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

Abstract

The present application provides compounds represented by Formula (I) or pharmaceutically acceptable salts thereof, compositions comprising the compounds, methods of using the compounds to treat various diseases associated with HPK1, and methods of making the compounds.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 084059, filed September 28, 2020. The entire disclosure of the application specified in this paragraph is incorporated herein by reference. TECHNICAL FIELD

[0003] The present application relates to hematopoietic progenitor kinase 1 (HPK1) inhibitors, pharmaceutical compositions comprising the inhibitors, methods of using the inhibitors to treat various diseases associated with HPK1, and methods of making these compounds. BACKGROUND

[0004] Immunotherapy is a treatment method that utilizes the human body’s own immune system to fight cancer and other diseases. In recent years, this relatively new method, especially in combination with the joint application of immune checkpoint inhibitor therapy and chimeric antigen T cell therapy, has achieved great success in the clinical treatment of various tumors. The most studied checkpoint inhibitors, including CTLA4, PD-1 or PD-L1 inhibitors, show significant anti-tumor activity by overcoming the immunosuppressive mechanisms at the tumor site.

[0005] Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a serine / threonine kinase and a member of the MAP4K family. HPK1 is significantly expressed in a subset of hematopoietic cell lines. It has been recently discovered that HPK1 is a key negative regulator of T lymphocyte and dendritic cell activation. Recent studies have shown that HPK1 kinase activity plays an important role as a new intracellular checkpoint molecule in anti-cancer immunity, as well as potential advantages in combination therapy with existing checkpoint regimens. HPK1 inhibition is expected to have a dual function, 1. long-term activation of T cells; 2. dendritic cell enhancement of APC function. This dual targeting works synergistically to achieve an effective immune response in the tumor microenvironment. Therefore, HPK1 has been confirmed as a new target for anti-cancer immunotherapy. Examples of cancers that can be treated using the compounds of the present application include, but are not limited to, all forms of cancer, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including but not limited to bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma, and Wilms tumor.

[0006] Inhibition of HPK1 with small molecule inhibitors may be used to treat cancer and other diseases [Hernandez, S., et al. (2018) Cell Reports 2580-94]. Summary of the Invention

[0007] This invention provides novel indazole compounds and pharmaceutically acceptable salts as potent HPK1 inhibitors and dual activators of T cells and dendritic cells.

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

[0009]

[0010] Or its pharmaceutically acceptable salts, hydrates, or solvates, wherein R 1 R 1 R 3 R 4、 R 5 Het, M, and L are as defined in the specific implementation.

[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 another embodiment, a method of treating a subject suffering from a disease or condition related to HPK1 regulation is provided, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0013] The following description is merely illustrative in nature and is not intended to limit the invention, application, or use.

[0014] Definitions

[0015] For clarity, the general terms used in this invention are defined herein.

[0016] The terms “substituent”, “free radical”, “group”, “part” and “fragment” may be used interchangeably in this specification.

[0017] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one unsaturated site, i.e., a carbon-carbon, sp2 double bond. In one embodiment, the alkenyl group has 2 to 12 carbon atoms. In some embodiments, the alkenyl group is C2-C. 10Alkenyl or C2-C6 alkenyl. Examples of alkenyl include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0018] As used herein, the term "alkoxy" is RO- where R is an alkyl group. Non-limiting examples of alkoxy include methoxy, ethoxy, and propoxy.

[0019] As used herein, the term "alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl include methoxymethyl, methoxyethyl, methoxypropyl, and ethoxyethyl.

[0020] 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-C6 alkyl group. Non-limiting examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. 10 Alkyl or C1-C6 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" refers to an alkyl group having from 1 to 4 carbon atoms.

[0021] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon. In one embodiment, the alkyl group has from 1 to 12 carbon atoms. In some embodiments, the alkyl group is a C1-C6 alkyl group. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 10 Alkyl or C1-C6 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" refers to an alkyl group having from 1 to 4 carbon atoms.

[0022] As used herein, if the term "C1-C6" is used, it means that the number of carbon atoms is from 1 to 6. For example, C1-C6 alkyl means an alkyl group of any integer from 1 to 6 carbons.

[0023] As used herein, the term "alkylamino" refers to an amino group substituted with one or more alkyl groups. "N-(alkyl)amino" is RNH- and "N,N-(alkyl)2amino" is R2N- where the R groups are alkyl groups as defined herein and are the same or different. In various embodiments, R is a C1-C6 alkyl group. 10 Alkyl or C1-C6 alkyl. Examples of alkylamino include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and methylethylamino.

[0024] As used herein, the term "alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, where alkylamino is as defined herein. Examples of alkylaminoalkyl include methylaminomethyl and ethylaminomethyl.

[0025] As used herein, the term "alkynyl" refers to a straight chain or branched chain carbon chain radical having at least one unsaturation, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl group has 2 to 12 carbon atoms. In some embodiments, the alkynyl is a C2-C6alkynyl. Examples of alkynyl include ethynyl (-C≡CH) and propargyl (-CH2C≡CH). 10 alkynyl or C2-C6alkynyl. Examples of alkynyl include ethynyl (-C≡CH) and propargyl (-CH2C≡CH).

[0026] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic radical of up to 7 atoms in each ring, at least one of which is aromatic, or an aromatic ring system of 5 to 14 carbon atoms, including carbocyclic aromatic radicals fused with 5- or 6-membered ring alkanes. Representative examples of aryl include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthryl, fluorenyl, indenyl, azulenyl, and indanly. The carbocyclic aromatic radical can be unsubstituted or optionally substituted.

[0027] As used herein, the term "cycloalkyl" is a hydrocarbon radical that includes at least one saturated or partially unsaturated ring structure and is attached via a ring carbon. In various embodiments, it refers to saturated or partially unsaturated C3-C 12 cyclic moiety, saturated or partially unsaturated C3-C 12 Examples of cyclic moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. "Cycloalkoxy" is RO-, where R is cycloalkyl.

[0028] As used herein, the terms "halogen" and "halo" refer to chlorine (-Cl), bromine (-Br), fluorine (-F), or iodine (-I). "Haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, and examples of haloalkoxy include, but are not limited to, -OCF3, -OCHF2, and -OCH2F. "Haloalkoxyalkyl" refers to an alkyl moiety substituted with a haloalkoxy group, where haloalkoxy is as defined herein. Examples of haloalkoxyalkyl include trifluoromethoxy methyl, trifluoroethoxymethyl, and trifluoromethoxy ethyl. "Haloalkyl" refers to an alkyl moiety substituted with one or more halogen groups. Examples of haloalkyl include -CF3and -CHF2.

[0029] As used herein, the term "heteroalkyl" refers to a straight chain or branched chain alkyl group having 2 to 14 carbons (in some embodiments, 2 to 10 carbons) in the chain, wherein one or more has been replaced with a heteroatom selected from S, O, P, and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.

[0030] As used herein, the term "heterocyclyl" includes heteroaryl as defined below and refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic radical of 2 to 14 ring carbon atoms, in addition to the ring carbon atoms there are 1 to 4 heteroatoms selected from P, N, O, and S. In various embodiments, the heterocyclyl is attached to another moiety through a carbon or through a heteroatom, and is optionally substituted with carbon or heteroatoms. Examples of heterocyclyl include azetidinyl, benzimidazolyl, benzofuranyl, benzofuranazinyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrid-2-yl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotazolyl, dihydroazetidinyl, methylenedioxo-benzoyl, tetrahydrofuranyl, and tetrahydrothiophenyl, and N-oxides thereof. "Heterocyclyloxy" is RO-, where R is heterocyclyl. "Heterocyclylthio" is RS-, where R is heterocyclyl.

[0031] As used herein, the term "3- or 4-membered heterocyclyl" refers to a monocyclic radical having 3 or 4 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S. Non-limiting examples of 3- or 4-membered heterocyclyl include aziridinyl, 2H-aziridinyl, oxetanyl, thiethanyl, azetidinyl, 2,3-dihydroazetidinyl, azepinyl, 1,3-diazepinyl, oxetidinyl, 2H-oxetidinyl, thietidinyl, and 2H-thiethanyl.

[0032] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring having up to 7 atoms in each ring, at least one of which is aromatic and containing 1-4 heteroatoms selected from N, O, and S in the ring. Non-limiting examples of heteroaryl groups include pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothiophenyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thionaphthenyl, and pyrazinyl. Attachment of a heteroaryl group can occur through an aromatic ring, or, if the heteroaryl group is bicyclic or tricyclic and one of the rings is not aromatic or does not contain a heteroatom, through 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 groups. "Heteroaryloxy" is RO-, where R is heteroaryl.

[0033] As used herein, the term "hydroxyalkyl" refers to a straight-chain or branched-chain monovalent C1-C6alkyl group substituted with at least one hydroxyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0034] As used herein, the term "hydroxyalkyl" refers to a straight-chain or branched-chain monovalent C1-C 10 hydrocarbyl groups, and examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0035] As used herein, the term "pharmaceutically acceptable" means suitable for use in pharmaceutical manufacture, generally considered safe for such use by regulatory agencies of the Federal or state governments, officially approved by a regulatory agency for such use, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0036] As used herein, the term "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, or vehicle, or other ingredient with which a compound of the application is administered.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts, and amine salts. Examples of acid addition salts formed with inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of acid addition salts formed with organic acids include salts of acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanespropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy- benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Examples of metal salts include salts of sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts of ammonia and organic nitrogen bases strong enough to form salts with carboxylic acids.

[0038] As used herein, the term "substituted" refers to any of the groups described above (i.e., alkyl, aryl, heteroaryl, heterocycle, or cycloalkyl), wherein at least one of the hydrogen atoms of the substituted moiety is replaced with a substituent. In one embodiment, each carbon atom of a substituted group is substituted with no more than two substituents. In another embodiment, each carbon atom of a substituted group is substituted with no more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced with an oxygen, which is attached to a carbon by a double bond. Unless specifically provided, substituents include halo, hydroxyl, (lower)alkyl, haloalkyl, mono- or di-alkylamino, aryl, heterocycle, -NO2, B(OH)2, BPin, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a R b , -N R aC(=O)OR b , -NR a SO2R b , -OR a , -CN, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)R a , -OC(=O)OR a, -OC(=O)NR a R b , -NR a SO2R b , -PO3R a , -PO(OR a )(OR b ), -SO2R a , -S(O)R a , -SO(N)R a (e.g., sulfoximine), -(R a )S=NR b (e.g., alkylsulfenylimine) and -SRa, wherein R a and R b are the same or different and independently -H, halo, amino, alkyl, haloalkyl, aryl or heterocycle, or wherein R a and R b together with the nitrogen atom to which they are attached form a heterocycle. R a and R b may be plural in number based on the atom to which they are attached.

[0039] As used herein, the term "therapeutically effective amount" means, when applied to a compound of the present application, an amount of the compound that is sufficient to ameliorate, alleviate, stabilize, reverse, slow or delay the progression of, or development of, a condition or disease state, or symptoms of a condition or disease. In one embodiment, the methods of the present application provide for administration of a combination of compounds. In this case, a "therapeutically effective amount" is an amount of a compound of the present application in the combination that is sufficient to cause the intended biological effect.

[0040] As used herein, the term "treat" means to ameliorate or reverse the progression or severity of a disease or condition, or to ameliorate or reverse one or more symptoms or side effects of such disease or condition. As used herein, "treat" also means to inhibit or block, such as to delay, retard, restrain, hinder or impede, the progression of a system, symptom or state of a disease or condition. To achieve the objects of the present application, "treat" further means a method of obtaining beneficial or desired clinical results, wherein "beneficial or desired clinical results" include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or illness, stabilized (i.e., not worsening) state of disease or condition, delay or slowing of disease or condition state, amelioration or remission of disease or condition state, and partial or complete remission of disease or condition.

[0041] Compounds

[0042] The present application provides a compound of formula (I):

[0043]

[0044] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

[0045] X is O or S;

[0046] L is a bond, -O-, -S-, or -NR 6 -;

[0047] R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more substituents independently selected from R 7 ;

[0048] R 6 is -H or C 1-6 alkyl;

[0049] R 7 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, oxo, cyano, hydroxyl, -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -OR 9 , -OC(O)R 9 , -OC(O)NR 10 R 11 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -S(O)(=NH)R 10 , -S(O)2NR 10 R 11 , -NR 10 R 11 , -N(R 6 )NR 10 R 11 , -N(R 6 )OR 9 , -N(R 6 )C(O)R 9 , -N(R 6 )C(O)OR 9 , -N(R 6 )C(O)NR 10 R 11 , -N(R 6 )S(O)2R 9 , -N(R 6 )S(O)2NR 10 R 11, or -P(O)R 12 R 13 ;

[0050] 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;

[0051] 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 a 4- to 12-membered heterocyclyl group, which heterocyclyl is optionally substituted with one or more of the following: halo, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO2, -NR 10 R 11 , -NR 10 C(=O)R 9 , -NR 10 C(=O)NR 10 R 11 , -NR 10 C(=O)OR 9 , -OR 9 , -C(=O)R 9 , -C(=O)OR 9 , -C(=O)NR 10 R 11 , -OC(=O)R 9 , -OC(=O)OR 9 , and -OC(=O)NR 10 R 11 ;

[0052] each R 12 and R 13 is independently C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, or R 12 and R 13 , together with the phosphorus atom to which they are attached, form a 4- to 8-membered heterocyclyl group, which heterocyclyl is optionally substituted with one or more of the following: halo, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO2, -NR 10 R 11-NR 10 C(=O)R 9 -NR 10 C(=O)NR 10 R 11 -NR 10 C(=O)OR 9 -OR 9 -C(=O)R 9 -C(=O)OR 9 -C(=O)NR 10 R 11 -OC(=O)R 9 -OC(=O)OR 9 -OC(=O)NR 10 R 11 ;

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

[0054]

[0055] R a , R b , and R c are each independently -H, -D, halo, CF3, CF2H, CH2F, CN, OR 9 , or NR 10 R 11 ;

[0056] R 2 is -H, -D, -CD3, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, hydroxyl, -CD2OH, -CN, -NO2, haloalkyl, trimethylsiloxymethyl, -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 alkenyl, C 2-6 The alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups may optionally be substituted by one or more of the following groups: halogenated, 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 ,

[0057] R 3 -H, -D, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, halogenated, cyano, hydroxyl, -CH2OH, -CD2OH, -OH, -CN, -NO2, haloalkyl, -C(O)R 9 -C(O)OR9 -C(O)NR 10 R 11 -OR 9 -OC(O)R 9 -OC(O)NR 10 R 11 -SR 9 -S(O)R 9 -S(O)2R 9 -S(O)(=NH)R 10 -S(O)2NR 10 R 11 -NR 10 R 11 -N(R 6 )NR 10 R 11 -N(R 6 )OR 9 -N(R 6 )C(O)R 9 -N(R 6 )C(O)OR 9 -N(R 6 )C(O)NR 10 R 11 -N(R 6 )S(O)2R 9 -N(R 6 )S(O)2NR 10 R 11 , or -P(O)R 12 R 13 ;

[0058] M is a bond, -O-, -S-, or -NR 6 -;

[0059] R 6 is -H or C 1-6 alkyl;

[0060] R 4 is -H, -D, C 1-6 alkyl, C 2-6 alkenyl, C2-6alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxyl, -C(O)R 9 , -C(O)OR 9 , -C(O)NR 10 R 11 , -S(O)2R 9 , -S(O)(=NH)R 10 , -S(O)2NR 10 R 11, or -P(O)R 12 R 13 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted by one or more groups selected from the following: halogenated, hydroxylated, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD3, -NO2, -NR 10 R 11 -NR 10 C(=O)R 9 -NR 10 C(=O)NR 10 R 11 -NR 10 C(=O)OR 9 -NR 10 S(O)2R 9 -OR 9 -C(=O)R 9 -C(=O)OR 9 -C(=O)NR 10 R 11 -OC(=O)R 9 -OC(=O)OR 9 , and -OC(=O)NR 10 R 11 ;and

[0061] R 5 -H, -D, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, halogenated, hydroxyl, -CH2OH, -CD2OH, -CN or haloalkyl.

