Indazole as a hematopoietic progenitor cell kinase 1 (HPK1) inhibitor and its method of use

Abstract

The present disclosure provides compounds of formula (I) or pharmaceutically 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. TIFF2023542724000142.tif59153

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims benefit and priority to U.S. Provisional Patent Application No. 63 / 084,059, filed on 28 September 2020. The entire disclosure of the application identified in this paragraph is incorporated herein by reference.

[0002] field This disclosure is directed to inhibitors of hematopoietic progenitor kinase 1 (HPK1), pharmaceutical compositions comprising such inhibitors, methods of using such inhibitors to treat various disorders associated with HPK1, and methods for preparing these compounds. [Background technology]

[0003] background 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 remarkable clinical success in the treatment of various types of tumors in recent years, particularly with immune checkpoint inhibitor treatments and chimeric antigen T-cell therapies. Most of the studied checkpoint inhibitors, including CTLA4, PD-1, or PD-L1 inhibitors, have demonstrated significant antitumor activity by overcoming immunosuppressive mechanisms at the tumor site.

[0004] Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a member of the serine / threonine kinase and MAP4K group. 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. In addition to the crucial role of HPK1 kinase activity in anti-cancer immunotherapy as a novel intracellular checkpoint molecule, the potential benefits of combination therapy with existing checkpoint regimens have recently been demonstrated. HPK1 inhibition is expected to have a dual function: 1. prolonged activation of T cells; and 2. enhanced APC function by dendritic cells. This dual targeting may work synergistically together 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 that can be treated with the compounds of this disclosure include, but are not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias, including, but not limited to, bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid cancer and nephroblastoma (Wilms' tumor).

[0005] Inhibition of HPK1 with small molecule inhibitors has potential for the treatment of cancer and other disorders [Non-Patent Literature 1]. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hernandez, S., et. al., (2018) Cell Reports 25, 80-94 [Non-Patent Document 2] Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000 [Non-Patent Document 3] Handbook of Pharmaceutical Excipients (7th ed.) [Non-Patent Document 4] Encyclopedia of Pharmaceutical Technology (3rd ed.) [Non-Patent Document 5] Sustained and Controlled Release Drug Delivery Systems (1978) [Overview of the Initiative]

[0007] summary This disclosure provides novel indazole compounds and pharmaceutically acceptable salts as effective HPK1 inhibitors and dual activators for T cells and dendritic cells.

[0008] One embodiment of the present invention is given by formula (I):

[0009] [ka]

[0010] A compound of or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in which R 1 , R 2 , R 3 , R 4 , R 5 Het, M, and L are defined in the detailed description.

[0011] In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In yet another embodiment, a method is provided for treating a subject having a disease or disorder associated with HPK1 modulation, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0013] Detailed explanation The following statements are illustrative in nature and are not intended to limit the scope of this disclosure, application, or use.

[0014] definition Common terms used in this disclosure are defined herein for clarity.

[0015] This specification uses the terms "substituent," "radical," "group," "part," and "fragment." Use words interchangeably.

[0016] As used herein, the term "alkenyl" refers to a linear or branched hydrocarbonyl group having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond. In one embodiment, the alkenyl has 2 to 12 carbon atoms. In some embodiments, the alkenyl has C2 to C2 10 These are alkenyl groups or C2-C6 alkenyl groups. 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).

[0017] As used herein, the term "alkoxy" means RO- (wherein R is alkyl). Non-exclusive examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0018] As used herein, the term "alkoxysikialkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxysikialkyl groups include methoxymethyl, methoxyethyl, methoxypropyl and ethoxyethyl.

[0019] As used herein, the term "alkoxycarbonyl" is ROC(O)-, where R is an alkyl group as defined herein. In various embodiments, R is a C1-C 10 alkyl group or a C1-C6 alkyl group.

[0020] As used herein, the term "alkyl" refers to a straight-chain or branched-chain hydrocarbyl group. In one embodiment, alkyl has 1 to 12 carbon atoms. In some embodiments, alkyl is a C1-C 10 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 having 1 to 4 carbon atoms.

[0021] 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 an alkyl having any integer number of carbon atoms from 1 to 6.

[0022] 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 group is an alkyl as defined herein, the same or different. In various embodiments, R is a C1-C 10They are alkyl groups or C1-C6 alkyl groups. Examples of alkylamino groups include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and methylethylamino.

[0023] As used herein, the term "alkylaminoalkyl" refers to the alkyl moiety substituted with an alkylamino group, where alkylamino is as defined herein. Examples of alkylaminoalkyl (alkylaminoakyl) groups include methylaminomethyl and ethylaminomethyl.

[0024] As used herein, the term "alkynyl" refers to a linear or branched carbon chain group having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl has 2 to 12 carbon atoms. Some embodiments In this case, alkynyl is C2~C 10 These are alkynyl groups or C2-C6 alkynyl groups. Examples of alkynyl groups include acetylene (-C≡CH) and propargyl (-CH2C≡CH).

[0025] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring containing up to seven atoms in each ring, with at least one ring being aromatic, or to an aromatic ring system of 5 to 14 carbon atoms containing a carbocyclic aromatic group fused with a 5 or 6-membered cycloalkyl group. Typical examples of aryl groups include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azlenyl, and indanyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0026] As used herein, the term "cycloalkyl" refers to a hydrocarbyl group containing at least one saturated or partially unsaturated ring structure and bonded via a ring carbon. In various embodiments, it is a saturated or partially unsaturated C3-C3 group. 12 This refers to the cyclic part, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. "Cycloalkyloxy" is RO- (where R is cycloalkyl).

[0027] 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, and 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 and -CHF2.

[0028] As used herein, the term "heteroalkyl" refers to a linear or branched alkyl group having 2 to 14 carbon atoms (2 to 10 carbon atoms in some embodiments) in the chain, wherein one or more of the carbon atoms are replaced by heteroatoms selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, amides, and alkyl sulfides.

[0029] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic group comprising 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, including the heteroaryl as defined below. In various embodiments, the heterocyclic group is bonded to another part via carbon or via heteroatoms, and the carbon or heteroatoms are optionally substituted. Examples of heterocyclines include azetidinil, benzimidazolyl, benzofuranil, benzoflazanil, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carborinil, cinnolinil, furanil, imidazolyl, indolinil, indolyl, indazinil, indazolyl, isobenzofuranil, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanil, pyranil, pyrazinil, pyrazolyl, pyridadinil, pyridopyridinil, pyridadinil, pyridyl, pyrimidyl, pyrrolyl, quinazolinil, quinolyl, quinoxalinil, tetrahydropyranil, tetrahydro Thiopyranil, tetrahydroisoquinolinil, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinil, 1,4-dioxanil, hexahydroazepinyl, piperazinil, piperidinil, pyridine-2-onyl, pyrrolidinil, morpholinil, thiomorpholinil, dihydrobenzimidazolyl, dihydrobenzofuranil, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranil, dihydroimidazolyl, dihydroindolyl, dihydro This includes diisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroxazolyl, dihydropyradinyl, dihydropyradinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and their N-oxides. "Heterocyclyloxy" is RO- (wherein R is heterocyclyl). "Heterocyclylthio" is RS- (wherein R is heterocyclyl).

[0030] As used herein, the term “3- or 4-membered heterocyclyl” means a monocyclic ring having 3 or 4 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O, and S. Non-limiting examples of 3- or 4-membered heterocyclyls include azilidinyl, 2H-azilinyl, oxyranyl, thyranyl, azetidinyl, 2,3-dihydroazetyl, azetyl, 1,3-diazetidinyl, oxetanyl, 2H-oxetyl, thietanyl, and 2H-thiethyl.

[0031] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring having up to seven atoms in each ring, wherein at least one ring is aromatic, and which contains one to four heteroatoms selected from the group consisting of N, O, and S. Non-limiting examples of heteroaryls include pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridadinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, prinyl, thianaphthenyl, and pyrazinyl. Heteroaryl bonding can occur via an aromatic ring, or, if the heteroaryl is bicyclic or tricyclic and one of the rings is not aromatic or does not contain a heteroatom, it can occur via a non-aromatic ring or a ring that does not contain a heteroatom. "Heteroaryl" is also understood to include N-oxide derivatives of any nitrogen-containing heteroaryl. "Heteroaryloxy" is RO- (where R is heteroaryl).

[0032] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxyl group (-OH) such that alkoxy is as defined herein. An example of a hydroxyalkoxy is hydroxyethoxy.

[0033] As used herein, the term "hydroxyalkyl" refers to a linear or branched monovalent C1-C molecule substituted with at least one hydroxyl group. 10 The term refers to a hydrocarbon group, and examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0034] As used herein, the term “pharmaceutically acceptable” means pharmaceutical preparation This means that it is suitable for use in an object, is generally considered safe for such use, is publicly approved for such use by a national or state regulatory body, or is listed in the United States Pharmacopeia or any other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0035] As used herein, the term “pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, or carrier, or any other pharmaceutically acceptable component with which the compound of the present invention is administered.

[0036] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts, metal salts, and amine salts formed with inorganic or organic acids. Examples of acid addition salts formed with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids include, for example, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, and p-chlorobenzenesulfonic acid. Examples of acid addition salts formed with carboxylic acids include 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoeth)ic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoethic acid, salicylic acid, stearic acid, and muconic acid. Examples of metal salts include salts with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogen-containing bases strong enough to form salts with carboxylic acids.

[0037] As used herein, the term “substituted” means any of the above groups (i.e., alkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl) in which at least one hydrogen atom of the substituted moiety is replaced by a substituent. In one embodiment, each carbon atom of the substituted group is replaced by two or fewer substituents. In another embodiment, each carbon atom of the substituted group is replaced by one or fewer substituents. In the case of keto substituents, two hydrogen atoms are replaced by oxygen atoms bonded to the carbon via a double bond. Unless otherwise defined, substituents are halo, hydroxyl, (lower) alkyl, haloalkyl, mono- or di-alkylamino, aryl, heterocyclic, -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 (For example, sulfoximine), -(R a )S=NR b (For example, sulfirimine) and -SR a (In the formula, R a and R bThese are the same or different, and independently -H, halo, amino, alkyl, haloalkyl, aryl or heterocyclic, or R a and R b (These include nitrogen atoms to which they are bonded, forming a heterocycle.) a and R b There may be multiple atoms based on the atoms to which they are bonded.

[0038] As used herein, the term “therapeutic dose” means, when applied to the compounds of the present invention, a dose that relieves, alleviates, stabilizes, reverses, slows or delays the progression of a disorder or disease condition or the symptoms of a disorder or disease. This means that it is intended to represent a sufficient amount of the compound. In one embodiment, the method of the present invention provides an administration of a combination of compounds. In such an example, the “therapeutic dose” is the amount of the compounds of the present invention in a combination sufficient to produce the intended biological effect.

[0039] As used herein, the terms “treatment” or “to treat” mean to induce remission or reversal of the progression or severity of a disease or disorder, or to induce remission or reversal of one or more symptoms or side effects of such disease or disorder. “Treatment” or “to treat” also means, as used herein, to inhibit or block the progression of a system, state or condition of a disease or disorder, e.g., to delay, stop, suppress, interfere with or prevent it. For the purposes of the present invention, “treatment” or “to treat” further means an approach to obtain a beneficial or desired clinical outcome, where “beneficial or desired clinical outcome” includes, without limitation, symptom reduction, reduction of the degree of disorder or disease, stabilization (i.e., no worsening) of a disease or disorder condition, delay or slowing of a disease or disorder condition, remission or temporary relief of a disease or disorder condition, and improvement of the disease or disorder, whether partial or whole.

[0040] compound This disclosure is based on formula (I):

[0041] [ka]

[0042] A compound of or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the formula is: X is either O or S; L stands for bond, -O-, -S-, or -NR 6 -and; R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, and R 1 R 7 It is optionally substituted with one or more substituents independently selected from; R 6 is -H or C 1~6 It is alkyl; R 7 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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)2NR 10 R 11 , -NR 10 R 11 , -N(R 6 )NR 10 R 11 , -N(R 6 )OR 9 , -N(R 6 )C(O)R9 ,-N(R 6 )C(O)OR 9 ,-N(R 6 )C(O)NR 10 R 11 ,-N(R 6 )S(O)2R 9 ,-N(R 6 )S(O)2NR 10 R 11 、or -P(O)R 12 R 13 ; R 9 is -H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R 10 and R 11 is independently -H, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form 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 11It forms a 4- to 12-membered heterocycline, which is optionally substituted with one or more groups selected from the group consisting of; Each R 12 and R 13 Independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 It is cycloalkyl, aryl, heteroaryl, 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, -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 It forms a 4- to 8-membered heterocycline, which is optionally substituted with one or more groups selected from the group consisting of; Het is

[0043] [ka]

[0044] Selected from the group consisting of; R a , R b and R c Each of these is independently -H, -D, Halo, -CF3, -CF2H, -CH2F, -CN, -OR 9 or -NR 10 R 11and; R 2 -H, -D, -CD3, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, hydroxyl, -CD2OH, -CN, -NO2, haloalkyl, trimethylsilylethoxymethyl, -C(O)R 9 , -C(O)OR 9 -C(O)NR 10 R 11 , -OR 9 ,-OC(O)R 9 -OC(O)NR 10 R 11 , -SR 9 ,-S(O)R 9 -S(O)2R 9 -S(O)(=NH)R 10 -S(O)2NR 10 R 11 , -NR 10 R 11 , -N(R 6 )NR 10 R 11 , -N(R 6 )OR 9 , -N(R 6 )C(O)R 9 , -N(R 6 )C(O)R 9 , -N(R 6 )C(O)OR 9 , -N(R 6 )C(O)NR 10 R 11 , -N(R 6 )S(O)2R 9 , -N(R 6 )S(O)2NR 10 R 11 , or -P(O)R 12 R 13 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6Alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl 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 It is optionally substituted with one or more groups selected from the group consisting of; R 3 -H, -D, -CD3, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 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)2NR 10 R 11 , -NR 10 R 11 , -N(R 6 )NR 10 R 11 , -N(R6 )OR 9 , -N(R 6 )C(O)R 9 , -N(R 6 )C(O)OR 9 , -N(R 6 )C(O)NR 10 R 11 , -N(R 6 )S(O)2R 9 , -N(R 6 )S(O)2NR 10 R 11 , or -P(O)R 12 R 13 and; M stands for -O-, -S-, or -NR. 6 -and; R 6 is -H or C 1~6 It is alkyl; R 4 -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 , -C(O)OR 9 -C(O)NR 10 R 11 , - -S(O)2R 9 -S(O)(=NH)R 10 -S(O)2NR 10 R 11 , or -P(O)R 12 R 13 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl are 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 , -NR10 C(=O)OR 9 , -NR 10 S(O)2R 9 , -OR 9 -C(=O)R 9 , -C(=O)OR 9 -C(=O)NR 10 R 11 -OC(=O)R 9 , -OC(=O)OR 9 , and -OC(=O)NR 10 R 11 It is optionally substituted with one or more groups selected from the group consisting of; and R 5 -H, -D, -CD3, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkynyl, cycloalkyl, halo, hydroxyl, -CH2OH, -CD2OH, -CN, or haloalkyl, The present invention provides compounds or their pharmaceutically acceptable salts, hydrates, or solvates.

