mmol, 1.2 equiv.) in ACN (117 mL) was added MsCl (4.57 mL, 58.7 mmol, 2.5 equiv.) and 3-picoline (11.38 mL, 117 mmol, 5.0 equiv.) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was poured into ice water, causing a yellow solid to precipitate. The mixture was filtered, and the filter cake was washed with a small amount of water and dried under vacuum to give (1S,2S)—N-(6-bromoimidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide (5.81 g, 19.42 mmol, 83%) as a yellow solid.

[0167] Step 2) (1S,2S)-2-Fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide

[0168] 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 equiv.) in 1,4-dioxane (97 mL) was added bis(tributylyin) (24.5 mL, 48.6 mmol, 2.5 equiv.), Pd2(dba)3 (1779 mg, 1.942 mmol, 0.1 equiv.), tricyclohexylphosphine (1089 mg, 3.88 mmol, 0.2 equiv.) and LiCl (4.94 g, 117 mmol, 6.0 equiv.). The reaction mixture was degassed and purged with N2 three times, then stirred at 110 °C for 16 h. The mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated 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.

[0169] Synthesis of compounds of formula (I) The following compounds were prepared using synthetic methods A-J. Below, illustrative synthetic examples of some compounds of the present disclosure are described, and other compounds may be prepared by methods similar to those described below using different starting or reactant materials.

[0170] Synthesis method A

[0171] Example 14. 6-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)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-carboxamide)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0172] [ka]

[0173] Step 1) (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl (amino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0174] To a solution of intermediate 1H (644 mg, 1.26 mmol, 1.3 equiv) and intermediate 1A (380 mg, 0.973 mmol, 1.0 equiv) in EtOH (4.86 mL) was added Ad2nBuP-Pd-G3 (71 mg, 0.097 mmol, 0.1 equiv). The mixture was degassed and purged with N2 three times, then stirred at 90 °C for 16 h under N2 atmosphere. 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.

[0175] Step 2) (2R,3R,4S,5S,6S)-2-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0176] To a solution of compound 1 (0.4 g, 754.76 μmol, 1 equiv) in DCM (40 mL) was added compound 2 (541.91 mg, 1.13 mmol, 1.5 equiv) and BF3·Et2O (214.25 mg, 1.51 mmol, 186.30 μL, 2 equiv). The mixture was stirred at 20 °C for 2 h. The desired MS was found by LC-MS. The mixture was poured into saturated NaHCO3 (30 mL) and extracted with DCM (30 mL). The organic layer was concentrated. The residue was purified by preparative TLC (SiO2, DCM:MeOH=20:1). Example 18 (200 mg, 244.06 μmol, 10.78% yield, 93% purity) was obtained as a white solid.

[0177] 1 H NMR (400MHz, CDCl3-d) δ 12.21(br s, 1H), 9.11(br s, 1H), 8.97(br s, 1H), 8.51(s, 1H), 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=9.4Hz, 1H), 4.25(d, J=9.9Hz, 1H), 3.90(s, 3H), 3.62(td, J=6.6, 13.2Hz, 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) + .

[0178] Step 3) (2S,3S,4S,5R,6R)-6-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-yl)(isopropyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0179] To a solution of Example 18 (150 mg, 196.82 μmol, 1 equiv) in THF (2 mL) was added MeOH (2 mL) / H2O (1 mL) and LiOH-H2O (104.91 mg, 2.5 mmol, 12.70 equiv). The mixture was stirred at 0° C. for 5 min. The mixture was neutralized to pH 7.0 with 1M HCl and concentrated. The mixture was purified by preparative HPLC: Column: Phenomenex C18 150×25 mm×10 um; Mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-35%, 8 min. The desired product was obtained after lyophilization. Example 14 (50 mg, 79.59 μmol, 40.44% yield, 99% purity) was obtained as a white solid.

[0180] 1 H NMR (400MHz, DMSO-d6) δ 13.62(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) + .

[0181] Synthesis method B

[0182] Example 20. (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

[0183] [ka]

[0184] Step 1) Methyl (1S,2R)-2-((6-bromoimidazo[1,2-a]pyrazine 2-(2-yl)carbamoyl)cyclopropane-1-carboxylate

[0185] To a solution of compound 3 (430 mg, 2.02 mmol, 1 equiv.) and (1R,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (436.36 mg, 3.03 mmol, 1.5 equiv.) in DCM (5 mL) was added EDCI (580.41 mg, 3.03 mmol, 1.5 equiv.). The mixture was stirred at 15 °C for 16 h. The mixture was then warmed to 30 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash reverse phase (0.5% FA conditions, 25% to 33% ACN). Compound 4 (50 mg, 147.43 μmol, 7.30% yield) was obtained as a white solid.