[0062] In various implementation schemes, L is the key, and R... 1 It is a cycloalkyl group, which is optionally substituted by one or more groups selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, halogenated, cyano, hydroxyl, -C(O)R 9 -C(O)OR 9 -C(O)R 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)N R10 R 11 . In various embodiments, each of R 2 and R 3 is independently -H, halo, alkylsulfanyl, haloalkyl, or alkyl. In various embodiments, M is a bond, -O-, or -NR 6 -; R 4 is -H, -D, C 1-6 1-6alkyl, C 2-6 2-6alkenyl, C 2-6 2-6alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, cyano, hydroxyl, -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 , wherein C 1-6 1-6alkyl, C2-6alkenyl, C 2-6 2-6alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups selected from halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD3, -NR 10 R 11 , -NR 10 S(O)2R 9 , and -NR 10 C(=O)R 9 .

[0063] In another embodiment, there is provided a compound represented by formula (II):

[0064]

[0065] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , M and L are as defined above for formula (I).

[0066] In various embodiments, L is a bond, R 1 is cyclopropyl optionally substituted with one or more groups selected from halo, C 1-3 alkylthio, C 1-3 alkyl, C 1-3 hydroxyalkyl, and C1-3 haloalkyl; R 2 is -H, alkyl, halo, haloalkyl, or alkylthio; R 3 is -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -; R 4 is -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, dimethylamino, dimethylaminoethyl, dimethylaminocarbonyl, methylaminooxyethyl, aminocarbonylalkyl, ethylendiaminetetraacetate, propylaminoethyl, methylaminoethyl, aminoalkyl, methylaminocarbonylmethyl, alkoxyalkyl, azetidinyl, or azetidinylmethyl; R 5 is -H, alkyl, or halo.

[0067] Non-limiting example compounds of Formula (II) include the compounds of Examples 1-145 of Table 1. In particular embodiments, the compound is selected from the group consisting of the compounds of Examples 58, 80, 82, 85, 87, 92, 94, 97, 98, 110, 111, 118, 123, 125, 129, and 134.

[0068] In another embodiment, a compound is provided by Formula (III):

[0069]

[0070] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , M, and L are as defined above in Formula (I).

[0071] In various embodiments, L is a bond, R 1 is cyclopropyl optionally substituted with one or more groups selected from halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, and C 1-3 haloalkyl; R 2 is -H, alkyl, halo, haloalkyl, or alkylthio; R 3 is -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -; R 4is -H, halo, alkyl, hydroxyalkyl, dimethylamino, dimethylaminoethyl, dimethylaminocarbonyl, methylaminooxyethyl, aminocarbonylalkyl, ethylaminoethyl, or alkoxyalkyl; R 5 is -H, alkyl, or halo.

[0072] Non-limiting exemplary compounds of Formula (III) include the compounds of Examples 146-218 of Table 1. In particular embodiments, the compound is selected from the group consisting of the compounds of 149, 152, 156, 159, 161-163, 167, 169, 170, 172-175, 178, 184, 193, 194, 196, 199, and 218.

[0073] In another embodiment, a compound is provided by Formula (IV):

[0074]

[0075] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , M and L are as defined above in Formula (I).

[0076] In some embodiments, L is a bond, R 1 is cyclopropyl, optionally substituted with one or more groups selected from halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, and C 1-3 haloalkyl; R 2 is -H, alkyl, halo, haloalkyl, or alkylthio; R 3 is -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -; R 4-H, halogenated, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, dimethylamino, dimethylaminoethyl, dimethylaminocarbonyl, methylaminooxyethyl, aminocarbonylalkyl, acetamidoethyl, propylaminoethyl, methylaminoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, alkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamide ethyl, imidazolinyl ethyl, dioxoaryl, cyclobutane alkylcarbonylaminoethyl, difluoroacetamylethyl, trifluoroacetamylethyl, methylthiomethyl, methylthioethyl, aziridine, aziridinemethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamyl)methyl, propyl-1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl; R 5 It can be –H, alkyl, or halogenated.

[0077] Non-limiting example compounds of formula (IV) include the compounds of Examples 219 and 220 in Table 1.

[0078] In another embodiment, a compound of formula (V) is provided:

[0079]

[0080] Where R 1 R 2 R 3 R 4 R 5 R a R b M and L are defined as in equation (I) above.

[0081] In some implementations, L is the key, and R is the key. 1 It is a cycloalkyl group, which is optionally selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, halogenated, cyano, hydroxyl, -C(O)R 9 -C(O)OR 9 -C(O)NR 10 R 11 -OR 9 -OC(O)R 9 -OC(O)NR 10 R 11 -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 One or more groups in R are substituted. In some other embodiments, R 1 It is a cycloalkyl group, optionally selected from halogenated, C-shaped, or alkyl groups. 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 One or more groups of a haloalkyl group are substituted.

[0082] The non-limiting example compounds shown in formula (V) include the compounds in Examples 221-445 of Table 1.

[0083] In some embodiments, R1 is cyclopropyl, optionally selected from halogenated, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 alkyl groups. 1- One or more groups of a C3 haloalkyl group are substituted; R 2 –H, alkyl, alkylthio, haloalkyl, or halogenated; R 3 –H, alkyl, or halo; M is a bond, -O-, or -NR. 6 -;R 4 It is –H, halogenated, alkyl, monoalkylamino, or dialkylamino; R 5 It is –H, alkyl, or halogenated. Non-limiting example compounds include one of the following:

[0084] (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazol[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide;

[0085] (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazol[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide;

[0086] (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(methylthio)-1H-indazol-4-yl)imidazol[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide;

[0087] (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazol[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide;

[0088] (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indol-4-yl)imidazo[1,2- a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide; and

[0089] (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indol-4-yl)imidazo[1,2- a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide; and

[0090] In some embodiments, R 1 is cyclopropyl optionally substituted with one or more groups selected from halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, and C 1-3 haloalkyl; R 2 is -H, alkyl, halo, haloalkyl, or alkylthio; R 3 is -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -; R 4 is -H, halo, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, monoalkylamino, or dialkylamino; and R 5 is -H, alkyl, or halo. Non-limiting example compounds include a compound selected from the group consisting of: Examples 258, 261, 265, 266, 269, 272, 275, 280, 288, 291, 293, 296, 297, 300, 304, 306, 310, 318, 320, 324, 327, 329, 330, 332, 334, 336, 341, 345, 349, 353, 356, 358, 359, 361, 366, 371, 372, 374, 390, 391, 393, 404, 405, 408, 410, 414, 417, 419, 422, 423, 425, 426, 428, 430, 433, 434, 436, 439, 441, and 445.

[0091] In some embodiments, R 1 is cyclopropyl optionally substituted with one or more groups selected from halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, and C 1-3 haloalkyl; R 2 is -H, alkyl, halo, haloalkyl, or alkylthio; R 3 is -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -; R 4halo, alkyl, alkylcarbonyl, dialkylaminocarbonyl, oxopyrrolidinyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, pyridinyl, monoalkylamino, or dialkylamino; R 5 is -H, alkyl, or halo. Non-limiting example compounds include those from Examples 258, 261, 265, 266, 268, 269, 271-273 275, 280, 281, 288, 290, 291, 293, 296-298, 300, 304, 306, 307, 310, 316, 318, 320, 324, 326, 327, 329, 330-334, 336, 339, 341, 345, 346, 349, 353, 356, 358, 359, 361-363, 365-367, 370-374, 377-379, 383, 388, 390, 391, 393, 398, 401, 404-406, 408-410, 414, 415, 417, 419, 421-426, 428, 430, 433, 434, 436, 439, 441, and 445.

[0092] In another embodiment, a compound is provided having the formula (VI):

[0093]

[0094] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , M and L are as defined in formula (I).

[0095] In some embodiments, L is a bond, R 1 is cyclopropyl optionally substituted with one or more groups selected from halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, and C 1-3 haloalkyl; R 2 is -H, alkyl, halo, haloalkyl, or alkylthio; R 3 is -H, alkyl, or halo; M is a bond, -O-, -S-, or -NR 6 -; R 4haloalkyl, haloalkylaminoalkyl, haloalkylcarbonylaminoalkyl, alkylaminoalkyl, hydroxyhaloalkyl, haloalkenyl, cycloalkyl, cyano, cyanoalkyl, dimethylamino, dimethylaminoethyl, methylaminocarbonyl, dimethylaminocarbonyl, methylaminooxyethyl, aminocarbonyl, ethylaminoethyl, dialkylaminocycloalkyl, aminocycloalkyl, methylaminocycloalkyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, cycloalkylamidoalkyl, cycloalkylaminocarbonyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxycarbonyl, alkylcarbonyl, alkylamidoalkyl, alkoxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxo, azetidinyl, azetidinylmethyl, tetrahydrofuranyl, furanyl, pyrimidinyl, pyridinyl, pyrrolyl, halo pyrrolidinyl, pyrrolidinyl, methylpyrrolyl, isoxazolyl, tetrazolyl, methylpyrazolyl, or methylpyrazolylmethyl; R 5 is -H, alkyl, or halo.

[0096] Non-limiting exemplary compounds of Formula (VI) include the compounds of Examples 446-666 of Table 1. In particular embodiments, the compound is selected from Examples 464, 466, 467, 476, 477, 480, 484, 485, 487, 488, 490-494, 496, 497, 502-505, 509, 513, 514, 519-521, 523-525, 529-532, 534, 541, 543, 548, 550, 552, 556-558, 561-565, 568-574, 577, 579, 581, 585, 586, 588, 592, 596-600, 602, 607, 612, 615, 617-619, 621, 623, 625, 629, 634, 636-642, 644, 646, 650-652, 655-657, and 659-665.

[0097] 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.

[0098] Medical uses of the compounds and methods of treatment using the compounds

[0099] The present application provides a method of treating a subject having a disease or disorder associated with HPK1 modulation, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with HPK1 modulation is cancer, metastasis, inflammation, or an immune disease including an autoimmune disease.

[0100] In some other embodiments, the disease is a cancer, a metastasis, an inflammatory disease, or an autoimmune disease. In particular embodiments, the cancer is selected from the group consisting of carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including but not limited to bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular cancer, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid cancer, and Wilms tumor.

[0101] In some embodiments, the autoimmune disease is inflammatory bowel disease, Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, hemolytic anemia, autoimmune hepatitis, Behcet's disease, Berger's disease, bullous pemphigoid, cardiomyopathy, ascites, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, cold agglutinin disease, diabetes mellitus type 1, discoid lupus, essential mixed cryoglobulinemia, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hypothyroidism, autoimmune lymphoproliferative syndrome (ALPS), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic 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

[0102] In another embodiment, there is provided use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting HPK1 activity in a subject in need thereof. In some embodiments, the use comprises treatment of a cancer.

[0103] Suitable subjects to be treated according to the present application include mammalian subjects. Mammals according to the present application include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and the like, and include mammals in utero. The subject can be of any gender and at any stage of development. In one embodiment, a suitable subject to be treated according to the present application is a human.

[0104] The compounds of the present application are generally administered in a therapeutically effective amount. The compounds of the present application can be administered by any suitable route, in the form of a pharmaceutical composition adapted to the chosen route of administration, and at a dose effective for the treatment intended. The effective dose is typically about 0.001 to about 100 mg, preferably about 0.01 to about 50 mg per kg of body weight per day, in single or divided doses. Lower or higher doses can be appropriate depending on the age, species, and disease or condition of the subject. In other cases, larger doses can be used without harm. Large doses can be divided into several smaller doses for administration throughout the day. Methods of determining appropriate dosages are well known in the art to which the present application pertains. For example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th edition, 2000, can be used.

[0105] Pharmaceutical compositions, dosage forms, and routes of administration

[0106] For the treatment of the diseases or conditions described above, the compounds of the present application, or pharmaceutically acceptable salts thereof, can be administered as follows:

[0107] Oral administration

[0108] The compounds of the present application can be administered orally, including by swallowing, so that the compound enters the gastrointestinal tract, or by direct absorption into the blood stream from the lining of the mouth, e.g., sublingually. Suitable compositions for oral administration include solid, liquid, gel and powder formulations, and have a dosage form, such as tablets, troches, capsules, granules or powders. Compositions for oral administration can be formulated as immediate or modified release, including delayed release or sustained release, optionally with enteric coatings. Liquid formulations can include solutions, syrups and suspensions, which can be used in soft or hard capsules. Such formulations can include a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose or an oil. The formulation can also include one or more emulsifying and / or suspending agents.

