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

Abstract

The present disclosure provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof, compositions containing the compounds, methods of using the compounds to treat various diseases associated with HPK1, and methods of making these compounds.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 084,059, filed September 28, 2020. The entire disclosure of that application, as defined in this paragraph, is incorporated herein by reference. Technical Field

[0003] This disclosure relates to inhibitors of hematopoietic progenitor cell kinase 1 (HPK1), pharmaceutical compositions containing the inhibitor, methods of using the inhibitor to treat various HPK1-related diseases, and methods of preparing these compounds. Background Technology

[0004] Immunotherapy is a treatment approach that utilizes the body's own immune system to help fight cancer and other diseases. In recent years, this relatively new method has achieved significant clinical success in treating various tumor types, particularly in the use of immune checkpoint inhibitors and chimeric antigen T-cell therapy. The most studied checkpoint inhibitors include CTLA4, PD-1, or PD-L1 inhibitors, which have shown significant anti-tumor activity by overcoming immunosuppressive mechanisms at tumor sites.

[0005] Hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1) is a serine / threonine kinase and a member of MAP4K. HPK1 is significantly expressed in subsets of hematopoietic cell lineages. HPK1 is a newly discovered key negative regulator in the activation of T lymphocytes and dendritic cells. Recently, the kinase activity of HPK1 has been demonstrated as a novel intracellular checkpoint molecule with important roles in anticancer immunity and potential advantages in combination therapy with existing checkpoint therapy protocols. HPK1 inhibition is expected to have a dual function: 1. prolonging T cell activation; 2. enhancing APC function through dendritic cells. This dual targeting may work synergistically for an effective immune response in the tumor microenvironment. Therefore, HPK1 has been identified as a novel target for anticancer immunotherapy. Examples of cancers treated with the compounds disclosed herein include, but are not limited to, all forms of epithelial cancer, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including, but not limited to, bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdomyosarcoma, and nephroblastoma (Wilme's tumor).

[0006] Inhibiting HPK1 with small molecule inhibitors has the potential to treat cancer and other diseases [Hernandez, S., et al., (2018) Cell Reports 25, 80-94]. Summary of the Invention

[0007] This disclosure provides novel indazole compounds and pharmaceutically acceptable salts that are effective HPK1 inhibitors and dual activators of T cells and dendritic cells.

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

[0009]

[0010] Or its pharmaceutically acceptable salts, hydrates, or solvates, wherein R 1 R 2 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 yet another embodiment, a method is provided for treating a subject suffering from a disease or condition related to HPK1 regulation, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0013] The following description is exemplary in nature and is not intended to limit this disclosure, application, or use.

[0014] definition

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

[0016] This specification uses the terms “substituent”, “free radical”, “group”, “part” and “fragment” interchangeably.

[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 2-12 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 groups 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 groups 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 C1-C 10 Alkyl or C1-C6 alkyl.

[0021] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon group. In one embodiment, the alkyl group has 1-12 carbon atoms. In some embodiments, the alkyl group is C1-C2. 10 Alkyl or C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" refers to alkyl groups having 1 to 4 carbon atoms.

[0022] As used herein, the term "C1-C6" indicates a number of carbon atoms from 1 to 6. For example, C1-C6 alkyl refers to an alkyl group with any integer number of carbon atoms from 1 to 6.

[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-, wherein the R group is an alkyl group as defined herein and may be the same or different. In various embodiments, R is C1-C. 10 Alkyl or C1-C6 alkyl. Examples of alkylamino groups 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, wherein the alkylamino group is as defined herein. Examples of alkylaminoalkyl groups include methylaminomethyl and ethylaminomethyl.

[0025] As used herein, the term "alkynyl" refers to a straight-chain or branched carbon chain group having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl group has 2-12 carbon atoms. In some embodiments, the alkynyl group is C2-C. 10 Alkynyl or C2-C6 alkynyl. Examples of alkynyl groups include alkynyl (—C≡CH) and propynyl (—CH2C≡CH).

[0026] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring with up to seven atoms in each ring, wherein at least one ring is an aromatic ring, or an aromatic ring system comprising 5-14 carbon atoms of a carbocyclic aromatic group fused to a 5- or 6-membered cycloalkyl group. Representative examples of aryl groups include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracel, fluorenyl, indene, azulel, and indanyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0027] As used herein, the term "cycloalkyl" is a hydrocarbon group containing at least one saturated or partially unsaturated ring structure linked via a ring carbon. In various embodiments, it refers to a 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 a cycloalkyl group.

[0028] As used herein, the terms “halogen” and “halogen group” refer to chlorine (—Cl), bromine (—Br), fluorine (—F), or iodine (—I). “Haloalkoxy” refers to an alkoxy group substituted with one or more halogen groups, examples of which include, but are not limited to, —OCF3, —OCHF2, and —OCH2F. “Haloalkoxyalkyl” refers to an alkyl moiety substituted with a haloalkoxy group, wherein the haloalkoxy group is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl, and trifluoromethoxyethyl. “Haloalkyl” refers to an alkyl moiety substituted with one or more halogen groups. Examples of haloalkyl groups include —CF3 and —CHF2.

[0029] As used herein, the term "heteroalkyl" refers to a straight-chain or branched alkyl group having 2 to 14 carbons (2 to 10 carbons in some embodiments) in the chain, wherein one or more of the carbons are replaced by heteroatoms selected from S, O, P, and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc.

[0030] As used herein, the term "heterocyclic group" includes heteroaryl groups as defined below, and refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic group having 2-14 ring carbon atoms and 1-4 heteroatoms in addition to the ring carbon atoms, the heteroatoms being selected from P, N, O, and S. In various embodiments, the heterocyclic group is attached to another part via carbon or via a heteroatom, and optionally is substituted on the carbon or heteroatom. Examples of heterocyclic groups include azirrobutyl, benzimidazolyl, benzofuranyl, benzofuranazolyl, benzopyrazolyl, benzotriazolyl, benzobenzylthio, benzoxazolyl, carbazoyl, carbaolinyl, cinnamyl, furanyl, imidazoyl, dihydroindolyl, indolyl, indolazinyl, indolazinyl, indolazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthiazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxazoline, oxazoline, oxacyclobutyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolylpyridinyl, thiadiazolyl, thiazolyl Thiopheneyl, triazolyl, aziridine, 1,4-dioxane, hexahydroaziridine, piperazinyl, piperidinyl, pyridin-2-one, pyrrolyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzobenzylthio, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroleyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiazolyl, dihydrothiopheneyl, dihydrotriazolyl, dihydroaziridine, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothiopheneyl, and their N-oxides. "Heterocyclic oxy group" is RO-, where R is a heterocyclic group. "Heterocyclic thio group" is RS-, where R is a heterocyclic group.

[0031] As used herein, the term "3- or 4-membered heterocyclic group" refers to a monocyclic ring having 3 or 4 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O, and S. Non-limiting examples of 3- or 4-membered heterocyclic groups include aziridinyl, 2H-aziridinyl, ethylene oxide, thiocyclopropane, aziridine, 2,3-dihydroaziridinebutadienyl, aziridinebutadienyl, 1,3-diazacyclobutane, oxadienyl, 2H-oxadienyl, thiocyclobutane, and 2H-thiobutane.

[0032] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring having up to seven atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from the group consisting of N, O, and S. Non-limiting examples of heteroaryl groups include pyridinyl, thiopheneyl, furanyl, pyrimidinyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrroleyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzophenylthio, benzothiopheneyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoydinolyl, benzotriazolyl, purinel, thiopheneyl, and pyrazinyl. The linkage of heteroaryl groups can occur via an aromatic ring, or, if the heteroaryl group is bicyclic or tricyclic and one of the rings is not an aromatic ring or does not contain a heteroatom, it can be linked via a non-aromatic ring or a ring without a heteroatom. "Heteroaryl" should also be understood to include N-oxide derivatives of any nitrogen-containing heteroaryl group. "Heteroaryloxy group" is RO-, where R is a heteroaryl group.

[0033] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxyl group (-OH), wherein the alkoxy group is as defined herein. An example of a hydroxyalkoxy group is a hydroxyethoxy group.

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

[0035] As used herein, the term “pharmaceutical acceptable” means that a pharmaceutical preparation is generally considered safe for such use, has been formally approved for such use by a national or state regulatory agency, or is listed in the United States Pharmacopeia or other recognized pharmacopoeias for use in animals, especially humans.

[0036] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a diluent, adjuvant, excipient, or carrier, or other pharmaceutically acceptable components that are administered together with the compounds of the present invention.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that enhances the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts, metal salts, and amine salts that form with inorganic or organic acids. Examples of acid addition salts that form with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of acid addition salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis(3-hydroxy-2-naphthylmethyl) acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. Examples of metal salts include those formed with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include those formed with ammonia and organic nitrogenous bases, which are strong enough to form salts with carboxylic acids.

[0038] As used herein, the term "substituted" refers to any of the aforementioned groups (i.e., alkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl) wherein at least one hydrogen atom of the substituted portion is substituted by a substituent. In one embodiment, each carbon atom of the substituted group is substituted by no more than two substituents. In another embodiment, each carbon atom of the substituted group is substituted by no more than one substituent. In the case of ketone substituents, two hydrogen atoms are substituted by oxygen atoms attached to the carbon atom via a double bond. Unless specifically defined, substituents include halogens, hydroxyl groups, (lower) alkyl groups, haloalkyl groups, mono- or dialkylamino groups, aryl groups, heterocyclic groups, -NO2, B(OH)2, BPi, and -NR. a R b -NR a C(=O)R b -NR a C(=O)NR a R b -NR a C(=O)OR b -NR a SO2R b -OR a -CN, -C(=O)R a -C(=O)OR a -C(=O)NR a R b -OC(=O)R a -OC(=O)ORa -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., sulfoxide imine), -(R a S = NR b (e.g., thioimine) and -SR a , where R a and R b Identical or different, and independently -H, halogen, amino, alkyl, haloalkyl, aryl or heterocyclic, or wherein R a and R b Together with the nitrogen atoms they are attached to, they form heterocycles. Based on the atoms they are attached to, R a and R b It can be in plural form.

[0039] As used herein, the term "therapeuticly effective amount" means, when applied to the compounds of the present invention, an amount sufficient to improve, alleviate, stabilize, reverse, slow, or delay the progression or state of a disease, or symptoms of a symptom or disease. In one embodiment, the method of the present invention provides administration of a combination of compounds. In this case, the "therapeuticly effective amount" is the amount of the compounds of the present invention in the combination sufficient to cause the desired biological effect.