[0186] 1 H NMR(400MHz, DMSO-d6) δ 11.40(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).

[0187] 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

[0188] To a solution of compound 4 (50 mg, 147.43 μmol, 1 equiv.) and intermediate 1B (70.99 mg, 162.17 μmol, 1.1 equiv.) in dioxane (2 mL) was added Pd(dppf)Cl2 (10.79 mg, 14.74 μmol, 0.1 equiv.) and K2CO3 (61.13 mg, 442.29 μmol, 3 equiv.). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (0.5% FA condition, 53%-59% ACN). Compound 5 (20 mg, 35.97 μmol, 24.40% yield) was obtained as a yellow solid.

[0189] 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

[0190] 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 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 11 min) and lyophilized to give the product. Example 20 (5 mg, 10.60 μmol, 29.46% yield, 100% purity) was obtained as a white solid.

[0191] 1H NMR (400MHz, DMSO-d6) δ 13.22-13.11(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) + .

[0192] Synthesis method C

[0193] Example 32. Methyl (1S,2R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylate

[0194] [ka]

[0195] Step 1) N-(6-(tributylstannyl)imidazo[1,2-a]pyrazine-2- (yl)acetamide

[0196] To a solution of compound 6 (18.9 g, 74.10 mmol, 1 equiv) in dioxane (200 mL) was added Pd2(dba)3 (1.36 g, 1.48 mmol, 0.02 equiv), PCy3 (831.15 mg, 2.96 mmol, 960.87 μL, 0.04 equiv) and LiCl (18.85 g, 444.58 mmol, 9.11 mL, 6 equiv). The mixture was degassed and purged with N2 three times. The mixture was heated to 110 °C, then (SnBu3)2 (92.54 g, 159.53 mmol, 79.78 mL, 2.15 equiv) was added dropwise to the mixture. The mixture was stirred at 110 °C for 48 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1 to 1 / 2) to give compound 7 (7.9 g, 16.98 mmol, 22.92% yield) as a yellow solid.

[0197] 1 H NMR (400MHz, DMSO-d6) δ 10.89(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).

[0198] Step 2) N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)acetamide

[0199] To a solution of compound 7 (1 g, 2.15 mmol, 1 equiv.) and intermediate 1A (839.77 mg, 2.15 mmol, 1 equiv.) in EtOH (10 mL) was added Ad2n-BuP-Pd-G3 (156.54 mg, 214.95 μmol, 0.1 equiv.). The mixture was stirred at 90° C. for 16 h under N2 atmosphere. The reaction mixture was quenched by addition of saturated aqueous KF solution (20 mL) and the mixture was stirred at 15° C. for 1 h. EtOAc (50 mL) was added to the mixture and then filtered. The filtrate was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (80 mL×2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc=10 / 1 to 1 / 5). Compound 8 (250 mg, 622.16 μmol, 28.94% yield) was obtained as a yellow solid.

[0200] Step 3) 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-amine

[0201] To a solution of compound 8 (250 mg, 622.16 μmol, 1 equiv.) in MeOH (10 mL) was added LiOH-HO (130.54 mg, 3.11 mmol, 5 equiv.). The mixture was stirred at 70° C. for 16 h. The mixture was then stirred at 70° C. for another 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (conditions: 0.5% FA in HO / ACN, 21% to 27% ACN). Compound 9 (90 mg, 250.15 μmol, 40.21% yield) was obtained as a yellow solid.

[0202] Step 4) Methyl (1S,2R)-2-((6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)carbamoyl)cyclopropane-1-carboxylate

[0203] To a solution of compound 9 (20 mg, 55.59 μmol, 1 equiv.) and (1R,2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (9.61 mg, 66.71 μmol, 1.2 equiv.) in THF (2 mL) was added T3P (53.06 mg, 83.38 μmol). mol, 49.59 μL, 50% purity, 1.5 eq.) and Py (21.99 mg, 277.94 μmol, 22.43 μL, 5 eq.) were added. The mixture was stirred at 15° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH4HCO3)-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.

[0204] 1 H NMR(400MHz, DMSO-d6) δ 13.28-13.07(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) + .