[0109] In tablet dosage forms, the amount of drug present can range from about 0.05% to about 95% by weight of the dosage form, more usually about 2% to about 50%. In addition, tablets can include a disintegrant, which can range from about 0.5% to about 35% by weight of the dosage form, more usually about 2% to about 25%. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, crosscarmellose sodium, maltodextrin or mixtures thereof.

[0110] Suitable lubricants for tablets are present in an amount of about 0.1% to about 5% by weight, and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

[0111] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gums, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and the like. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0112] Suitable solubilizers for use in tablets can be present in amounts 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 TM (Nikkol), oleate, Gelucire TM 50 / 13, sorbitan fatty acid esters, and Solutol HS TM .

[0113] Parenteral administration

[0114] The compounds of the present application can be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable ways of parenteral administration include intravenous, intramuscular, subcutaneous, intraarterial, intraperitoneal, intrathecal, intracranial, and the like. Suitable devices for parenteral administration include syringes (including needle and needle-free syringes) and infusion methods.

[0115] Compositions for parenteral administration can be formulated for immediate or modified release, including delayed or sustained release. Most parenteral formulations are aqueous solutions containing excipients, including salts, buffering agents, and isotonic agents. Parenteral formulations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, such as sterile water. Solubilizers can also be used in the preparation of parenteral solutions.

[0116] Transdermal administration

[0117] The compounds of the present application can be administered topically to the skin or transdermally. Formulations for such topical administration can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for use in topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycols, and the like. Topical or transdermal administration can also be carried out by electroporation, iontophoresis, sonophoresis, and the like. Compositions for topical administration can be formulated for immediate release or modified release, including delayed release or sustained release.

[0118] Combination therapy

[0119] The pharmaceutical composition according to the present application can comprise one or more additional therapeutic agents, for example, to improve efficacy or reduce side effects. Thus, in some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from active ingredients useful for treating or inhibiting a disease mediated directly or indirectly by HPK1. Examples of such active ingredients include, but are not limited to, agents that treat cancer, metastasis, inflammation, or autoimmune pathogenesis. In some embodiments, the compound represented by Formula (I) is administered using an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA4 agent.

[0120] References for preparing pharmaceutical compositions

[0121] Methods for preparing pharmaceutical compositions for treating or preventing a disease or disorder are well known in the art to which the present application pertains. For example, pharmaceutically acceptable excipients, carriers, additives, etc. can be selected according to the Handbook of Pharmaceutical Excipients (7th edition), Remington: The Science and Practice of Pharmacy (20th edition), Encyclopedia of Pharmaceutical Technology (3rd edition), or Controlled Release of Drug Delivery Systems (1978), and then mixed with the compound of the present application to prepare a pharmaceutical composition.

[0122] The present application provides a compound having various pharmacological effects by inhibiting HPK1 activity, a pharmaceutical composition using the same as an effective agent, and medical uses of the compound, particularly for treating a disease or disorder modulated by HPK1, and a treatment or prevention method comprising administering the compound to a subject in need of such treatment or prevention. The compound of the present application and pharmaceutically acceptable salts thereof have good safety and high selectivity for HPK1, and thus exhibit excellent performance as a pharmaceutical.

[0123] Compound preparation

[0124] The following preparation examples illustrate the preparation of intermediate compounds used to prepare the compound represented by Formula (I). The novel intermediate compounds described herein and the synthetic methods for preparing the intermediate compounds represent embodiments of the present application.

[0125] Intermediate 1A. 1-(tetrahydro-2H-pyran-2-yl)-5-(thiophen-2-yl)-1H-indazol-4-yl trifluoromethylsulfonate

[0126]

[0127] Step 1) 3-bromo-4-chloro-5-fluoro-2-methylaniline

[0128] To a solution of 3-bromo-5-fluoro-2-methylaniline (50 g, 245 mmol, 1 eq) in AcOH (100 mL) was added N-chlorosuccinimide (36 g, 270 mmol, 1.1 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum, and the residue was extracted with dichloromethane (200 mL*2). The combined organic layers were washed with 200 mL of saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was obtained as a black oil (66 g, crude).

[0129] Step 2) 4-bromo-5-chloro-6-fluoro-lH-indazole

[0130] 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), H2O (0.065 L, 1.5 M) was added sodium nitrite (8.96 g, 130 mmol, 1.2 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum, and the residue was extracted with dichloromethane (1 L*2). The combined organic layers were washed with saturated NaHCO3 (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was obtained as a brown solid (23.6 g, crude).

[0131] Step 3) 4-bromo-5-chloro-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0132] To a solution of 4-bromo-5-chloro-6-fluoro-lH-indazole (1.98 g, 7.97 mmol, 1 eq) in THP (40 mL) was added 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq). The reaction mixture was stirred at 70 °C for 14 h. The reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic residue was purified by column chromatography (silica gel, Hex: ethyl acetate = 1:0 to 4:1). 4-bromo-5-chloro-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (1.51 g, 4.54 mmol, 57% yield) was obtained.

[0133] 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.00 (dd, J = 9.3, 1.1 Hz, 1H), 5.85 (dd, J = 9.6, 2.5 Hz, 1H), 3.87 (d, J = 12.6 Hz, 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).

[0134] Intermediate 1B. 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)- 2H indazole

[0135]

[0136] Step 1) 4-Bromo-5-chloro-6-fluoro-7-iodo-1H-indazole

[0137] To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (2 g, 8.02 mmol) in sulfuric acid (1.7 mL) was added N-iodosuccinimide (2.7 g, 12.03 mmol) in portions. The mixture was stirred at 0 °C for 3 hours. After the reaction was completed, the mixture was poured into ice water, quenched with solid NaOH, and then extracted with dichloromethane. The combined organic residue was concentrated under vacuum. (2.99 g, crude).

[0138] 1 H NMR (400 MHz, DMSO-d6) δ 13.91 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H).

[0139] Step 2) 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H indazole

[0140] To a solution of 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole (2.99 g, 7.97 mmol, 1 eq) in THF (40 mL) was added 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic residue was purified by column chromatography (silica gel, Hex: ethyl acetate = 1:0 to 4:1). 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H indazole (1.64 g, 7.97 mmol, 60.7% yield) was obtained.

[0141] 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, 1H), 2.08 - 1.91 (m, 2H), 1.79 - 1.45 (m, 4H).

[0142] Intermediate 1C. 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)- 2H-indazol-7-amine

[0143]

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

[0145] To a mixture of HNO3 (12.63 g, 200.43 mmol, 9.02 mL, 5 eq) in H2SO4 (50 mL) was added 4-bromo-5-chloro-6-fluoro-1H-indazole (10 g, 40.09 mmol, 1 eq) slowly with stirring at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 2 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed all reactants were consumed and a new major spot appeared. The mixture was poured into ice water, the mixture was extracted with ethyl acetate (50 mL*3), the combined organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated to give 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (12 g, crude) as a yellow solid.

[0146] Step 2) 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H indazole

[0147] 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) was added 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq). The reaction mixture was stirred at 60 °C for 14 h. The reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic residue was purified by column chromatography (silica gel, Hex: ethyl acetate = 1:0 to 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.

[0148] Step 3) 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7- amine

[0149] To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)- 2H-indazole (600 mg, 1.58 mmol, 1 eq) in EtOH (5 mL) and H2O (5 mL) was added NH4CI (508.66 mg, 9.51 mmol, 6 eq) and Fe (531.04 mg, 9.51 mmol, 6 eq), then the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL*2), then the organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Si02, petroleum ether / ethyl acetate = 1:1). 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine (390 mg, 1.12 mmol, 70.59% yield) was obtained as a yellow oil.

[0150] 1 H NMR (400 MHz, DMSO-d6) d 8.41 (s, 1H), 5.85 (br s, 2H), 5.71 (br d, J = 8.0 Hz, 1H), 4.00 (br d, J = 11.3 Hz, 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).

[0151] Intermediate 1D. 4-Bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-7-amine

[0152]

[0153] Step 1) 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole

[0154] To a solution of intermediate 1A (900 mg, 3.61 mmol, 1 eq) in H2SO4 (10 mL) (98% purity) was added HNO3 (419.69 mg, 4.33 mmol, 299.78 uL, 1.2 eq) (65% purity) dropwise at -15 °C, then the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was slowly poured into ice water (20 mL), then the pH of the mixture was adjusted to pH = 7 using saturated aqueous NaOH solution, then the mixture was extracted with ethyl acetate (30 mL*2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, not processed) was obtained as a yellow solid.

[0155] 1 H NMR (400 MHz, DMSO-d6) d 14.36 (br s, 1H), 8.37 (br s, 1H).

[0156] Step 2) 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H indazole

[0157] To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, 3.06 mmol, 1 eq) (not processed) in DCM (10 mL) was added TsOH.H2O (58.14 mg, 305.64 umol, 0.1 eq) and DHP (771.27 mg, 9.17 mmol, 838.34 uL, 3 eq), then the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and the mixture was washed with saturated aqueous NaHCO3 solution (15 mL*2), the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 40 / 1 to 25:1, 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H indazole eluted at petroleum ether / ethyl acetate = 40 / 1, 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H indazole eluted 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.

[0158] 4-bromo-5-chloro-6-fluoro-7-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0159] 1 HNMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 5.50 (dd, J = 2.8, 7.8 Hz, 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, 13.6 Hz, 1H), 1.68 (ddt, J = 4.0, 10.1, 13.9 Hz, 1H), 1.59-1.36 (m, 2H).

[0160] 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 5.86 (dd, J = 2.7, 9.7 Hz, 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).

[0162] Step 3) 4-bromo-5-chloro-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-7-amine

[0163] To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (200 mg, 528.29 umol, 1 eq) in EtOH (5 mL) and H2O (5 mL) was added NH4CI (169.55 mg, 3.17 mmol, 6 eq) and Fe (177.03 mg, 3.17 mmol, 6 eq), then the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated to remove EtOH, then the mixture was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL*2), then the organic layer was dried over Na2S04, the organic layer was filtered and concentrated under reduced pressure to give a residue. 4-bromo-5-chloro-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-7-amine (140 mg, without processing) was obtained as a yellow solid.

[0164] Step 4) 4-bromo-5-chloro-6-fluoro-N,N-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-7-amine

[0165] To a solution of 4-bromo-5-chloro-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-7- amine (120 mg, 344.24 pmol, 1 eq) in THF (5 mL) was added NaH (34.42 mg, 860.59 pmol, 60% purity, 2.5 eq) in portions at 0 °C under N2, then the mixture was stirred at 0 °C under N2for 30 min, then Mel (293.16 mg, 2.06 mmol, 128.58 uL, 6 eq) was added dropwise, then the reaction mixture was stirred at 20 °C under N2for 12 h. The reaction mixture was poured into saturated aqueous NH4C1 solution (20 mL), then the mixture was extracted with ethyl acetate (20 mL*2), the combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Si02, petroleum ether / ethyl acetate = 5: 1). Intermediate IE (30 mg, 78.06 pmol, 22.68% yield, 98% purity) was obtained as a yellow oil.

[0166] Intermediate IE. 4-bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H- indazol-7-amine

[0167]

[0168] To a solution of Intermediate IB (100 mg, 0.218 mmol, 1 eq) in 2-methyl-2-butanol (1.09 mL) was added Xantphos Pd G3 (21 mg, 21.8 pmol, 0.1 eq) and Cs2C03 (142 mg, 0.436 mmol, 2.0 eq). The mixture was degassed and purged with nitrogen 3 times, then propan-2-amine (0.19 mL, 2.18 mmol, 10 eq) was added. The mixture was stirred at 90 °C in a sealed tube for 3 h. The reaction mixture was diluted with H20 (40 mL), then the mixture was extracted with DCM (50 mL*3). The combined organic layers were dried over Na2S04, filtered, the filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (product eluted with hexane / ethyl acetate = 10 / 1) to give Intermediate IE (47 mg, 0.120 mmol, 55% yield) as a beige solid.

[0169] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H),5.74(dd,J=9.6,2.5Hz,1H),5.29(dd,J=9.9,3.3Hz,1H),4.63-4.57(m,1H),3. 99(d,J=11.0Hz,1H),3.74-3.68(m,1H),2.23-2.17(m,1H),2.05-1.95(m,2H),1.74-1.57(m,3H),1.23-1.18(m,6H).

[0170] Intermediate 1F. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-N-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0171]

[0172] 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 min. Sodium cyanoborohydride (290 mg, 4.61 mmol, 3.0 eq) was added, and the mixture was stirred at room temperature for 16 h. 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 give the residue. The residue was purified by silica gel chromatography (the product was produced at hexane / ethyl acetate = 100 / 4) to give intermediate 1F (292 mg, 0.722 mmol, 47% yield) as a brown oil.

[0173] 1 HNMR (400MHz, DMSO-d6) δ8.51 (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, 3H), 1.75-1.60 (m, 3H), 1.17 (d, J=6, 6Hz, 6H).

[0174] Intermediate 1G. 4-Bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine

[0175]

[0176] Step 1) 4-bromo-5-chloro-6-fluoro-1H-indazol-7-amine

[0177] 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) was added Fe (6.83 g, 122.26 mmol, 3 eq) and NH4CI (6.54 g, 122.26 mmol, 3 eq). The reaction mixture was heated to 80 °C and reacted for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1). 4-bromo-5-chloro-6-fluoro-1H-indazol-7-amine (5 g, 18.90 mmol, 46.39% yield) was obtained as a yellow solid.

[0178] Step 2) N-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)acetamide

[0179] To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazol-7-amine (3 g, 11.34 mmol, 1 eq) in AcOH (30 mL) was added Ac2O (1.39 g, 13.61 mmol, 1.27 mL, 1.2 eq), the reaction mixture was heated to 80 °C and reacted for 3 h. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give N-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)acetamide (3 g, 9.79 mmol, 86.29% yield) as a yellow solid.

[0180] Step 3) 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazol-7-amine

[0181] To a solution of LAH (520 mg, 13.70 mmol, 1.5 eq) in THF (50 mL) was added dropwise N-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)acetamide (2.8 g, 9.13 mmol, 1 eq) THF at 0 °C under N2. After the addition was complete, the reaction mixture was allowed to warm to 25 °C and reacted for 16 h. The mixture was poured into water (500 mL) and extracted with ethyl acetate (100 mL*2), the combined organic phase was dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazol-7-amine (1 g, 3.42 mmol, 37.42% yield) as a yellow solid.