[0045] In some embodiments, L is a bond, and R 1 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, cycloalkyl, halo, 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 , -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 , and -N(R 6)C(O)NR 10 R 11 It is a cycloalkyl group that is optionally substituted with one or more groups selected from the group consisting of the following.

[0046] In some embodiments, R 2 and R 3 Each of these is independently -H, halo, alkylthio, haloalkyl, or alkyl.

[0047] In some embodiments, M is bonded, -O-, or -NR 6 - and R 4 -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 -C(O)NR 10 R 11 -S(O)2R 9 -S(O)(=NH)R 10 , or -S(O)2NR 10 R 11 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl are halo, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD3, -NR 10 R 11 , -NR 10 S(O)2R 9 , and -NR 10 C(=O)R 9 Select one or more groups from the group consisting of the above and place them as arbitrarily. It has been replaced.

[0048] In another embodiment, formula (II):

[0049] [ka]

[0050] The compound is provided, In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b M and L are defined above for equation (I).

[0051] In some embodiments, L is a bond; R 1 Hello, C 1~3 Alkyl, C 1~3 Hydroxyalkyl and C 1~3 Cyclopropyl is optionally substituted with one or more groups selected from the group consisting of haloalkyl groups; R 2 R is -H, alkyl, halo, haloalkyl, or alkylthio; 3 -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -and;R 4 These are -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamindoethyl, propionamideethyl, formamideethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamideethyl, imidazolylethyl, dioxanyl, cyclobutanylcarbonylaminoethyl, difluoroacetamideethyl, trifluoroacetamideethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamide)methyl, propanyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl, or methylpyrazolylmethyl; and R 5is -H, alkyl, or halo. Non-limiting exemplary compounds of formula (II) include Examples 1 and 2 in Table 1.

[0052] In another embodiment, formula (III):

[0053] [ka]

[0054] The compound is provided, In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b M and L are defined above for equation (I).

[0055] In some embodiments, L is a bond; R 1 Hello, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, and C 1~3 Cyclopropyl is optionally substituted with one or more groups selected from the group consisting of haloalkyl groups; R 2 R is -H, alkyl, halo, haloalkyl, or alkylthio; 3 -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -and;R 4These are -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamideethyl, imidazolylethyl, dioxanyl, cyclobutanylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propanyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl, or methylpyrazolylmethyl; and R 5 is -H, alkyl, or halo. Non-limiting exemplary compounds of formula (III) include Examples 3 and 23 in Table 1.

[0056] In another embodiment, formula (IV):

[0057] [ka]

[0058] The compound is provided, In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b M, L, and M are as defined above for formula (I). Non-limiting exemplary compounds of formula (IV) include Examples 24 and 307 in Table 1.

[0059] In some embodiments, L is a bond, and R 1 C 1~6Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, cycloalkyl, halo, 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 , -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 , and -N(R 6 )C(O)NR 10 R 11 It is a cycloalkyl group that is optionally substituted with one or more groups selected from the group consisting of the following.

[0060] In some embodiments, L is a bond; R 1 Hello, C 1~3 Alkyl, C 1~3 Hydroxyalkyl and C 1~3 The cycloalkyl group is optionally substituted with one or more groups selected from the group consisting of haloalkyl groups. In certain embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl.

[0061] In some embodiments, L is a bond; R 1 R is a cyclopropyl that is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; 2 R is -H, alkyl, haloalkyl, or halo; 3 -H, alkyl, or halo; M is a bond, -O-, or -NR 6-and;R 4 R is -H, halo, alkyl, monoalkylamino, or dialkylamino; 5 is -H, alkyl, or halo. In certain embodiments, L is a bond; R a is -H and R b is -H and R 1 R is a cyclopropyl substituted with chloro, fluoro, C1-C3 alkyl, C1-C3 hydroxyalkyl or C1-C3 haloalkyl; 2 R is -H, alkyl, chloro, or fluoro; 3 is -H, alkyl, chloro, or fluoro; M is bond, or -NH-; R 4 is -H, chloro, fluoro, methyl, ethyl, propyl, isopropyl, butyl, methylamino, or dimethylamino; and R 5 is -H or alkyl. In certain embodiments, L is a bond; R a is -H and R b is -H and R 1 is a cyclopropyl substituted with chloro or fluoro; R 2 is -H, chloro, or fluoro; R 3 is -H, chloro, or fluoro; M is a bond, or -NH-; R 4 is -H, ku Rolo, fluoro, methyl, ethyl, propyl, or isopropyl; and R 5 is -H. Non-limiting exemplary compounds having such substituents include Examples 61, 64, 84, 85, 86, 155, 156, and 157 in Table 1.

[0062] In some embodiments, L is a bond; R 1 R is a cyclopropyl that is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; 2 R is -H, alkyl, halo, haloalkyl, or alkylthio; 3-H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -and;R 4 is -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, monoalkylamino, or dialkylamino; and R 5 The substituent is -H, alkyl, or halo. Non-limiting exemplary compounds having such substituents include Examples 33, 39, 40, 46, 82, 102, 141, 166, 228, and 286 in Table 1.

[0063] In some embodiments, L is a bond; R 1 R is a cyclopropyl that is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; 2 R is -H, alkyl, halo, haloalkyl, or alkylthio; 3 -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -and;R 4 These are -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamideethyl, imidazolylethyl, dioxanyl, cyclobutanylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propanyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl, or methylpyrazolylmethyl; and R5 The substituent is -H, alkyl, or halo. Non-limiting exemplary compounds having such substituents are shown in Examples 26, 27, 34, 38, 41-44, 50, 58, 62, 63, 66, 68, 73, 77, 79, 80, 83, 87, 88, 90-92, 94, 96, 101, 105, 107, 110, 113, 116, 118-120, 128, 130, 131, 133, 134, 136, 141, 153, 160, 162, 16 Includes 6-168, 170, 173-176, 179, 181, 183, 186, 188, 190, 191, 194, 208, 210, 213, 215-219, 221, 223, 226, 228, 232, 235, 237, 248, 250, 252, 257, 261, 262, 264, 266, 268, 269, 272, 273, 284-290, 295, 300, and 302-305.

[0064] In one embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0065] Medical uses and treatment methods for the compound. This disclosure provides a method for treating a subject having a disease or disorder associated with HPK1 modulation, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject in need. In some embodiments, the disease or disorder associated with HPK1 modulation is cancer, metastasis, inflammation It is an immune disorder, including a disease or autoimmune disease.

[0066] In some other embodiments, the disease is cancer, metastasis, inflammation, or autoimmune disease. In certain embodiments, cancer is selected from the group consisting of carcinomas, melanomas, blastomas, sarcomas, lymphomas, and leukemias, including, without limitation, bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid cancer, and nephroblastoma (Wilms' tumor).

[0067] In some embodiments, autoimmune diseases include inflammatory bowel disease, Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, hemolytic anemia, autoimmune hepatitis, Behçet's disease, Buerger's disease, bullous pemphigoid, cardiomyopathy, celiac sprue, chronic fatigue immunodeficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, cold agglutinin disease, type 1 diabetes mellitus, discoid lupus, essential mixed cryoglobulinemia, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hypothyroidism, autoimmune lymphoproliferative syndrome (ALPS), idiopathic pulmonary fibrosis, and idiopathic hemoptysis. These include leptomeningeal purpura (ITP), juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polychondritis, autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's arteritis, giant cell arteritis, ulcerative colitis, uveitis, vasculitis, or granulomatous diseases with polyangiitis.

[0068] In another embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for the production of a pharmacopoeia for inhibiting HPK1 activity in subjects requiring inhibition of HPK1 activity. In some embodiments, the use includes the treatment of cancer.

[0069] Preferred subjects to be treated pursuant to this disclosure include mammalian subjects. Mammals as defined herein include, but are not limited to, humans, dogs, cattle, cattle, goats, horses, sheep, pigs, rodents, lagomorphs, and primates, and also include mammals in utero. Subjects may be of any sex and any stage of development. In one embodiment, a preferred subject to be treated pursuant to this disclosure is a human.

[0070] The compounds of this disclosure are generally administered in therapeutically effective doses. The compounds of this disclosure may be administered by any preferred route in the form of a pharmaceutical composition adapted to such route, and in doses effective for the intended treatment. Effective doses are typically in the range of about 0.01 to about 1000 mg / kg body weight / day, preferably about 0.01 to about 500 mg / kg / day, in single or divided doses. Depending on age, species, and the disease or condition being treated, dose levels below the lower end of this range may be preferred. In other cases, higher doses may be used without adverse side effects. Higher doses may also be divided into several smaller doses for administration throughout the day. Methods for determining a preferred dose are well known in the art relating to this disclosure. For example, Non-Patent Literature 2 may be used.

[0071] Pharmaceutical composition, dosage form, and route of administration For the treatment of any disease or condition mentioned above, the compounds described herein or their pharmaceutically acceptable salts may be administered as follows:

[0072] Oral administration The compounds of this disclosure may be administered orally, including by ingestion, so that the compounds enter the gastrointestinal tract, or 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, and optionally with enteric coating. Liquid formulations may include solutions, syrups, and suspensions, which may be used in soft or hard capsules. Such formulations may contain pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations may also contain one or more emulsifiers and / or suspending agents.

[0073] In tablet formulations, the amount of drug present may be approximately 0.05% to 95% of the weight of the formulation, more typically 2% to 50% of the weight. Additionally, tablets may contain disintegrants comprising approximately 0.5% to 35% of the weight of the formulation, more typically 2% to 25%. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0074] 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, and sodium stearyl fumarate.

[0075] Suitable binders for use in tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Suitable diluents for use in tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0076] 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, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR® (Nikkol), oleyl esters, Gelucire®, caprylic / caprylic / diglyceride, sorbitan fatty acid esters, and Solutol HS®.

[0077] Parenteral administration The compounds of this disclosure may be administered directly into the bloodstream, muscles, or viscera. Preferred means for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, and intracranial methods. Preferred devices for parenteral administration include syringes (needle and needle-free syringes) and methods of administration.

[0078] 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, including salts, buffers, and isotonic agents. Parenteral formulations may also be prepared in a dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations It can be used with a suitable medium, such as sterile water. Solubility enhancers may also be used in the preparation of parenteral solutions.

[0079] Transdermal administration The compounds of this disclosure may be administered topically to the skin or transdermally. Formulations for topical administration may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, and patches. Physically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, and polyethylene glycol. Topical or transdermal administration may also be carried out by electroporation, iontophoresis, and phonophoresis. Compositions for topical administration may be formulated as immediate or modified releases, including delayed or sustained releases.

[0080] Combination therapy The pharmaceutical compositions according to this disclosure may contain one or more additional therapeutic agents, for example, those for increasing efficacy or reducing side effects. Thus, in some embodiments, the pharmaceutical composition 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 are, without limitation, agents for treating cancer, metastasis, inflammation, or autoimmune pathologies. 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.

[0081] References for preparing pharmaceutical compositions Methods for preparing pharmaceutical compositions for treating or preventing diseases or conditions are well known in the art relating to this disclosure. For example, based on Non-Patent Document 3, Non-Patent Document 2, Non-Patent Document 4, or Non-Patent Document 5, pharmaceutically acceptable excipients, carriers, additives, etc., can be selected and then mixed with the compounds of this disclosure to make a pharmaceutical composition.

[0082] This disclosure provides compounds having various pharmacological effects by inhibiting HPK1 activity, pharmaceutical compositions having said compounds as effective agents, medical uses of said compounds, particularly for treating diseases or disorders modulated by HPK1, and methods of treatment or prevention comprising administering said compounds to subjects requiring such treatment or prevention. The compounds of this disclosure and their pharmaceutically acceptable salts have good safety and high selectivity for HPK1, and therefore exhibit excellent properties as drugs. [Examples]

[0083] Preparation of compounds The following preparation examples illustrate the preparation of intermediate compounds useful for preparing the compound of formula (I). In addition to the novel intermediate compounds described herein, synthetic processes useful for preparing intermediate compounds represent embodiments of the present invention.

[0084] Intermediate 1A. 1-(tetrahydro-2H-pyran-2-yl)-5-(thiophen-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate

[0085] [ka]

[0086] Step 1) 3-bromo-4-chloro-5-fluoro-2-methylaniline N-chlorosuccinimide (36 g, 270 mmol, 1.1 eq) was added to a solution of 3-bromo-5-fluoro-2-methylaniline (50 g, 245 mmol, 1 eq) in AcOH (100 mL). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum, and the residue was extracted with dichloromethane (200 mL x 2). The combined organic layers were washed with saturated NaHCO3 (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product (66 g, crude) was obtained as black oil.

[0087] Step 2) 4-bromo-5-chloro-6-fluoro-1H-indazole Sodium nitrite (8.96 g, 130 mmol, 1.2 eq) was added to a solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (25.8 g, 108 mmol, 1 eq) in AcOH (1.96 L, 0.05 M) and H2O (0.065 L, 1.5 M). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum, and the residue was extracted with dichloromethane (1 L x 2). The combined organic layers were washed with saturated NaHCO3 (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product (23.6 g, crude) was obtained as a brown solid.

[0088] Step 3) 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (1.98 g, 7.97 mmol, 1 eq) in THP (40 mL), 3,4-dihydro-2H-pyran (2.18 ml, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq) were added. The reaction mixture was stirred at 70°C for 14 hours. The reaction mixture was extracted with ethyl acetate and dried on MgSO4. The organic residue was purified by column chromatography (silical gel, Hex:ethyl acetate = 1:0 → 4:1). 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.51 g, 4.54 mmol, 57% yield) was obtained.

[0089] 1 H NMR (400MHz, DMSO-d6) δ 8.16(s, 1H), 8.00(dd, J=9.3, 1.1Hz, 1H), 5.85(dd, J=9.6, 2.5Hz , 1H), 3.87(d, J=12.6Hz, 1H), 3.79-3.72(m, 1H), 2.38-2.30(m, 1H), 2.04-1.94(m, 2H), 1.77-1.55(m, 3H).

[0090] Intermediate 1B. 4-bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0091] [ka]

[0092] Step 1) 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole N-iodosuccinimide (2.7 g, 12.03 mmol) was added in fractions to a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (2 g, 8.02 mmol) in sulfuric acid (1.7 mL). The mixture was stirred at 0°C for 3 hours. After the reaction was complete, the mixture was poured into ice water, quenched with solid NaOH, and then extracted with dichloromethane. The combined organic residue was concentrated under vacuum (2.99 g, crude).

[0093] 1 H NMR (400MHz, DMSO-d6) δ 13.91 (s, 1H), 8.27 (d, J=1.6Hz, 1H).