[0040] As used herein, the term "treatment" or "treating" means improving or reversing the progression or severity of a disease or condition, or improving or reversing one or more symptoms or side effects of such a disease or condition. As used herein, "treatment" or "treating" also means inhibiting or blocking the progression of a system, symptom, or state of a disease or condition, such as delaying, blocking, restraining, hindering, or impeding it. For the purposes of this invention, "treatment" or "treating" further means a method of obtaining a beneficial or desired clinical outcome, wherein "beneficial or desired clinical outcome" includes, but is not limited to, the reduction of symptoms, a decrease in the severity of a condition or disease, stabilization (i.e., non-deterioration) of a disease or condition state, delay or mitigation of a disease or condition state, improvement or alleviation of a disease or condition state, and remission of a disease or condition, partially or completely.

[0041] compound

[0042] This disclosure provides compounds of formula (I):

[0043]

[0044] Or its pharmaceutically acceptable salts, hydrates or solvates, wherein:

[0045] X is either O or S;

[0046] L represents a key, -O-, -S-, or -NR. 6 -;

[0047] R 1 It is an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein R 1 Optionally selected by one or more independently chosen from R 7 Substituents of the substituents;

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

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

[0050] R 9 -H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic;

[0051] Each R 10 and R 11 Independently -H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic, or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they form 4-12 membered heterocyclic groups, optionally substituted with one or more groups, selected from halogen, 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 The group formed;

[0052] Each R 12 and R 13 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclic, or R 12 and R 13Together with the phosphorus atoms to which they are attached, they form 4-8 membered heterocyclic groups that may be optionally substituted with one or more groups, selected from halogen, 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 The group formed;

[0053] Het selects from the following groups:

[0054]

[0055] R a R b and R c Each can be independently represented as -H, -D, halogen, -CF3, -CF2H, -CH2F, -CN, or -OR. 9 or -NR 10 R 11 ;

[0056] R 2 -H, -D, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, halogen, hydroxyl, -CD2OH, -CN, -NO2, haloalkyl, trimethylsilylethoxymethyl, -C(O)R 9 -C(O)OR 9 -C(O)NR 10 R 11 -OR 9 -OC(O)R 9 -OC(O)NR 10 R 11 -SR 9 -S(O)R 9 -S(O)2R9 -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 , where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more groups selected from halogen, 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 The group formed;

[0057] R 3 -H, -D, -CD3, C 1-6Alkyl, 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)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 ;

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

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

[0060] R 4 -H, -D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, halogen, cyano, hydroxyl, -C(O)R 9 -C(O)OR9 -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 , where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more groups selected from halogen, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD3, -NO2, and -NR. 10 R 11 -NR 10 C(=O)R 9 -NR 10 C(=O)NR 10 R 11 -NR 10 C(=O)OR 9 -NR 10 S(O)2R 9 -OR 9 -C(=O)R 9 -C(=O)OR 9 -C(=O)NR 10 R 11 -OC(=O)R 9 -OC(=O)OR 9 and -OC(=O)NR 10 R 11 The group formed; and

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

[0062] In some implementations, L is the key, and R 1 It is a cycloalkyl group, which is optionally substituted with one or more groups, selected from C1 to C2. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R 9 -C(O)OR 9 -C(O)NR10 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 A group that is formed.

[0063] In some implementations, R 2 and R 3 Each can be independently -H, halogen, alkylthio, haloalkyl, or alkyl.

[0064] In some implementations, M is a key, -O-, or -NR. 6 -; and R 4 -H, -D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, aryl, heteroaryl, heterocyclic, halogen, 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 , where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted by one or more groups selected from halogen, 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 A group that is formed.

[0065] In another embodiment, a compound of formula (II) is provided:

[0066]

[0067] Among them, R 1 R 2 R 3 R 4 R 5 R a R b M and L are defined as in equation (I) above.

[0068] In some implementations, L is the key; R 1 It is a cyclopropyl group, which may optionally be substituted with one or more groups, selected from halogens, C... 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 The group consisting of alkyl halogens; R 2 It is -H, alkyl, halogen, haloalkyl or alkylthio; R 3 -H, alkyl, or halogen; M is a bond, -O-, -S-, or -NR. 6 -;R 4 The following are not part of the given name: -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionylaminoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonylaminoethyl, imidazolylethyl, dioxyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl; and R 5 –H, alkyl, or halogen. Non-limiting exemplary compounds of formula (II) include Examples 1 and 2 of Table 1.

[0069] In another embodiment, a compound of formula (III) is provided:

[0070]

[0071] Among them, R 1 R 2 R 3 R 4 R 5 R a R bM and L are defined as in equation (I) above.

[0072] In some implementations, L is the key; R 1 It is a cyclopropyl group, which may optionally be substituted with one or more groups, selected from halogens, C... 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 The group consisting of alkyl halogens; R 2 It is -H, alkyl, halogen, haloalkyl or alkylthio; R 3 -H, alkyl, or halogen; M is a bond, -O-, -S-, or -NR. 6 -;R 4 The following are not part of the given name: -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionylaminoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonylaminoethyl, imidazolylethyl, dioxyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl; and R 5 –H, alkyl, or halogen. Non-limiting exemplary compounds of formula (III) include Examples 3 and 23 of Table 1.

[0073] In another embodiment, a compound of formula (IV) is provided:

[0074]

[0075] Among them, R 1 R 2 R 3 R 4 R 5 R a R b M and L are as defined in formula (I) above. Non-limiting exemplary compounds of formula (IV) include Examples 24 and 307 in Table 1.

[0076] In some implementations, L is the key, and R 1 It is a cycloalkyl group, which is optionally substituted with one or more groups, selected from C1 to C2. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R9 -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 A group that is formed.

[0077] In some implementations, L is the key; R 1 It is a cycloalkyl group, which may be optionally substituted with one or more groups, the groups being selected from halogens, C... 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 The group consisting of haloalkyl groups. In a particular embodiment, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl.

[0078] In some implementations, L is the key; R 1 It is cyclopropyl, optionally substituted by one or more groups selected from the group consisting of halogens, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, and C1-C3 haloalkyl groups; R 2 -H, alkyl, haloalkyl, or halogen; R 3 -H, alkyl, or halogen; M is a bond, -O-, or -NR. 6 -;R 4 It is -H, halogen, alkyl, monoalkylamino, or dialkylamino; R 5 It is -H, alkyl, or halogen. In certain embodiments, L is a bond; R a -H;R b -H;R 1 Cyclopropyl groups substituted with chlorine, fluorine, C1-C3 alkyl, C1-C3 hydroxyalkyl, or C1-C3 haloalkyl; R 2 -H, alkyl, chlorine, or fluorine; R 3 -H, alkyl, chlorine, or fluorine; M is a bond or -NH-; R 4It is -H, chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, methylamino, or dimethylamino; and R 5 It is -H or alkyl. In certain embodiments, L is a bond; R is a alkyl group. a -H;R b -H;R 1 It is a cyclopropyl group substituted with chlorine or fluorine; R 2 -H, chlorine, or fluorine; R 3 -H, chlorine, or fluorine; M is a bond or -NH-; R 4 It is -H, chlorine, fluorine, methyl, ethyl, propyl, or isopropyl; and R 5 The substituent is -H. Non-limiting exemplary compounds having this substituent include Examples 61, 64, 84, 85, 86, 155, 156 and 157 of Table 1.

[0079] In some implementations, L is the key; R 1 It is cyclopropyl, optionally substituted by one or more groups selected from the group consisting of halogens, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, and C1-C3 haloalkyl groups; R 2 It is -H, alkyl, halogen, haloalkyl or alkylthio; R 3 -H, alkyl, or halogen; M is a bond, -O-, -S-, or -NR. 6 -;R 4 It is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, monoalkylamino or dialkylamino; and R 5 The substituent is -H, alkyl, or halogen. Non-limiting exemplary compounds having such substituents include Examples 33, 39, 40, 46, 82, 102, 141, 166, 228, and 286 of Table 1.

[0080] In some implementations, L is the key; R 1 It is cyclopropyl, optionally substituted by one or more groups selected from the group consisting of halogens, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, and C1-C3 haloalkyl groups; R 2 It is -H, alkyl, halogen, haloalkyl or alkylthio; R 3 -H, alkyl, or halogen; M is a bond, -O-, -S-, or -NR. 6 -;R 4The following are not part of the given name: -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propionylaminoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonylaminoethyl, imidazolylethyl, dioxyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl; and R 5 The substituent is –H, alkyl, or halogen. Non-limiting exemplary compounds having this substituent include Examples 26, 27, 34, 38, 41-44, 50, 58, 62, 63, 66, 68, 73, 77, 79, 80, 83, 87, 88, 90-92, 94, 96, 101, 105, 107, 110, 113, 116, 118-120, 128, 130, 131, 133, 134, 136, 141, 153, 160, 162, 16 6-168, 170, 173-176, 179, 181, 183, 186, 188, 190, 191, 194, 208, 210, 213, 215-219, 221, 223, 226, 228, 232, 235, 237, 248, 250, 252, 257, 261, 262, 264, 266, 268, 269, 272, 273, 284-290, 295, 300 and 302-305.

[0081] 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.

[0082] Medical uses and treatments using this compound

[0083] This disclosure provides a method of treating a subject suffering from a disease or condition associated with HPK1 regulation, comprising administering to the subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition associated with HPK1 regulation is cancer, metastasis, inflammation, or an immune disease including an autoimmune disease.

[0084] In some other embodiments, the disease is cancer, metastasis, inflammation, or an autoimmune disease. In a particular embodiment, cancer is selected from the group consisting of epithelial carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including but not limited to bladder cancer, brain tumors, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdomyosarcoma, and nephroblastoma (Wilme's tumor).

[0085] In some implementations, autoimmune diseases include inflammatory bowel disease, Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, hemolytic anemia, autoimmune hepatitis, Behcet's disease, Bergey's disease, bullous pemphigoid, cardiomyopathy, celiac disease, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, cold agglutinin disease, type 1 diabetes, discoid lupus, primary mixed cryoglobulinemia, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hypothyroidism, autoimmune lymphoblastic syndrome (ALPS), and idiopathic thyroiditis. 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 polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Rhett's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff-person syndrome, high-stress arteritis, giant cell arteritis, ulcerative colitis, uveitis, vasculitis or granuloma with polyangiitis.

[0086] In another embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for preparing a medicament for inhibiting HPK1 activity in a subject requiring inhibition of HPK1 activity. In some embodiments, this use includes treating cancer or autoimmune diseases.

[0087] Suitable subjects for treatment according to this disclosure include mammalian subjects. Mammals according to this disclosure include, but are not limited to, humans, dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, etc., and include mammals in the womb. Subjects can be of any sex and can be at any developmental stage. In one embodiment, the suitable subject for treatment according to this disclosure is a human.