[0182] Step 4) 4-bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazol-7- amine

[0183] To a solution of 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazol-7-amine (1.4 g, 4.79 mmol, 1 eq) and HCHO (718.48 mg, 23.93 mmol, 659.16 uL, 5 eq) in methanol (50 mL) was added NaBH3CN (902.21 mg, 14.36 mmol, 3 eq) and AcOH (287.38 mg, 4.79 mmol, 273.70 uL, 1 eq). 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 to 5 / 1) to give 4-bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazol-7-amine (1.4 g, 4.57 mmol, 95.42% yield) as a white solid.

[0184] Intermediate 1H. 4-bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole

[0185]

[0186] 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) at -78 °C was added LDA (2 M, 1.87 mL, 2.5 eq) dropwise. After the addition, the mixture was stirred at -78 °C for 2 and a half hours, then Mel (319.12 mg, 2.25 mmol, 139.97 uL, 1.5 eq) was added dropwise at -78 °C. The resulting 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 to 10 / 1). We obtained 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) as a white solid.

[0187] Intermediate 1I. 4-bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazol-7-amine

[0188]

[0189] Step 1) 4-bromo-6-fluoro-7-nitro-1H-indazole

[0190] To a solution of 4-bromo-6-fluoro-lH-indazole (10 g, 46.51 mmol, 1 eq) in H2SO4(80 mL) (98% purity) was added KNO3(4.70 g, 46.51 mmol, 1 eq) portion wise at 0 °C, then the mixture was stirred at 0 °C for 1 h. Then the reaction mixture was poured into ice water (200 ml) and the mixture was extracted with ethyl acetate (100 ml*2), the combined organic layers were washed with saturated aqueous NaHCO3(100 ml*2) and brine (100 ml), the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1 to 1 / 1, the product 4-bromo-6-fluoro-7-nitro-lH-indazole eluted at petroleum ether / ethyl acetate = 8 / 1) to give 4-bromo-6-fluoro-7-nitro-lH-indazole as a yellow solid (2.7 g, 10.38 mmol, 22.32%) and crude 4-bromo-6-fluoro-7-nitro-lH-indazole (2.7 g, 10.38 mmol, 22.32%). The crude product was purified by MPLC (petroleum ether / ethyl acetate) to give 4-bromo-6-fluoro-7-nitro-lH-indazole as a yellow solid (3.57 g, 13.73 mmol, 29.52% yield).

[0191] Step 2) 4-bromo-6-fluoro-5-iodo-7-nitro-lH-indazole

[0192] To a solution of 4-bromo-6-fluoro-7-nitro-lH-indazole (2.7 g, 10.38 mmol, 1 eq) in H2SO4(30 mL) was added NIS (7.01 g, 31.15 mmol, 3 eq) at 25 °C. The mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with ice water (50 mL). Then the mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with aqueous Na2SO3(20 mL*2), aqueous NaHCO3(20 mL*2) and brine (20 mL), the combined organic layers were dried over sodium sulfate, filtered, the filtrate was concentrated in vacuo to give 4-bromo-6-fluoro-5-iodo-7-nitro-lH-indazole as a yellow solid (3.4 g, 8.81 mmol, 84.85%).

[0193] 1 H NMR (400 MHz, DMSO-d6) d 14.28 (br s, 1H), 8.30 (s, 1H).

[0194] Step 3) 4-bromo-6-fluoro-5-iodo-lH-indazol-7-amine

[0195] To a solution of 4-bromo-6-fluoro-5-iodo-7-nitro-lH-indazole (3.4 g, 8.81 mmol, 1 eq) in EtOH (50 mL) and water (25 mL) was added NH4CI (2.83 g, 52.86 mmol, 6 eq) followed by Fe (2.95 g, 52.86 mmol, 6 eq) portionwise at 60 °C. The mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered through celite while still hot. The filtrate was then concentrated in vacuo to remove EtOH. The resulting aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic layers were rinsed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (MPLC, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1, product was produced at petroleum ether / ethyl acetate = 2 / 1) to give 4-bromo-6-fluoro-5-iodo-lH-indazole-7-amine (2.2 g, 6.18 mmol, 70.16% yield) as a grey solid.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (br s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 5.62 (s, 2H).

[0197] Step 4) 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-lH-indazol-7-amine

[0198] To a solution of 4-bromo-6-fluoro-5-iodo-lH-indazole-7-amine (2.2 g, 6.18 mmol, 1 eq) in MeOH (50 mL) was added AcOH (1.11 g, 18.54 mmol, 1.06 mL, 3 eq), HCHO (5.02 g, 61.81 mmol, 4.60 mL, 10 eq) followed by NaBH3CN (3.88 g, 61.81 mmol, 10 eq) portionwise at 40 °C. Gas was released and the temperature was raised. The suspension was stirred at 25 °C for 16 h. The reaction mixture was poured into water (50 mL) and then the mixture was concentrated to remove MeOH, then the mixture was extracted with ethyl acetate (50 mL*2) and the combined organic layers were washed with brine (50 mL), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1 to 8 / 1, product was produced at petroleum ether / ethyl acetate = 8 / 1) to give 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-lH-indazol-7-amine (2.05 g, 5.34 mmol, 86.37% yield) as an off-white solid.

[0199] Step 5) 4-Bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1 H-indazol-7-amine

[0200] To a 100 mL flask equipped with a magnetic stir bar was added 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1 H-indazol-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 umol, 0.2 eq), K2CO3(1.30 g, 9.38 mmol, 3 eq), dioxane (20 mL) and Pd2(dba)3(286.17 mg, 312.51 umol, 0.1 eq) sequentially. The flask was evacuated and backfilled with nitrogen. The mixture was then stirred at 90 °C for 16 hours under a nitrogen atmosphere. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 20 / 1 to 8 / 1, product eluted in petroleum ether / ethyl acetate = 10 / 1) to give 4-bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1 H-indazol-7-amine (540 mg, 1.78 mmol, 56.81 %) as an orange solid.

[0201] 1 H NMR (400 MHz, DMSO-d6) d 13.59 (br s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 2.91 (d, J = 2.4 Hz, 6H), 2.39 (s, 3H).

[0202] Intermediate 1J. 4-Bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1 H-indazol-7-amine

[0203]

[0204] To a solution of 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazol-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 uL, 2 eq) in DMF (10 mL) was added Cul (994.63 mg, 5.22 mmol, 2 eq). The mixture was stirred at 100 °C for 6 hours under nitrogen atmosphere. The reaction mixture was filtered, the filtrate was diluted with 50 mL of water and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1). 4-bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazol-7-amine (502 mg, 1.54 mmol, 58.91% yield) was obtained as a yellow solid.

[0205] Intermediate 1K. 4-bromo-5-ethyl-6-fluoro-1H-indazole

[0206]

[0207] Step 1) 4-bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole

[0208] To a solution of diisopropylamine (132.75 mg, 1.31 mmol, 185.41 uL, 1.2 eq) in THF (5 mL) was slowly added n-BuLi (2.5 M, 481.04 uL, 1.1 eq) at -78 °C under N2atmosphere, then a solution of 4-bromo-6-fluoro-2-triphenyl-2H-indazole (500 mg, 1.09 mmol, 1 eq) in THF (2 mL) was added dropwise to the solution. After the mixture was stirred at -78 °C for half an hour, a solution of EtI (204.62 mg, 1.31 mmol, 104.93 uL, 1.2 eq) in THF (2 mL) was added to the mixture, and the solution was heated to 15 °C and stirred for 2 hours under N2atmosphere. The reaction mixture was quenched by adding 3 mL of saturated aqueous NH4Cl solution at 15 °C, the mixture was diluted with 20 mL of water and extracted with ethyl acetate (30 mL*2). The combined organic layers were washed with brine (30 mL*2), the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. 4-bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole (500 mg, crude) was obtained as a yellow solid.

[0209] Step 2) 4-bromo-5-ethyl-6-fluoro-1H-indazole

[0210] To a solution of 4-bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole (500 mg, 1.03 mmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 26.22 eq). The mixture was stirred at 15 °C for 4 hours. The reaction mixture was pH adjusted to 7 with saturated aqueous NaHC03solution, and the mixture was extracted with dichloromethane (30 mL*2). The combined organic layers were washed with brine (30 ml*2), the combined organic layers were dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%-70%, 10 min). The fraction was concentrated under reduced pressure to remove ACN, the aqueous solution was pH adjusted to 7 with saturated aqueous NaHC03solution. The aqueous solution was extracted with ethyl acetate (10 ml*2). The combined organic layers were washed with brine (10 mL*2), the combined organic layers were dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure to give the product. 4-bromo-5-ethyl-6-fluoro-lH-indazole was obtained as a yellow solid (70 mg, 287.98 pmol, 27.96% yield).

[0211] 1 H NMR (400 MHz, DMSO-d6) d 13.39 (br s, 1H), 8.01 - 7.98 (m, 1H), 7.41 (d, J = 9.9 Hz, 1H), 2.83 (dq, J = 2.4, 7.5 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H).

[0212] Intermediate 1L. 4-bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5- amine

[0213]

[0214] Step 1) 6-fluoro-5-nitro-lH-indazole

[0215] To a solution of 6-fluoro-lH-indazole (4.4 g, 32.32 mmol, 1 eq) in H2SO4(30 mL) was added HNO3(2.44 g, 38.79 mmol, 1.75 mL, 1.2 eq) dropwise at -15 °C, the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was slowly poured into ice water (100 mL), then the mixture was extracted with ethyl acetate (100 mL*2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-fluoro-5-nitro-lH-indazole (5.4 g, crude) as a yellow solid.

[0216] Step 2) 6-Fluoro-5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0217] To a mixture of 6-fluoro-5-nitro-lH-indazole (4.9 g, 27.05 mmol, 1 eq) (crude) in DCM (50 mL) was added 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 h. The reaction mixture was poured into saturated NaHCO3solution (100 mL), then the mixture was extracted with dichloromethane (50 mL*2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 15:1). 6-Fluoro-5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (3 g, 11.31 mmol, 41.81% yield) was obtained as a yellow solid.

[0218] 1 H NMR (400 MHz, DMSO-d6) d 8.78 (d, J = 7.3 Hz, 1H), 8.41 (s, 1H), 7.97 (d, J = 12.1 Hz, 1H), 5.90 (dd, J = 2.1, 9.7 Hz, 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).

[0219] Step 3) 6-Fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-amine

[0220] To a solution of 6-fluoro-5-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (2.9 g, 10.93 mmol, 1 eq) in MeOH (30 mL) was added wet Pd / C (300 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred at 15 °C under H2 (15 Psi) for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 15 / 1 to 8:1). 6-Fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-amine (1.5 g, 5.87 mmol, 53.65% yield, 92% purity) was obtained as a brick red solid.

[0221] 1 H NMR (400 MHz, DMSO-d6) d 7.82 (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 5.66 (dd, J = 2.3, 9.7 Hz, 1H), 4.91 (s, 2H), 3.85 (br d, J = 12.1 Hz, 1H), 3.77 - 3.62 (m, 1H), 2.42 - 2.27 (m, 1H), 2.07 - 1.96 (m, 1H), 1.95 - 1.86 (m, 1H), 1.76 - 1.63 (m, 1H), 1.59 - 1.51 (m, 2H); LCMS (electrospray) m / z 236.1 (M+H)+.

[0222] Step 4) 4-Bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-amine

[0223] To a solution of 6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-amine (1.45 g, 5.67 mmol, 1 eq) in MeCN (10 mL) was added NBS (1.21 g, 6.80 mmol, 1.2 eq) portionwise at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated to give a residue. The residue was then dissolved in ethyl acetate (30 ml), and the mixture was washed with brine (15 ml*2), the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1). 4-Bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-amine (1.3 g, 4.14 mmol, 72.98% yield) was obtained as a brown solid.

[0224] 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.60 (d, J = 10.6 Hz, 1H), 5.71 (dd, J = 2.5, 9.6 Hz, 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 (brdd, J = 4.6, 8.5 Hz, 1H), 1.96 - 1.90 (m, 1H), 1.76 - 1.65 (m, 1H), 1.60 - 1.52 (m, 2H).

[0225] Intermediate 1M. 3-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol

[0226]

[0227] Step 1) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7- carboxyaldehyde

[0228] To a mixture of Intermediate 1A (3 g, 8.99 mmol, 1 eq) in THF (60 mL) was added LDA (2 M, 17.99 mL, 4 eq) dropwise at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 h. Then HCO2Et (3.17 g, 35.97 mmol, 3.52 mL, 4 eq) in THF (8 mL) was added dropwise at -78 °C, then the mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched by adding saturated NH4Cl solution (20 mL) at -78 °C, then extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 to 20 / 1). 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carboxyaldehyde (2.78 g, 7.69 mmol, 85.49% yield) was obtained as an off-white solid.

[0229] 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.35 (s, 1H), 6.09 (dd, J = 2.6, 8.9 Hz, 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)+.

[0230] Step 2) 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)but-3- en-1-ol

[0231] To a mixture of 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7- carboxyaldehyde (2.2 g, 6.08 mmol, 1 eq) in THF (60 mL), allyl magnesium bromide (1 M, 9.13 mL, 1.5 eq) was added dropwise at 0 °C under N2. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl solution (20 mL) at 0 °C, then extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1). 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)but-3-en-1-ol (2 g, 4.95 mmol, 81.43% yield) was obtained as a colorless oil.

[0232] 1H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.21 (m, 1H), 8.20 - 8.18 (m, 1H), 6.61 (br d, J = 9.0 Hz, 1H), 6.23 (d, J = 4.0 Hz, 1H), 6.18 (br d, J = 8.3 Hz, 1H), 5.95 (d, J = 5.0 Hz, 1H), 5.90 - 5.75 (m, 2H), 5.36 (dt, J = 4.3, 7.5 Hz, 1H), 5.30 (td, J = 5.9, 7.9 Hz, 1H), 5.10 - 4.97 (m, 4H), 3.97 (br d, J = 11.5 Hz, 1H), 3.89 (br d, J = 11.3 Hz, 1H), 3.69 - 3.55 (m, 2H), 2.87 - 2.74 (m, 2H), 2.70 - 2.55 (m, 4H), 2.06 (br d, J = 10.8 Hz, 3H), 1.96 - 1.87 (m, 1H), 0.90 - 0.78 (m, 1H); LCMS (electrospray) m / z 302.9 (M+H)+.