[0094] Step 2) 4-bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole To a solution of 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole (2.99 g, 7.97 mmol, 1 eq) in THF (40 mL), 3,4-dihydro-2H-pyran (2.18 ml, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq) were added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was extracted with ethyl acetate and dried over MgSO4. The organic residue was purified by column chromatography (silica gel, Hex:ethyl acetate = 1:0 → 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.

[0095] 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 5.80 (dd, J = 9.9, 2.7 Hz, 1H), 5.66 (s, 1H), 4.02 (t, J = 6.6 Hz, 1H), 3.85 - 3.70 (m, 1H), 2.33 - 2.21 (m, 1 H), 2.08 - 1.91 (m, 2H), 1.79 - 1.45 (m, 4H).

[0096] Intermediate 1C. 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

[0097]

Chemical Structure

[0098] Step 1) 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole 4-Bromo-5-chloro-6-fluoro-1H-indazole (10 g, 40.09 mmol, 1 eq) was slowly added to a mixture of HNO3 (12.63 g, 200.43 mmol, 9.02 mL, 5 eq) in H2SO4 (50 mL) stirred at 0 °C. After the addition, the mixture was stirred at 0 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 3:1) indicated that all reactants were consumed and a major new spot appeared. The mixture was poured into ice water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated to obtain 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (12 g, crude) as a yellow solid.

[0099] Step 2) 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (2.34 g, 7.97 mmol, 1 eq) in THF (40 mL), 3,4-dihydro-2H-pyran (2.18 ml, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq) were added. The reaction mixture was stirred at 60°C for 14 hours. The reaction mixture was extracted with ethyl acetate and dried over MgSO4. The organic residue was purified by column chromatography (silica gel, Hex:ethyl acetate = 1:0 → 4:1). 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.65 g, 4.35 mmol, 54.7% yield) was obtained.

[0100] Step 3) 4-bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole in EtOH (5 mL) and H2O (5 mL) To a solution of (600 mg, 1.58 mmol, 1 eq), NH4Cl (508.66 mg, 9.51 mmol, 6 eq) and Fe (531.04 mg, 9.51 mmol, 6 eq) were added, and the reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1). 4-bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine (390 mg, 1.12 mmol, 70.59% yield) was obtained as a yellow oil.

[0101] 1 H NMR (400MHz, DMSO-d6) δ 8.41(s, 1H), 5.85(br s, 2H), 5.71(br d, J=8.0Hz, 1H), 4.00(br d, J=11.3Hz, 1H), 3.77 - 3.59(m, 1H), 2.29 - 2.17 (m, 1H), 2.10 - 1.91 (m, 2H), 1.78 - 1.54 (m, 3H).

[0102] Intermediate 1D,4-bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine

[0103] [ka]

[0104] Step 1) 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole To a solution of intermediate 1A (900 mg, 3.61 mmol, 1 eq) in H2SO4 (10 mL) (98% purity), HNO3 (419.69 mg, 4.33 mmol, 299.78 μL, 1.2 eq) (65% purity) was added dropwise at -15°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was slowly poured into ice water (20 mL), and the pH of the mixture was adjusted to pH=7 using a saturated aqueous solution of NaOH. The mixture was then extracted with ethyl acetate (30 mL x 2), the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, crude) was obtained as a yellow solid.

[0105] 1 H NMR (400MHz, DMSO-d6) δ 14.36 (br s, 1H), 8.37 (br s, 1H).

[0106] Step 2) 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, 3.06 mmol, 1 eq) (crude) in DCM (10 mL), TsOH.H2O (58.14 mg, 305.64 µl, 0.1 eq) and DHP (771.27 mg, 9.17 mmol, 838.34 µL, 3 eq) were added, and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), the mixture was washed with saturated aqueous solution of NaHCO3 (15 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 40 / 1 → 25:1; 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole emerged at petroleum ether / ethyl acetate = 40 / 1, and 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole emerged at petroleum ether / ethyl acetate = 25 / 1). 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 528.29 umol, 17.28% yield) was obtained as a brown solid. 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (600 mg, 1.58 mmol, 51.85% yield) was obtained as a yellow solid.

[0107] 4-Bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0108] 1H NMR (400MHz, DMSO-d6) δ 8.43(s, 1H), 5.50(dd, J=2.8, 7.8Hz, 1H), 3.45 - 3.38(m, 2H), 2.35 - 2.27(m, 1H), 2.23 - 2.14 (m, 1H), 1.92 (td, J=4.6, 13.6Hz, 1H), 1.68 (ddt, J=4.0, 10.1, 13.9Hz, 1H), 1.59 - 1.36 (m, 2H).

[0109] 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0110] 1 H NMR (400MHz, DMSO-d6) δ 8.99(s, 1H), 5.86(dd, J=2.7, 9.7Hz, 1H), 4.08 - 3.96(m, 1H), 3.81 - 3.68(m, 1H), 2.28 - 2.14(m, 1H), 2.14 - 2.02 (m, 1H), 2.02 - 1.89 (m, 1H), 1.78 - 1.67 (m, 1H), 1.64 - 1.56 (m, 2H).

[0111] Step 3) 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 528.29 ml, 1 eq) in EtOH (5 mL) and H2O (5 mL), NH4Cl (169.55 mg, 3.17 mmol, 6 eq) and Fe (177.03 mg, 3.17 mmol, 6 eq) were added, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated to remove EtOH, the mixture was then diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine (140 mg, crude) was obtained as a yellow solid.

[0112] Step 4) 4-Bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine A solution of 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine (120 mg, 344.24 umol, 1 eq) in THF (5 mL) was added NaH (34.42 mg, 860.59 umol, 60% purity, 2.5 eq) portionwise at 0 °C under N2. Next, the mixture was stirred at 0 °C for 30 min under N2, and then MeI (293.16 mg, 2.06 mmol, 128.58 uL, 6 eq) was added dropwise. The reaction mixture was stirred at 20 °C for 12 h under N2. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (20 mL), and then the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5:1). Intermediate 1E (30 mg, 78.06 umol, 22.68% yield, 98% purity) was obtained as a yellow oil.

[0113] Intermediate 1E. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0114]

Chemical Structure

[0115] To a solution of intermediate 1B (100 mg, 0.218 mmol, 1 eq) in 2-methyl-2-butanol (1.09 mL), Xantphos Pd G3 (21 mg, 21.8 μmol, 0.1 eq) and Cs2CO3 (142 mg, 0.436 mmol, 2.0 eq) were added. The mixture was degassed, purged three times with N2, and then propan-2-amine (0.19 mL, 2.18 mmol, 10 eq) was added. The mixture was stirred in a sealed tube at 90°C for 3 hours. The reaction mixture was diluted with H2O (40 mL) and then extracted with DCM (50 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (the product emerged at hexane / ethyl acetate = 10 / 1) to obtain intermediate 1E (47 mg A beige solid (0.120 mmol, 55% yield) was obtained.

[0116] 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).

[0117] Intermediate 1F.4-bromo-5-chloro-6-fluoro-N-isopropyl-N-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0118] [ka]

[0119] To a solution of intermediate 1E (600 mg, 1.54 mmol, 1.0 eq) in methanol (7.7 mL), formaldehyde (0.572 mL, 7.68 mmol, 5.0 eq) and acetic acid (88 μL, 1.54 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 10 minutes. Sodium borohydride cyanohydride (290 mg, 4.61 mmol, 3.0 eq) was added, and the mixture was then stirred at room temperature for 16 hours. The reaction mixture was quenched with H2O and extracted with ethyl acetate (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (the product emerged at hexane / ethyl acetate = 100 / 4) to obtain intermediate 1F (292 mg, 0.722 mmol, 47% yield) as brown oil.

[0120] 1 H NMR (400MHz, DMSO-d6) δ 8.51(s, 1H), 5.75(dd, J=9.3, 2.7Hz, 1H), 4.14-4.05(m, 1H), 4.00-3.93(m, 1H), 3.78-3.67(m, 1H), 2 .92(d, J=4.4Hz, 3H), 2.23-2.20(m, 1H), 2.05-1.95(m, 2H), 1.75-1.60(m, 3H), 1.17(d, J=6.6Hz, 6H).

[0121] Intermediate 1G.4-bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine

[0122] [ka]

[0123] Step 1) 4-bromo-5-chloro-6-fluoro-1H-indazole-7-amine To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (12 g, 40.75 mmol, 1 eq) in EtOH (100 mL) and H2O (40 mL), Fe (6.83 g, 122.26 mmol, 3 eq) and NH4Cl (6.54 g, 122.26 mmol, 3 eq) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The reaction mixture was filtered through a Celite cake, and the filtrate was concentrated to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 → 3 / 1). 4-bromo-5-chloro-6-fluoro-1H-indazole-7-amine (5 g, 18.90 mmol, 46.39% yield) was obtained as a yellow solid.

[0124] Step 2) N-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)acetamide To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole-7-amine (3 g, 11.34 mmol, 1 eq) in AcOH (30 mL), Ac2O (1.39 g, 13.61 mmol, 1.27 mL, 1.2 eq) was added, and the reaction mixture was heated to 80 °C and reacted for 3 hours. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 → 4 / 1) to obtain N-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)acetamide (3 g, 9.79 mmol, 86.29% yield) as a yellow solid.

[0125] Step 3) 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazole-7-amine To a solution of LAH (520.00 mg, 13.70 mmol, 1.5 eq) in THF (50 mL), a solution of N-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)acetamide (2.8 g, 9.13 mmol, 1 eq) in THF (100 mL) was added dropwise under N2 conditions at 0°C. After addition, the reaction mixture was warmed to 25°C and allowed to react for 16 hours. The mixture was poured into water (500 mL), extracted with ethyl acetate (100 mL x 2), the combined organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 → 2 / 1) to obtain 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazole-7-amine (1 g, 3.42 mmol, 37.42% yield) as a yellow solid.

[0126] Step 4) 4-Bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine To a solution of 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazole-7-amine (1.4 g, 4.79 mmol, 1 eq) and HCHO (718.48 mg, 23.93 mmol, 659.16 μL, 5 eq) in MeOH (50 mL), NaBH3CN (902.21 mg, 14.36 mmol, 3 eq) and AcOH (287.38 mg, 4.79 mmol, 273.70 μL, 1 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 → 5 / 1) to obtain 4-bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine (1.4 g, 4.57 mmol, 95.42% yield) as a white solid.

[0127] Intermediate 1H,4-bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0128] [ka]

[0129] To a solution of 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.50 mmol, 1 eq) in THF (10 mL), LDA (2 M, 1.87 mL, 2.5 eq) was added dropwise at -78°C. After the addition, the mixture was stirred at this temperature for 2.5 hours, and then MeI (319.12 mg, 2.25 mmol, 139.97 μL, 1.5 eq) was added dropwise at -78°C. The resulting mixture The mixture was stirred at 20°C for 16 hours. The mixture was poured into saturated NH4Cl and extracted with EA (20 mL). The organic layer was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 → 10 / 1). The desired product, 4-bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.38 g, 1.09 mmol, 72.93% yield), was obtained as a white solid.

[0130] Intermediate 1I,4-bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazole-7-amine

[0131] [ka]

[0132] Step 1) 4-bromo-6-fluoro-7-nitro-1H-indazole To a solution of 4-bromo-6-fluoro-1H-indazole (10 g, 46.51 mmol, 1 eq) in H2SO4 (80 mL) (98% purity), KNO3 (4.70 g, 46.51 mmol, 1 eq) was added in fractions at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was then poured into ice water (200 mL), the mixture was extracted with ethyl acetate (100 mL x 2), the combined organic layer was washed with saturated aqueous solution of NaHCO3 (100 mL x 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1 → 1 / 1; the product 4-bromo-6-fluoro-7-nitro-1H-indazole appeared at petroleum ether / ethyl acetate = 8 / 1) to obtain 4-bromo-6-fluoro-7-nitro-1H-indazole (2.7 g, 10.38 mmol, 22.32% yield) as a yellow solid and crude product. The crude product was purified by MPLC (petroleum ether / ethyl acetate) to obtain 4-bromo-6-fluoro-7-nitro-1H-indazole (3.57 g, 13.73 mmol, 29.52% yield) as a yellow solid.

[0133] Step 2) 4-bromo-6-fluoro-5-iodo-7-nitro-1H-indazole To a solution of 4-bromo-6-fluoro-7-nitro-1H-indazole (2.7 g, 10.38 mmol, 1 eq) in H2SO4 (30 mL), NIS (7.01 g, 31.15 mmol, 3 eq) was added at 25 °C. The reaction mixture was stirred at 50 °C for 16 hours. The mixture was quenched with ice water (50 mL). The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with aqueous solutions of Na2SO3 (20 mL x 2), NaHCO3 (20 mL x 2), and brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain 4-bromo-6-fluoro-5-iodo-7-nitro-1H-indazole (3.4 g, 8.81 mmol, 84.85% yield) as a yellow solid.

[0134] 1 H NMR (400MHz, DMSO-d6) δ 14.28 (br s, 1H), 8.30 (s, 1H).

[0135] Step 3) 4-bromo-6-fluoro-5-iodo-1H-indazole-7-amine To a solution of 4-bromo-6-fluoro-5-iodo-7-nitro-1H-indazole (3.4 g, 8.81 mmol, 1 eq) in EtOH (50 mL) and H2O (25 mL), NH4Cl (2.83 g, 52.86 mmol, 6 eq) was added, followed by the addition of Fe (2.95 g, 52.86 mmol, 6 eq) in fractions at 60°C. The mixture was stirred at 80°C for 1 hour. The reaction mixture was filtered through Celite while it was still warm. The filtrate was then concentrated under vacuum to remove EtOH. The resulting aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (MPLC, petroleum ether / ethyl acetate = 5 / 1 → 2 / 1; the product emerged at petroleum ether / ethyl acetate = 2 / 1) to obtain 4-bromo-6-fluoro-5-iodo-1H-indazole-7-amine (2.2 g, 6.18 mmol, 70.16% yield) as a gray solid.

[0136] 1 H NMR (400MHz, DMSO-d6) δ 13.09 (br s, 1H), 7.86 (d, J=1.7Hz, 1H), 5.62 (s, 2H).

[0137] Step 4) 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine To a solution of 4-bromo-6-fluoro-5-iodo-1H-indazole-7-amine (2.2 g, 6.18 mmol, 1 eq) in MeOH (50 mL), AcOH (1.11 g, 18.54 mmol, 1.06 mL, 3 eqs) and HCHO (5.02 g, 61.81 mmol, 4.60 mL, 10 eqs) were added, followed by the addition of NaBH3CN (3.88 g, 61.81 mmol, 10 eqs) in fractions at 40°C. Gas was released and the temperature rose. The suspension was stirred at 25°C for 16 hours. The reaction mixture was poured into water (50 mL), the mixture was concentrated to remove MeOH, and then the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1 → 8 / 1; the product emerged at petroleum ether / ethyl acetate = 8 / 1) to obtain 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine (2.05 g, 5.34 mmol, 86.37% yield) as an off-white solid.