[0088] The compounds disclosed herein are typically administered in therapeutically effective amounts. The compounds of this disclosure may be administered via any suitable route in the form of a pharmaceutical composition suitable for such route and at a dose effective for the intended treatment. Effective doses are generally in the range of about 0.01 to about 1000 mg / kg body weight / day, preferably about 0.01 to about 500 mg / kg / day, in a single or divided dose. Depending on age, species, and the disease or condition being treated, dose levels below the lower limit of this range may be appropriate. In other cases, larger doses may be used without harmful side effects. Larger doses may also be divided into several smaller doses for administration throughout the day. Methods for determining appropriate doses are well known in the art to which this disclosure pertains. For example, Remington: [The Science and Practice of Pharmacy, Mack Publishing Co., 2010] th ed., 2000.

[0089] Drug composition, dosage form and route of administration

[0090] For the treatment of the diseases or conditions mentioned above, the compounds described herein or their pharmaceutically acceptable salts may be administered as follows:

[0091] Oral administration

[0092] The compounds disclosed herein can be administered orally, including by swallowing, allowing the compounds to enter the gastrointestinal tract, or by direct absorption into the bloodstream from the mouth (e.g., buccal or sublingual administration). Compositions suitable for oral administration include solid, liquid, gel, or powder formulations, and have dosage forms such as tablets, lozenges, capsules, granules, or powders. Compositions for oral administration can be formulated for immediate release or modified release, including delayed release or sustained release, optionally with an enteric coating. Liquid formulations may include solutions, syrups, and suspensions, and may be used in soft or hard capsules. Such formulations may include pharmaceutically acceptable carriers such as water, ethanol, polyethylene glycol, cellulose, or oil. Formulations may also include one or more emulsifiers and / or suspending agents.

[0093] In tablet dosage forms, the amount of drug present, by weight of the dosage form, may be from about 0.05% to about 95% by weight, and more typically from about 2% to about 50% by weight. Additionally, tablets may contain disintegrants, by weight, from about 0.5% to about 35% by weight, and more typically from about 2% to about 25% by weight. Examples of disintegrants include, but are not limited to, lactose, starch, sodium glycolate starch, crospovidone, crospovidone carboxymethyl cellulose sodium, maltodextrin, or mixtures thereof.

[0094] Suitable lubricants for tablets may be from about 0.1% to about 5% by weight, and include, but are not limited to, talc, silica, stearic acid, calcium stearate, zinc stearate or magnesium stearate, sodium stearate fumarate, etc.

[0095] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0096] Suitable solubilizers for tablets may be from 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, isosorbide dimethyl ether, castor oil, polyethylene glycol (natural or hydrogenated), and HCOR. TM (Nikkol), oil-based esters, Gelucire TM Caprylic / caprylic mono / diglycerides, sorbitan fatty acid esters, and Solutol HS TM .

[0097] Parenteral administration

[0098] The compounds disclosed herein can be administered directly into the bloodstream, muscles, or internal organs. Suitable routes of parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, and intracranial administration. Suitable devices for parenteral administration include syringes (including needle-type and needle-free syringes) and infusion methods.

[0099] Compositions for parenteral administration can be formulated for immediate release or modified release, including delayed release or sustained release. Most parenteral formulations are aqueous solutions containing excipients, including salts, buffers, 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 suitable carriers, such as sterile water. Solubility enhancers can also be used to prepare parenteral solutions.

[0100] transdermal drug delivery

[0101] The compounds disclosed herein can be administered topically to the skin or transdermally. Formulations for such topical administration may include emulsions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohols, mineral oils, glycerin, polyethylene glycol, etc. Topical or transdermal administration may also be performed via electroporation, iontophoresis, sonosing, etc. Compositions for topical administration may be formulated for immediate release or modified release, including delayed release or sustained release.

[0102] combination therapy

[0103] The pharmaceutical compositions according to this disclosure may contain one or more additional therapeutic agents, for example, to increase efficacy or reduce side effects. Therefore, in some embodiments, the pharmaceutical composition further contains one or more additional therapeutic agents selected from active ingredients used to treat or inhibit diseases directly or indirectly mediated by HPK1. Examples of such active ingredients are, but are not limited to, agents for treating cancer, metastasis, inflammation, or autoimmune pathogenesis. In some embodiments, the compound of formula (I) is administered co-administered with an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA4 agent.

[0104] References for the preparation of pharmaceutical compositions

[0105] Methods for preparing pharmaceutical compositions for treating or preventing diseases or conditions are well known in the art to which this disclosure pertains. For example, according to Handbook of Pharmaceutical Excipients (7 th ed.), Remington:TheScience and Practice of Pharmacy(20 th ed.), Encyclopedia of Pharmaceutical Technology(3 rd (ed.) or Sustained and Controlled Release Drug Delivery Systems (1978), may select pharmaceutically acceptable excipients, carriers, additives, etc., and then mix them with the compounds disclosed herein to prepare a pharmaceutical composition.

[0106] This disclosure provides compounds that have a variety of pharmacological effects by inhibiting HPK1 activity, pharmaceutical compositions having the compound as an effective agent, medical uses, particularly for treating diseases or conditions regulated by HPK1, and methods of treatment or prevention, including administering the compound to a subject requiring such treatment or prevention. The compounds of this disclosure and their pharmaceutically acceptable salts exhibit good safety and high selectivity for HPK1, and therefore demonstrate excellent properties as pharmaceuticals.

[0107] Compound preparation

[0108] The following preparation examples illustrate the preparation of intermediate compounds that can be used to prepare compounds of formula (I). The novel intermediate compounds and synthetic methods for preparing the intermediate compounds described herein represent embodiments of the present invention.

[0109] Intermediate 1A. 1-(tetrahydro-2H-pyran-2-yl)-5-(thiophen-2-yl)-1H-indazole-4-yl trifluoromethanesulfonate

[0110]

[0111] Step 1) 3-Bromo-4-chloro-5-fluoro-2-methylaniline

[0112] N-chlorosuccinimide (36 g, 270 mmol, 1.1 eq) was added to a solution of 3-bromo-5-fluoro-2-methylaniline (50 g, 245 mmol, 1 eq) in AcOH (100 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum and the residue was extracted with dichloromethane (200 mL x 2). The combined organic layers were washed with 200 mL of saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. A crude product (66 g, crude product) was obtained as a black oil.

[0113] Step 2) 4-Bromo-5-chloro-6-fluoro-1H-indazole

[0114] Sodium nitrite (8.96 g, 130 mmol, 1.2 eq) was added to a solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (25.8 g, 108 mmol, 1 eq) in AcOH (1.96 L, 0.05 M) and H₂O (0.065 L, 1.5 M). The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum and the residue was extracted with dichloromethane (1 L * 2). The combined organic layers were washed with saturated NaHCO₃ (1 L), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. A crude product (23.6 g, crude product) was given as a brown solid.

[0115] Step 3) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0116] To a THP (40 mL) solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (1.98 g, 7.97 mmol, 1 eq), 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq) were added. The reaction mixture was stirred at 70 °C for 14 hours. The reaction mixture was extracted with ethyl acetate and dried over MgSO4. The organic residues were purified by column chromatography (silica gel, hexane:ethyl acetate = 1:0–4:1). 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.51 g, 4.54 mmol, 57% yield) was obtained.

[0117] 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),8.00(dd,J=9.3,1.1Hz,1H),5.85(dd,J=9.6,2.5Hz,1H),3. 87(d,J=12.6Hz,1H),3.79-3.72(m,1H),2.38-2.30(m,1H),2.04-1.94(m,2H),1.77-1.55(m,3H).

[0118] Intermediate 1B. 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0119]

[0120] Step 1) 4-Bromo-5-chloro-6-fluoro-7-iodo-1H-indazole

[0121] N-iodosuccinimide (2.7 g, 12.03 mmol) was added fractionally to a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (2 g, 8.02 mmol) in 1.7 mL of sulfuric acid. The mixture was stirred at 0 °C for 3 hours. After the reaction was complete, the mixture was poured into ice water and quenched with solid NaOH, followed by extraction with dichloromethane. The combined organic residues were concentrated under vacuum (2.99 g, crude product).

[0122] 1 H NMR (400MHz, DMSO-d6) δ13.91 (s, 1H), 8.27 (d, J = 1.6Hz, 1H).

[0123] Step 2) 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0124] To a THP (40 mL) solution of 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole (2.99 g, 7.97 mmol, 1 eq), 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq) were added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was extracted with ethyl acetate and dried over MgSO4. The organic residues were purified by column chromatography (silica gel, hexane:ethyl acetate = 1:0–4:1). 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.64 g, 7.97 mmol, 60.7% yield) was obtained.

[0125] 1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),5.80(dd,J=9.9,2.7Hz,1H),5.66(s,1H),4.02(t,J =6.6Hz,1H),3.85-3.70(m,1H),2.33-2.21(m,1H),2.08-1.91(m,2H),1.79-1.45(m,4H).

[0126] Intermediate 1C. 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0127]

[0128] Step 1) 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole

[0129] 4-Bromo-5-chloro-6-fluoro-1H-indazole (10 g, 40.09 mmol, 1 eq) was slowly added to a mixture of HNO3 (12.63 g, 200.43 mmol, 9.02 mL, 5 eq) and H2SO4 (50 mL) under stirring at 0 °C. The mixture was stirred at 0 °C for 2 hours after the addition. TLC (petroleum ether: ethyl acetate = 3:1) showed that all reactants were consumed and a new major spot appeared. The mixture was poured into ice water and extracted with ethyl acetate (50 mL * 3). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated to obtain 12 g of crude 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole as a yellow solid.

[0130] Step 2) 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0131] To a THF (40 mL) solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (2.34 g, 7.97 mmol, 1 eq), 3,4-dihydro-2H-pyran (2.18 mL, 23.9 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (300 mg, 1.59 mmol, 0.2 eq) were added. The reaction mixture was stirred at 60 °C for 14 hours. The reaction mixture was extracted with ethyl acetate and dried over MgSO4. The organic residues were purified by column chromatography (silica gel, hexane:ethyl acetate = 1:0–4:1). 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.65 g, 4.35 mmol, 54.7% yield) was obtained.

[0132] Step 3) 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0133] 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), NH₄Cl (508.66 mg, 9.51 mmol, 6 eq) and Fe (531.04 mg, 9.51 mmol, 6 eq) were added, and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (20 mL), and the mixture was washed with water (20 mL x 2). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO₂, petroleum ether / ethyl acetate = 1:1). 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine (390 mg, 1.12 mmol, 70.59% yield) was obtained as a yellow oil.