[0233] Step 3) 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-lH-indazole

[0234] To a mixture of 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-7-yl)but-3-en-1-ol (2 g, 4.95 mmol, 1 eq) in DCM (20 mL) was added Br2(1.19 g, 7.43 mmol, 383.11 ul, 1.5 eq) at -20 °C under nitrogen. The mixture was stirred at -10 °C for 3 hours. The mixture was quenched by adding Na2SO3solution (30 mL), then diluted with DCM (30 mL). The organic layer was washed with Na2SO3solution (30 mL*2), dried over anhydrous Na2SO4, filtered and concentrated to get a 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 stopped by adding water (20 mL), and extracted with EA (30 mL*3), dried over Na2SO4, filtered and concentrated to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3:1). The crude product was purified by reverse phase high performance liquid chromatography (0.1% FA condition). 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-lH-indazole (300 mg, 752.91 umol, 15.20% yield) was obtained as a white solid.

[0235] 1H NMR (400 MHz, 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, 7.5 Hz, 1H), 4.97 (s, 1H), 4.83 - 4.76 (m, 2H), 4.47 (dd, J = 3.7, 10.1 Hz, 1H), 4.22 (dd, J = 5.5, 10.1 Hz, 1H), 4.15 (dd, J = 2.3, 10.6 Hz, 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)+.

[0236] Step 4) 3-(4-bromo-5-chloro-6-fluoro-lH-indazol-7-yl)cyclopentyl acetate

[0237] To a mixture of 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-lH-indazole (100 mg, 250.97 umol, 1 eq) in DMSO (2 mL) was added KOAc (73.89 mg, 752.91 umol, 3 eq) at 20 °C under nitrogen. Then the mixture was heated to 70 °C and stirred for 3 hours. The reaction was stopped by adding water (15 ml), then extracted with EA (20 ml*3), the combined organic layers were washed with brine (20 ml*2), dried over Na2S04, filtered and concentrated to get a residue. 3-(4-bromo-5-chloro-6-fluoro-lH-indazol-7-yl)cyclopentyl acetate (100 mg, crude, brown oil) was used directly in the next step without further purification.

[0238] LCMS (electrospray) m / z 378.8 (m+H)+.

[0239] Step 5) 3-(4-bromo-5-chloro-6-fluoro-lH-indazol-7-yl)cyclopentan-l-ol

[0240] To a solution of 3-(4-bromo-5-chloro-6-fluoro-lH-indazol-7-yl)cyclopentyl acetate (80 mg, 211.87 umol, 1 eq) in a mixture of MeOH (4 mL) and water (0.8 mL) was added K2CO3 (442.15 mg, 3.20 mmol, 15.1 eq) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by the addition of water (15 mL) at 20 °C, then extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 2). 3-(4-bromo-5-chloro-6-fluoro-lH-indazol-7-yl)cyclopentan-l-ol (50 mg, 149.01 umol, 70.33% yield) was obtained as a white solid.

[0241] LCMS (electrospray) m / z 336.9 (m+H)+.

[0242] Intermediate 1N. 4-bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-2H-indazol-7-amine

[0243]

[0244] Step 1) 5-fluoro-2-iodo-4-(trifluoromethyl)benzenamine

[0245] To a solution of 3-fluoro-4-(trifluoromethyl)benzenamine (4 g, 22.33 mmol, 1 eq) in MeCN (40 mL) was added NIS (5.53 g, 24.57 mmol, 1.1 eq) at 15 °C, then the reaction mixture was stirred at 15 °C for 15 hours. The reaction mixture was diluted with water (100 mL), and the mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 5-fluoro-2-iodo-4- (trifluoromethyl)benzenamine (5.6 g, crude) was obtained as a brown oil.

[0246] LCMS (electrospray) m / z 305.9 (m+H)+.

[0247] Step 2) 5-fluoro-2-methyl-4-(trifluoromethyl)benzenamine

[0248] To a solution of 5-fluoro-2-iodo-4-(trifluoromethyl)phenylamine (6.0 g, 19.67 mmol, 1 eq) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborinane (8.82 g, 29.51 mmol, 9.82 mL, 42% purity, 1.5 eq) in DME (60 mL) at 15 °C was added Pd(PPh3)4 (1.14 g, 983.57 umol, 0.05 eq) and K2CO3 (8.16 g, 59.01 mmol, 3 eq) and the reaction mixture was stirred at 100 °C for 60 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 3 / 1, Petroleum ether / Ethyl acetate = 2:1, Rf = 0.3). 5-fluoro-2-methyl-4-(trifluoromethyl)phenylamine (1.6 g, 4.06 mmol, 20.64% yield, 49% purity) was obtained as a yellow oil.

[0249] LCMS (Electrospray) m / z 194.1.9 (m+H)+.

[0250] Step 3) 6-fluoro-5-(trifluoromethyl)-1H-indazole

[0251] To a solution of 5-fluoro-2-methyl-4-(trifluoromethyl)phenylamine (1 g, 5.18 mmol, 1 eq) in AcOH (15 ml) at 0 °C was added NaNO2 (357.25 mg, 5.18 mmol, 1 eq) and water (3 ml) and the reaction mixture was stirred at 15 °C for 2 h. The reaction was stopped by adding water (60 mL) at 20 °C and the resulting mixture was extracted using EtOAc (50 mL*3). The combined organic layers were washed with water (50 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1, Petroleum ether / Ethyl acetate = 3:1, Rf = 0.5). 6-fluoro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.45 mmol, yield 47.31%) was obtained as a yellow solid.

[0252] LCMS (Electrospray) m / z 205.2 (m+H)+.

[0253] Step 4) 6-fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole

[0254] To a solution of 6-fluoro-5-(trifluoromethyl)-lH-indazole (500 mg, 2.45 mmol, 1 eq) in H2SO4(5 mL, 95% purity) was added KNO3(249 mg, 2.46 mmol, 1.01 eq) at 0 °C, then the reaction mixture was stirred at 15 °C for 15 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were treated with saturated sodium bicarbonate solution until pH = 7, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 6-Fluoro-7-nitro-5-(trifluoromethyl)-lH-indazole (500 mg) was obtained as a yellow solid.

[0255] LCMS (electrospray) m / z 250.2 (m+H)+.

[0256] Step 5) 6-Fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole

[0257] To a solution of 6-fluoro-7-nitro-5-(trifluoromethyl)-lH-indazole (500 mg, 2.01 mmol, 1 eq) in THF (10 mL) was added PPTS (50.44 mg, 200.71 umol, 0.1 eq) and DHP (844.13 mg, 10.04 mmol, 917.53 uL, 5 eq) at 0 °C. Then the reaction mixture was stirred at 60 °C for 15 h. The reaction mixture was diluted with solvent H2O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with H2O (50 mL*3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 6-Fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole (1 g, crude) was obtained as a yellow oil.

[0258] Step 6) 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine

[0259] 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) was added NH4Cl (642.08 mg, 12.00 mmol, 5 eq) and Fe (268.13 mg, 4.80 mmol, 2 eq) at 0 °C, then the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with H2O (30 mL*2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1, Petroleum ether: Ethyl acetate = 3:1, Rf = 0.3). 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine (500 mg, 1.65 mmol, 68.68% yield) was obtained as a yellow solid.

[0260] LCMS (Electrospray) m / z 220.2 (m+H)+.

[0261] Step 7) 4-Bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H- indazol-7-amine

[0262] To a solution of 6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7- amine (200 mg, 659.51 umol, 1 eq) in DMF (1 mL) was added NBS (129.12 mg, 725.46 umol, 1.1 eq) at 20 °C, then the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EtOAc (10 mL*3). The combined organic layers were washed with H2O (10 mL*2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 4-Bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7- amine (120 mg, crude) was obtained as a yellow solid.

[0263] LCMS (Electrospray) m / z 297.9 (m+H)+.

[0264] Step 8) 4-Bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazol-7-amine

[0265] To a solution of 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-2H-indazol-7-amine (100 mg, 335.53 pmol, 1 eq) in MeOH (1 mL) was added AcOH (40.30 mg, 671.06 pmol, 38.38 pi, 2 eq) and acetone (97.44 mg, 1.68 mmol, 123.34 pi, 5 eq) at 20 °C, then NaBH3CN (105.42 mg, 1.68 mmol, 5 eq) was added, and the reaction mixture was stirred at 20 °C for 2 h. Then to the mixture was added acetone (97.44 mg, 1.68 mmol, 123.34 uL, 5 eq), NaBH3CN (105.43 mg, 1.68 mmol, 5 eq) and AcOH (60.45 mg, 1.01 mmol, 57.57 uL, 3 eq), and the reaction mixture was stirred at 20 °C for 20 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with H2O (10 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 3: 1, Rf= 0.4). 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-lH-indazol-7-amine (60 mg, 165.83 pmol, 49.42% yield, 94% purity) was obtained as a white solid.

[0266] LCMS (electrospray) m / z 340.1 (m+H)+.

[0267] Step 9) 4-bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-2H-indazol-7-amine

[0268] To a solution of 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-lH-indazol-7- amine (50 mg, 147.01 umol, 1 eq) in THF (1 mL) was added PPTS (3.69 mg, 14.70 umol, 0.1 eq) and DHP (61.83 mg, 735.05 umol, 67.21 uL, 5 eq) at 0 °C, then the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with H2O (50 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-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-indazol-7-amine (50 mg, 117.86 μmol, 80.17% yield) was obtained as yellow oil.

[0269] LCMS (electrospray) m / z 424.1 (m+H)+.

[0270] Intermediate 10. 4-bromo-5-cyclopropyl-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH indazole

[0271]

[0272] Step 1) 3-bromo-5-fluoro-2-methylaniline

[0273] To a mixture of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (23 g, 98.28 mmol, 1 eq) in EtOH (80 mL) and water (80 mL) was added Fe (27.44 g, 491.41 mmol, 5 eq) and NH4CI (26.29 g, 491.41 mmol, 5 eq). The mixture was stirred at 100 °C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove ethanol. The resulting mixture was extracted with DCM (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which gave 3-bromo-5-fluoro-2-methylaniline (20.6 g, crude) as a yellow liquid.

[0274] 1 H NMR (400 MHz, DMSO-d6) δ 6.59 (br d, J = 8.4 Hz, 1H), 6.42 (br d, J = 11.2 Hz, 1H), 5.51 (br s, 2H), 2.09 (s, 3H).

[0275] Step 2) 3-bromo-5-fluoro-4-iodo-2-methylaniline

[0276] To a mixture of 3-bromo-5-fluoro-2-methylaniline (18 g, 88.22 mmol, 1 eq) (crude) in CH3COOH (200 mL) was added NaNO2(5.52 g, 80.02 mmol, 1.2 eq) dissolved in water (40 mL) at 0 °C. The mixture was stirred at 30 °C for 16 h. The mixture was poured into saturated NaHCO3(1000 mL), the resulting mixture was extracted with EtOAc (200 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, Petroleum ether / Ethyl acetate = 15 / 1, 5 / 1) to give 4-bromo-6-fluoro-5-iodo-lH-indazole (7.5 g, 22.00 mmol, 32.99% yield) as a brown solid. H3 CN (150 mL) was added NIS (19.85 g, 88.22 mmol, 1 eq) portion wise at 0 °C. The mixture was stirred at 30 °C for 3 h. After 3 h, LCMS showed compound 2 remained and a major peak with desired mass was detected. The mixture was then stirred at 30 °C for another 12 h. LCMS showed no compound 2 remained and a major peak with desired mass was detected. The mixture was quenched with saturated Na2SO3(200 mL) and the resulting mixture was extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a 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 give 3-bromo-5-fluoro-4-iodo-2-methylaniline (22 g, 66.68 mmol, 75.58% yield) as a brown solid.

[0277] 1 H NMR (400 MHz, DMSO-d6) d 6.55 (d, J = 10.5 Hz, 1H), 5.67 (s, 2H), 2.25 (d, J = 0.8 Hz, 3H).

[0278] Step 3) 4-bromo-6-fluoro-5-iodo-lH-indazole

[0279] To a mixture of 3-bromo-5-fluoro-4-iodo-2-methylaniline (22 g, 66.68 mmol, 1 eq) in CH3COOH (200 mL) was added NaNO2(5.52 g, 80.02 mmol, 1.2 eq) dissolved in water (40 mL) at 0 °C. The mixture was stirred at 30 °C for 16 h. The mixture was poured into saturated NaHCO3(1000 mL), the resulting mixture was extracted with EtOAc (200 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, Petroleum ether / Ethyl acetate = 15 / 1, 5 / 1) to give 4-bromo-6-fluoro-5-iodo-lH-indazole (7.5 g, 22.00 mmol, 32.99% yield) as a brown solid.

[0280] 1H NMR (400 MHz, DMSO-d6) δ 13.58 (br s, 1H), 8.00 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 3.32 (s, 1H).

[0281] Step 4) 4-Bromo-6-fluoro-5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0282] To a mixture of 4-bromo-6-fluoro-5-iodo-lH-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 added DHP (5.55 g, 66.00 mmol, 6.03 mL, 3 eq) slowly. The mixture was stirred at 30 °C for 1 h. The mixture was washed with saturated NaHC03(30 mL*3) and brine (30 mL*3). The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 50 / 1) to give 4-bromo-6-fluoro-5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (7.4 g, 17.41 mmol, 79.14% yield) as a yellow solid.

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.80 (dd, J = 0.7, 8.4 Hz, 1H), 5.83 (dd, J = 2.4, 9.6 Hz, 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).

[0284] Step 5) 4-Bromo-5-cyclopropyl-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0285] To a mixture of 4-bromo-6-fluoro-5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-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 added Na2CO3(748.10 mg, 7.06 mmol, 2 eq) and Pd(dppf)Cl2(258.23 mg, 352.91 umol, 0.1 eq) under nitrogen. The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 20: 1) to give 4-bromo-5-cyclopropyl-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (0.21 g, 619.10 umol, 17.54% yield) as colorless oil.

[0286] 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 0.6 Hz, 1H), 7.20 (d, J = 10.4 Hz, 1H), 5.61 (dd, J = 2.8, 9.1 Hz, 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).