[0205] Synthesis method D

[0206] Example 17. (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

[0207] [ka]

[0208] Intermediate 1E (35 mg, 0.114 mmol, 1.0 To a solution of Ad2nBuP-Pd-G3 (9 mg, 0.011 mmol, 0.1 equiv.) and Intermediate 1H (70 mg, 0.136 mmol, 1.2 equiv.) was added Ad2nBuP-Pd-G3 (9 mg, 0.011 mmol, 0.1 equiv.). The mixture was degassed and purged with N2 three times, then stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1, DCM / MeOH = 15 / 1) to give Example 17 (0.87 mg, 0.001945 mmol, 2%) as a yellow solid.

[0209] 1 H NMR (400MHz, DMSO-d6) 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=52.5Hz, 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) + .

[0210] Synthesis method E

[0211] Example 19. (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

[0212] [ka]

[0213] Intermediate 1F (275 mg, 0.656 mmol, 1.0 To a solution of Ad2nBuP-Pd-G3 (48 mg, 0.066 mmol, 0.1 equiv.) and intermediate 1H (401 mg, 0.787 mmol, 1.2 equiv.) was added Ad2nBuP-Pd-G3 (48 mg, 0.066 mmol, 0.1 equiv.). The mixture was degassed and purged with N2 three times, then stirred at 90° C. for 16 h under N2 atmosphere. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (product came out in MeOH / DCM=10 / 100) to give Example 19 (47.7 mg, 0.101 mmol, 15%) as a yellow solid, and compound 10 (25 mg, 0.045 mmol, 7%).

[0214] 1 H NMR(400MHz, DMSO-d6) δ 13.33(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, 1H), 4.65(q, J=3.8Hz, 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) + .

[0215] Synthesis method F

[0216] Example 28. (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

[0217] [ka]

[0218] Step 1) (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-methyl- -(Isopropylamino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0219] To a solution of intermediate 1G (137 mg, 0.337 mmol, 1.0 equiv) and intermediate 1H (189 mg, 0.371 mmol, 1.1 equiv) in EtOH (1.69 mL) was added Ad2nBuP-Pd-G3 (25 mg, 0.034 mmol, 0.1 equiv). The mixture was degassed and purged with N2 three times, then stirred at 90 °C for 16 h under N2 atmosphere. 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.

[0220] 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

[0221] To a solution of compound 11 (19 mg, 0.035 mmol, 1.0 equiv) in EtOAc (0.17 mL) was added 1N HCl in EtOAc solution (0.871 mL, 0.871 mmol, 25.0 equiv). The mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched with saturated NaHCO3 and diluted with EtOAc (20 mL). The organic layer was washed with saturated NaHCO3 (15 mL×2). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified twice by preparative TLC (MC:MeOH=20:1, 10:1) to give Example 28 as a yellow solid.

[0222] 1H NMR (400MHz, DMSO-d6) δ 13.54-13.09(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). +

[0223] Synthesis method G

[0224] 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

[0225] [ka]

[0226] Step 1) (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide

[0227] To a solution of (S)-2-methylpropane-2-sulfinamide (3.00 g, 24.75 mmol, 1 equiv.) and acetaldehyde (9.81 g, 222.77 mmol, 12.50 mL, 9 equiv.) in DCM (30 mL) was added PPTS (622.03 mg, 2.48 mmol, 0.1 equiv.) and MgSO4 (8.94 g, 74.26 mmol, 3 equiv.). The mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (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.

[0228] 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-sulfinamide

[0229] To a solution of compound 14 (1 g, 3.00 mmol, 1 equiv) in THF (20 mL) was added LDA (2 M, 2.25 mL, 1.5 equiv) at −78° C. under argon atmosphere. The reaction was stirred at −78° C. for 30 min, then compound 13 (662.57 mg, 4.50 mmol, 62.60 μL, 1.5 equiv) in THF (3 mL) was added. The reaction was warmed to 20° C. for 2 h. An aqueous solution of NH4Cl (50 mL) 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:EtOAc=100:1 to 10:1) to give the product. TLC (petroleum ether:EtOAc=2:1). Compound 15 (1.1 g, 2.29 mmol, 76.26% yield) was obtained as a yellow oil.