[0134] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),5.85(br s,2H),5.71(br d,J=8.0Hz,1H),4.00(br d,J=11.3Hz,1H),3.77-3.59(m,1H),2.29-2.17(m,1H),2.10-1.91(m,2H),1.78-1.54(m,3H).

[0135] Intermediate 1D. 4-Bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine

[0136]

[0137] Step 1) 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole

[0138] HNO3 (419.69 mg, 4.33 mmol, 299.78 μL, 1.2 eq) (65% purity) was added dropwise to a solution of intermediate 1A (900 mg, 3.61 mmol, 1 eq) in 10 mL of H₂SO₄ (98% purity) at -15 °C, and the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was slowly poured into ice water (20 mL), and the pH of the mixture was adjusted to pH 7 with a saturated aqueous solution of NaOH. The mixture was then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, crude) was obtained as a yellow solid.

[0139] 1 H NMR (400MHz, DMSO-d6) δ14.36(br s,1H),8.37(br s,1H).

[0140] Step 2) 4-Bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0141] To a solution of crude 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, 3.06 mmol, 1 eq) in DCM (10 mL), TsOH·H₂O (58.14 mg, 305.64 μmol, 0.1 eq) and DHP (771.27 mg, 9.17 mmol, 838.34 μL, 3 eq) were added, and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with a saturated aqueous solution of NaHCO₃ (15 mL x 2). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 40 / 1-25:1, 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole appeared at petroleum ether / ethyl acetate = 40 / 1, and 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole appeared 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 μmol, 17.28% yield) was given as a brown solid. 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole was given as a yellow solid (600 mg, 1.58 mmol, 51.85% yield).

[0142] 4-Bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0143] 1 H NMR(400MHz, DMSO-d6)δ8.43(s,1H),5.50(dd,J=2.8,7.8Hz,1H),3.45-3.38(m,2H),2.35-2.27(m,1H), 2.23-2.14(m,1H),1.92(td,J=4.6,13.6Hz,1H),1.68(ddt,J=4.0,10.1,13.9Hz,1H),1.59-1.36(m,2H).

[0144] 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0145] 1 H NMR(400MHz, DMSO-d6)δ8.99(s,1H),5.86(dd,J=2.7,9.7Hz,1H),4.08-3.96(m,1H),3.81-3.68(m, 1H),2.28-2.14(m,1H),2.14-2.02(m,1H),2.02-1.89(m,1H),1.78-1.67(m,1H),1.64-1.56(m,2H).

[0146] Step 3) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine

[0147] To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 528.29 μmol, 1 eq) in EtOH (5 mL) and H₂O (5 mL), NH₄Cl (169.55 mg, 3.17 mmol, 6 eq) and Fe (177.03 mg, 3.17 mmol, 6 eq) were added, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove EtOH. The mixture was then diluted with ethyl acetate (20 mL), washed with water (20 mL x 2), and the organic layer was dried over Na₂SO₄. The residue was filtered and concentrated under reduced pressure to obtain the residue. 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine (140 mg, crude) was obtained as a yellow solid.

[0148] Step 4) 4-Bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine

[0149] NaH (34.42 mg, 860.59 μmol, 60% purity, 2.5 eq) was added dropwise to a solution of 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-amine (120 mg, 344.24 μmol, 1 eq) in THF (5 mL) under N2 at 0 °C. The mixture was then stirred under N2 at 0 °C for 30 min, followed by dropwise addition of MeI (293.16 mg, 2.06 mmol, 128.58 μL, 6 eq), and the reaction mixture was stirred under N2 at 20 °C for 12 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (20 mL), and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 5:1). Intermediate 1E (30 mg, 78.06 μmol, 22.68% yield, 98% purity) was obtained as a yellow oil.

[0150] Intermediate 1E. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0151]

[0152] Xantphos Pd G3 (21 mg, 21.8 μmol, 0.1 eq) and Cs2CO3 (142 mg, 0.436 mmol, 2.0 eq) were added to a solution of intermediate 1B (100 mg, 0.218 mmol, 1 eq) in 1.09 mL of 2-methyl-2-butanol. The mixture was degassed and purged three times with N2, and then propan-2-amine (0.19 mL, 2.18 mmol, 10 eq) was added. The mixture was stirred in a sealed tube at 90 °C for 3 h. The reaction mixture was diluted with H2O (40 mL) and then extracted with DCM (50 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 appeared at hexane / ethyl acetate = 10 / 1) to provide intermediate 1E (47 mg, 0.120 mmol, 55% yield) as a beige solid.

[0153] 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).

[0154] Intermediate 1F. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-N-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole-7-amine

[0155]

[0156] To a methanol (7.7 mL) solution of intermediate 1E (600 mg, 1.54 mmol, 1.0 eq), 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 appeared at hexane / ethyl acetate = 100 / 4) to provide intermediate 1F (292 mg, 0.722 mmol, 47% yield) as a brown oil.

[0157] 1 H NMR (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,2H),1.75-1.60(m,3H),1.17(d,J=6.6Hz,6H).

[0158] Intermediate 1G. 4-Bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine

[0159]

[0160] Step 1) 4-Bromo-5-chloro-6-fluoro-1H-indazole-7-amine

[0161] Fe (6.83 g, 122.26 mmol, 3 eq) and NH4Cl (6.54 g, 122.26 mmol, 3 eq) were added to a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (12 g, 40.75 mmol, 1 eq) in EtOH (100 mL) and H2O (40 mL). The reaction mixture was heated to 80 °C and reacted for 2 hours. The reaction mixture was filtered through a diatomaceous earth filter cake, and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1-3 / 1). 4-Bromo-5-chloro-6-fluoro-1H-indazole-7-amine (5 g, 18.90 mmol, 46.39% yield) was given as a yellow solid.

[0162] Step 2) N-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)acetamide

[0163] To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole-7-amine (3 g, 11.34 mmol, 1 eq) in AcOH (30 mL), Ac₂O (1.39 g, 13.61 mmol, 1.27 mL, 1.2 eq) was added, and the reaction mixture was heated to 80 °C and reacted for 3 h. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 50 / 1-4 / 1) to obtain N-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)acetamide (3 g, 9.79 mmol, 86.29% yield) as a yellow solid.

[0164] Step 3) 4-Bromo-5-chloro-N-ethyl-6-fluoro-1H-indazole-7-amine

[0165] Under N2 and at 0°C, a solution of N-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)acetamide (2.8 g, 9.13 mmol, 1 eq) in THF (100 mL) was added dropwise. After addition, the reaction mixture was heated to 25°C and reacted for 16 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were 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 / 1-2 / 1) to obtain 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazole-7-amine (1 g, 3.42 mmol, 37.42% yield) as a yellow solid.

[0166] Step 4) 4-Bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine

[0167] To a solution of 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazole-7-amine (1.4 g, 4.79 mmol, 1 eq) and HCHO (718.48 mg, 23.93 mmol, 659.16 μL, 5 eq) in MeOH (50 mL), NaBH3CN (902.21 mg, 14.36 mmol, 3 eq) and AcOH (287.38 mg, 4.79 mmol, 273.70 μL, 1 eq) were added. The reaction mixture was stirred at 25 °C for 16 h. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1–5 / 1) to obtain 4-bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazole-7-amine (1.4 g, 4.57 mmol, 95.42% yield) as a white solid.

[0168] Intermediate 1H. 4-Bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0169]

[0170] LDA (2M, 1.87mL, 2.5eq) was added dropwise to a solution of 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5g, 1.50mmol, 1eq) in 10mL of THF at -78°C. After addition, the mixture was stirred at this temperature for 2.5 hours, and then MeI (319.12mg, 2.25mmol, 139.97µL, 1.5eq) 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 20mL of EA. The organic layer was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1-10 / 1). We obtained the desired product, yielding 4-bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a white solid (0.38 g, 1.09 mmol, 72.93% yield).

[0171] Intermediate 1I. 4-Bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazole-7-amine

[0172]

[0173] Step 1) 4-Bromo-6-fluoro-7-nitro-1H-indazole

[0174] KNO3 (4.70 g, 46.51 mmol, 1 eq) was added in portions to a solution of 4-bromo-6-fluoro-1H-indazole (10 g, 46.51 mmol, 1 eq) in H2SO4 (80 mL) (98% purity) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was then poured into ice water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated NaHCO3 aqueous solution (100 mL x 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1-1 / 1, the product 4-bromo-6-fluoro-7-nitro-1H-indazole appeared at petroleum ether / ethyl acetate = 8 / 1) to give 4-bromo-6-fluoro-7-nitro-1H-indazole (2.7 g, 10.38 mmol, 22.32% yield) as a yellow solid and the crude product. The crude product was purified by MPLC (petroleum ether / ethyl acetate) to give 4-bromo-6-fluoro-7-nitro-1H-indazole (3.57 g, 13.73 mmol, 29.52% yield) as a yellow solid.

[0175] Step 2) 4-Bromo-6-fluoro-5-iodo-7-nitro-1H-indazole

[0176] NIS (7.01 g, 31.15 mmol, 3 eq) was added to a solution of 4-bromo-6-fluoro-7-nitro-1H-indazole (2.7 g, 10.38 mmol, 1 eq) in H₂SO₄ (30 mL) at 25 °C. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with ice water (50 mL). The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aqueous solutions of Na₂SO₃ (20 mL x 2), NaHCO₃ (20 mL x 2), and brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give 4-bromo-6-fluoro-5-iodo-7-nitro-1H-indazole (3.4 g, 8.81 mmol, 84.85% yield) as a yellow solid.

[0177] 1 H NMR (400MHz, DMSO-d6) δ14.28(br s,1H),8.30(s,1H).

[0178] Step 3) 4-Bromo-6-fluoro-5-iodo-1H-indazole-7-amine

[0179] To a solution of 4-bromo-6-fluoro-5-iodo-7-nitro-1H-indazole (3.4 g, 8.81 mmol, 1 eq) in EtOH (50 mL) and H₂O (25 mL), NH₄Cl (2.83 g, 52.86 mmol, 6 eq) was added, followed by the addition of Fe (2.95 g, 52.86 mmol, 6 eq) in portions at 60 °C. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered hot through diatomaceous earth. The filtrate was then concentrated under vacuum to remove EtOH. The resulting aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (MPLC, petroleum ether / ethyl acetate = 5 / 1–2 / 1, the product appeared at petroleum ether / ethyl acetate = 2 / 1) to give 4-bromo-6-fluoro-5-iodo-1H-indazole-7-amine (2.2 g, 6.18 mmol, 70.16% yield) as a gray solid.