[0287] Intermediate 1P. 4-bromo-6-fluoro-5-isopropyl-lH-indazole

[0288]

[0289] Step 1) 4-bromo-6-fluoro-5-(prop-l-en-2-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0290] To a mixture of 4-bromo-6-fluoro-5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (1.5 g, 3.53 mmol, 1 eq) and potassium; trifluoro(isopropenyl)boronate (626.67 mg, 4.23 mmol, 1.2 eq) in dioxane (10 mL) and H20 (2 mL) was added Pd(dppf)Cl2(258.23 mg, 352.91 umol, 0.1 eq) and Na2C03(748.10 mg, 7.06 mmol, 2 eq) under N2. The mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure to give a 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 give 0.9 g of yellow oil. The oil was purified by prep-TLC (petroleum ether: ethyl acetate = 20:1) to give 4-bromo-6-fluoro-5-(prop-l-en-2-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole as yellow oil (0.55 g, 1.62 mmol, 45.94% yield).

[0291] 1 H NMR (400 MHz, CDC13) δ 8.00 (d, J = 0.6 Hz, 1H), 7.28 (d, J = 0.9 Hz, 0.5H), 7.26 (d, J = 0.7 Hz, 0.5H), 5.64 (dd, J = 2.8, 9.0 Hz, 1H), 5.46 (t, J = 1.6 Hz, 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).

[0292] Step 2) 4-bromo-6-fluoro-5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0293] To a solution of 4-bromo-6-fluoro-5-(prop-l-en-2-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (0.4 g, 1.18 mmol, 1 eq) in MeOH (10 mL) was added PtO2 under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 30 °C under H2 (15 Psi) for 2 half hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 50 / 1) to give 4-bromo-6-fluoro-5-isopropyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (0.3 g, 879.20 umol, 74.56% yield) as colorless oil.

[0294] Step 3) 4-bromo-6-fluoro-5-isopropyl-lH-indazole

[0295] To a solution of 4-bromo-6-fluoro-5-isopropyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (0.3 g, 879.20 umol, 1 eq) in DCM (1 mL) was added TFA (2.30 g, 20.14 mmol, 1.49 mL, 22.91 eq). The mixture was stirred at 30 °C for half an hour. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with DCM (10 mL) and the pH value of the resulting mixture was adjusted to about 8 with TEA. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate = 30 / 1, 5 / 1) to give 4-bromo-6-fluoro-5-isopropyl-lH-indazole (0.2 g, 777.90 umol, 88.48% yield) as colorless oil.

[0296] 1 H NMR (400 MHz, CDC13) δ 8.04 (s, 1H), 7.11 (d, J = 11.2 Hz, 1H), 3.75-3.63 (m, 1H), 1.38 (dd, J = 1.7, 7.1 Hz, 6H).

[0297] Intermediate 1Q. 4-bromo-6-fluoro-5-methoxy-lH-indazole

[0298]

[0299] Step 1) 2-bromo-4-fluoro-3-methoxy-1 -toluene

[0300] To a solution of 2-bromo-6-fluoro-3-methylphenol (4.8 g, 23.41 mmol, 1 eq) in acetone (50 mL) was added K2CO3(6.47 g, 46.82 mmol, 2 eq) and iodomethane (9.97 g, 70.24 mmol, 4.37 mL, 3 eq) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to get a residue. The residue was dissolved in ethyl acetate (50 mL), the mixture was filtered and the filtrate was concentrated to get a yellow oily residue (4.6 g, 21.00 mmol, 89.70 % yield).

[0301] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.05 - 6.85 (m, 2H), 3.95 (d, J = 1.2 Hz, 3H), 2.38 (s, 3H).

[0302] Step 2) 3-Bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene

[0303] To a solution of 2-bromo-4-fluoro-3-methoxy-1 -tolyl (4.4 g, 20.09 mmol, 1 eq) in H2SO4(40 mL) (98%) was added KNO3(2.23 g, 22.10 mmol, 1.1 eq) portion wise at 0 °C and the mixture was stirred at 25 °C for 1 h. The reaction mixture was slowly poured into ice water (200 ml) and then the mixture was extracted with ethyl acetate (200 ml*2), the combined organic layers were dried over Na2SO4, filtered and concentrated to a residue. 3-Bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene was obtained as a brown oily residue (4.6 g, crude).

[0304] 1 H 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).

[0305] Step 3) 3-Bromo-5-fluoro-4-methoxy-2-methylaniline

[0306] 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 water (30 mL) was added Fe (5.84 g, 104.53 mmol, 6 eq) and NH4CI (5.59 g, 104.53 mmol, 6 eq), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, the filtrate was concentrated to remove EtOH, then the mixture was diluted with EA (50 mL), the mixture was washed with water (20 mL*2), then the organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. 3-bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, crude) was obtained as a brown oil.

[0307] 1 H 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).

[0308] Step 4) 4-bromo-6-fluoro-5-methoxy-1H-indazole

[0309] 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) was added dropwise a solution of NaNCte (1.24 g, 17.94 mmol, 1.2 eq) in water (4 mL) at 0 °C. Then the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ice water (100 mL), and the mixture was adjusted to pH 7 using KOH, then the mixture was extracted with EA (100 mL*2), the combined organic layers were washed with brine (50 mL*2), the combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 20 / 1 to 15:1). 4-bromo-6-fluoro-5-methoxy-1H-indazole (600 mg, 2.45 mmol, 16.37% yield) was obtained as a brown solid.

[0310] 1 H 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).

[0311] Synthesis of compounds of Formula (I)

[0312] Synthetic Methods A to J were used to prepare the following compounds. Exemplary syntheses of some compounds of the application are described below, and other compounds can be prepared by similar methods described below using different starting or reaction materials.

[0313] Synthetic Method A

[0314] Example 2. (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)benzo[d]thiazol-2- yl)cyclopropane-1-carboxamide Example 58 (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)benzo[d]thiazol-

[0315]

[0316] To a solution of compound 1 (0.2 g, 0.462 mmol, 1 eq) (5-methyl-1H-indazol-4- yl)boronic acid (0.081 g, 0.462 mmol, 1 eq) in dioxane (4 mL) and H2O (1 mL) was added Na2CO3(0.146 g, 1.38 mmol, 3 eq) and Pd(dppf)Cl2(33 mg, 0.046 mmol, 0.1 eq). The mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 ml x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography to get example 2 (135 mg, 0.369 mmol, 80% yield) as a yellow solid.

[0317] 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, NH), 12.76 (s, CONH), 8.05 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.63 (s, 2H), 7.49 - 7.44 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 5.05 (td, J12= 3.3 Hz, J13= 65.7 Hz, 1H), 2.24 (s, 3H), 2.23 - 2.24 (m, 1H), 1.78 - 1.73 (m, 1H), 1.31 - 1.23 (m, 1H); LCMS (electrospray) m / z 367.1 (M+H)+.

[0318] Synthetic Method B

[0319] 2-yl)-2-fluorocyclopropane-1-carboxamide. 2TFA Example 149. (1S,2S)-N-(5-(5-chloro-7-ethoxy-6-fluoro-1H-indazol-4-yl)thiazolo[5,4-b]

[0320]

[0321] Example 58

[0322] Step 1) (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-2-(tetrahydro-2H-pyran-2-yl)- 2H-indazol-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide

[0323] To a solution of compound 3 (4.4 g, 11.59 mmol, 1 eq) in dioxane (100 mL) and H2O (20 mL) was added compound 2 (4.20 g, 11.59 mmol, 1 eq), Pd(dppf)Cl2(847.97 mg, 1.16 mmol, 0.1 eq) and Na2CO3(2.46 g, 23.18 mmol, 2 eq) under N2. The reaction mixture was stirred at 90 °C for 12 h. Water (100 mL) was added, and the aqueous phase was extracted with EA (200 mL*2). The combined organic phase was washed with saturated brine (200 ml*2) and concentrated in vacuum. The mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound 4 (3.9 g, 7.29 mmol, 62.90% yield) as a light yellow solid.

[0324] 1 H NMR (400 MHz, DMSO-d6) d 8.00 - 7.95 (m, 2H), 7.92 - 7.85 (m, 1H), 7.59 (dd, J = 1.8, 8.4 Hz, 1H), 5.70 (dd, J = 2.5, 9.5 Hz, 1H), 5.07 - 4.79 (m, 1H), 3.82 - 3.63 (m, 1H), 2.72 (d, J = 0.9 Hz, 3H), 2.35 - 2.23 (m, 1H), 2.04 - 1.94 (m, 2H), 1.81 - 1.48 (m, 4H), 1.46 - 1.33 (m, 2H).

[0325] Step 2) (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)benzo[d]thiazol-2- yl)-2-fluorocyclopropane-1-carboxamide. 2TFA salt

[0326] To a solution of compound 4 (3.80 g, 7.10 mmol, 1 eq) in DCM (100 mL) was added TFA (9.86 g, 86.51 mmol, 6.41 mL, 12.18 eq) under N2. The reaction mixture was stirred at 20 °C for 4 hours. DCM (10 ml) was added, followed by slow addition of MeOH (200 ml). The reaction mixture was stirred at 20 °C for half an hour. The reaction mixture was filtered and the filter cake was concentrated to give the product. The filtrate was concentrated in vacuo to give the product. The crude product was then lyophilized to give Example 58 (3.1 g, 4.26 mmol, 59.98% yield, 2TFA) as a light yellow solid.

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 13.76 (br s, 1H), 12.82 (br s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 7.96-7.82 (m, 2H), 7.59 (dd, J = 1.8, 8.4 Hz, 1H), 5.26-4.85 (m, 1H), 2.57 (s, 3H), 2.30-2.19 (m, 1H), 1.84-1.69 (m, 1H), 1.33 (tdd, J = 6.4, 9.0, 12.9 Hz, 1H); LCMS (electrospray) m / z 450.8 (M+H)+.

[0328] Synthetic Method C

[0329] pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide. 2TFA Example 152. (1S,2S)-N-(5-(5-ethyl-6-fluoro-1H-indazol-4-yl)thiazolo[5,4-b]pyridin-2-

[0330]

[0331] Step 1) (1S,2S)-2-fluoro-N-(5-(trifbutylphosphonium)thiazolo[5,4-b]pyridine-2- yl)cyclopropane-1-carboxamide

[0332] To a solution of compound 5 (2.5 g, 7.91 mmol, 1 eq) in dioxane (30 mL) was added (SnBu3)2 (6.88 g, 11.86 mmol, 5.93 mL, 1.5 eq), Pd(PPh3)4 (913.78 mg, 790.77 umol, 0.1 eq) and LiCl (1.01 g, 23.72 mmol, 485.85 uL, 3 eq) under N2. The reaction mixture was stirred at 110 °C for 16 hours under N2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10: 1 to 3: 1). Compound 6 (1.3 g, 2.47 mmol, 31.24% yield) was obtained as a yellow oil.

[0333] Step 2) (1S,2S)-N-(5-(5-chloro-7-ethoxy-6-fluoro-1H-indazol-4-yl)thiazol[5,4- b]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide. 2TFA

[0334] To a solution of 4-bromo-5-chloro-7-ethoxy-6-fluoro-1H-indazole (100 mg, 264.81 umol, 1 eq) in dioxane (2 mL) was added compound 6 (167.24 mg, 317.77 umol, 1.2 eq), Pd(PPh3)4 (30.60 mg, 26.48 umol, 0.1 eq) and LiCl (33.68 mg, 794.42 umol, 16.27 uL, 3 eq). The mixture was stirred at 140 °C under microwave for 2 h. Then, 10 mL saturated aqueous K2CO3 solution was added to the reaction mixture and stirred at 20 °C for 15 min. The mixture was diluted with 10 mL water and extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel plate, petroleum ether: ethyl acetate = 1:2) to give a crude product. The crude product was purified by prep HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 55%-85%, 10 min). Example 149 (60 mg, 112.36 umol, 42.43% yield) was obtained as a yellow oil.

[0335] 1 H NMR (400 MHz, DMSO-d6) d 12.97 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 6.12-6.06 (m, 1H), 5.20-4.96 (m, 1H), 4.46-4.34 (q, J = 7.0 Hz, 2H), 3.97 (m, 1H), 3.73-3.61 (m, 1H), 2.47-2.40 (m, 1H), 2.32-2.22 (m, 1H), 2.04 (m, 2H), 1.83-1.69 (m, 2H), 1.57 (m, 2H), 1.49 (t, J = 7.0 Hz, 3H), 1.41-1.28 (m, 1H).

[0336] Synthetic Method D

[0337] yl)-2-fluorocyclopropane-1-carboxamide Example 221. (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-

[0338]

[0339] To a solution of intermediate 1K (45 mg, 185.13 umol, 1 eq) in EtOH (2 mL) was added compound 6 (116.92 mg, 222.15 umol, 1.2 eq) and Ad2nBuP-Pd-G3 (13.48 mg, 18.51 umol, 0.1 eq). The reaction mixture was then stirred at 90 °C for 16 h under N2atmosphere. The reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (20 mL*2), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(0.1%TFA)-ACN]; B%: 33%-63%, 10 min) to give the crude product. The crude product was purified by prep TLC (silica gel plate, petroleum ether: ethyl acetate = 1:1). Example 152 was obtained as a white solid (9.7 mg, 24.29 umol, 13.12% yield, 100% purity). a2 SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(0.1%TFA)-ACN]; B%: 33%-63%, 10 min) to give the crude product. The crude product was purified by prep TLC (silica gel plate, petroleum ether: ethyl acetate = 1:1). Example 152 was obtained as a white solid (9.7 mg, 24.29 umol, 13.12% yield, 100% purity).

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 12.94 (br s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 10.1 Hz, 1H), 5.20-4.95 (m, 1H), 2.65 (dq, J = 2.4, 7.2 Hz, 2H), 2.27 (m, 1H), 1.85-1.69 (m, 1H), 1.34 (m, 1H), 1.11 (t, J = 7.0 Hz, 3H); LCMS (electrospray) m / z 400.4 (M+H)+.

[0341] Synthetic Method E

[0342] yl)cyclopropane-1-carboxamide Example 223. N-(6-(5-chloro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropane carboxamide salt

[0343]

[0344] Example 221

[0345] Step 1) (1S,2S)-2-fluoro-N-(6-iodoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1- carboxamide

[0346] A mixture of compound 7 (5.890 g, 22.737 mmol), (1S,2S)-2-fluorocyclopropane-1- carboxylic acid (3.076 g, 29.558 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI, 6.538 g, 34.105 mmol) in dichloromethane (100 mL) was treated with N,N-diisopropylethylamine (2.376 mL, 13.642 mmol) at room temperature and stirred at the same temperature for 40 h. The precipitate was collected by filtration, washed with dichloromethane and dried to give compound 8 as a beige solid (3.870 g, 49.3%).