[0230] 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

[0231] To a solution of compound 15 (550.00 mg, 1.14 mmol, 1 equiv) in EtOH (20 mL) was added intermediate 1H (582.51 mg, 1.14 mmol, 1 equiv) and Ad2nBuP-Pd-G3 (83.31 mg, 114.39 μmol, 0.1 equiv). The suspension was degassed and purged with N2 for 1 min, then the reaction mixture was stirred at 90 °C for 15 h under N2. 5 mL of saturated KF aqueous solution was added to quench the reaction mixture. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by back-flush (MeCN / H2O, 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.

[0232] 150mg of the mixture was taken and purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150x50mmx3um; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 7min) to obtain the product. Example 132 (10.6mg, 19.46μmol, 8.04% yield, 98.4% purity) was obtained as a pale yellow solid. Compound 16 (60mg, 96.76μmol, 40.00% yield) was obtained as a pale yellow solid.

[0233] 1 H NMR (400MHz, DMSO-d6) δ 13.40(br s, 1H), 11.47-11.35(m, 1H), 9.07(br s, 1H), 9.0 2(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)+ .

[0234] 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

[0235] To a solution of compound 16 and example 132 (130 mg, 209.64 μmol, 1 equiv) in dioxane (1 mL) was added HCl / dioxane (4 M, 52.41 μL, 1 equiv). The reaction was stirred at 20° C. for 1 h. The reaction mixture was concentrated. The residue was purified by back-flush (MeCN / H2O, 0.05% TFA, 25%-30%) to give the product. Compound 17 (83 mg, 152.06 μmol, 72.53% yield, TFA) was obtained as a pale yellow solid.

[0236] 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

[0237] 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 min. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 10 min) to obtain the product. Example 146 (50.2 mg, 95.11 μmol, 53.66% yield, 100% purity) was obtained as a white solid.

[0238] 1H NMR (400MHz, DMSO-d6) δ 13.52(s, 1H), 11.41(s, 1H), 9.98(br d, J=6.2Hz, 1H), 9.08(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), 5.09-4.86(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) + .

[0239] Synthesis method H

[0240] Example 91. 5-Chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-amine

[0241] [ka]

[0242] 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

[0243] To a solution of intermediate 1B (3.5 g, 8.00 mmol, 1 equiv.) and compound 18 (2.72 g, 8.80 mmol, 1.1 equiv.) in dioxane (50 mL) and H2O (5 mL) was added Pd(dppf)Cl2 (585.04 mg, 799.56 μmol, 0.1 equiv.) and K3PO4 (5.09 g, 23.99 mmol, 3 equiv.). The mixture was stirred at 80 °C for 6 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (80 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc = 10 / 1 to 1 / 1). Compound 19 (2 g, 3.70 mmol, 46.33% yield) was obtained as a red solid.

[0244] Step 2) 6-[5-chloro-6-fluoro-7-(isopropylamino)-2-tetrahydropyran-2-yl-indazol-4-yl]imidazo[1,2-a]pyrazin-2-amine

[0245] To a solution of compound 19 (2.1 g, 3.89 mmol, 1 equiv.) in MeOH (20 mL) and H2O (6 mL) was added K2CO3 (2.69 g, 19.45 mmol, 5 equiv.). The mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase [water (0.5% FA) / ACN condition, 51%-57% ACN]. Compound 20 (1.2 g, 2.70 mmol, 69.50% yield) was obtained as a yellow solid.

[0246] Step 3) 5-chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazo[1,2-a]pyrazin-6-yl)-2-tetrahydropyran-2-yl-indazol-7-amine

[0247] To a solution of compound 20 (100.00 mg, 225.27 μmol, 1 equiv.) in DMA (1 mL) was added DIPEA (58.23 mg, 450.55 μmol, 78.48 μL, 2 equiv.) and compound 21 (78.37 mg, 337.91 μmol, 42.36 μL, 1.5 equiv.). The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by back-flush (ACN, water (FA 0.05%) to give compound 22 (30 mg, 58.37 μmol, 25.91% yield) as a yellow solid.

[0248] LCMS (electrospray) m / z 514.1 (M+H) + .

[0249] Step 4) 5-chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazo[1,2-a]pyrazin-6-yl)-1H-indazol-7-amine

[0250] Compound 22 (30 mg, 58.37 μmol, 1 eq) was dissolved in HCl / dioxane (4M, 2 mL, 137.06 eq). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; 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.

[0251] 1 H NMR (400MHz, DMSO-d6) δ 13.15(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) + .