[0138] Step 5) 4-bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazole-7-amine In a 100 mL bottle equipped with a magnetic stirring rod, 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine (1.2 g, 3.13 mmol, 1 eq), NaSMe (328.56 mg, 4.69 mmol, 1.5 eq), Xantphos (361.65 mg, 625.02 mmol, 0.2 eq), K2CO3 (1.30 g, 9.38 mmol, 3 eq), dioxane (20 mL), and Pd2(dba)3( 286.17 mg, 312.51 ml, 0.1 eq) were added sequentially. The bottle was vacuumed and refilled with nitrogen. The mixture was then stirred under a nitrogen atmosphere at 90°C for 16 hours. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 20 / 1 → 8 / 1, the product appeared at petroleum ether / ethyl acetate = 10 / 1) to obtain 4-bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazole-7-amine (540 mg, 1.78 mmol, 56.81% yield) as an orange solid.

[0139] 1 H NMR (400MHz, DMSO-d6) δ 13.59 (br s, 1H), 8.00 (d, J=1.6Hz, 1H), 2.91 (d, J=2.4Hz, 6H), 2.39 (s, 3H).

[0140] Intermediate 1J,4-bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazole-7-amine

[0141] [ka]

[0142] To a solution of 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine (1.0 g, 2.61 mmol, 1 eq) and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.00 g, 5.22 mmol, 664.45 μL, 2 eq) in DMF (10 mL), CuI (994.63 mg, 5.22 mmol, 2 eq) was added. The mixture was stirred at 100 °C for 6 hours under an N2 atmosphere. The reaction mixture was filtered, the filtrate was diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 → 10:1). 4-bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazole-7-amine (502 mg, 1.54 mmol, 58.91% yield) was obtained as a yellow solid.

[0143] Intermediate 1K, 4-bromo-5-ethyl-6-fluoro-1H-indazole

[0144] [ka]

[0145] Step 1) 4-bromo-5-ethyl-6-fluoro-2-trityl-2H-indazole To a solution of diisopropylamine (132.75 mg, 1.31 mmol, 185.41 μL, 1.2 eq) in THF (5 mL), n-BuLi (2.5 M, 481.04 μL, 1.1 eq) was slowly added at -78°C for 0.5 hours under an N2 atmosphere. Next, a solution of 4-bromo-6-fluoro-2-trityl-2H-indazole (500 mg, 1.09 mmol, 1 eq) in THF (2 mL) was added dropwise to the solution. After stirring the mixture at -78°C for 0.5 hours, a solution of EtI (204.62 mg, 1.31 mmol, 104.93 μL, 1.2 eq) in THF (2 mL) was added to the mixture, and the solution was warmed to 15°C and stirred under an N2 atmosphere for 2 hours. The reaction mixture was quenched at 15°C by adding aqueous saturated NH4Cl (3 mL), diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. 4-bromo-5-ethyl-6-fluoro-2-trityl-2H-indazole (500 mg, crude) was obtained as a yellow solid.

[0146] Step 2) 4-bromo-5-ethyl-6-fluoro-1H-indazole To a solution of 4-bromo-5-ethyl-6-fluoro-2-trityl-2H-indazole (500 mg, 1.03 mmol, 1 eq) in DCM (6 mL), TFA (3.08 g, 27.01 mmol, 2.00 mL, 26.22 eq) was added. The mixture was stirred at 15°C for 4 hours. The pH of the reaction mixture was adjusted to 7 with saturated aqueous NaHCO3, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex® luna C18 150 × 40 mm × 15 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%~70%, 10 min). The fraction was concentrated under reduced pressure to remove ACN, and the pH of the aqueous solution was adjusted to 7 with saturated aqueous NaHCO3. The aqueous solution was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the product. 4-bromo-5-ethyl-6-fluoro-1H-indazole (70 mg, 287.98 umol, 27.96% yield) was obtained as a yellow solid.

[0147] 1 H NMR (400MHz, DMSO-d6) δ 13.39 (br s, 1H), 8.01 - 7.98 (m, 1H), 7.41 (d, J=9.9Hz, 1H), 2.83 (dq, J=2.4, 7.5Hz, 2H), 1.14 (t, J=7.5Hz, 3H).

[0148] Intermediate 1L: 4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine

[0149] [ka]

[0150] Step 1) 6-Fluoro-5-nitro-1H-indazole To a solution of 6-fluoro-1H-indazole (4.4 g, 32.32 mmol, 1 eq) in H2SO4 (30 mL), HNO3 (2.44 g, 38.79 mmol, 1.75 mL, 1.2 eq) was added dropwise at -15°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was slowly poured into ice water (100 mL), and the mixture was then extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 6-fluoro-5-nitro-1H-indazole (5.4 g, crude) as a yellow solid.

[0151] Step 2) 6-Fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A mixture of crude 6-fluoro-5-nitro-1H-indazole (4.9 g, 27.05 mmol, 1 eq) in DCM (50 mL) was mixed with DHP (6.83 g, 81.16 mmol, 7.42 mL, 3 eq) and TsOH.H2O (514.60 mg, 2.71 mmol, 0.1 eq), and the reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO3 (100 mL), and the mixture was then extracted with dichloromethane (50 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 → 15:1). 6-Fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3 g, 11.31 mmol, 41.81% yield) was obtained as a yellow solid.

[0152] 1 H NMR (400MHz, DMSO-d6) δ 8.78(d, J=7.3Hz, 1H), 8.41(s, 1H), 7.97(d, J=12.1Hz, 1H), 5.90(dd, J=2.1, 9.7Hz, 1H), 3.94 - 3.85(m, 1H), 3. 82 - 3.72 (m, 1H), 2.43 - 2.28 (m, 1H), 2.10 - 1.93(m, 2H), 1.82 - 1.34(m, 3H).

[0153] Step 3) 6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine A solution of 6-fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.9 g, 10.93 mmol, 1 eq) in MeOH (30 mL) was mixed with wet Pd / C (300 mg, 10% purity) under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 15°C for 4 hours under H2 (15 Psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 → 8:1). 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine (1.5 g, 5.87 mmol, 53.65% yield, 92% purity) was obtained as a red brick-colored solid.

[0154] 1 H NMR (400MHz, DMSO-d6) δ 7.82(s, 1H), 7.43(d, J=11.6Hz, 1H), 6.98(d, J=8.6Hz, 1H), 5.66(dd, J=2.3, 9.7Hz, 1H), 4.91(s, 2H), 3.85(br d. 1.51(m, 2H); LCMS (electrospray) m / z 236.1(M+H)+.

[0155] Step 4) 4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine To a solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine (1.45 g, 5.67 mmol, 1 eq) in MeCN (10 mL), NBS (1.21 g, 6.80 mmol, 1.2 eq) was added in fractions at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to obtain the residue. Next, the residue was dissolved in ethyl acetate (30 mL), the mixture was washed with brine (15 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1). 4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine (1.3 g, 4.14 mmol, 72.98% yield) was obtained as a brown solid.

[0156] 1 H NMR (400MHz, DMSO-d6) δ 7.80(s, 1H), 7.60(d, J=10.6Hz, 1H), 5.71(dd, J=2.5, 9.6Hz, 1H), 5.15(s, 2H), 3.88 - 3.82(m, 1H), 3.76 - 3.68 (m, 1H), 2.36 - 2.27 (m, 1H), 2.02 (br dd, J=4.6, 8.5Hz, 1H), 1.96 - 1.90 (m, 1H), 1.76 - 1.65 (m, 1H), 1.60 - 1.52 (m, 2H).

[0157] Intermediate 1M.3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentan-1-ol

[0158] [ka]

[0159] Step 1) 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carboaldehyde To a mixture of intermediate 1A (3g, 8.99 mmol, 1eq) in THF (60 mL), LDA (2M, 17.99 mL, 4eq) was added dropwise under N2 at -78°C. The mixture was stirred at -78°C for 1 hour. Then, HCO2Et (3.17g, 35.97 mmol, 3.52 mL, 4eq) in THF (8 mL) was added dropwise at -78°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched at -78°C by adding saturated NH4Cl solution (20 mL), and then extracted with EA (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 → 20 / 1). 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carboaldehyde (2.78 g, 7.69 mmol, 85.49% yield) was obtained as an off-white solid.

[0160] 1 ¹H NMR (400MHz, DMSO-d6) δ 10.40 (s, 1H), 8.35 (s, 1H), 6.09 (dd, J=2.6, 8.9Hz, 1H), 3.71 - 3.63 (m, 1H), 3.63 - 3.52 (m, 1H), 2.42 - 2.30 (m, 1H), 2.21 - 2.10 (m, 1H), 2.07 - 1.95 (m, 1H), 1.77 - 1.63 (m, 2H), 1.60 - 1.40 (m, 2H); LCMS (electrospray) m / z 278.9 (M+H)+.

[0161] Step 2) 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-yl)buta-3-en-1-ol 4-bromo-5-chloro-6-fluoro-1-(tetrahydro) in THF (60 mL) A mixture of -2H-pyran-2-yl)-1H-indazole-7-carbaldehyde (2.2 g, 6.08 mmol, 1 eq) was mixed with allyl magnesium bromide (1 M, 9.13 mL, 1.5 eq) dropwise at 0°C under N2 conditions. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched at 0°C by adding saturated NH4Cl solution (20 mL), and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 5 / 1). 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-yl)buta-3-en-1-ol (2 g, 4.95 mmol, 81.43% yield) was obtained as a colorless oil.

[0162] 1 H NMR (400MHz, DMSO-d6) δ 8.25 - 8.21(m, 1H), 8.20 - 8.18(m, 1H), 6.61(br d, J=9.0Hz, 1H), 6.23(d, J=4.0Hz, 1H), 6.18(br d. d, J=11.5Hz, 1H), 3.89(br d, J=11.3Hz, 1H), 3.69 - 3.55 (m, 2H), 2.87 - 2.74 (m, 2H), 2.70 - 2.55 (m, 4H), 2.06 (br d, J=10.8Hz, 3H), 1.96 - 1.87 (m, 1H), 0.90 - 0.78 (m, 1H); LCMS (Electrospray) m / z 302.9 (M+H)+.

[0163] Step 3) 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole To a mixture of 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-yl)buta-3-en-1-ol (2 g, 4.95 mmol, 1 eq) in DCM (20 mL), Br2 (1.19 g, 7.43 mmol, 383.11 uL, 1.5 eq) in DCM (2 mL) was added dropwise under N2 at -20°C. The mixture was stirred at -10°C for 3 hours. The mixture was quenched by adding Na2SO3 solution (30 mL) and then diluted with DCM (30 mL). The organic layer was washed with Na2SO3 solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was dissolved in MeOH (15 mL), then K2CO3 (2.05 g, 14.86 mmol, 3 eq) was added, and the resulting mixture was stirred at 20°C for 16 hours. The reaction was quenched by adding water (20 mL), extracted with EA (30 mL x 3), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 3:1). The crude product was purified by reverse-phase HPLC (0.1% FA conditions). 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole (300 mg, 752.91 ml, 15.20% yield) was obtained as a white solid.

[0164] 1 H NMR (400MHz, DMSO-d6) δ 13.44 - 13.37 (m, 2H), 8.14 - 8.11 (m, 2H), 5.71 - 5.67 (m, 1H), 5.44 (dt, J=1.2, 7.5Hz, 1H), 4.97 (s, 1H), 4.83 - 4.76(m, 2H), 4.47(dd, J=3.7, 10.1Hz, 1H), 4.22(dd, J=5.5, 10.1Hz, 1H), 4.15(dd, J=2.3, 10.6Hz, 1H), 3.20 - 3.13(m, 1H), 2.69 - 2.64(m, 1H), 2.34 - 2.27 (m, 2H); LCMS (electrospray) m / z 398.8 (M+H)+.

[0165] Step 4) 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentyl acetate To a mixture of 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole (100 mg, 250.97 umol, 1 eq) in DMSO (2 mL), KOAc (73.89 mg, 752.91 umol, 3 eq) was added in one part under N2 at 20 °C. The mixture was then heated to 70 °C and stirred for 3 hours. The reaction was quenched by the addition of water (15 mL), then extracted with EA (20 mL x 3), the combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentyl acetate (100 mg, crude, brown oil) was used directly in the next step without further purification.

[0166] LCMS (Electrospray) m / z 378.8(M+H)+.

[0167] Step 5) 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentan-1-ol A mixture of 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentyl acetate (80 mg, 211.87 ml, 1 eq) in MeOH (4 mL) and H2O (0.8 mL) was partially mixed with K2CO3 (442.15 mg, 3.20 mmol, 15.1 eq) under N2 at 20°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched at 20°C by adding water (15 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 → 1 / 2). 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentan-1-ol (50 mg, 149.01 umol, 70.33% yield) was obtained as a white solid.

[0168] LCMS (Electrospray) m / z 336.9 (M+H)+.

[0169] Intermediate 1N,4-bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine

[0170] [ka]

[0171] Step 1) 5-Fluoro-2-iodo-4-(trifluoromethyl)aniline To a solution of 3-fluoro-4-(trifluoromethyl)aniline (4 g, 22.33 mmol, 1 eq) in MeCN (40 mL), NIS (5.53 g, 24.57 mmol, 1.1 eq) was added at 15°C, and the reaction mixture was stirred at 15°C for 15 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with ELISA (100 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 5-fluoro-2-iodo-4-(trifluoromethyl)aniline (5.6 g, crude) was obtained as brown oil.

[0172] LCMS (Electrospray) m / z 305.9 (M+H)+.

[0173] Step 2) 5-Fluoro-2-methyl-4-(trifluoromethyl)aniline To a solution of 5-fluoro-2-iodo-4-(trifluoromethyl)aniline (6.0 g, 19.67 mmol, 1 eq) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (8.82 g, 29.51 mmol, 9.82 mL, 42% purity, 1.5 eq) in DME (60 mL), Pd(PPh3)4 (1.14 g, 983.57 mmol, 0.05 eq) and K2CO3 (8.16 g, 59.01 mmol, 3 eq) were added at 15°C, and the reaction mixture was stirred at 100°C for 60 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 → 3 / 1, petroleum ether / ethyl acetate = 2:1, Rf = 0.3). 5-Fluoro-2-methyl-4-(trifluoromethyl)aniline (1.6 g, 4.06 mmol, 20.64% yield, 49% purity) was obtained as a yellow oil.

[0174] LCMS (Electrospray) m / z 194.1.9 (M+H)+.

[0175] Step 3) 6-fluoro-5-(trifluoromethyl)-1H-indazole To a solution of 5-fluoro-2-methyl-4-(trifluoromethyl)aniline (1 g, 5.18 mmol, 1 eq) in AcOH (15 mL), NaNO2 (357.25 mg, 5.18 mmol, 1 eq) and H2O (3 mL) were added at 0°C, and the reaction mixture was stirred at 15°C for 2 hours. The reaction was quenched at 20°C by adding H2O (60 mL), and the resulting mixture was extracted with ELISA (50 mL x 3). The combined organic layer was washed with H2O (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 5 / 1, petroleum ether / ethyl acetate = 3:1, Rf = 0.5). 6-fluoro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.45 mmol, 47.31% yield) was obtained as a yellow solid.