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.87 (s, 1H), 8.02 (s, 1H), 7.36-7.23 (m, 2H), 4.97-4.77 (m, 1H), 2.09-2.07 (m, 1H), 1.65-1.57 (m, 1H), 1.16-1.09 (m, 1H).

[0348] Step 2) (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamide

[0349] A mixture of compound 8 (0.750 g, 2.173 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (0.459 g, 2.608 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, 0.159 g, 0.217 mmol) and cesium carbonate (1.416 g, 4.346 mmol) in tetrahydrofuran (15 mL) / water (4 mL) was mixed at room temperature and then heated under microwave at 120 °C for 1 h, cooled to room temperature, filtered through a pad of celite to remove the solids and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, separated, dried (magnesium sulfate anhydrous), filtered and concentrated in vacuo. The residue was chromatographed (SiO2, 30 g cartridge; ethyl acetate / hexanes = 100%) and the crude product was crystallized using diethyl ether (5 mL) at room temperature. The resulting precipitate was filtered, washed with diethyl ether and dried to give Example 221 as a light yellow solid (0.550 g, 72.4%).

[0350] 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.70 (s, 1H), 9.00 (s, 1H), 8.66 (d, J = 9.2 Hz, 1H), 8.59 (s, 1H), 8.55 (d, J = 9.2 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 5.91-5.71 (m, 1H), 3.11 (s, 3H), 3.05-3.00 (m, 1H), 2.54-2.48 (m, 1H), 2.07-2.03 (m, 1H); LCMS (electrospray) m / z 350.0 (M+H)+.

[0351] Synthetic Method F

[0352] acid Example 231. N-(6-(5-bromo-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropane carboxamide 2TFA salt

[0353]

[0354] Step 1) (2-amino-6-iodoimidazo[l,2-a]pyridin-3-yl)(cyclopropyl)methanone

[0355] To a solution of cyclopropanecarboxylic acid (3.17 g, 36.78 mmol, 2.91 mL, 1.3 eq) in DCM (50 mL) was added EDCI (6.51 g, 33.95 mmol, 1.2 eq) and DIPEA (10.97 g, 94.9 mmol, 14.79 mL, 3 eq). The mixture was stirred at 20 °C for 1 h. Then compound 7 (6 g, 28.30 mmol, 1 eq) was added. Finally the mixture was stirred at 20 °C for 18 h. The mixture was poured into H2O (200 mL), extracted with ethyl acetate (300 mL*3), the organic phase was washed with brine (500 mL*2), dried over anhydrous sodium sulfate (Na2S04), filtered and concentrated in vacuo. The residue was purified by trituration with ethyl acetate (50 mL), filtered and the filter cake was concentrated to give compound 9 (1.9 g, 6.78 mmol, 23.96% yield) as a yellow solid.

[0356] 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (d, J = 1.2 Hz, 1H), 7.60 (dd, J = 2.1, 9.3 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 6.62 (s, 2H), 2.46-2.37 (m, 1H), 1.02-0.90 (m, 4H).

[0357] Step 2) (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamide dihydrochloride

[0358] To a solution of compound 9 (10.22 g, 31.27 mmol, 1 eq) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (B2pin2, 11.12 g, 43.78 mmol, 1.4 eq) in dioxane (100 mL) was added KOAc (9.21 g, 93.82 mmol, 3 eq) and Pd(dppf)Cl2(1.14 g, 1.56 mmol, 0.05 eq). The mixture was heated to 90 °C for 3 h. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (200 ml*2). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. TLC (petroleum ether / ethyl acetate = 0:1) showed one major spot. The residue was purified by silica gel chromatography, eluted with petroleum ether / ethyl acetate = 0:1. Compound 10 (11 g, crude) was obtained as a yellow solid. The crude product was purified by trituration with petroleum ether (20 ml) and ethyl acetate (4 ml), filtered and the filter cake was concentrated. Compound 10 (6.3 g, 19.26 mmol, 48.46% yield) was obtained as a white solid.

[0359] Step 3) N-(6-(5-chloro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide.

[0360] Dihydrochloride

[0361] To a solution of compound 10 (100 mg, 305.64 umol, 1 eq) and 4-bromo-5- chloro-lH-indazole (84.90 mg, 366.76 umol, 1.2 eq) in dioxane (3 mL) and H20 (1 mL) was added Na2C03(97.18 mg, 916.91 umol, 3 eq) and Pd(dppf)C12(11.18 mg, 15.28 umol, 0.05 eq). The mixture was stirred at 90 °C for 10 h. The mixture was poured into petroleum ether (10 mL), filtered with silica gel, and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi CI 8 150*25*10um; mobile phase: [water(0.05%HCl)-ACN]; B%: 14%-34%, 9 min), then lyophilized. Example 223 (36.8 mg, 85.95 umol, 28.12% yield, 99.2% purity, 2HC1) was obtained as a white solid.

[0362] 1 H NMR (400 MHz, METHANOL-d4) d 8.92 (s, 1H), 8.13 (s, 1H), 7.99-7.91 (m, 3H), 7.68 (dd, J = 1.0, 8.9 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 1.95-1.87 (m, 1H), 1.12-1.07 (m, 2H), 1.05-0.98 (m, 2H); LCMS (electrospray) m / z 352.0 (M+H)+.

[0363] Synthetic Method G

[0364] Example 258. (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0365]

[0366] A mixture of CuBr (137.29 mg, 957.04 umol, 29.15 uL, 1 eq) and t-BuONO (98.69 mg, 957.04 umol, 113.83 uL, 1 eq) in MeCN (5 mL) was stirred at 0 °C for 30 min, then a solution of Example 227 (662 mg, 957.04 umol, 1 eq) in MeCN (1 mL) was added, and the mixture was stirred at 20 °C for 2 h, then CuBr (137.29 mg, 957.04 umol, 29.15 uL, 1 eq) and t-BuONO (98.69 mg, 957.04 umol, 113.83 uL, 1 eq) were added, followed by stirring of the mixture at 20 °C for another 12 h. The reaction mixture was concentrated to give a residue, which was dissolved in ethyl acetate (50 mL), then the mixture was washed with diluted ammonium hydroxide (3%, 20 mL*2], the organic layer was washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%-50%, 9 min). Example 231 (14 mg, 22.01 umol, 2.3% yield, 2 TFA) was obtained as a yellow solid.

[0367] 1 H NMR (400 MHz, DMSO-d6) d 13.49 (br s, 1H), 11.05 (s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.32 (dd, J = 1.7, 9.2 Hz, 1H), 2.05 - 1.86 (m, 1H), 0.85 - 0.79 (m, 4H); LCMS (electrospray) m / z 414.1 (M+H)+.

[0368] Synthetic Method H

[0369] Example 393. (1S,2S)-N-(6-(7-(1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4- yl)imidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide Example 446. (1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2- yl)cyclopropane carboxamide

[0370]

[0371] Example 258

[0372] Step 1) (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indol-4-yl)imidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0373] To a solution of intermediate 1D (30 mg, 78.06 umol, 1 eq) and compound 11 (32.33 mg, 93.67 umol, 1.2 eq) in dioxane (1 mL) and H2O (0.2 mL) was added Pd(dppf)Cl2(5.71 mg, 7.81 umol, 0.1 eq) and Na2CO3(24.82 mg, 234.17 umol, 3 eq), then the mixture was stirred at 80 °C for 12 h under N2. The reaction mixture was concentrated to get a residue. The residue was purified by prep-TLC (SiO2, dichloromethane:methanol = 10:1). Compound 12 (34 mg, 57.44 umol, 73.59% yield, 87% purity) was obtained as a yellow oil.

[0374] Step 2) (1S,2S)-N-(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0375] To a solution of compound 12 (34 mg, 57.44 umol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 1 ml, 69.64 eq), then the mixture was stirred at 20 °C for 2 h under N2. The reaction mixture was diluted with ethyl acetate (20 mL) and the mixture was washed with saturated NaHCO3 aqueous solution (15 mL*2), the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to get a residue. The residue was purified by prep HPLC (column: Phenomenex luna C 18 150*25 10u; mobile phase: [water (0.1% TFA) - ACN]; B%: 23% - 53%, 10 min). Example 258 (8.7 mg, 13.05 umol, 22.72% yield, 2TFA) was obtained as a white solid.

[0376] 1H NMR (400 MHz, DMSO-d6) δ 13.55 (br s, 1H), 11.21 (s, 1H), 8.80 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 5.08-4.77 (m, 1H), 3.01 (s, 3H), 3.00 (s, 3H), 2.16 (td, J = 7.0, 13.8 Hz, 1H), 1.76-1.57 (m, 1H), 1.27-1.11 (m, 1H); LCMS (electrospray) m / z 431.2 (M+H)+.

[0377] Synthetic Method I

[0378] Evaluation of compounds ​

[0379]

[0380] Step 1) 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)ethan-1-one

[0381] A solution of intermediate 1A (3.29 g, 9.86 mmol, 1 eq) in THF (49 mL) was cooled to -78 °C, then LDA (7.39 mL, 14.7 mmol, 1.5 eq) was slowly added to the reaction mixture, which was stirred at the same temperature for 30 minutes. Acetic anhydride (1.11 mL, 11.8 mmol, 1.2 eq) was then added dropwise, and the reaction mixture was stirred at rt for 2 hours. After consumption of intermediate 1A, the reaction was quenched with water and extracted with DCM, separated, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (product eluted with hexane / ethyl acetate = 10 / 1) to give compound 13 as an orange solid (1.86 g, 4.95 mmol, 50.2% yield).

[0382] Step 2) 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)ethan-1-ol

[0383] A solution of compound 13 (1.86 mg, 4.95 mmol, 1 eq) in MeOH (24 mL) was cooled to 0 °C, then sodium borohydride (375 mg, 9.90 mmol, 2 eq) was added proportionally. The reaction mixture was stirred at room temperature for 2 hours. After consumption of compound 13, the reaction mixture was concentrated and extracted with DCM, washed with water, separated, dried over anhydrous MgS04, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (product eluted with hexane / ethyl acetate = 7 / 3) to give compound 14 (615 mg, 1.62 mmol, 32% yield) as an ivory solid.

[0384] Step 3) 7-(1-(2H-Tetrazol-2-yl)ethyl)-4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0385] To a solution of compound 14 (100 mg, 0.265 mmol, 1.0 eq) in THF (1.33 mL) was added 1H tetrazole (0.89 mL, 0.398 mmol, 1.5 eq) and PPh3 (104 mg, 0.398 mmol, 1.5 eq). The mixture was cooled to 0 °C, and DEAD (0.181 mL, 0.398 mmol, 1.5 eq) was added slowly at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with DCM (30 mL*3). The combined organic layers were dried over Na2S04, filtered, and the filtrate was concentrated in vacuum. The crude product was purified by silica gel chromatography (product eluted with hexane / ethyl acetate = 10 / 2) to give compound 15 (62 mg, 0.144 mmol, 54% yield) as a white solid.

[0386] Step 4) (1S,2S)-N-(6-(7-(1-(2H-Tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0387] To a solution of compound 15 (62 mg, 0.144 mmol, 1 eq) in 1,4-dioxane (0.577 mL) / H20 (0.144 mL) was added compound 11 (54 mg, 0.159 mmol, 1.1 eq), Pd(dppf)Cl2(5 mg, 0.007 mmol, 0.05 eq), Na2C03(30 mg, 0.289 mmol, 2 eq). The mixture was degassed and purged with nitrogen 3 times. The mixture was stirred at 120 °C for 30 min in a microwave reactor. The reaction mixture was filtered through celite, the filtrate was extracted with DCM. The combined organic layers were dried over Na2S04, filtered, the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (product eluted with hexane / ethyl acetate = 2 / 8) to give compound 16 (68 mg, 0.120 mmol, 83%) as a yellow solid.

[0388] Step 5) (1S,2S)-N-(6-(7-(1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4- yl)imidazo[1,2-a]pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0389] To a solution of compound 16 (66 mg, 0.116 mmol, 1 eq) in ethyl acetate (0.6 mL) was added 1 N HC1 EA solution (1.16 mL, 1.16 mmol, 10 eq). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHC03, extracted with EA, dried over Na2S04, filtered, the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (product eluted with DCM / MeOH = 10 / 1) to give Example 393 (4 mg, 0.008 mmol, 7%) as an ivory solid.

[0390] 1 H NMR (400 MHz, DMSO-d6) δ 13.77 (s, 1H), 11.07 (s, 1H), 8.99 (s, 1H), 8.80 (s, 1H), 8.14 - 8.04 (m, 2H), 7.58 - 7.54 (m, 1H), 7.35 (dd, J = 9.3, 1.6 Hz, 1H), 6.74 (q, J = 7.1 Hz, 1H), 5.00 - 4.79 (m, 1H), 2.23 (d, J = 7.2 Hz, 3H), 2.16 - 2.09 (m, 1H), 1.68 - 1.57 (m, 1H), 1.18 - 1.09 (m, 1H)); LCMS (electrospray) m / z 485.10 (M+H)+.

[0391] Synthetic Method J

[0392] ​ ​

[0393]

[0394] Example 446

[0395] Step 1) (1S,2S)-N-(5-bromopyrazolo[1,5-a]pyridin-2-yl)-2-fluorocyclopropane-1- carboxamide

[0396] To a mixture of compound 17 (3.1 g, 14.62 mmol, 1 eq) and (1S,2S)-2-fluorocyclopropane carboxylic acid (1.67 g, 16.08 mmol, 1.1 eq) in CH3CN (40 mL) was added MsCl (3.35 g, 29.24 mmol, 2.26 mL, 2 eq) and 3-methylpyridine (6.81 g, 73.10 mmol, 7.12 mL, 5 eq) slowly at 0 °C under N2. The mixture was stirred at 30 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved with ethyl acetate (200 mL), the resulting mixture was washed with 10% citric acid (30 mL*2), saturated Na2CO3(30 mL*2), brine (30 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 5 / 1, 3 / 1) to give compound 18 (2.3 g, 7.72 mmol, 52.81% yield) as a white solid.