[0252] Synthesis method I

[0253] Example 101. 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyrazin-2-amine

[0254] [ka]

[0255] Step 1) 6-[5-chloro-6-fluoro-7-(isopropylamino)-2-tetrahydrofuran Hydropyran-2-yl-indazol-4-yl]-N-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-2-amine

[0256] Compound 23 (38.79 mg, 450.55 μmol, 2 equiv.) and compound 20 (100 mg, 225.27 μmol, 1 equiv.) and AcOH (1.35 mg, 22.53 μmol, 1.29 μL, 0.1 equiv.) were dissolved in MeOH (2 mL). After 0.5 h, NaBH3CN (28.31 mg, 450.55 μmol, 2 equiv.) was added to the mixture. The reaction mixture was stirred at 25° C. for 15.5 h. 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), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 24 (100 mg, 194.55 μmol, 86.36% yield) as a yellow solid.

[0257] Step 2) 6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyrazin-2-amine

[0258] Compound 24 (100 mg, 194.55 μmol, 1 eq) was dissolved in HCl / dioxane (4M, 2 mL, 41.12 eq). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; 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 pale yellow solid.

[0259] 1 H NMR (400MHz, DMSO-d6) δ 13.29-12.99(m, 1H), 8.72(s, 1H), 8.64(s, 1H), 7.93(br d, 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) + .

[0260] Synthesis method J

[0261] [ka]

[0262] Step 1) Compound 1 (184g, 347mmol, 1.00 in MeOH (1.00L) To a solution of the product (160 g, 358 mmol, 1.00 eq) in MeOH (1000 mL) was added HCl / MeOH (4.00 M, 86.8 mL, 1.00 eq). The mixture was stirred at 15° C. for 6 h. The reaction was concentrated in vacuum. The residue was purified by preparative HPLC column: Phenomenex Luna C18 (250×80 mm×15 um); mobile phase: [water (0.05% HCl)-CAN]; B%: 35%-60%, 35 min. The eluent was made basic with saturated aqueous NaHCO3 solution, the mixture was concentrated in vacuum, and the mixture was extracted with EtOAc (3.00 L×2). The combined organic layers were separated, washed with brine (5.00 L), and dried over Na2SO4. To a solution of the product (160 g, 358 mmol, 1.00 eq) in MeOH (1000 mL) was added HCl / MeOH (4.00 M, 800 mL, 8.92 eq). The mixture was stirred for 1 h at 25° C. 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.

[0263] 1 H NMR (400MHz, DMSO-d6) 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, 66.0Hz, 1H), 4.14(dq, J=4.0, 6.4Hz, 1H), 2.23-2.20(m, 1H), 1.72-1.68(m, 1H), 1.26(d, J=6.4Hz, 6H), 1.23-1.21(m, 1H); LCMS (electrospray) m / z=446.1(M+H). + .

[0264] To a solution of compound 25 (120 mg, 0.269 mmol, 1.0 equiv) in 1,4-dioxane (1.35 mL) was added Pd(dppf)Cl2 (98 mg, 0.135 mmol, 0.5 equiv) and sodium tert-butoxide (38.8 mg, 0.404 mmol, 1.5 equiv) at 25° C. The reaction mixture was degassed under N2 and heated to 160° C. for 3 h in a microwave reactor. After cooling, the reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc (20 mL×3), then dried over MgSO4 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.

[0265] 1 H NMR(500MHz, DMSO-d6) δ 13.07(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=14.2Hz, 2H), 5.11-4.76(m, 2H), 4.00(d, J=11.3Hz, 1H), 2.19(t, J=7.2Hz, 1H), 1.70(dd, J=23.2, 3.8Hz, 1H), 1.22(d, J=6.3Hz, 7H); LCMS (electrospray) m / z 412.15(M+H) + .

[0266] Table 1 below lists example compounds along with the general synthetic methods used to make the compounds and characterization data.