[0176] LCMS (Electrospray) m / z 205.2(M+H)+.

[0177] Step 4) 6-Fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole To a solution of 6-fluoro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.45 mmol, 1 eq) in H2SO4 (5 mL, 95% purity), KNO3 (249 mg, 2.46 mmol, 1.01 eq) was added at 0°C, and the reaction mixture was stirred at 15°C for 15 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was treated with saturated sodium bicarbonate solution to pH=7, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 6-fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole (500 mg) was obtained as a yellow solid.

[0178] LCMS (Electrospray) m / z 250.2(M+H)+.

[0179] Step 5) 6-Fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole To a solution of 6-fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.01 mmol, 1 eq) in THF (10 mL), PPTS (50.44 mg, 200.71 µl, 0.1 eq) and DHP (844.13 mg, 10.04 mmol, 917.53 µL, 5 eq) were added at 0°C, and the reaction mixture was stirred at 60°C for 15 hours. The reaction mixture was diluted with solvent H2O (50 mL) and extracted with siRNA (50 mL x 3). The combined organic layer was washed with H2O (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole (1 g, crude) was obtained as a yellow oil.

[0180] Step 6) 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine To a solution of 6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole (800 mg, 2.40 mmol, 1 eq) and H2O (2 mL) in EtOH (10 mL), NH4Cl (642.08 mg, 12.00 mmol, 5 eq) and Fe (268.13 mg, 4.80 mmol, 2 eq) were added at 0°C, and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with H2O (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 5 / 1, petroleum ether:ethyl acetate = 3:1, Rf = 0.3). 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (500 mg, 1.65 mmol, 68 mg). A yellow solid was obtained (with a yield of 68%).

[0181] LCMS (Electrospray) m / z 220.2(M+H)+.

[0182] Step 7) 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine To a solution of 6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (200 mg, 659.51 umol, 1 eq) in DMF (1 mL), NBS (129.12 mg, 725.46 umol, 1.1 eq) was added at 20°C, and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layers were washed with H2O (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (120 mg, crude) was obtained as a yellow solid.

[0183] LCMS (Electrospray) m / z 297.9 (M+H)+.

[0184] Step 8) 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazole-7-amine To a solution of 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (100 mg, 335.53 umol, 1 eq) in MeOH (1 mL), AcOH (40.30 mg, 671.06 umol, 38.38 uL, 2 eq) and acetone (97.44 mg, 1.68 mmol, 123.34 uL, 5 eq) were added at 20°C, followed by the addition of NaBH3CN (105.42 mg, 1.68 mmol, 5 eq), and the reaction mixture was stirred at 20°C for 2 hours. Subsequently, acetone (97.44 mg, 1.68 mmol, 123.34 μL, 5 eq), NaBH3CN (105.43 mg, 1.68 mmol, 5 eq), and AcOH (60.45 mg, 1.01 mmol, 57.57 μL, 3 eq) were added to the mixture, and the reaction mixture was stirred at 20°C for 20 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with SiO2 (10 mL x 3). The combined organic layer was washed with H2O (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.4). 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazole-7-amine (60 mg, 165.83 umol, 49.42% yield, 94% purity) was obtained as a white solid.

[0185] LCMS (Electrospray) m / z 340.1(M+H)+.

[0186] Step 9) 4-bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine To a solution of 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazole-7-amine (50 mg, 147.01 umol, 1 eq) in THF (1 mL), PPTS (3.69 mg, 14.70 umol, 0.1 eq) and DHP (61.83 mg, 735.05 umol, 67.21 uL, 5 eq) were added at 0°C, and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with siRNA (50 mL x 3). The combined organic layer was washed with H2O (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.6). 4-bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl) )-5-(trifluoromethyl)-2H-indazole-7-amine (50 mg, 117.86 umol, 80.17% yield) was obtained as a yellow oil.

[0187] LCMS (Electrospray) m / z 424.1(M+H)+.

[0188] Intermediate 10,4-bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0189] [ka]

[0190] Step 1) 3-bromo-5-fluoro-2-methylaniline A mixture of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (23 g, 98.28 mmol, 1 eq) in EtOH (80 mL) and H2O (80 mL) was mixed with Fe (27.44 g, 491.41 mmol, 5 eq) and NH4Cl (26.29 g, 491.41 mmol, 5 eq). The mixture was stirred at 100°C for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, thereby yielding 3-bromo-5-fluoro-2-methylaniline (20.6 g, crude) as a yellow liquid.

[0191] 1 H NMR (400MHz, DMSO-d6) δ 6.59 (br d, J=8.4Hz, 1H), 6.42 (br d, J=11.2Hz, 1H), 5.51 (br s, 2H), 2.09 (s, 3H).

[0192] Step 2) 3-bromo-5-fluoro-4-iodo-2-methylaniline To a mixture of 3-bromo-5-fluoro-2-methylaniline (18 g, 88.22 mmol, 1 eq) (crude) in CH3CN (150 mL), NIS (19.85 g, 88.22 mmol, 1 eq) was added in small portions at 0°C. The mixture was stirred at 30°C for 3 hours. After 3 hours, LC-MS showed that compound 2 remained, and the desired mass was also detected. The mixture was then stirred at 30°C for a further 12 hours. LC-MS showed that no compound 2 remained and one main peak with the desired mass was detected. The mixture was quenched with saturated Na2SO3 (200 mL), and the resulting mixture was extracted with siRNA (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 50 / 1, 30 / 1; TLC (petroleum ether:ethyl acetate = 10:1; Rf = 0.28)) to obtain 3-bromo-5-fluoro-4-iodo-2-methylaniline (22 g, 66.68 mmol, 75.58% yield) as a brown solid.

[0193] 1 H NMR (400MHz, DMSO-d6) δ 6.55 (d, J=10.5Hz, 1H), 5.67 (s, 2H), 2.25 (d, J=0.8Hz, 3H).

[0194] Step 3) 4-bromo-6-fluoro-5-iodo-1H-indazole To a mixture of 3-bromo-5-fluoro-4-iodo-2-methylaniline (22 g, 66.68 mmol, 1 eq) in CH3COOH (200 mL), NaNO2 (5.52 g, 80.02 mmol, 1.2 eq) dissolved in water (40 mL) at 0°C was added. The mixture was stirred at 30°C for 16 hours. The mixture was poured into saturated NaHCO3 (1000 mL), and the resulting mixture was extracted with ELISA (200 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1, 5 / 1) to obtain 4-bromo-6-fluoro-5-iodo-1H-indazole (7.5 g, 22.00 mmol, 32.99% yield) as a brown solid.

[0195] 1H NMR (400MHz, DMSO-d6) δ 13.58 (br s, 1H), 8.00 (s, 1H), 7.51 (d, J=8.1Hz, 1H), 3.32 (s, 1H).

[0196] Step 4) 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A mixture of 4-bromo-6-fluoro-5-iodo-1H-indazole (7.5 g, 22.00 mmol, 1 eq) and 4-methylbenzenesulfonic acid hydrate (418.47 mg, 2.20 mmol, 0.1 eq) in DCM (100 mL) was slowly mixed with DHP (5.55 g, 66.00 mmol, 6.03 mL, 3 eq). The mixture was stirred at 30°C for 1 hour. The mixture was washed with saturated NaHCO3 (30 mL x 3) and brine (30 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 50 / 1) to obtain 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7.4 g, 17.41 mmol, 79.14% yield) as a yellow solid.

[0197] 1 H NMR (400MHz, DMSO-d6) δ 8.06(s, 1H), 7.80(dd, J=0.7, 8.4Hz, 1H), 5.83(dd, J=2.4, 9.6Hz, 1H), 3.88 - 3.85(m, 1H), 3.80 - 3.70(m, 2H), 2.40 - 2.27 (m, 1H), 2.07 - 1.94 (m, 2H), 1.81 - 1.63 (m, 2H), 1.62 - 1.53 (m, 2H).

[0198] Step 5) 4-bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A mixture of 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.53 mmol, 1 eq) and cyclopropylboronic acid (303.14 mg, 3.53 mmol, 1 eq) in dioxane (10 mL) and H2O (2.5 mL) was mixed with Na2CO3 (748.10 mg, 7.06 mmol, 2 eq) and Pd(dppf)Cl2 (258.23 mg, 352.91 µm, 0.1 eq) under N2. The mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 20:1) to obtain 4-bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.21 g, 619.10 umol, 17.54% yield) as a colorless oil.

[0199] 1 H NMR(400MHz、CDCl3) δ 7.98(d、J=0.6Hz、1H)、7.20(d、J=10.4Hz、1H)、5.61(dd、J=2.8、9.1Hz、1H)、4.03 - 3.94(m、1H)、3.76-3.69(m、1H)、2.55 - 2.42(m、1H)、2.19 - 2.06(m、2H)、1.91-1.86(m、1H)、1.81 - 1.64(m、3H)、1.12 - 1.05(m、2H)、0.87 - 0.81(m、2H)。

[0200] Intermediate 1P,4-bromo-6-fluoro-5-isopropyl-1H-indazole

[0201] [ka]

[0202] Step 1) 4-bromo-6-fluoro-5-(propa-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A mixture of 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.53 mmol, 1 eq) and potassium trifluoro(isopropenyl)boranoid (626.67 mg, 4.23 mmol, 1.2 eq) in dioxane (10 mL) and H2O (2 mL) was mixed with Pd(dppf)Cl2 (258.23 mg, 352.91 mmol, 0.1 eq) and Na2CO3 (748.10 mg, 7.06 mmol, 2 eq) under N2. The mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 50 / 1; TLC (petroleum ether:ethyl acetate = 10:1; Rf = 0.61)) to obtain 0.9 g of yellow oil. This oil was purified by preparative TLC (petroleum ether:ethyl acetate = 20:1) to obtain 4-bromo-6-fluoro-5-(propa-1-en-2-yl) -1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.55 g, 1.62 mmol, 45.94% yield) was obtained as a yellow oil.

[0203] 1 H NMR(400MHz、CDCl3) δ 8.00(d、J=0.6Hz、1H)、7.28(d、J=0.9Hz、0.5H)、7.26(d、J=0.7Hz、0.5H)、5.64(dd、J=2.8、9.0Hz、1H)、5.46(t、J=1.6Hz、1H)、5.01(s、1H)、4.05 - 3.97(m、1H)、3.80 - 3.69(m、1H)、2.57 - 2.42(m、1H)、2.19 - 2.09(m、2H)、2.07(s、3H)、1.81 - 1.66(m、4H)。

[0204] Step 2) 4-bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A solution of 4-bromo-6-fluoro-5-(propa-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.4 g, 1.18 mmol, 1 eq) in MeOH (10 mL) was added with PtO2 under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 30°C under H2 (15 Psi) for 2.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 50 / 1) to obtain 4-bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.3 g, 879.20 umol, 74.56% yield) as a colorless oil.

[0205] Step 3) 4-bromo-6-fluoro-5-isopropyl-1H-indazole To a solution of 4-bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.3 g, 879.20 umol, 1 eq) in DCM (1 mL), TFA (2.30 g, 20.14 mmol, 1.49 mL, 22.91 eq) was added. The mixture was stirred at 30°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was diluted with DCM (10 mL), and the pH of the resulting mixture was adjusted to approximately 8 with TEA. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 30 / 1, 5 / 1) to obtain 4-bromo-6-fluoro-5-isopropyl-1H-indazole (0.2 g, 777.90 umol, 88.48% yield) as a colorless oil.

[0206] 1 H NMR(400MHz、CDCl3) δ 8.04(s、1H)、7.11(d、J=11.2Hz、1H)、3.75 - 3.63(m、1H)、1.38(dd、J=1.7、7.1Hz、6H)。

[0207] Intermediate 1Q.4-bromo-6-fluoro-5-methoxy-1H-indazole

[0208] [ka]

[0209] Step 1) 2-Bromo-4-fluoro-3-methoxy-1-methylbenzene To a solution of 2-bromo-6-fluoro-3-methylphenol (4.8 g, 23.41 mmol, 1 eq) in acetone (50 mL), K2CO3 (6.47 g, 46.82 mmol, 2 eqs) and iodomethane (9.97 g, 70.24 mmol, 4.37 mL, 3 eqs) were added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain the residue. The residue was dissolved in ethyl acetate (50 mL), the mixture was filtered, and the filtrate was concentrated to obtain the residue (4.6 g, 21.00 mmol, 89.70% yield) as yellow oil.

[0210] 1 ¹H NMR (400 MHz, chloroform-d): δ 7.05 - 6.85 (m, 2H), 3.95 (d, J=1.2 Hz, 3H), 2.38 (s, 3H).

[0211] Step 2) 3-Bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene To a solution of 2-bromo-4-fluoro-3-methoxy-1-methylbenzene (4.4 g, 20.09 mmol, 1 eq) in H2SO4 (40 mL) (98%), KNO3 (2.23 g, 22.10 mmol, 1.1 eq) was added in small portions at 0°C, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was slowly poured into ice water (200 mL), and the mixture was then extracted with ethyl acetate (200 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 3-bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (4.6 g, crude) was obtained as brown oil.

[0212] 1¹H NMR (400 MHz, chloroform-d) δ 7.70 (d, J=10.9 Hz, 1H), 4.08 (d, J=2.7 Hz, 3H), 2.61 (d, J=1.1 Hz, 3H).

[0213] Step 3) 3-bromo-5-fluoro-4-methoxy-2-methylaniline To a solution of 3-bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (4.6 g, 17.42 mmol, 1 eq) in EtOH (30 mL) and H2O (30 mL), Fe (5.84 g, 104.53 mmol, 6 eq) and NH4Cl (5.59 g, 104.53 mmol, 6 eq) were added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated to remove EtOH, the mixture was then diluted with EA (50 mL), the mixture was washed with water (20 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 3-bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, crude) was obtained as brown oil.

[0214] 1 ¹H NMR (400 MHz, chloroform-d) δ 6.44 (d, J=11.9 Hz, 1H), 3.83 (s, 3H), 3.76 - 3.48 (m, 2H), 2.24 (d, J=1.0 Hz, 3H).

[0215] Step 4) 4-bromo-6-fluoro-5-methoxy-1H-indazole A solution of NaNO2 (1.24 g, 17.94 mmol, 1.2 eq) in H2O (4 mL) was added dropwise to a mixture of 3-bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, 14.95 mmol, 1 eq) (crude) in AcOH (20 mL) at 0 °C, and then the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ice water (100 mL), the mixture was adjusted to pH 7 by using KOH, then the mixture was extracted with EA (100 mL × 2), the combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 → 15:1). 4-Bromo-6-fluoro-5-methoxy-1H-indazole (600 mg, 2.45 mmol, 16.37% yield) was obtained as a brown solid.

[0216] 1 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br s, 1H), 8.00 (s, 1H), 7.52 (br d, J = 10.4 Hz, 1H), 3.84 (s, 3H).