[0180] 1 H NMR (400MHz, DMSO-d6) δ13.09 (br s, 1H), 7.86 (d, J = 1.7Hz, 1H), 5.62 (s, 2H).

[0181] Step 4) 4-Bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine

[0182] To a MeOH (50 mL) solution of 4-bromo-6-fluoro-5-iodo-1H-indazole-7-amine (2.2 g, 6.18 mmol, 1 eq), AcOH (1.11 g, 18.54 mmol, 1.06 mL, 3 eq) and HCHO (5.02 g, 61.81 mmol, 4.60 mL, 10 eq) were added in portions, followed by the addition of NaBH3CN (3.88 g, 61.81 mmol, 10 eq) at 40 °C. The gas was released and the temperature was increased. The suspension was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (50 mL), and the mixture was concentrated to remove MeOH. The mixture was then extracted with ethyl acetate (50 mL x 2), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1-8 / 1, the product appeared at petroleum ether / ethyl acetate = 8 / 1) to give 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine (2.05 g, 5.34 mmol, 86.37% yield) as a grayish-white solid.

[0183] Step 5) 4-Bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazole-7-amine

[0184] To a 100 mL flask equipped with a magnetic stir bar, add 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine (1.2 g, 3.13 mmol, 1 eq), NaSMe (328.56 mg, 4.69 mmol, 1.5 eq), Xantphos (361.65 mg, 625.02 μmol, 0.2 eq), K₂CO₃ (1.30 g, 9.38 mmol, 3 eq), dioxane (20 mL), and Pd₂(dba)₃ (286.17 mg, 312.51 μmol, 0.1 eq). Evacuate the flask and backfill with nitrogen. Then, stir the mixture 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 / 1-8 / 1, the product appeared when petroleum ether / ethyl acetate = 10 / 1) to give 4-bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazole-7-amine (540 mg, 1.78 mmol, 56.81% yield) as an orange solid.

[0185] 1 H NMR (400MHz, DMSO-d6) δ13.59 (br s, 1H), 8.00 (d, J = 1.6Hz, 1H), 2.91 (d, J = 2.4Hz, 6H), 2.39 (s, 3H).

[0186] Intermediate 1J. 4-Bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazole-7-amine

[0187]

[0188] CuI (994.63 mg, 5.22 mmol, 2 eq) was added to a DMF (10 mL) solution of 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazole-7-amine (1.0 g, 2.61 mmol, 1 eq) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.00 g, 5.22 mmol, 664.45 μL, 2 eq). The mixture was stirred at 100 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0–10:1). 4-Bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazole-7-amine was obtained as a yellow solid (502 mg, 1.54 mmol, 58.91% yield).

[0189] Intermediate 1K. 4-Bromo-5-ethyl-6-fluoro-1H-indazole

[0190]

[0191] Step 1) 4-Bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole

[0192] Under a nitrogen atmosphere and at -78°C, a solution of diisopropylamine (132.75 mg, 1.31 mmol, 185.41 μL, 1.2 eq) in THF (5 mL) was slowly added to a solution of n-butyllithium (2.5 M, 481.04 μL, 1.1 eq) for 0.5 hours. 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. After stirring the mixture at -78°C for 0.5 hours, a solution of EtI (204.62 mg, 1.31 mmol, 104.93 μL, 1.2 eq) in THF (2 mL) was added to the mixture, and the solution was heated to 15°C and stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched by adding 3 mL of saturated NH4Cl aqueous solution at 15 °C, 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), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. 4-Bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole (500 mg, crude) was obtained as a yellow solid.

[0193] Step 2) 4-Bromo-5-ethyl-6-fluoro-1H-indazole

[0194] TFA (3.08 g, 27.01 mmol, 2.00 mL, 26.22 eq) was added to a DCM (6 mL) solution of 4-bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole (500 mg, 1.03 mmol, 1 eq). The mixture was stirred at 15 °C for 4 hours. The pH of the reaction mixture was adjusted to 7 with a saturated aqueous solution of NaHCO3, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (0.1% TFA) - ACN]; B%: 40%-70%, 10 min). The fractional-liquid solution was concentrated under reduced pressure to remove ACN, and the pH of the aqueous solution was adjusted to 7 with saturated NaHCO3 aqueous solution. The aqueous solution was extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. 4-Bromo-5-ethyl-6-fluoro-1H-indazole (70 mg, 287.98 μmol, 27.96% yield) was given as a yellow solid.

[0195] 1 H NMR (400MHz, DMSO-d6) δ13.39 (br s, 1H), 8.01-7.98 (m, 1H), 7.41 (d, J = 9.9Hz, 1H), 2.83 (dq, J = 2.4, 7.5Hz, 2H), 1.14 (t, J = 7.5Hz, 3H).

[0196] 1 L of intermediate. 4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine

[0197]

[0198] Step 1) 6-Fluoro-5-nitro-1H-indazole

[0199] HNO3 (2.44 g, 38.79 mmol, 1.75 mL, 1.2 eq) was added dropwise to a solution of 6-fluoro-1H-indazole (4.4 g, 32.32 mmol, 1 eq) in H2SO4 (30 mL) at -15 °C, and the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was then slowly poured into ice water (100 mL), and 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 obtain 6-fluoro-5-nitro-1H-indazole (5.4 g, crude product) as a yellow solid.

[0200] Step 2) 6-Fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0201] To a mixture of crude 6-fluoro-5-nitro-1H-indazole (4.9 g, 27.05 mmol, 1 eq) and DCM (50 mL), DHP (6.83 g, 81.16 mmol, 7.42 mL, 3 eq) and TsOH·H₂O (514.60 mg, 2.71 mmol, 0.1 eq) were added, and the reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ (100 mL), and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1-15:1) to give 6-fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3 g, 11.31 mmol, 41.81% yield) as a yellow solid.

[0202] 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=7.3Hz,1H),8.41(s,1H),7.97(d,J=12.1Hz,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).

[0203] Step 3) 6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine

[0204] Under a nitrogen atmosphere, wet Pd / C (300 mg, 10% purity) was added to a MeOH (30 mL) solution of 6-fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.9 g, 10.93 mmol, 1 eq). The suspension was degassed and purged three times with H2. The mixture was stirred at 15 °C for 4 hours under H2 (15 Psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1-8:1). 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine (1.5 g, 5.87 mmol, 53.65% yield, 92% purity) was given as a brick-red solid.

[0205] 1H NMR (400MHz, DMSO-d6) δ 7.82 (s, 1H), 7.43 (d, J = 11.6Hz, 1H), 6.98 (d, J = 8.6Hz, 1H), 5.66 (dd, J = 2.3, 9.7Hz, 1H), 4.91 (s, 2H), 3.85 (br d, J = 12.1Hz, 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)+.

[0206] Step 4) 4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine

[0207] NBS (1.21 g, 6.80 mmol, 1.2 eq) was added fractionally to a MeCN (10 mL) solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine (1.45 g, 5.67 mmol, 1 eq) at 0 °C. 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 x 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-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine (1.3 g, 4.14 mmol, 72.98% yield) was given as a brown solid.

[0208] 1 H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 7.60 (d, J = 10.6Hz, 1H), 5.71 (dd, J = 2.5, 9.6Hz, 1H), 5.15 (s, 2H), 3.88-3.82 (m, 1H), 3. 76-3.68(m,1H),2.36-2.27(m,1H),2.02(brdd,J=4.6,8.5Hz,1H),1.96-1.90(m,1H),1.76-1.65(m,1H),1.60-1.52(m,2H).

[0209] Intermediate 1M. 3-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol

[0210]

[0211] Step 1) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbonal

[0212] Under N2 atmospheres and at -78°C, LDA (2M, 17.99mL, 4eq) was added dropwise to a mixture of intermediate 1A (3g, 8.99mmol, 1eq) and THF (60mL). The mixture was stirred at -78°C for 1 hour. Then, a solution of HCO2Et (3.17g, 35.97mmol, 3.52mL, 4eq) in THF (8mL) was added dropwise at -78°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched at -78°C by adding saturated NH4Cl solution (20mL), followed by extraction with EA (30mL x 3). The combined organic layers were washed with brine (30mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1-20 / 1). 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbonal was given as a grayish-white solid (2.78 g, 7.69 mmol, 85.49% yield).

[0213] 1 H NMR (400MHz, DMSO-d6) δ 10.40 (s, 1H), 8.35 (s, 1H), 6.09 (dd, J = 2.6, 8.9Hz, 1H), 3.71-3.63 (m, 1H), 3.63-3.52 (m, 1H), 2.42-2.30 (m, 1H), 2.21-2.10 (m, 1H), 2.07-1.95 (m, 1H), 1.77-1.63 (m, 2H), 1.60-1.40 (m, 2H); LCMS (electrospray) m / z 278.9 (M+H)+.

[0214] Step 2) 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)but-3-en-1-ol

[0215] Under N2 and at 0 °C, allyl magnesium bromide (1 M, 9.13 mL, 1.5 eq) was added dropwise to a mixture of 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbonal (2.2 g, 6.08 mmol, 1 eq) and THF (60 mL). The mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched at 0 °C by adding 20 mL of saturated NH4Cl solution, followed by extraction with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1-5 / 1). 1-(4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)but-3-en-1-ol (2 g, 4.95 mmol, 81.43% yield) was obtained as a colorless oil.

[0216] 1 H NMR (400MHz, DMSO-d6) δ8.25-8.21(m,1H),8.20-8.18(m,1H),6.61(br d,J=9.0Hz,1H),6.23(d,J=4.0Hz,1H),6.18(br d,J=8.3Hz,1H),5.95(d,J=5.0Hz,1H),5.90-5.75(m,2H),5.36(dt,J=4.3,7.5Hz,1H),5.30(td,J=5.9,7.9Hz,1H),5.10-4.97(m,4H),3.97(br d,J=11.5Hz,1H),3.89(br d,J=11.3Hz,1H),3.69-3.55(m,2H),2.87-2.74(m,2H),2.70-2.55(m,4H),2.06(br d,J=10.8Hz,3H),1.96-1.87(m,1H),0.90-0.78(m,1H);LCMS (electrospray) m / z 302.9(M+H)+.