[0267] [Table 1-1]

[0268] [Table 1-2]

[0269] [Table 1-3]

[0270]

Table 1-4

[0271]

Table 1-5

[0272]

Table 1-6

[0273]

Table 1-7

[0274]

Table 1-8

[0275]

Table 1-9

[0276]

Table 1-10

[0277]

Table 1-11

[0278]

Table 1-12

[0279]

Table 1-13

[0280]

Table 1-14

[0281]

Table 1-15

[0282]

Table 1-16

[0283]

Table 1-17

[0284]

Table 1-18

[0285]

Table 1-19

[0286]

Table 1-20

[0287]

Table 1-21

[0288]

Table 1-22

[0289]

Table 1-23

[0290]

Table 1-24

[0291]

Table 1-25

[0292]

Table 1-26

[0293]

Table 1-27

[0294]

Table 1-28

[0295]

Table 1-29

[0296]

Table 1-30

[0297]

Table 1-31

[0298]

Table 1-32

[0299]

Table 1-33

[0300]

Table 1-34

[0301]

Table 1-35

[0302]

Table 1-36

[0303]

Table 1-37

[0304]

Table 1-38

[0305]

Table 1-39

[0306]

Table 1-40

[0307]

Table 1-41

[0308]

Table 1-42

[0309]

Table 1-43

[0310]

Table 1-44

[0311]

Table 1-45

[0312]

Table 1-46

[0313]

Table 1-47

[0314]

Table 1-48

[0315]

Table 1-49

[0316]

Table 1-50

[0317]

Table 1-51

[0318]

Table 1-52

[0319]

Table 1-53

[0320]

Table 1-54

[0321] [Table 1-55]

[0322] [Table 1-56]

[0323] [Table 1-57]

[0324] [Table 1-58]

[0325] [Table 1-59]

[0326] Compound evaluation

[0327] HPK1 kinase assay

[0328] HPK1 kinase activity was measured by Promega's ADP-Glo™ Kinase Assay. In this assay, 5 ng of recombinant human HPK1 (signalchem) is incubated 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 MgCl2; 0.1 mg / ml BSA; 50 μM DTT.). The assay was initiated by incubating the reaction mixture at 30° C. for 40 minutes in a 96-well plate. After incubation, 25 μL of 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 50 μL of detection reagent per well. Luminescence was detected on a Molecular device I3X plate reader after 30 minutes of incubation at room temperature. IC values ​​were calculated from a series of percent inhibition values ​​determined over a range of inhibitor concentrations using GraphPad Prism 7 software and the software routine as implemented in SigmaPlot 13.0. 50 The value was calculated.

[0329] Table 2 shows the IC of the compounds of the invention. 50 Values ​​are shown, with + representing >1000nM, ++ representing 501-1000nM, +++ representing 101-500nM, and ++++ representing <100nM.

[0330] [Table 2-1]

[0331] [Table 2-2]

Claims

1. Equation (I): 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt, hydrate, or solvate thereof, During the ceremony, A is -NH-C(O)-LR １ ,-NH-R １ , or -R １ And; L represents a bond, -NH-, -O-, or -CH ２ - and; R １ is -H, -D, -CD ３ , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, 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 [[ID=A6]] ６ )NR １０ R / １１ , -N(R ６ )OR ９ , -N(R ６ )C(O)R ９ , -N(R ６ [[ID=B6]] 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 [[ID=8)) １２ R １３ and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be substituted with one or more substituents independently selected from R ７ ; R ２ -H, -D, -CD ３ Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, 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 said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxyl, 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 may be optionally substituted with one or more groups selected from the group consisting of; R ３ -H, -D, -CD ３ Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxy, -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 And; M represents a bond, -O-, -S-, -CHR ６ -, or -NR ６ - and; R ４ -H, -D, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxy, -C(O)R ９ , -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 The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is a halo, hydroxyl, 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 It may be substituted with one or more groups selected from the group consisting of; R ５ -H, -D, -CD ３ Alkyl, alkenyl, alkynyl, cycloalkyl, halo, hydroxyl, -CH ２ OH, -CD ２ It is OH, -CN, or haloalkyl; R ６ is -H, C １～６ Alkyl or cycloalkyl; R ７ Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, oxo, cyano, hydroxy, -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 And; R ９ is -H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R １０ and R １１ Independently, -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, or R １０ and R １１ These, together with the nitrogen atom to which they are bonded, form halo, hydroxyl, 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 It forms a 4- to 12-membered heterocycline which may be substituted with one or more groups selected from the group consisting of; Each R １２ and R １３ These are independently alkyl, alkoxyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, or R １２ and R １３ These, together with the phosphorus atom to which they are bonded, form halo, hydroxyl, 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 They form a 4- to 8-membered heterocycline which may be substituted with one or more groups selected from the group consisting of; and R ａ and R ｃ Each of these is independently -H, -D, halo, haloalkyl, -CN, -OR ９ or -NR １０ R １１ That is, A compound or its pharmaceutically acceptable salt, hydrate, or solvate.