[0217] Synthesis of the compound of formula (I) The following compounds were prepared using synthetic methods A - F. In the following, exemplary synthesis examples of some compounds of the present disclosure are described, and other compounds can be prepared by methods similar to those described below using different starting or reaction materials.

[0218] Synthetic method A Example 1. (1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)cyclopropane-1-carboxamide

[0219]

Chemical formula

[0220] Step 1) Methyl 5-amino-1-(3-methoxy-3-oxopropane-1-en-1-yl)-1H-pyrazole-3-carboxylate To a solution of compound 1 (9.1 g, 64.48 mmol, 1 eq) in EtOH (700 mL), methyl propiolate (27.11 g, 322.40 mmol, 26.84 mL, 5 eq) was added. The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure until all solids precipitated, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 2 (7.8 g, crude) was obtained as a yellow solid.

[0221] 1 H NMR (400MHz, DMSO-d6) δ 8.09(d, J=14.8Hz, 1H), 7.05(s, 1H), 6.68(br s, 2H), 6.63(d, J=14.8Hz, 1H), 3.88(s, 3H), 3.76(s, 3H).

[0222] Step 2) Ethyl 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate Compound 2 (3.9 g, 17.32 mmol, 1 eq) in EtOH (15 mL) was mixed with EtONa (1.77 g, 25.98 mmol, 1.5 eq). The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The aqueous layer was filtered, and the resulting filtration cake was concentrated under reduced pressure to obtain compound 3 (5.4 g, crude) as a yellow solid.

[0223] 1 H NMR (400MHz, DMSO-d6) δ 12.62(br s, 1H), 7.99(d, J=7.5Hz, 1H), 6.58(s, 1H), 5.82(d, J=7.5Hz, 1H), 4.35(q, J=7.1Hz, 2H), 1.34(t, J=7.2Hz, 3H).

[0224] Step 3) Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate To a solution of compound 3 (1 g, 4.83 mmol, 1 eq) in MeCN (5 mL), N,N-dimethylaniline (1.17 g, 9.65 mmol, 1.22 mL, 2 eqs), benzyl(triethyl)ammonium chloride (5.50 g, 24.13 mmol, 5 eqs), and POCl3 (7.40 g, 48.27 mmol, 4.49 mL, 10 eqs) were added under a N2 atmosphere. The reaction mixture was stirred at 100 °C for 16 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was quenched with water (100 mL) and treated with saturated sodium bicarbonate solution to pH=7. The mixture was then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 → 1:1). Compound 4 (900 mg, 3.99 mmol, 82.64% yield) was obtained as a yellow solid.

[0225] 1 H NMR(400MHz、DMSO-d6) δ 8.63(d、J=4.5Hz、1H)、7.61(d、J=4.5Hz、1H)、7.36(s、1H)、4.40(d、J=7.1Hz、2H)、1.36(t、J=7.1Hz、3H)。

[0226] Step 4) Ethyl 5-(5-methyl-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate A mixture of compound 4 (900 mg, 3.99 mmol, 1 eq), (5-methyl-1H-indazole-4-yl)boronic acid (701.95 mg, 3.99 mmol, 1 eq), and Na2CO3 (845.55 mg, 7.98 mmol, 2 eq) in dioxane (5 mL) and H2O (1 mL) was mixed with Pd(dppf)Cl2 (145.93 mg, 199.44 mmol, 0.05 eq) under an N2 atmosphere. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to column chromatography. The compound was purified using silica gel, petroleum ether, and ethyl acetate (1:0 → 0:1). Compound 5 (450 mg, 1.40 mmol, 35.10% yield) was obtained as a yellow solid.

[0227] 1 H NMR (400MHz, DMSO-d6) δ 13.28(s, 1H), 8.81 - 8.78(m, 1H), 7.71(d, J=8.5Hz, 1H), 7.66(s, 1H), 7.44(d, J=8.5Hz, 1H), 7.34(d, J= 4.1Hz, 1H), 7.31(s, 1H), 4.30(q, J=7.1Hz, 2H), 2.14(s, 3H), 1.27(t, J=7.1Hz, 3H).

[0228] Step 5) 5-(5-methyl-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid To a solution of compound 5 (450 mg, 1.40 mmol, 1 eq) in THF (5 mL) and H2O (5 mL), LiOH·H2O (117.53 mg, 2.80 mmol, 2 eq) was added. The mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined aqueous layer was treated with HCl (1 M) to pH 4, stirred until all solids precipitated, filtered, and concentrated under reduced pressure to obtain the residue. Compound 6 (330 mg, crude) was obtained as a yellow solid.

[0229] 1 H NMR(400MHz、DMSO-d6) δ 13.51 - 13.06(m, 1H), 8.77(d, J=4.2Hz, 1H), 7.71(d, J=8.6Hz, 1H), 7.66(d, J=0.9Hz , 1H), 7.43(d, J=8.7Hz, 1H), 7.31(d, J=4.2Hz, 1H), 7.24(s, 1H), 2.14(s, 3H).

[0230] Step 6) 5-(5-methyl-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-amine To a solution of compound 6 (230 mg, 784.23 µl, 1 eq) in toluene (2 mL), TEA (87.29 mg, 862.66 µl, 120.07 µL, 1.1 eq) and DPPA (237.40 mg, 862.66 µl, 186.93 µL, 1.1 eq) were added under an N2 atmosphere. The mixture was stirred at 110 °C for 16 hours. H2O (1.00 g, 55.51 mmol, 1 mL, 70.78 eq) was added to the mixture under an N2 atmosphere. The mixture was stirred at 110 °C for 3 hours under an N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 0:1). Compound 7 (70 mg, 264.87 umol, 33.77% yield) was obtained as a yellow solid.

[0231] 1 H NMR(400MHz、DMSO-d6) δ 13.19(s、1H)、8.32(d、J=4.3Hz、1H)、7.63 - 7.59(m、2H)、7.35(d、J=8.6Hz、1H)、6.71(d、J=4.4Hz、1H)、5.79(s、1H)、5.71 - 5.63(m、2H)、2.15(s、3H)。

[0232] Step 7) (1S,2S)-2-fluoro-N-(5-(5-methyl-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-yl)cyclopropane-1-carboxamide To a solution of compound 7 (70 mg, 264.87 µl, 1 eq), (1S,2S)-2-fluorocyclopropanecarboxylic acid (33.08 mg, 317.84 µl, 1.2 eq), and 3-methylpyridine (123.33 mg, 1.32 mmol, 128.95 µL, 5 eq) in MeCN (2 mL), MsCl (45.51 mg, 397.30 µl, 30.75 µL, 1.5 eq) was added at 0°C under an N2 atmosphere. The mixture was heated at 25°C for 1 The mixture was stirred under an N2 atmosphere for 6 hours. The reaction mixture was added dropwise to water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 0:1). The residue was then purified by preparative HPLC (column: Phenomenex® luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%:%→%, 10 min) and lyophilized. Example 1 (4.3 mg, 12.27 μmol, 4.63% yield, 100% purity) was obtained as a yellow solid.

[0233] 1 H NMR (400MHz, methanol-d4) δ 8.57(d、J=4.3Hz、1H)、7.66(d、J=8.6Hz、1H)、7.64(d、J=2.3Hz、1H)、7.44(d、J=8.8Hz、1H)、7.13(s、1H)、7.04(d、J=4.3Hz、1H)、4.75 - 4.61 (m, 1H), 2.26 (s, 3H), 1.98 - 1.90 (m, 1H), 1.83 - 1.72 (m, 1H), 1.19 - 1.11 (m, 1H).

[0234] Synthesis method B Example 3. (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)cyclopropane-1-carboxamide

[0235] [ka]

[0236] Step 1) N-(6-chloropyridazine-3-yl)-4-methylbenzenesulfonamide To a solution of compound 8 (25 g, 192.98 mmol, 1 eq) in pyridine (300 mL), TsCl (40.47 g, 212.28 mmol, 1.1 eq) was added, and the mixture was stirred at 90°C for 6 hours under N2. Water (100 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was then dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under vacuum to obtain compound 9 (56.5 g, crude) as a gray solid. .

[0237] 1 H NMR (400MHz, DMSO-d6) δ 8.67 - 8.59 (m, 1H), 7.82 - 7.77 (m, 2H), 7.61 - 7.54 (m, 1H), 7.52 - 7.46 (m, 1H), 7.38 (d, J=8.3Hz, 2H), 2.35 (s, 3H).

[0238] Step 2) (E)-2-(3-chloro-6-(tosylimino)pyridazine-1(6H)-yl)acetamide To a solution of compound 9 (53 g, 186.79 mmol, 1 eq) in DMF (300 mL), DIPEA (26.56 g, 205.47 mmol, 35.79 mL, 1.1 eq) and 2-bromoacetamide (28.35 g, 205.47 mmol, 1.1 eq) were added, and the mixture was stirred at 25°C for 20 hours. Water (1000 mL) was added to the mixture, the mixture was filtered, the filtered cake was collected, and the mixture was concentrated under vacuum to obtain compound 10 (40 g, 117.38 mmol, 62.84% yield) as a brown solid.

[0239] 1 H NMR (400MHz, DMSO-d6) δ 8.00(d, J=9.8Hz, 1H), 7.79(d, J=9.8Hz, 1H), 7.70(br d, J=7.1Hz, 3H), 7.38(br s, 1H), 7.32(br d, J=7.8Hz, 2H), 4.88 - 4.77(m, 2H), 2.40 - 2.30(m, 3H).

[0240] Step 3) N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2,2,2-trifluoroacetamide To a solution of compound 10 (35 g, 102.70 mmol, 1 eq) in DCE (250 mL), TFAA (258.85 g, 1.23 mol, 171.43 mL, 12 eq) was added, and the mixture was stirred at 60°C for 3 hours. Water (1000 mL) was added to the mixture, and then sufficient NaHCO3 was added to adjust the pH to 8. The mixture was then filtered, and the filter cake was collected. This was then extracted with water (500 mL) and ethyl acetate (500 mL). The organic phase was then dried with Na2SO4 and concentrated under vacuum to obtain compound 11 (21 g, 79.37 mmol, 77.28% yield) as a white solid.

[0241] 1 H NMR (400MHz, DMSO-d6) δ 12.88 - 12.57 (m, 1H), 8.41 (s, 1H), 8.19 (d, J=9.4Hz, 1H), 7.43 (d, J=9.4Hz, 1H).

[0242] Step 4) 6-Chloroimidazo[1,2-b]pyridazine-2-amine To a solution of compound 11 (21 g, 79.37 mmol, 1 eq) in MeOH (200 mL) and H2O (200 mL), K2CO3 (54.85 g, 396.84 mmol, 5 eq) was added, and the mixture was stirred at 75°C for 3 hours. Water (100 mL) was poured over the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was then dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound 60 (13.5 g, crude).

[0243] 1 H NMR (400MHz, DMSO-d6) δ 7.68 (d, J=9.2Hz, 1H), 7.36 (s, 1H), 7.03 (d, J=9.2Hz, 1H), 5.65 (s, 2H).

[0244] Step 5) (1S,2S)-N-(6-chloroimidazo[1,2-b]pyridazine-2-yl)-2-fluorocyclopropane-1-carboxamide Compound 12 (2g, 11.86 mmol, 1eq) in DCM (50mL), (1S,2S)-2-fluorocyclopropanecarboxylic acid (1.56g, 14.24 mmol, 1 EDCI (3.41 g, 17.80 mmol, 1.5 eq) was added to a solution of 0.2 eq) and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum to obtain the residue. Water (100 mL) was then poured into the mixture and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was then dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound 13 (3.8 g, crude) as a white solid.

[0245] 1 H NMR (400MHz, DMSO-d6) δ 11.37 - 11.22(m, 1H), 8.32 - 8.23(m, 1H), 8.07(d, J=9.4Hz, 1H), 7.72 - 7.64(m, 1H), 5.07 - 4.80(m, 1H), 2.21 - 2.12(m, 1H), 1.73 - 1.61(m, 1H), 1.13 - 1.05(m, 1H).

[0246] Step 6) (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)cyclopropane-1-carboxamide.2TFA To a solution of compound 13 (170 mg, 667.59 umol, 1 eq) in dioxane (6 mL) and H2O (2 mL) and Na2CO3 (141.51 mg, 1.34 mmol, 2 eq), (5-methyl-1H-indazole-4-yl)boronic acid (117.48 mg, 667.59 umol, 1 eq) and Pd(dppf)Cl2 (48.85 mg, 66.76 umol, 0.1 eq) were added, and the mixture was stirred under N2 at 90°C for 16 hours. The reaction mixture was purified by preparative HPLC (column: Phenomenex® luna C18 150*25mm* 10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 19%~49%, 10 min) to obtain Example 3 (56.8 mg, 93.88 umol, 14.06% yield, 95.6% purity, 2 TFA) as a pale yellow solid.

[0247] 1 H NMR (400MHz, DMSO-d6) δ 11.27(s, 1H), 8.31(s, 1H), 8.10(d, J=9.3Hz, 1H), 7.84(d, J=0.9Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.38(dd, J=8.9, 16.1Hz, 2H), 5.08 - 4.82(m、1H)、2.38(s、3H)、2.23 - 2.14(m、1H)、1.77 - 1.62(m、1H)、1.23 - 1.12 (m, 1H).

[0248] Synthesis method C Example 24. (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropanecarboxamide.2TFA

[0249] [ka]

[0250] Step 1) (1S,2S)-N-(6-bromoimidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropanecarboxamide (1S,2S)-2-fluorocyclopropanecarboxylic acid (5) in NMP (20 mL) To a solution of 37.41 mg, 5.16 mmol, 1.1 eq) and compound 14 (1 g, 4.69 mmol, 1 eq), T3P (2.99 g, 9.39 mmol, 2.79 mL, 2 eq) and DIPEA (1.42 g, 11.03 mmol, 1.92 mL, 2.35 eq) were added. The reaction mixture was stirred at 25°C for 16 hours. Water (15 mL) was added, and the aqueous phase was extracted with SiO (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2) and concentrated under vacuum. The crude product was purified by back flush (MeCN / H2O, 0.05% TFA) to obtain compound 15 (750 mg, 2.51 mmol, 53.42% yield) as a pale yellow solid.

[0251] 1 H NMR(400MHz、DMSO-d6) δ 11.39(s、1H)、8.93(d、J=1.2Hz、1H)、8.75(s、1H)、8.29(s、1H)、5.17 - 4.76(m、1H)、2.23 - 2.11(m, 1H), 1.67(tdd, J=3.3, 6.9, 19.9Hz, 1H), 1.25 - 1.13(m, 1H).