[0217] Step 3) 4-Bromo-7-(3-Bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole

[0218] Under N2 atmosphere and at -20°C, Br2 (1.19 g, 7.43 mmol, 383.11 μL, 1.5 eq) of DCM (2 mL) was added dropwise 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) and DCM (2 mL). The mixture was stirred at -10°C for 3 hours. The mixture was quenched by adding 30 mL of Na2SO3 solution and then diluted with 30 mL of DCM. The organic layer was washed with 30 mL of Na2SO3 solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was dissolved in MeOH (15 mL), then K₂CO₃ (2.05 g, 14.86 mmol, 3 eq) was added, and the resulting mixture was stirred at 20 °C for 16 hours. The reaction was quenched with water (20 mL), extracted with EA (30 mL * 3), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1-3:1). The crude product was purified by reversed-phase HPLC (0.1% FA conditions). 4-Bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole (300 mg, 752.91 μmol, 15.20% yield) was given as a white solid.

[0219] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.44–13.37 (m, 2H), 8.14–8.11 (m, 2H), 5.71–5.67 (m, 1H), 5.44 (dt, J = 1.2, 7.5 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)+.

[0220] Step 4) 3-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentyl acetate

[0221] Under N2 and at 20°C, a portion of KOAc (73.89 mg, 752.91 μmol, 3 eq) was added to a mixture of 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole (100 mg, 250.97 μmol, 1 eq) and DMSO (2 mL). The mixture was then heated to 70°C and stirred for 3 hours. The reaction was quenched with water (15 mL), followed by extraction with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentyl acetate (100 mg, crude, brown oil) was used directly for the next step without further purification.

[0222] LCMS (electrospray) m / z 378.8(M+H)+.

[0223] Step 5) 3-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol

[0224] Under N2 conditions at 20°C, a partial amount of K2CO3 (442.15 mg, 3.20 mmol, 15.1 eq) was added to a mixture of 3-(4-bromo-5-chloro-6-fluoro-1H-indazole-7-yl)cyclopentyl acetate (80 mg, 211.87 μmol, 1 eq) in MeOH (4 mL) and H2O (0.8 mL). The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched at 20°C by adding water (15 mL), followed by extraction with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1-1 / 2). 3-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol was given as a white solid (50 mg, 149.01 μmol, 70.33% yield).

[0225] LCMS (electrospray) m / z 336.9(M+H)+.

[0226] Intermediate 1N. 4-Bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine

[0227]

[0228] Step 1) 5-Fluoro-2-iodo-4-(trifluoromethyl)aniline

[0229] NIS (5.53 g, 24.57 mmol, 1.1 eq) was added to a MeCN (40 mL) solution of 3-fluoro-4-(trifluoromethyl)aniline (4 g, 22.33 mmol, 1 eq) at 15 °C, and the reaction mixture was stirred at 15 °C for 15 hours. The reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. 5-fluoro-2-iodo-4-(trifluoromethyl)aniline (5.6 g, crude) was obtained as a brown oil.

[0230] LCMS (electrospray) m / z 305.9(M+H)+.

[0231] Step 2) 5-Fluoro-2-methyl-4-(trifluoromethyl)aniline

[0232] At 15 °C, Pd(PPh3)4 (1.14 g, 983.57 μmol, 0.05 eq) and K2CO3 (8.16 g, 59.01 mmol, 3 eq) were added to a DME (60 mL) solution of 5-fluoro-2-iodo-4-(trifluoromethyl)aniline (6.0 g, 19.67 mmol, 1 eq) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (8.82 g, 29.51 mmol, 9.82 mL, 42% purity, 1.5 eq). The reaction mixture was then stirred at 100 °C for 60 h. The reaction mixture was concentrated under reduced pressure to provide the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1–3 / 1, petroleum ether / ethyl acetate = 2:1, Rf = 0.3). 5-Fluoro-2-methyl-4-(trifluoromethyl)aniline (1.6 g, 4.06 mmol, 20.64% yield, 49% purity) was obtained as a yellow oil.

[0233] LCMS (electrospray) m / z 194.1.9(M+H)+.

[0234] Step 3) 6-Fluoro-5-(trifluoromethyl)-1H-indazole

[0235] To a solution of 5-fluoro-2-methyl-4-(trifluoromethyl)aniline (1 g, 5.18 mmol, 1 eq) in AcOH (15 mL), NaNO₂ (357.25 mg, 5.18 mmol, 1 eq) and H₂O (3 mL) were added at 0 °C, and the reaction mixture was stirred at 15 °C for 2 h. The reaction was quenched by adding H₂O (60 mL) at 20 °C, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H₂O (50 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1-5 / 1, petroleum ether / ethyl acetate = 3:1, Rf = 0.5). 6-fluoro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.45 mmol, 47.31% yield) was given as a yellow solid.

[0236] LCMS (electrospray) m / z 205.2(M+H)+.

[0237] Step 4) 6-Fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole

[0238] KNO3 (249 mg, 2.46 mmol, 1.01 eq) was added to a solution of 6-fluoro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.45 mmol, 1 eq) in H₂SO₄ (5 mL, 95% purity) at 0 °C, and the reaction mixture was then stirred at 15 °C for 15 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were treated with saturated sodium bicarbonate solution to pH 7, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. 6-fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole (500 mg) was given as a yellow solid.

[0239] LCMS (electrospray) m / z 250.2(M+H)+.

[0240] Step 5) 6-Fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole

[0241] At 0 °C, PPTS (50.44 mg, 200.71 μmol, 0.1 eq) and DHP (844.13 mg, 10.04 mmol, 917.53 μL, 5 eq) were added to a THF (10 mL) solution of 6-fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.01 mmol, 1 eq), and the reaction mixture was stirred at 60 °C for 15 hours. The reaction mixture was diluted with solvent H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H2O (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. A yellow oily product of 6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole (1 g, crude) was obtained.

[0242] Step 6) 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine

[0243] At 0 °C, NH4Cl (642.08 mg, 12.00 mmol, 5 eq) and Fe (268.13 mg, 4.80 mmol, 2 eq) were added 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 10 mL of EtOH. The reaction mixture was then stirred at 60 °C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with H2O (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1-5 / 1, petroleum ether:ethyl acetate = 3:1, Rf = 0.3). 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine was obtained as a yellow solid (500 mg, 1.65 mmol, 68.68% yield).

[0244] LCMS (electrospray) m / z 220.2(M+H)+.

[0245] Step 7) 4-Bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine

[0246] NBS (129.12 mg, 725.46 μmol, 1.1 eq) was added to a DMF (1 mL) solution of 6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (200 mg, 659.51 μmol, 1 eq) at 20 °C, and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with 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 the residue. A yellow solid of 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (120 mg, crude) was obtained.

[0247] LCMS (electrospray) m / z 297.9(M+H)+.

[0248] Step 8) 4-Bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazole-7-amine

[0249] At 20 °C, AcOH (40.30 mg, 671.06 μmol, 38.38 μL, 2 eq) and acetone (97.44 mg, 1.68 mmol, 123.34 μL, 5 eq) were added to a MeOH (1 mL) solution of 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine (100 mg, 335.53 μmol, 1 eq), followed by the addition of NaBH3CN (105.42 mg, 1.68 mmol, 5 eq), and the reaction mixture was stirred at 20 °C for 2 hours. Then, acetone (97.44 mg, 1.68 mmol, 123.34 μL, 5 eq), NaBH3CN (105.43 mg, 1.68 mmol, 5 eq), and AcOH (60.45 mg, 1.01 mmol, 57.57 μL, 3 eq) were added to the mixture, and the reaction mixture was stirred at 20 °C for 20 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with H2O (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 3:1, Rf = 0.4). 4-Bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazole-7-amine (60 mg, 165.83 μmol, 49.42% yield, 94% purity) was obtained as a white solid.

[0250] LCMS (electrospray) m / z 340.1(M+H)+.

[0251] Step 9) 4-Bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7-amine

[0252] At 0 °C, PPTS (3.69 mg, 14.70 μmol, 0.1 eq) and DHP (61.83 mg, 735.05 μmol, 67.21 μL, 5 eq) were added to a THF (1 mL) solution of 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazole-7-amine (50 mg, 147.01 μL, 1 eq), and 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 x 3). The combined organic layers were washed with H2O (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by 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-indazole-7-amine (50 mg, 117.86 μmol, 80.17% yield) was obtained as a yellow oil.

[0253] LCMS (electrospray) m / z 424.1(M+H)+.

[0254] Intermediate 1O. 4-Bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0255]

[0256] Step 1) 3-Bromo-5-fluoro-2-methylaniline

[0257] Fe (27.44 g, 491.41 mmol, 5 eq) and NH4Cl (26.29 g, 491.41 mmol, 5 eq) were added to a mixture of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (23 g, 98.28 mmol, 1 eq) with EtOH (80 mL) and H2O (80 mL). The mixture was stirred at 100 °C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue of 3-bromo-5-fluoro-2-methylaniline (20.6 g, crude product) as a yellow liquid.

[0258] 1H NMR (400MHz, DMSO-d6) δ6.59 (br d, J = 8.4Hz, 1H), 6.42 (br d, J = 11.2Hz, 1H), 5.51 (br s, 2H), 2.09 (s, 3H).

[0259] Step 2) 3-Bromo-5-fluoro-4-iodo-2-methylaniline

[0260] At 0 °C, NIS (19.85 g, 88.22 mmol, 1 eq) was added fractionally to a mixture of 3-bromo-5-fluoro-2-methylaniline (18 g, 88.22 mmol, 1 eq) and CH3CN (150 mL). The mixture was stirred at 30 °C for 3 hours. After 3 hours, LCMS showed residual compound 2, and the desired amount was also detected. The mixture was then stirred at 30 °C for another 12 hours. LCMS showed no residual compound 2 and a main peak with the desired amount was detected. The mixture was quenched with saturated Na2SO3 (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 50 / 1, 30 / 1; TLC (petroleum ether:ethyl acetate = 10:1; Rf = 0.28)) to give 3-bromo-5-fluoro-4-iodo-2-methylaniline (22 g, 66.68 mmol, 75.58% yield) as a brown solid.

[0261] 1 H NMR (400MHz, DMSO-d6) δ6.55 (d, J = 10.5 Hz, 1H), 5.67 (s, 2H), 2.25 (d, J = 0.8 Hz, 3H).

[0262] Step 3) 4-Bromo-6-fluoro-5-iodo-1H-indazole

[0263] At 0 °C, a mixture of 22 g (66.68 mmol, 1 eq) of 3-bromo-5-fluoro-4-iodo-2-methylaniline (CH3COOH) (200 mL) was dissolved in 40 mL of NaNO2 (5.52 g, 80.02 mmol, 1.2 eq). The mixture was stirred at 30 °C for 16 hours. The mixture was poured into saturated NaHCO3 (1000 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 15 / 1, 5 / 1) to give 4-bromo-6-fluoro-5-iodo-1H-indazole (7.5 g, 22.00 mmol, 32.99% yield) as a brown solid.