2. R ２ and R ３ Each of these independently comprises -H, -D, halo, alkoxy, alkylthio, haloalkyl, alkyl, hydroxyalkyl, -COOH, and -C(O)OCH. ３ , or -CN; R ５ However, it is -H, halo, or alkyl; R ａ and R ｃ Each of them is independently -H, halo, or alkyl; M is a bond, -O-, -CHR ６ -, or -NR ６ - and; as well as R ４ However, -H, -D, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxy, -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 And the above C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is a halo, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -C(O)CH ３ -CN, -CD ３ , -NR １０ R １１ , -NR １０ S(O) ２ R ９ , and -NR １０ C(=O)R ９ It may be substituted with one or more groups selected from the group consisting of, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ However, alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo, -COOH, -C(O)OCH ３ , or -CN; R ３ is halo or alkyl; and M-R ４ but, 【Chemistry 2】 Selected from the group consisting of, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Formula (II): 【Transformation 3】 (In the formula, R １ is one or two R ７ (It is a cyclopropyl that may be substituted with) A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. R １ but 【Chemistry 4】 The compound according to claim 4 or a pharmaceutically acceptable salt thereof.

6. (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(methoxy)methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-ethoxyethyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(1-methoxypropan-2-yl)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1,1-difluoropropan-2-yl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-methyl-7-(tetrahydrofuran-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-methyl-7-(3-oxocyclopent-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(1-hydroxypropan-2-yl)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(2-hydroxycyclopentyl)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-methyl-7-(1-(methylamino)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopent-1-en-1-yl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(dimethylamino)ethyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(dimethylamino)propane-2-yl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; 6-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-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-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(2-methoxycyclopentyl)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-7-(dimethylamino)- 6-Fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)(isopropyl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate; (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(1,3-dioxoisoindoline-2-yl)methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1,3-dioxoisoindoline-2-yl)propane-2-yl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(amino(cyclopropyl)methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminopropan-2-yl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminoethyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-2-fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2R)-2-fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1R,2S)-2-fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-(hydroxymethyl)-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(amino(cyclopropyl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyclopropyl)methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(amino(cyclopropyl)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminoethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(1,3-dioxoisoindoline-2-yl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(1-hydroxyethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(difluoromethyl)-7-(1-(1,3-dioxoisoindoline-2-yl)ethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyclopropyl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminoethyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyclopropyl)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamideformate; Methyl 6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-7-(isopropylamino)-1H-indazole-5-carboxylate; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropanecarboxamideformate; (1S,2S)-N-(6-(7-(1-(1,3-dioxoisoindoline-2-yl)ethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropanecarboxamideformate; (1S,2S)-N-(6-(7-(cyclopropanecarboxamide(cyclopropyl )methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1,3-dioxoisoindoline-2-yl)ethyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(cyclopropanecarboxamide)ethyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-methyl-7-(1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-cyano-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; 6-Fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-7-(isopropylamino)-1H-indazole-5-carboxylic acid; (1S,2S)-N-(6-(5-(difluoromethyl)-6-fluoro-7-(1-formamidoethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(cyclopropanecarboxamide)ethyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropanecarboxamide(cyclopropyl)methyl)-5-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(1-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-((tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-((tert-butylsulfinyl)amino)ethyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(1-formamidoethyl)-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(((tert-butylsulfinyl)amino)(cyclopropyl)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-aminopropan-2-yl)-6-fluoro -5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamideformate; (1S,2S)-N-(6-(7-(1-acetamidopropan-2-yl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(2,2,2-trifluoroacetamide)methyl)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(formamide)methyl)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-methoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(1-hydroxyethyl)-5-methoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((R)-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1-acetylazetidine-3-yl)oxy)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(azetidine-3-yloxy)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamideformate; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; and (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide A compound according to claim 5 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

7. R １ but, 【Transformation 5】 A compound according to claim 4 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

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

9. Formula (III): 【Transformation 6】 (In the formula, R １ Alkyl, alkenyl, alkynyl, halo, 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 The alkyl, alkenyl, or alkynyl is R ７ (May be substituted with one or more substituents independently selected from the above.) A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. R １ However, fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, Hydroxyethyl, hydroxypropyl, methyl, ethyl, ethyl, butyl, isopropyl, isobutyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, dimethylaminomethyl, methylmethylamino, ethylamino, isopropylamino, methoxy, ethoxy, isopropyloxy, 【Transformation 7】 A compound according to claim 9 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