[0397] Step 2) (1S,2S)-2-fluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzohydrazine-2-yl)pyrazolo[1,5- a]pyridin-2-yl)cyclopropane-1-carboxamide

[0398] Compound 18 (0.345 g, 1.159 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (B2pin2, 0.588 g, 2.318 mmol), [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)Cl2, 0.084 g, 0.115 mmol) and potassium acetate (0.398 g, 4.056 mmol) were mixed in DMSO (10 mL) at room temperature, then the mixture was stirred at 90 °C for 18 hours, cooled to room temperature, filtered through a pad of celite to remove solids, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed (SiO2, 12 g cartridge; ethyl acetate / hexanes = 0% to 100%) to give compound 19 (0.289 g, 72.3%) as a brown solid.

[0399] Step 3) (1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-2- yl)cyclopropanecarboxamide

[0400] To a mixture of compound 19 (6 g*, 17.34 mmol, 1 eq) and 4-bromo-5-methyl- 1H-indazole (3.6 g, 17.34 mmol, 1 eq) in dioxane (120 mL) and H2O (24 mL) was added Na2CO3(3.67 g, 34.68 mmol, 2 eq) and Pd(dppf)Cl2(1.28 g, 1.73 mmol, 0.1 eq) under N2. The mixture was stirred at 90 °C for 4 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 5 / 1, 1 / 1; TLC (petroleum ether: ethyl acetate = 1:1; Rf= 0.08) to give 2.5 g of yellow solid. The solid was triturated with CH3CN (10 mL) twice. The mixture was filtered and the filter cake was collected. The filter cake was dispersed with H2O / CH3CN (5:1; 10 mL) and the resulting mixture was lyophilized for the third time to give Example 446 (1.53 g, 4.37 mmol, 25.20% yield, 96.98% purity) as off-white solid.

[0401] 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.13 (s, 1H), 8.61 (d, J = 7.1 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 0.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.91 (s, 1H), 6.86 (dd, J = 1.9, 7.0 Hz, 1H), 5.06 - 4.98 (m, 1H), 4.88 - 4.84 (m, 1H), 2.34 (s, 3H), 2.15 (td, J = 6.9, 13.8 Hz, 1H), 1.74 - 1.61 (m, 1H), 1.21 - 1.13 (m, 1H); LCMS (electrospray) m / z 350.1 (M+H)+.

[0402] The following Table 1 shows the compounds of the Examples as well as the general synthetic methods used to prepare the compounds and characterization data.

[0403] Table 1. Example Compounds

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] ​

[0560] HPK1 kinase assay

[0561] HPK1 kinase assay TM HPK1 kinase activity was determined by a kinase assay. During the assay, 5 ng of recombinant human HPK1 (signal chem) was incubated with 5 pL of compound (0.5% DMSO), 5 pL of MBP (0.5 pg / pL), and 5 pL of ATP (25 pM) in buffer (40 mM Tris, 7.5; 20 mM MgCl2; 0.1 mg / ml BSA; 50 pM DTT). The first step of detection was by incubating the reaction mixture in a 96-well plate at 30 °C for 40 minutes. After incubation, 25 pL of ADP-Glo reagent was added and the reaction was incubated at room temperature for 40 minutes to stop the reaction and degrade the remaining ATP. The ADP product was then converted to ATP by adding 50 pL of detection reagent per well. Luminescence was detected after incubation at room temperature for 30 minutes with an EnVision® microplate reader I3X plate reader. IC50 values were calculated from a series of percent inhibition values determined over a range of inhibitor concentrations using software routines implemented in GraphPad Prism 7 software or SigmaPlot 13.0. 50

[0562] Table 2 shows the IC50 values for the compounds of the application 50 ​Values, where + means > 1000 nM, ++ means 501-1000 nM, +++ means 101-500 nM, ++++ means < 100 nM.

[0563] Table 2 in vitro activity in terms of HPK1 data

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570] IFNy and IL-2 analysis of human peripheral blood pan T cells

[0571] Human peripheral blood pan T cells were purchased from STEMCELL TM Technologies Inc. Human peripheral blood pan T cells were thawed and suspended in DMEM medium (10% FBS and 1% penicillin / streptomycin). 8 X 10 4 cells were seeded in 96-well plates and incubated with different concentrations of compounds and 100 nM prostaglandin E2 for 1 hour. T cells were stimulated using Dynabeads Human T-Activator CD3 / CD28 (Life Technologies) at a 1:3 cell / bead ratio. Cytokine secretion was measured at 24 hours post-stimulation using MSD V-PLEX Human Cytokine kits following the manufacturer’s recommendations. Data were analyzed using MESO Quickplex SQ120.

[0572] In Table 3, + means > 1000 nM, ++ means 200-1000 nM, +++ means < 200 nM, - means not determined.

[0573] Table 3 IFNy and IL-2 secretion of compounds of the invention in human peripheral blood pan T cells

[0574]

[0575]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: Compound 1: Compound 2: Compound 4: Compound 5: Compound 6: Compound 7: Compound 11: Compound 15: Compound 16: Compound 17: Compound 24: Compound 25: Compound 28: Compound 29: Compound 30: Compound 32: Compound 33: Compound 35: Compound 36: Compound 37: Compound 39: Compound 40: Compound 41: Compound 42: Compound 43: Compound 44: Compound 46: Compound 47: Compound 48: Compound 49: Compound 50: Compound 51: Compound 53: Compound 55: Compound 56: Compound 57: Compound 58: Compound 59: Compound 61: Compound 62: Compound 63: Compound 64: Compound 65: Compound 66: Compound 67: Compound 68: Compound 69: Compound 70: Compound 71: Compound 72: Compound 73: Compound 74: Compound 75: Compound 76: Compound 77: Compound 78: Compound 79: Compound 80: Compound 81: Compound 82: Compound 83: Compound 84: Compound 85: Compound 86: Compound 87: Compound 88: Compound 89: Compound 90: Compound 91: Compound 92: Compound 93: Compound 94: Compound 95: Compound 96: Compound 97: Compound 98: Compound 99: Compound 100: Compound 101: Compound 102: Compound 103: Compound 104: Compound 105: Compound 106: Compound 107: Compound 108: Compound 109: Compound 110: Compound 111: Compound 112: Compound 113: Compound 114: Compound 115: Compound 116: Compound 117: Compound 118: Compound 119: Compound 120: Compound 122: Compound 123: Compound 125: Compound 126: Compound 127: Compound 128: Compound 129: Compound 130: Compound 131: Compound 132: Compound 133: Compound 134: Compound 136: Compound 137: Compound 138: Compound 139: Compound 143: Compound 144: Compound 146: Compound 147: Compound 149: Compound 150: Compound 152: Compound 153: Compound 154: Compound 155: Compound 156: Compound 157: Compound 158: Compound 159: Compound 160: Compound 161: Compound 162: Compound 163: Compound 165: Compound 166: Compound 167: Compound 168: Compound 169: Compound 170: Compound 172: Compound 173: Compound 174: Compound 175: Compound 176: Compound 177: Compound 178: Compound 179: Compound 180: Compound 181: Compound 183: Compound 184: Compound 185: Compound 186: Compound 187: Compound 189: Compound 190: Compound 191: Compound 192: Compound 193: Compound 194: Compound 195: Compound 196: Compound 197: Compound 198: Compound 199: Compound 200: Compound 202: Compound 203: Compound 204: Compound 205: Compound 206: Compound 207: Compound 208: Compound 209: Compound 210: Compound 211: Compound 217: Compound 218: Compound 219: Compound 221: Compound 222: Compound 223: Compound 224: Compound 226: Compound 229: Compound 232: Compound 233: Compound 235: Compound 236: Compound 237: Compound 238: Compound 239: Compound 240: Compound 242: Compound 243: Compound 244: Compound 245: Compound 246: Compound 247: Compound 248: Compound 249: Compound 250: Compound 252: Compound 253: Compound 254: Compound 255: Compound 256: Compound 257: Compound 258: Compound 260: Compound 261: Compound 262: Compound 263: Compound 264: Compound 265: Compound 266: Compound 267: Compound 268: Compound 269: Compound 270: Compound 271: Compound 272: Compound 273: Compound 274: Compound 275: Compound 276: Compound 277: Compound 279: Compound 280: Compound 281: Compound 282: Compound 283: Compound 284: Compound 285: Compound 287: Compound 288: Compound 290: Compound 291: Compound 292: Compound 293: Compound 294: Compound 295: Compound 296: Compound 297: Compound 298: Compound 299: Compound 300: Compound 301: Compound 302: Compound 303: Compound 304: Compound 305: Compound 306: Compound 307: Compound 308: Compound 309: Compound 310: Compound 311: Compound 312: Compound 315: Compound 316: Compound 317: Compound 318: Compound 319: Compound 320: Compound 321: Compound 322: Compound 323: Compound 324: Compound 326: Compound 327: Compound 328: Compound 329: Compound 330: Compound 331: Compound 332: Compound 333: Compound 334: Compound 335: Compound 336: Compound 337: Compound 338: Compound 339: Compound 340: Compound 341: Compound 342: Compound 343: Compound 344: Compound 345: Compound 346: Compound 347: Compound 348: Compound 349: Compound 350: Compound 351: Compound 352: Compound 353: Compound 356: Compound 357: Compound 358: Compound 359: Compound 360: Compound 361: Compound 362: Compound 363: Compound 364: Compound 365: Compound 366: Compound 367: Compound 368: Compound 369: Compound 370: Compound 371: Compound 372: Compound 373: Compound 374: Compound 375: Compound 376: Compound 377: Compound 378: Compound 379: Compound 380: Compound 381: Compound 382: Compound 383: Compound 384: Compound 385: Compound 386: Compound 387: Compound 388: Compound 389: Compound 390: Compound 391: Compound 392: Compound 393: Compound 394: Compound 395: Compound 396: Compound 397: Compound 398: Compound 399: Compound 400: Compound 401: Compound 402: Compound 404: Compound 405: Compound 406: Compound 407: Compound 408: Compound 409: Compound 410: Compound 411: Compound 412: Compound 413: Compound 414: Compound 415: Compound 416: Compound 417: Compound 418: Compound 419: Compound 420: Compound 421: Compound 422: Compound 423: Compound 424: Compound 425: Compound 426: Compound 427: Compound 428: Compound 429: Compound 430: Compound 431: Compound 432: Compound 433: Compound 434: Compound 435: Compound 436: Compound 437: Compound 438: Compound 439: Compound 440: Compound 441: Compound 442: Compound 443: Compound 444: Compound 445: Compound 446: Compound 447: Compound 448: Compound 449: Compound 451: Compound 452: Compound 453: Compound 454: Compound 455: Compound 456: Compound 457: Compound 458: Compound 459: Compound 460: Compound 462: Compound 463: Compound 464: Compound 465: Compound 466: Compound 467: Compound 468: Compound 469: Compound 470: Compound 471: Compound 474: Compound 476: Compound 477: Compound 478: Compound 479: Compound 480: Compound 481: Compound 482: Compound 483: Compound 484: Compound 485: Compound 486: Compound 487: Compound 488: Compound 489: Compound 490: Compound 491: Compound 492: Compound 493: Compound 494: Compound 495: Compound 496: Compound 497: Compound 498: Compound 499: Compound 500: Compound 501: Compound 502: Compound 503: Compound 504: Compound 505: Compound 506: Compound 507: Compound 508: Compound 509: Compound 510: Compound 511: Compound 512: Compound 513: Compound 514: Compound 515: Compound 516: Compound 517: Compound 518: Compound 519: Compound 520: Compound 521: Compound 522: Compound 523: Compound 524: Compound 525: Compound 526: Compound 527: Compound 528: Compound 529: Compound 530: Compound 531: Compound 532: Compound 533: Compound 534: Compound 535: Compound 536: Compound 537: Compound 538: Compound 539: Compound 540: Compound 541: Compound 542: Compound 543: Compound 544: Compound 545: Compound 546: Compound 547: Compound 548: Compound 550: Compound 552: Compound 553: Compound 554: Compound 555: Compound 556: Compound 557: Compound 558: Compound 559: Compound 560: Compound 561: Compound 562: Compound 563: Compound 564: Compound 565: Compound 566: Compound 567: Compound 568: Compound 569: Compound 570: Compound 571: Compound 572: Compound 573: Compound 574: Compound 575: Compound 577: Compound 578: Compound 579: Compound 580: Compound 581: Compound 582: Compound 583: Compound 584: Compound 585: Compound 586: Compound 587: Compound 588: Compound 589: Compound 590: Compound 591: Compound 592: Compound 593: Compound 594: Compound 595: Compound 596: Compound 597: Compound 598: Compound 599: Compound 600: Compound 601: Compound 602: Compound 603: Compound 604: Compound 606: Compound 607: Compound 608: Compound 609: Compound 610: Compound 611: Compound 612: Compound 613: Compound 614: Compound 615: Compound 616: Compound 617: Compound 618: Compound 619: Compound 620: Compound 621: Compound 622: Compound 623: Compound 624: Compound 625: Compound 626: Compound 627: Compound 628: Compound 629: Compound 630: Compound 631: Compound 632: Compound 633: Compound 634: Compound 635: Compound 636: Compound 637: Compound 638: Compound 639: Compound 640: Compound 641: Compound 642: Compound 643: Compound 644: Compound 645: Compound 646: Compound 647: Compound 648: Compound 649: Compound 650: Compound 651: Compound 652: Compound 653: Compound 654: Compound 655: Compound 656: Compound 657: Compound 658: Compound 659: Compound 660: Compound 661: Compound 662: Compound 663: Compound 664: Compound 665: Compound 666:

2. A pharmaceutical composition comprising: A pharmaceutically acceptable carrier or diluent and the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

3. The use of a compound as described in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases or conditions related to HPK1 regulation.

4. The use of a pharmaceutical composition in the preparation of a medicament for treating cancers related to HPK1 regulation, characterized in that, The pharmaceutical composition include: The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and Anti-PD-1 agents, anti-PD-L1 agents, or anti-CTLA4 agents.

5. The application according to claim 3, characterized in that, The disease in question is cancer, inflammation, or an autoimmune disease.

6. The application according to claim 5, characterized in that, The cancers mentioned are selected from: epithelial carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia.

7. The application according to claim 5, characterized in that, The cancers mentioned are selected from: 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, rhabdomyosarcoma, rhabdomyosarcoma and nephroblastoma.

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