[0264] 1 H NMR (400MHz, DMSO-d6) δ13.58 (br s, 1H), 8.00 (s, 1H), 7.51 (d, J = 8.1Hz, 1H), 3.32 (s, 1H).

[0265] Step 4) 4-Bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0266] DHP (5.55 g, 66.00 mmol, 1 eq) was slowly added to a mixture of 4-bromo-6-fluoro-5-iodo-1H-indazole (7.5 g, 22.00 mmol, 1 eq) and 4-methylbenzenesulfonic acid hydrate (418.47 mg, 2.20 mmol, 0.1 eq) in DCM (100 mL). The mixture was stirred at 30 °C for 1 hour. The mixture was washed with saturated NaHCO3 (30 mL x 3) and brine (30 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 50 / 1) to give 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7.4 g, 17.41 mmol, 79.14% yield) as a yellow solid.

[0267] 1H NMR(400MHz, DMSO-d6)δ8.06(s,1H),7.80(dd,J=0.7,8.4Hz,1H),5.83(dd,J=2.4,9.6Hz,1H),3.88-3.8 5(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).

[0268] Step 5) 4-Bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0269] Under N2, Na2CO3 (748.10 mg, 7.06 mmol, 2 eq) and Pd(dppf)Cl2 (258.23 mg, 352.91 μmol, 0.1 eq) were added to a mixture of 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.53 mmol, 1 eq) and cyclopropylboronic acid (303.14 mg, 3.53 mmol, 1 eq) in dioxane (10 mL) and H2O (2.5 mL) were added. The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 20:1) to give 4-bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.21 g, 619.10 μmol, 17.54% yield) as a colorless oil.

[0270] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J = 0.6Hz, 1H), 7.20 (d, J = 10.4Hz, 1H), 5.61 (dd, J = 2.8, 9.1Hz, 1H), 4.03-3.94 (m, 1H), 3.76-3. 69(m,1H),2.55-2.42(m,1H),2.19-2.06(m,2H),1.91-1.86(m,1H),1.81-1.64(m,3H),1.12-1.05(m,2H),0.87-0.81(m,2H).

[0271] Intermediate 1P. 4-Bromo-6-fluoro-5-isopropyl-1H-indazole

[0272]

[0273] Step 1) 4-Bromo-6-fluoro-5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0274] Under N2, Pd(dppf)Cl2 (258.23 mg, 352.91 μmol, 0.1 eq) and Na2CO3 (748.10 mg, 7.06 mmol, 2 eq) were added to a mixture of 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.53 mmol, 1 eq) and potassium trifluoro(isopropenyl)borohydride (626.67 mg, 4.23 mmol, 1.2 eq) in dioxane (10 mL) and H2O (2 mL) were added. The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure to obtain 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. This oil was purified by prep-TLC (petroleum ether:ethyl acetate = 20:1) to give 4-bromo-6-fluoro-5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.55 g, 1.62 mmol, 45.94% yield) as a yellow oil.

[0275] 1 H NMR (400MHz, CDCl3) δ8.00(d,J=0.6Hz,1H),7.28(d,J=0.9Hz,0.5H),7.26(d,J=0.7Hz,0.5H),5.64(dd,J=2.8,9.0Hz,1H),5.46(t,J= 1.6Hz,1H),5.01(s,1H),4.05-3.97(m,1H),3.80-3.69(m,1H),2.57-2.42(m,1H),2.19-2.09(m,2H),2.07(s,3H),1.81-1.66(m,4H).

[0276] Step 2) 4-Bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0277] Under N2, PtO2 was added to a MeOH (10 mL) solution of 4-bromo-6-fluoro-5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.4 g, 1.18 mmol, 1 eq). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 30 °C for 2.5 h under H2 (15 Psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 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-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.3 g, 879.20 μmol, 74.56% yield) as a colorless oil.

[0278] Step 3) 4-Bromo-6-fluoro-5-isopropyl-1H-indazole

[0279] TFA (2.30 g, 20.14 mmol, 1.49 mL, 22.91 eq) was added to a DCM (1 mL) solution of 4-bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.3 g, 879.20 μmol, 1 eq). The mixture was stirred at 30 °C for 0.5 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with DCM (10 mL) and the resulting mixture was adjusted to pH approximately 8 with TEA. The mixture was concentrated under reduced pressure to obtain 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-1H-indazole (0.2 g, 777.90 μmol, 88.48% yield) as a colorless oil.

[0280] 1 H NMR (400MHz, CDCl3) δ8.04 (s, 1H), 7.11 (d, J = 11.2Hz, 1H), 3.75-3.63 (m, 1H), 1.38 (dd, J = 1.7, 7.1Hz, 6H).

[0281] Intermediate 1Q. 4-Bromo-6-fluoro-5-methoxy-1H-indazole

[0282]

[0283] Step 1) 2-Bromo-4-fluoro-3-methoxy-1-methylbenzene

[0284] To a solution of 2-bromo-6-fluoro-3-methylphenol (4.8 g, 23.41 mmol, 1 eq) in acetone (50 mL), K₂CO₃ (6.47 g, 46.82 mmol, 2 eq) and iodomethane (9.97 g, 70.24 mmol, 4.37 mL, 3 eq) were added, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give a residue. The residue was dissolved in ethyl acetate (50 mL), and the mixture was filtered. The filtrate was concentrated to give a yellow oily residue (4.6 g, 21.00 mmol, 89.70% yield).

[0285] 1 H NMR (400MHz, CHLOROFORM-d) δ7.05-6.85 (m, 2H), 3.95 (d, J = 1.2Hz, 3H), 2.38 (s, 3H).

[0286] Step 2) 3-Bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene

[0287] KNO3 (2.23 g, 22.10 mmol, 1.1 eq) was added in portions to a 98% solution of 2-bromo-4-fluoro-3-methoxy-1-methylbenzene (4.4 g, 20.09 mmol, 1 eq) in 40 mL of H₂SO₄, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was slowly poured into ice water (200 mL), and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. 3-bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (4.6 g, crude product) was obtained as a brown oil.

[0288] 1 H NMR (400MHz, CHLOROFORM-d) δ7.70 (d, J = 10.9 Hz, 1H), 4.08 (d, J = 2.7 Hz, 3H), 2.61 (d, J = 1.1 Hz, 3H).

[0289] Step 3) 3-Bromo-5-fluoro-4-methoxy-2-methylaniline

[0290] Fe (5.84 g, 104.53 mmol, 6 eq) and NH4Cl (5.59 g, 104.53 mmol, 6 eq) were added to a solution of 3-bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (4.6 g, 17.42 mmol, 1 eq) in EtOH (30 mL) and H2O (30 mL), and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove EtOH. The mixture was then diluted with EA (50 mL) and washed with water (20 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 3-bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, crude product) was obtained as a brown oil.

[0291] 1 H NMR (400MHz, CHLOROFORM-d) δ6.44 (d, J = 11.9 Hz, 1H), 3.83 (s, 3H), 3.76-3.48 (m, 2H), 2.24 (d, J = 1.0 Hz, 3H).

[0292] Step 4) 4-Bromo-6-fluoro-5-methoxy-1H-indazole

[0293] A solution of NaNO2 (1.24 g, 17.94 mmol, 1 eq) in H2O (4 mL) was added dropwise to a mixture of 3-bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, 14.95 mmol, 1 eq) (crude) in AcOH (20 mL) at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ice water (100 mL) and adjusted to pH 7 using KOH. The mixture was then extracted with EA (100 mL x 2), and the combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1-15:1). 4-Bromo-6-fluoro-5-methoxy-1H-indazole (600 mg, 2.45 mmol, 16.37% yield) was given as a brown solid.

[0294] 1 H NMR (400MHz, DMSO-d6) δ 13.44 (br s, 1H), 8.00 (s, 1H), 7.52 (br d, J = 10.4Hz, 1H), 3.84 (s, 3H).

[0295] Synthesis of compound (I)

[0296] The following compounds were prepared using synthetic method AF. Illustrative synthetic examples of some compounds of this disclosure are described below, and other compounds can be prepared using different starting or reacting materials by methods similar to those described below.

[0297] Synthesis Method A

[0298] Example 1 (1S,2S)-2-fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl) Cyclopropane-1-formamide

[0299]

[0300] Step 1) Methyl 5-amino-1-(3-methoxy-3-oxoprop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid

[0301] Methyl propargyl ester (27.11 g, 322.40 mmol, 26.84 mL, 5 eq) was added to a solution of compound 1 (9.1 g, 64.48 mmol, 1 eq) in EtOH (700 mL). The mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure until all solid precipitate formed, filtered, and concentrated under reduced pressure to give the crude product. Compound 2 (7.8 g, crude product) was given as a yellow solid.

[0302] 1 H NMR (400MHz, DMSO-d6) δ 8.09 (d, J = 14.8 Hz, 1H), 7.05 (s, 1H), 6.68 (br s, 2H), 6.63 (d, J = 14.8 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H).

[0303] Step 2) Ethyl 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0304] EtONa (1.77 g, 25.98 mmol, 1.5 eq) was added to EtOH (15 mL) containing compound 2 (3.9 g, 17.32 mmol, 1 eq). The mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with 200 mL of water and extracted with ethyl acetate (200 mL x 2). The aqueous layer was filtered, and the resulting filter cake was concentrated under reduced pressure to give compound 3 (5.4 g, crude product) as a yellow solid.

[0305] 1H NMR (400MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.99 (d, J = 7.5Hz, 1H), 6.58 (s, 1H), 5.82 (d, J = 7.5Hz, 1H), 4.35 (q, J = 7.1Hz, 2H), 1.34 (t, J = 7.2Hz, 3H).

[0306] Step 3) Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0307] Under a nitrogen atmosphere, N,N-dimethylaniline (1.17 g, 9.65 mmol, 1.22 mL, 2 eq), benzyl(triethyl)ammonium chloride (5.50 g, 24.13 mmol, 5 eq), and POCl3 (7.40 g, 48.27 mmol, 4.49 mL, 10 eq) were added to a MeCN (5 mL) solution of compound 3 (1 g, 4.83 mmol, 1 eq). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was quenched with water (100 mL) and treated with saturated sodium bicarbonate solution until pH = 7. The mixture was then extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0–1:1). Compound 4 was given as a yellow solid (900 mg, 3.99 mmol, 82.64% yield).