[0252] Step 2) (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropanecarboxamide.2TFA A solution of (5-methyl-1H-indazol-4-yl)boronic acid (58.84 mg, 334.34 μmol, 1 eq) in dioxane / H2O (3 mL) was added with Pd(dppf)Cl2 (12.23 mg, 16.72 μmol, 0.05 eq), compound 15 (100 mg, 334.34 μmol, 1 eq) and Na2CO3 (70.87 mg, 668.67 μmol, 2 eq) under N2. The mixture was stirred at 90 °C for 3 h. Water (10 mL) was added and the aqueous phase was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2) and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex® luna C18 150×25 mm×10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 13%→43%, 10 min) to give Example 24 (38.2 mg, 62.74 μmol, 18.77% yield, 95% purity, 2TFA) as a pale yellow solid.

[0253] 1 1H NMR (400 MHz, DMSO-d6) δ 11.48 - 11.28 (m, 1H), 9.06 (s, 1H), 8.83 (d, J = 1.3 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 5.15 - 4.79 (m, 1H), 2.43 - 2.35 (m, 3H), 2.26 - 2.14 (m, 1H), 1.78 - 1.62 (m, 1H), 1.37 - 1.06 (m, 1H).

[0254] Synthetic method D Example 25. (1S,2S)-N-(6-(5-Ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropanecarboxamide. 2TFA

[0255]

Chemical formula

[0256] Step 1) (1S,2S)-2-fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazine-2-yl)cyclopropanecarboxamide To a solution of tributyl(tributylstannyl)stananne (1.16 g, 2.01 mmol, 1.00 mL, 3 eq) and compound 16 (200 mg, 668.67 umol, 1 eq) in dioxane (3 mL), Pd(PPh3)4 (38.63 mg, 33.43 umol, 0.05 eq) and TBAI (246.99 mg, 668.67 umol, 1 eq) were added under N2. The reaction mixture was stirred at 110 °C for 32 hours. The reaction product was filtered, and the filtrate was concentrated to obtain the product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain compound 17 (130 mg, 255.28 umol, 38.18% yield) as a white solid.

[0257] Step 2) (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropanecarboxamide.2TFA Ad2n-BuP-Pd-G3 (11.98 mg, 16.46 mg, 0.1 eq) was added under N2 to a solution of 4-bromo-5-ethyl-6-fluoro-1H-indazole (40 mg, 164.56 mg, 1 eq) and compound 17 (92.18 mg, 181.01 mg, 1.1 eq) in EtOH (2 mL). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column: Phenomenex® Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 24% → 54%, 10 min) to obtain Example 25 (10 mg, 16.22 mg, 9.86% yield, 99% purity, 2 TFA) as a white solid.

[0258] 1¹H NMR (400MHz methanol-d4) δ 8.99 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.36 (d, J=10.4Hz, 1H), 5.00 - 4.97 (m, 1H), 2.76 - 2.72 (m, 2H), 2.16 - 2.15 (m, 1H), 1.86 - 1.79 (m, 1H), 1.26 - 1.24 (m, 1H), 1.19 - 1.16 (m, 3H).

[0259] Synthesis method E Example 61. (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide

[0260] [ka]

[0261] To a solution of compound 17 (456 mg, 0.896 mmol, 1.3 eq) and intermediate 1E (269 mg, 0.689 mmol) in EtOH (3.44 mL), Ad2nBuP-Pd-G3 (50 mg, 0.0689 mmol, 0.1 eq) was added. The mixture was degassed, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (the product emerged in ethyl acetate) to obtain Example 61 (86 mg, 0.162 mmol, 24% yield). The percentage was obtained as a yellow solid.

[0262] Synthesis method F Example 64. (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide

[0263] [ka]

[0264] Step 1) 4-bromo-5-chloro-6-fluoro-7-(propa-1-en-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole To a solution of intermediate 1B (2 g, 4.35 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (877.73 mg, 5.22 mmol, 1.2 eq) in dioxane (0.4 mL) and H2O (0.1 mL), Na2CO3 (922.69 mg, 8.71 mmol, 2 eq) and Pd(dppf)Cl2 (159.25 mg, 217.64 mmol, 0.05 eq) were added under an N2 atmosphere. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 → 20:1). Compound 18 (870 mg, 2.33 mmol, 53.49% yield) was obtained as yellow oil.

[0265] Step 2) 4-bromo-5-chloro-6-fluoro-7-isopropyl-1H-indazole To a solution of compound 18 (400 mg, 1.07 mmol, 1 eq) in MeOH (0.5 mL), PtO2 (40.00 mg, 176.15 µmol, 1.65 e-1 eq) was added under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25°C for 1 hour under H2 (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 → 4:1). Compound 19 (240 mg, 823.19 µmol, 76.90% yield) was obtained as a yellow solid.

[0266] 1H NMR (400MHz, DMSO-d6) δ 13.73 (br s, 1H), 8.09 (s, 1H), 3.59 - 3.49 (m, 1H), 1.39 (d, J=6.9Hz, 6H).

[0267] Step 3) (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide To a solution of compound 19 (70 mg, 240.10 umol, 1 eq) and compound 17 (134.50 mg, 264.11 umol, 1.1 eq) in EtOH (1 mL), Ad2nBuP-Pd-G3 (17.49 mg, 24.01 umol, 0.1 eq) was added under a N2 atmosphere. The mixture was stirred at 80°C for 12 hours under a N2 atmosphere. The reaction mixture was quenched by adding 5 mL of saturated KF aqueous solution. The mixture was dissolved in water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50mm×3um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%~60%, 10 min) and lyophilized. Example 64 (15 mg, 34.12 umol, 14.21% yield, 98% purity) was obtained as a white solid.

[0268] 1 H NMR (400MHz, DMSO-d6) δ 13.52(br s, 1H), 11.40(s, 1H), 9.14 - 8.87(m, 2H), 8.38(s, 1H), 8.04(br s, 1H), 5.17 - 4.75(m, 1H), 3.66 - 3.59 (m, 1H), 2.19 (td, J=7.0, 13.6Hz, 1H), 1.75 - 1.62 (m, 1H), 1.45 (br d, J=7.0Hz, 6H), 1.20 (tdd, J=6.3, 8.9, 12.3Hz, 1H); LCMS (electrospray) m / z 431.2 (M+H+).

[0269] Table 1 below shows the compounds used in the examples, along with the general synthesis methods and characterization data used to prepare them.

[0270] [Table 1]

[0271] [Table 2]

[0272] [Table 3]

[0273] [Table 4]

[0274] [Table 5]

[0275] [Table 6]

[0276] [Table 7]

[0277] [Table 8]

[0278] [Table 9]

[0279] [Table 10]

[0280] Table 11

[0281] Table 12

[0282] Table 13

[0283] Table 14

[0284] Table 15

[0285] Table 16

[0286] Table 17

[0287] Table 18

[0288] Table 19

[0289] Table 20

[0290] Table 21

[0291] Table 22

[0292] Table 23

[0293] Table 24

[0294] Table 25

[0295] Table 26

[0296] Table 27

[0297] Table 28

[0298] Table 29

[0299] Table 30

[0300] Table 31

[0301] Table 32

[0302] Table 33

[0303] Table 34

[0304] Table 35

[0305] Table 36

[0306] Table 37

[0307] Table 38

[0308] Table 39

[0309] Table 40

[0310] Table 41

[0311] Table 42

[0312] Table 43

[0313] Table 44

[0314] Table 45

[0315] Table 46

[0316] Table 47

[0317] Table 48

[0318] Table 49

[0319] Table 50

[0320] Table 51

[0321] Table 52

[0322] Table 53

[0323] Table 54

[0324] Table 55

[0325] Table 56

[0326] Table 57

[0327] Table 58

[0328] Table 59

[0329] Table 60

[0330] Table 61

[0331] Table 62

[0332] Table 63

[0333] Table 64

[0334] Table 65

[0335] Table 66

[0336] Table 67

[0337] Table 68

[0338] Table 69

[0339] Table 70

[0340] Table 71

[0341] Table 72

[0342] Table 73

[0343] Table 74

[0344] Table 75

[0345] Table 76

[0346] Table 77

[0347] Table 78

[0348] Table 79

[0349] Table 80

[0350] Table 81

[0351] Table 82

[0352] Table 83

[0353] Table 84

[0354] Table 85

[0355] Table 86

[0356] Table 87

[0357] Table 88

[0358] Table 89

[0359] Table 90

[0360] Table 91

[0361] Table 92

[0362] Table 93

[0363] [Table 94]

[0364] [Table 95]

[0365] [Table 96]

[0366] [Table 97]

[0367] [Table 98]

[0368] [Table 99]

[0369] [Table 100]

[0370] [Table 101]

[0371] Evaluation of compounds HPK1 kinase assay HPK1 kinase activity was measured using Promega's ADP-Glo® kinase assay. In this assay, 5 ng of recombinant human HPK1 (signalchem) was incubated with 5 μL of the compound (0.5% DMSO), 5 μL of MBP (0.5 μg / μl), and 5 μL of ATP (25 μM) in a 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 in a 96-well plate at 30°C for 40 minutes. After incubation, 25 μL of ADP-Glo ​​reagent was added, and the reaction was stopped by incubating the mixture at room temperature for 40 minutes to decompose residual ATP. The ADP product was then converted to ATP by adding 50 μL / well of detection reagent. The luminescence was detected using a Molecular device I3X plate reader after 30 minutes of incubation at room temperature. 50 The values ​​were calculated from a series of percentage inhibition values ​​determined within a certain range of inhibitor concentrations, using software routines implemented in GraphPad Prism 7 software and SigmaPlot 13.0.

[0372] Table 2 shows the ICs of the compounds of the present invention. 50 The values ​​are shown, with + representing >1000nM, ++ representing 501 to 1000nM, +++ representing 101 to 500nM, and ++++ representing <100nM.

[0373] [Table 102]

[0374] [Table 103]

[0375] [Table 104]

[0376] [Table 105]

[0377] IFNγ and IL-2 analysis of human peripheral pan-T cells Human peripheral blood panT cells were purchased from STEMCELL Technologies® Inc. The human peripheral blood panT cells were thawed and suspended in DMEM medium (10% FBS and 1% penicillin / streptomycin). 8 × 10⁶ cells were used. 4 T cells were seeded in 96-well plates and incubated with various concentrations of compounds and 100 nM prostaglandin E2 for 1 hour. T cells were stimulated with Dynabeads® Human T-Activator CD3 / CD28 (Life Technologies) in a 1:3 cell:beads ratio. Cytokine secretion was measured 24 hours after stimulation using the MSD V-PLEX® human cytokine kit as suggested by the manufacturer. Data were analyzed using MESO Quickplex® SQ120 (Mesoscale Discovery).

[0378] In Table 3, the values ​​are as follows: + indicates >1000nM, ++ indicates 200~1000nM, +++ indicates <200nM, and - indicates not determined.

[0379] [Table 106]

Claims

1. Equation (I): 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the formula is: X is either O or S; L is a bond, or -O-; R １ is a cycloalkyl or heterocyclyl, and R １ R ７ It is optionally substituted with one or more substituents independently selected from; R ６ is -H or C １～６ It is alkyl; R ７ C １～６ Alkyl, heteroaryl, or halo; R ９ is -H, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R １０ and R １１ These are independently -H, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ 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 , -OR ９ , -C(=O)R ９ , -C (=O) OR ９ -OC(=O)R ９ They form a 4- to 12-membered heterocycline which is optionally substituted with one or more groups selected from the group consisting of -OC(=O)OR9; Each R １２ and R １３ Independently, C １～６ Alkyl, C １～６ Alkoxy, C ３～８ It is cycloalkyl, aryl, heteroaryl, 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 It forms a 4- to 8-membered heterocycline which is optionally substituted with one or more groups selected from the group consisting of; Het is, 【Chemistry 2】 Selected from the group consisting of; R ａ , R ｂ and R ｃ Each of these is independently -H, -D, Halo, -CF ３ , -CF ２ H, -CH ２ F, -CN, -OR ９ or -NR １０ R １１ And; R ２ is -H, -D, -CD ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, hydroxyl, -CD ２ OH, -CN, -NO ２ , haloalkyl, trimethylsilylethoxymethyl, -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 ​​​​​​​​​​​​​​​​​​​​Alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl are 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 is optionally substituted with one or more groups selected from the group consisting of; R ３ -H, -D, -CD ３ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ 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 stands for bond, -O-, -S-, or -NR ６ - and; R ４ is -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 , -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 C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinil, Shik Roalkyl, aryl, heteroaryl, or heterocyclyl are defined as 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 is optionally substituted with one or more groups selected from the group consisting of; and R ５ -H, -D, -CD ３ , C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkynyl, cycloalkyl, halo, hydroxyl, -CH ２ OH, -CD ２ It is OH, -CN or haloalkyl, A compound or its pharmaceutically acceptable salt, hydrate, or solvate.

2. L is a bond, and R １ However, C １～６ The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the cycloalkyl is optionally substituted with one or more groups selected from the group consisting of alkyl and halo.

3. R ２ and R ３ A compound according to claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each of is independently -H, halo, alkylthio, haloalkyl, or alkyl.

4. M is a bond, -O-, or -NR ６ - and 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 , -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, -CN, -CD ３ , -NR １０ R １１ , -NR １０ S(O) ２ R ９ , and -NR １０ C(=O)R ９ A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is optionally substituted with one or more groups selected from the group consisting of the above.

5. Formula (II): 【Transformation 3】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

6. L is a bond, R １ However, Halo, and C １～３ A cyclopropyl compound that is optionally substituted with one or more groups selected from the group consisting of alkyl groups; R ２ However, it is -H, alkyl, halo, haloalkyl, or alkylthio; R ３ However, -H, alkyl, or It is a halo; M is a bond, -O-, -S- or -NR ６ - and; R ４ However, -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutanylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propanyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl, or methylpyrazolylmethyl; and R ５ The compound according to claim 5 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is -H, alkyl, or halo.

7. (1S,2S)-2-fluoro-N-(5-(5-methyl-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-yl)cyclopropane-1-carboxamide; or The compound according to claim 5 or 6, which is (1S,2S)-N-(5-(5-ethyl-6,7-difluoro-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-yl)-2-fluorocyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

8. Formula (III): 【Chemistry 4】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

9. L is a bond, and R １ However, C １～６ The compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the cycloalkyl is optionally substituted with one or more groups selected from the group consisting of alkyl and halo.

10. R １ However, Halo, and C １～３ A cyclopropyl compound that is optionally substituted with one or more groups selected from the group consisting of alkyl groups; R ２ However, it is -H, alkyl, halo, haloalkyl, or alkylthio; R ３ However, -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR ６ - and; R ４ However, -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamideethyl, imidazolylethyl, dioxy Sanyl, cyclobutanylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propanyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl, or methylpyrazolylmethyl; and R ５ The compound according to claim 8 or 9, wherein the compound is -H, alkyl, or halo, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6,7-difluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-difluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-amino-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-ethoxy-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-f Luorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-difluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6,7-difluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazine-2-yl)-2-fluorocyclopropane-1-carboxamide; and A compound according to any one of claims 8 to 10, selected from the group consisting of (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; and A compound according to claim 8 or 10, selected from the group consisting of (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

13. Formula (IV): 【Transformation 5】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

14. L is a bond, and R １ However, C １～６ The compound according to claim 13, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the cycloalkyl is optionally substituted with one or more groups selected from the group consisting of alkyl and halo.