11. N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)propionamide; N-(6-(7-(cyclopropyl(hydroxy)methyl)-6-fluoro-5-(trifluoromethyl)-2H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2,2,2-trifluoroacetamide; (S)-2-amino-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)propenamide; 2-amino-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)isobutylamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)pivaramide; N-(6-(6-fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; Isopropyl(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)carbamate; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(methylthio)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-N-methylacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(dimethylamino)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(methylthio)propenamide; (R)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H -Indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(dimethylamino)propenamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-methoxyacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)butylamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)formamide; Methyl (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)carbamate; Ethyl (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)carbamate; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)pentanamide; 1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-3-ethylurea; 1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-3-methylurea; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2,2-difluoroacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-hydroxyacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-3-hydroxypropanamide; N-(6-(7-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(7-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; (S)-N-(1-(4-(2-acetamidoimidazo[1,2-a]pyrazine-6-yl)-5-chloro-6-fluoro-1H-indazole-7-yl)ethyl)-2,2,2-trifluoroacetamide; (R)-N-(1-(4-(2-acetamidoimidazo[1,2-a]pyrazine-6-yl)-5-chloro-6-fluoro-1H-indazole-7-yl)ethyl)-2,2,2-trifluoroacetamide; (S)-N-(6-(5-chloro-6-fluoro-7-(1-formamidoethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(7-((1-acetylazetidine-3-yl)oxy)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(7-(azetidine-3-yloxy)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamideformate; N-(6-(5-chloro-6-fluoro-7-((1-(2-hydroxyacetyl)a Zethidine-3-yl)oxy)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((1-propionylazetidine-3-yl)oxy)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxyazetidine-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxypyrrolidine-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-7-(cyclopropyl(hydroxy)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-(difluoromethyl)-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)propionamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxy-3-methylazetidine-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-((3-hydroxy-3-methylpyrrolidine-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(1-(3-hydroxyazetidine-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide; N-(6-(6-fluoro-7-(isopropylamino)-5-methoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)propionamide; and N-(6-(5-chloro-6-fluoro-7-(1-(3-hydroxypyrrolidine-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)acetamide A compound according to claim 10 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

12. Formula (IV): 【Transformation 8】 (In the formula, R １ These are cycloalkyl, aryl, heteroaryl, or heterocyclyl compounds. Yes, the cycloalkyl, aryl, heteroaryl, or heterocyclyl is R ７ (May be substituted with one or more substituents independently selected from the above.) A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. R １ but, 【Chemistry 9】 A compound according to claim 12 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

14. N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)benzamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)picolinamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclobutanecarboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)pyrrolidine-3-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)morpholine-4-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(pyridine-3-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-morpholinoacetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-4-methylpiperazine-1-carboxamideformate; N-(6-(6-fluoro-7-(isopropylamino)-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(pyridine-3-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)azetidine-2-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)tetrahydrofuran 2-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-(oxetan-3-yl)acetamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)piperazine-1-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-1-methylpiperidine-4-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)pyrrolidine-1-carboxamide; N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)tetrahydrofuran-3-carboxamide; Cyclobutyl (6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)carbamateformate; and N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)oxetane-3-carboxamide A compound according to claim 13 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

15. Formula (V): 【Chemistry 10】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R １ but, 【Chemistry 11】 A compound according to claim 15 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

17. 1-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-1,5-dihydro-2H-pyrrole-2-one; and 5-Chloro-6-fluoro-N-isopropyl-4-(2-morpholinoimidazo[1, 2-a)pyrazine-6-yl)-1H-indazole-7-amine A compound according to claim 16 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

18. Equation (VI): 【Chemistry 12】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. R １ but, 【Chemistry 13】 A compound according to claim 19 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

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

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. The pharmaceutical composition according to claim 21 for treating a subject having a disease or disorder associated with the regulation of HPK1.

23. The pharmaceutical composition according to claim 22, wherein the disease is cancer, and the pharmaceutical composition is administered together with an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA4 agent.

24. The pharmaceutical composition according to claim 22, wherein the disease is cancer, metastasis, inflammation, or autoimmune disease.

25. The aforementioned cancers include bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, and uterine cancer. The pharmaceutical composition according to claim 24, selected from the group consisting of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias, including but not limited to 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 cancer and nephroblastoma (Wilms' tumor).

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