15. L is a bond; R １ However, Halo, and C １～３ The compound according to claim 13 or 14, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a cycloalkyl group optionally substituted with one or more groups selected from the group consisting of alkyl groups.

16. (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-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-5,7-bis(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6,7-difluoro-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-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1 H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-ethoxy-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-difluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-difluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-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-chloro-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-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-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-bromo-6,7-difluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6,7-difluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-bromo-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-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(pyrroridine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(piperidine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((3-hydroxypropyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(azetidine-1-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-thiomorpholino-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropyl(methyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1-cyanoethyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1H-pyrrole-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl) -2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-amino-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((cyanomethyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((2H-tetrazole-2-yl)methyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-hydroxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-vinyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-acetyl-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-cyclopropyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(2-ethoxypropane-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methoxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(tert-butylamino)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-fluoropyrrolidine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methyl-1H-pyrrole-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(2H-tetrazole-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-1-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-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-(prop (-1-en-2-yl)-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-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-propyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methyl-1H-pyrrole-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; 1-(5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)-N,N-dimethyl-1H-pyrrole-3-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methoxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-fluoropropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isobutylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((E)-propa-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(ethylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (3R,4S)-4-methyltetrahydrofuran-3-yl(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)carbamate; (1S,2S)-N-(6-(5-chloro-7-(2-(dimethylamino)-2-oxoethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((2-(dimethylamino)-2-oxoethyl)thio)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-fluoroethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3,3,3-trifluoropropane-1-en-2-yl)-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-methyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((methylamino)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((dimethylamino)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methyl-1H-pyrrole-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1H-pyrrole-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methyl-1H-pyrazole-5-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((1-hydroxy-2-methylpropane-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-pivaloyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-cyclopropoxy-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; 4-methyltetrahydrofuran-3-yl(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)carbamate; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-hydroxyethyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclobutylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2- Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopentylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-methoxyethyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1,1,1-trifluoropropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((1-hydroxypropane-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((1-methoxypropane-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R,3S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-methyl-3-(1-methyl-1H-pyrazole-4-yl)cyclopropane-1-carboxamide; (1S,2S,3S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-methyl-3-(1-methyl-1H-pyrazole-4-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-fluoropropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopenta-1-en-1-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-imidazole-1-yl)methyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(morpholinoamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(2-amino-2-oxoethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methylpropane-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((2,2-difluoroethyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(2-bromo-2-fluorocyclopropyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazi (n-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(allylamino)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-cyclopentyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((4-methylpiperazine-1-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-fluoroethyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1,3-dihydroxy-2-methylpropane-2-yl)amino)-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-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((1-methyl-1H-pyrazole-5-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((4-hydroxybutan-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2R,3S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-methyl-3-(1-methyl-1H-pyrazole-4-yl)cyclopropane-1-carboxamide; (1S,2S,3S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-methyl-3-(1-methyl-1H-pyrazole-4-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-pyrrole-1-yl)methyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-pyrazole-1-yl)methyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(pyrroridine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-hydroxypyrrolic acid) (Zin-1-yl)-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)-3-hydroxypyrrolidine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-oxocyclopenta-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methoxyethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(N-methylacetamido)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropyl(hydroxy)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-pyrazole-5-yl)amino)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methyl(1H-pyrazole-5-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methyl(1-methyl-1H-pyrazole-5-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isobutyryl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxy-2-methylpropyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(((1S,3R)-3-hydroxycyclopentyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-methyl-1H-imidazole-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2 -a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxycyclopentyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,1-difluoropropan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isobutyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methoxy-2-methylpropyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-fluoro-2-methylpropyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((4-methoxybutan-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((3-fluorocyclobutyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropyl(methoxy)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((E)-buta-2-en-2-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(buta-3-en-2-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butylamino)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-methyl-1H-pyrrole-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((4-methyl-1H-imidazole-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((4-methyl-1H-pyrazole-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-3-hydroxypyrrolidine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-hydroxycyclo Pentyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((tetrahydrofuran-3-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methoxycyclopentyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(((1S,3S)-3-hydroxycyclopentyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-(dimethylamino)-1-oxopropan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(2H-tetrazole-2-yl)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-((S)-1-(2H-tetrazole-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-cyanoethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(1H-tetrazole-1-yl)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-((S)-1-(1H-tetrazole-1-yl)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-amino-1-oxopropan-2-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((1-fluoropropan-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(furan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isoxazole-4-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(((1R,3S)-3-hydroxycyclopentyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-hydroxycyclopenta-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((3-methyl-1H-pyrazole-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methyl(tetrahydrofuran-3-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(2H-1,2,3-triazole-2-yl)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-(1H-1,2,4-triazole-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((3S,4S)-3,4-dihydroxypyrrolidine-1-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methoxypyrrolidine-1-yl)-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)-3-methoxypyrrolidine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-3-methoxypyrrolidine-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1-cyclopropylethyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((3,3-difluorocyclobutyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxypropane-2-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-acetamidoethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(2-cyanopropan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(5-methylfuran-2-yl)-2H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-5-(methylthio)-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((E)-buta-1,3-dien-1-yl)-5- Chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1,1,1-trifluoropropane-2-yl)-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)-1,1,1-trifluoropropane-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((cyclopropylmethyl)amino)-6-fluoro-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-methoxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1-methoxypropane-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-ethoxy-2,2,2-trifluoroethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1,2,2,2-tetrafluoroethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((3S,4S)-3,4-dimethoxypyrrolidine-1-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(furan-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-1,2-dien-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(hydroxy(tetrahydro-2H-pyran-3-yl)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-(isopropylamino)-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(5,6-dihydro-1,4-dioxin-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1H-pyrazole-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyra Din-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(((1R,3S)-3-hydroxycyclopentyl)(methyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(propa-1-en-2-yl)-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(5-methylfuran-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-hydroxypropane-1-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-2-in-1-ylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1,1-difluoropropane-2-yl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(4-hydroxytetrahydrofuran-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(3,3-dimethylazetidine-1-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((3-chloro-2,2-dimethylpropyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(4-methyl-1H-pyrazole-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(5-methyl-1H-pyrazole-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(3-methyl-1H-pyrazole-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(3,3-difluoroazetidine-1-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyanomethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methoxypropane-1-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(2,5-dihydrofuran-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-propionamidoethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-(3-hydroxypropanamide)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-formamidoethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((E)-4-hydroxybuta-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbuta-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbuta-2-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-(trimethylsilyl)propane-2-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; 1 formic acid; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxy-3-(trimethylsilyl)propane-2-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((3-hydroxybutan-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(5,5-dimethyltetrahydrofuran-3-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1H-imidazole-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(2-methyl-1H-imidazole-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((E)-3-(triethylsilyl)propane-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1,1-difluoropropane-2-yl)(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butyl)-5-chloro-6-fluoro-1 H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,4-dioxan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(tetrahydro-2H-pyran-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(4-methyl-1H-imidazole-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyanofluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyano)methyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(6,6-difluoro-2-azaspiro[3,3]heptan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(methylsulfonamide)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,1-difluoropropane-1-en-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1S,2R)-1,2-dihydroxypropyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-2-in-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbutan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbuta-2-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamidomethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-formyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; Ethyl 5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-carboxylate; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(((2R,3R)-3-methoxybutan-2-yl)(methyl)amino)-1H-indazole-4-yl) Midazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(((2R,3S)-3-methoxybutan-2-yl)(methyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-((1-cyanocyclopropyl)amino)ethyl)-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)ethyl acetate; (9H-fluoren-9-yl)methyl(5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)carbamate; (1S,2S)-N-(6-(5-chloro-7-(difluoromethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(hydroxy)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(1-(5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)ethyl)cyclobutanecarboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-fluorocyclopropyl)-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-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(tetrahydrofuran-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((methylthio)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(methylthio)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((methylsulfinyl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((methylsulfonyl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,3-dimethylureido)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl) -2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1S,2R)-1,2-dimethoxypropyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-(2,2-difluoroacetamido)ethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methyl-1H-imidazole-5-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(methylsulfonyl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(methylsulfinyl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-(ethylamino)-1-oxopropan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(2,2,2-trifluoroacetamide)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; Methyl 2-(5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)-3-(cyclobutylamino)-3-oxopropanoate; (1S,2S)-N-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)(cyano)methyl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(cyclopropanecarboxamide)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(2,2-difluoroacetamide)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((propan-2-yl-1,1,1,3,3,3-d6)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-6-fluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; and A compound according to any one of claims 13 to 15, selected from the group consisting of (1S,2S)-N-(6-(5-ethoxy-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

17. L is a bond; R １ However, Halo, and C １ ~C ３ Selected from the group consisting of alkyl groups Cyclopropyl is optionally substituted with one or more groups; R ２ However, it is -H, alkyl, haloalkyl, or halo; R ３ is -H, alkyl, or halo; M is bonded, -O-, or -NR ６ - and; R ４ However, these are -H, halo, alkyl, monoalkylamino, or dialkylamino; and R ５ The compound according to claim 13, wherein the compound is -H, alkyl, or halo, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

18. L is a bond; R ａ is -H; R ｂ is -H; R １ However, chloro, fluoro, or C １ ~C ３ It is an alkyl-substituted cyclopropyl; R ２ However, it is -H, alkyl, chloro, or fluoro; R ３ is -H, alkyl, chloro, or fluoro; M is bonded or -NH-; R ４ is -H, chloro, fluoro, methyl, ethyl, propyl, isopropyl, butyl, methylamino, or dimethylamino; and R ５ A compound according to claim 13 or 17, wherein is -H or alkyl, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

19. L is a bond; R ａ is -H; R ｂ is -H; R １ However, it is a cyclopropyl substituted with chloro or fluoro; R ２ However, it is -H, chloro, or fluoro; R ３ is -H, chloro, or fluoro; M is a bond or -NH-; R ４ However, it is -H, chloro, fluoro, methyl, ethyl, propyl, or isopropyl; and R ５ A compound according to any one of claims 13, 17, or 18, wherein -H, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

20. (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; and A compound according to any one of claims 13, 17, 18, or 19, selected from the group consisting of (1R,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

21. L is a bond; R １ However, Halo, and C １ ~C ３ Selected from the group consisting of alkyl groups Cyclopropyl is optionally substituted with one or more groups; R ２ However, it is -H, alkyl, halo, haloalkyl, or alkylthio; R ３ However, -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR ６ - and; R ４ However, these are -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, monoalkylamino, or dialkylamino; and R ５ The compound according to claim 13, wherein the compound is -H, alkyl, or halo, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

22. (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-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-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-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-(7-(dimethylamino)-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-(isopropylamino)-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-(isopropylamino)-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-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-isopropyl-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; and A compound according to claim 13 or 21, selected from the group consisting of (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

23. R １ However, Halo, and C １ ~C ３ A cyclopropyl compound that is optionally substituted with one or more groups selected from the group consisting of alkyl groups; R ２ However, it is -H, alkyl, halo, haloalkyl, or alkylthio; R ３ However, -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR ６ - and; R ４ However, -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamideethyl, imidazolylethyl, di Xanyl, cyclobutanylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propanyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl, or methylpyrazolylmethyl; and R ５ The compound according to claim 13, wherein the compound is -H, alkyl, or halo, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

24. (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-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-5,7-bis(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-ethoxy-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropyl(methyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1H-pyrrole-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((cyanomethyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)- 2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-cyclopropyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methyl-1H-pyrrole-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(2H-tetrazole-2-yl)ethyl)-5-chloro-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-5-methyl-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-propyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methyl-1H-pyrrole-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methoxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-fluoropropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(ethylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3,3,3-trifluoropropane-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(isopropylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-methyl-1H-pyrazole-5-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-cyclopropoxy-6-fluoro-1H -Indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclobutylamino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-methoxyethyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1,1,1-trifluoropropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((1-hydroxypropane-2-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropoxy-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methylpropane-1-en-1-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((2,2-difluoroethyl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(allylamino)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-cyclopentyl-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((2-fluoroethyl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropyl(hydroxy)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methyl(1-methyl-1H-pyrazole-5-yl)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-hydroxy-2-methylpropyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-isopropyl-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,1-difluoropropan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isobutyl-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-fluoro-2-methylpropyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyclopropyl(methoxy)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((E)-buta-2-en-2-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(buta-3-en-2-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butylamino)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((4-methyl-1H-pyrazole-1-yl)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-hydroxycyclopentyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-methoxycyclopentyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(2H-tetrazole-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-cyanoethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((S)-1-(1H-tetrazole-1-yl)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-amino-1-oxopropan-2-yl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isoxazole-4-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-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-chloro-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-5-(methylthio)-7-(propa-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2- a) Pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1,1,1-trifluoropropane-2-yl)-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)-1,1,1-trifluoropropane-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((cyclopropylmethyl)amino)-6-fluoro-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-methoxypropan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((S)-1-methoxypropane-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1,2,2,2-tetrafluoroethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(furan-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-chloro-7-(cyclopropyl(methyl)amino)-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-(isopropylamino)-5-(methylthio)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-fluoro-7-(propa-1-en-2-yl)-5-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(propa-2-in-1-ylamino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-((1,1-difluoropropane-2-yl)amino)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-propionamidoethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-formamidoethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbuta-1-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbuta-2-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1H-imidazole-1-yl)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-(sec-butyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,4-dioxan-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(4-methyl-1H-imidazole-1-yl)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetamido(cyano)methyl)-5-chloro-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(methylsulfonamide)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1,1-difluoropropane-1-en-2-yl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbutan-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(3-methylbuta-2-en-2-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(1-(5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)ethyl)cyclobutanecarboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(2-fluorocyclopropyl)-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-(trifluoromethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(tetrahydrofuran-3-yl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((methylthio)methyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(1-(methylthio)ethyl)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(1-(2,2-difluoroacetamido)ethyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(2,2,2-trifluoroacetamide)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-((5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)imidazo[1,2-a]pyrazine-6-yl)-1H-indazole-7-yl)(cyano)methyl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(cyclopropanecarboxamide)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-chloro-7-(cyano(2,2-difluoroacetamide)methyl)-6-fluoro-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide; and A compound according to claim 13 or 23, selected from the group consisting of (1S,2S)-N-(6-(5-chloro-6-fluoro-7-((propan-2-yl-1,1,1,3,3,3-d6)amino)-1H-indazole-4-yl)imidazo[1,2-a]pyrazine-2-yl)-2-fluorocyclopropane-1-carboxamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for treating a subject having a disease or disorder associated with HPK1 modulation.

27. The pharmaceutical composition according to claim 26, wherein the disease is cancer.

28. The pharmaceutical composition according to claim 26, wherein the disease is cancer, metastasis, inflammation, or autoimmune disease.

29. The pharmaceutical composition according to claim 28, wherein the cancer is selected from the group consisting of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias, without limitation, including bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid cancer and nephroblastoma (Wilms' tumor).

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