[0308] 1 H NMR (400MHz, DMSO-d6) δ8.63 (d, J = 4.5 Hz, 1H), 7.61 (d, J = 4.5 Hz, 1H), 7.36 (s, 1H), 4.40 (d, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0309] Step 4) Ethyl 5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate

[0310] Under a nitrogen atmosphere, Pd(dppf)Cl2 (145.93 mg, 199.44 μmol, 0.05 eq) was added to a mixture of compound 4 (900 mg, 3.99 mmol, 1 eq), (5-methyl-1H-indazol-4-yl)boric acid (701.95 mg, 3.99 mmol, 1 eq), and Na2CO3 (845.55 mg, 7.98 mmol, 2 eq) in dioxane (5 mL) and H2O (1 mL). The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0-0:1). Compound 5 was given as a yellow solid (450 mg, 1.40 mmol, 35.10% yield).

[0311] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),8.81-8.78(m,1H),7.71(d,J=8.5Hz,1H),7.66(s,1H),7.44(d,J=8 .5Hz,1H),7.34(d,J=4.1Hz,1H),7.31(s,1H),4.30(q,J=7.1Hz,2H),2.14(s,3H),1.27(t,J=7.1Hz,3H).

[0312] Step 5) 5-(5-methyl-1H-indazole-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

[0313] To a solution of compound 5 (450 mg, 1.40 mmol, 1 eq) in THF (5 mL) and H₂O (5 mL), LiOH·H₂O (117.53 mg, 2.80 mmol, 2 eq) was added. The mixture was stirred at 45 °C for 2 hours. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL * 2). The combined aqueous layers were treated with HCl (1 M) until pH 4, stirred until all solids precipitated, filtered, and concentrated under reduced pressure to obtain the residue. Compound 6 (330 mg, crude product) was given as a yellow solid.

[0314] 1H NMR (400MHz, DMSO-d6) δ13.51-13.06(m,1H),8.77(d,J=4.2Hz,1H),7.71(d,J=8.6Hz,1H),7 .66(d,J=0.9Hz,1H),7.43(d,J=8.7Hz,1H),7.31(d,J=4.2Hz,1H),7.24(s,1H),2.14(s,3H).

[0315] Step 6) 5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-amine

[0316] Under a nitrogen atmosphere, TEA (87.29 mg, 862.66 μmol, 120.07 μL, 1.1 eq) and DPPA (237.40 mg, 862.66 μmol, 186.93 μL, 1.1 eq) were added to a 2 mL toluene solution of compound 6 (230 mg, 784.23 μmol, 1 eq). The mixture was stirred at 110 °C for 16 h. Under a nitrogen atmosphere, H₂O (1.00 g, 55.51 mmol, 1 mL, 70.78 eq) was added to the mixture. The mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with 50 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (petroleum ether:ethyl acetate = 0:1). Compound 7 was obtained as a yellow solid (70 mg, 264.87 μmol, 33.77% yield).

[0317] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 8.32 (d, J = 4.3Hz, 1H), 7.63-7.59 (m, 2H), 7.35 (d,J=8.6Hz,1H),6.71(d,J=4.4Hz,1H),5.79(s,1H),5.71-5.63(m,2H),2.15(s,3H).

[0318] Step 7) (1S,2S)-2-fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)cyclopropane-1-carboxamide

[0319] Under a nitrogen atmosphere and at 0°C, MsCl (45.51 mg, 397.30 μmol, 30.75 μL, 1.5 eq) was added to a MeCN (2 mL) solution of compound 7 (70 mg, 264.87 μmol, 1 eq), (1S,2S)-2-fluorocyclopropanecarboxylic acid (33.08 mg, 317.84 μmol, 1.2 eq), and 3-methylpyridine (123.33 mg, 1.32 mmol, 128.95 μL, 5 eq). The mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction mixture was added dropwise to 20 mL of water and extracted with ethyl acetate (20 mL * 2). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 0:1). The residue was then purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: %-%, 10 min) and lyophilized. Example 1 (4.3 mg, 12.27 μmol, 4.63% yield, 100% purity) was obtained as a yellow solid.

[0320] 1 H NMR (400MHz, METHANOL-d4) δ8.57(d,J=4.3Hz,1H),7.66(d,J=8.6Hz,1H),7.64(d,J=2.3Hz,1H),7.44(d,J=8.8Hz,1H),7. 13(s,1H),7.04(d,J=4.3Hz,1H),4.75-4.61(m,1H),2.26(s,3H),1.98-1.90(m,1H),1.83-1.72(m,1H),1.19-1.11(m,1H).

[0321] Synthesis Method B

[0322] Example 3 (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl) Cyclopropane-1-formamide

[0323]

[0324] Step 1) N-(6-chloropyridazine-3-yl)-4-methylbenzenesulfonamide

[0325] TsCl (40.47 g, 212.28 mmol, 1.1 eq) was added to a pyridine (300 mL) solution of compound 8 (25 g, 192.98 mmol, 1 eq), and the mixture was stirred in N2 at 90 °C for 6 hours. Water (100 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was then dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under vacuum to obtain compound 9 (56.5 g, crude product) as a gray solid.

[0326] 1 H NMR (400MHz, DMSO-d6) δ 8.67-8.59 (m, 1H), 7.82-7.77 (m, 2H), 7.61-7.54 (m, 1H), 7.52-7.46 (m, 1H), 7.38 (d, J = 8.3Hz, 2H), 2.35 (s, 3H).

[0327] Step 2) (E)-2-(3-chloro-6-(toluenesulfonylimino)pyridazine-1(6H)-yl)acetamide

[0328] DIPEA (26.56 g, 205.47 mmol, 35.79 mL, 1.1 eq) and 2-bromoacetamide (28.35 g, 205.47 mmol, 1.1 eq) were added to a DMF (300 mL) solution of compound 9 (53 g, 186.79 mmol, 1 eq), and the mixture was stirred at 25 °C for 20 hours. Water (1000 mL) was added to the mixture, and the mixture was filtered. The filter cake was collected and concentrated under vacuum to give compound 10 (40 g, 117.38 mmol, 62.84% yield) as a brown solid.

[0329] 1 H NMR (400MHz, DMSO-d6) δ8.00(d,J=9.8Hz,1H),7.79(d,J=9.8Hz,1H),7.70(brd,J=7.1Hz,3H),7.38(br s,1H),7.32(br d,J=7.8Hz,2H),4.88-4.77(m,2H),2.40-2.30(m,3H).

[0330] Step 3) N-(6-chloroimidazolo[1,2-b]pyridazin-2-yl)-2,2,2-trifluoroacetamide

[0331] TFAA (258.85 g, 1.23 mol, 171.43 mL, 12 eq) was added to a DCE (250 mL) solution of compound 10 (35 g, 102.70 mmol, 1 eq), and the mixture was stirred at 60 °C for 3 hours. Water (1000 mL) was added to the mixture, and then sufficient NaHCO3 was added to adjust the pH to 8. The mixture was then filtered and the filter cake was collected. The mixture was then extracted with water (500 mL) and ethyl acetate (500 mL). The organic phase was dried with Na2SO4 and concentrated under vacuum to obtain compound 11 (21 g, 79.37 mmol, 77.28% yield) as a white solid.

[0332] 1 H NMR (400MHz, DMSO-d6) δ 12.88-12.57 (m, 1H), 8.41 (s, 1H), 8.19 (d, J = 9.4Hz, 1H), 7.43 (d, J = 9.4Hz, 1H).

[0333] Step 4) 6-Clomidazolo[1,2-b]pyridazine-2-amine

[0334] K₂CO₃ (54.85 g, 396.84 mmol, 5 eq) was added to a solution of compound 11 (21 g, 79.37 mmol, 1 eq) in MeOH (200 mL) and H₂O (200 mL), and the mixture was stirred at 75 °C for 3 hours. Water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was then dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 60 (13.5 g, crude).

[0335] 1 H NMR (400MHz, DMSO-d6) δ7.68 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 7.03 (d, J = 9.2 Hz, 1H), 5.65 (s, 2H).

[0336] Step 5)(1S,2S)-N-(6-chloroimidazolo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0337] EDCI (3.41 g, 17.80 mmol, 1.5 eq) was added to a DCM (50 mL) solution of compound 12 (2 g, 11.86 mmol, 1 eq) and (1S,2S)-2-fluorocyclopropanecarboxylic acid (1.56 g, 14.24 mmol, 1.2 eq), and the mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum to obtain a residue. Water (100 mL) was then added to the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum to give compound 13 (3.8 g, crude product) as a white solid.

[0338] 1 H NMR (400MHz, DMSO-d6) δ11.37-11.22(m,1H),8.32-8.23(m,1H),8.07(d,J=9.4Hz,1H),7.7 2-7.64(m,1H),5.07-4.80(m,1H),2.21-2.12(m,1H),1.73-1.61(m,1H),1.13-1.05(m,1H).

[0339] Step 6) (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)cyclopropane-1-carboxamide 2TFA salt.

[0340] To a solution of compound 13 (170 mg, 667.59 μmol, 1 eq), Na2CO3 (141.51 mg, 1.34 mmol, 2 eq) in dioxane (6 mL) and H2O (2 mL), (5-methyl-1H-indazol-4-yl)boronic acid (117.48 mg, 667.59 μmol, 1 eq) and Pd(dppf)Cl2 (48.85 mg, 66.76 μmol, 0.1 eq) were added, and the mixture was then stirred in N2 at 90 °C for 16 hours. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 19%-49%, 10 min) to obtain Example 3 (56.8 mg, 93.88 μmol, 14.06% yield, 95.6% purity, 2 TFA) as a pale yellow solid.

[0341] 1H NMR (400MHz, DMSO-d6) δ11.27(s,1H),8.31(s,1H),8.10(d,J=9.3Hz,1H),7.84(d,J=0.9Hz,1H),7.58(d,J=8.4Hz,1H), 7.38(dd,J=8.9,16.1Hz,2H),5.08-4.82(m,1H),2.38(s,3H),2.23-2.14(m,1H),1.77-1.62(m,1H),1.23-1.12(m,1H).

[0342] Synthesis method C

[0343] Example 24 ( 1S ,2S)-2-fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- 2TFA salt of cyclopropaneformamide.

[0344]

[0345] Step 1)(1S,2S)-N-(6-bromoimidazolo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropanecarboxamide

[0346] T3P (2.99 g, 9.39 mmol, 2.79 mL, 2 eq) and DIPEA (1.42 g, 11.03 mmol, 1.92 mL, 2.35 eq) were added to a solution of (1S,2S)-2-fluorocyclopropanecarboxylic acid (537.41 mg, 5.16 mmol, 1.1 eq) and compound 14 (1 g, 4.69 mmol, 1 eq) in NMP (20 mL). The reaction mixture was stirred at 25 °C for 16 h. Water (15 mL) was added, and the aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2) and concentrated under vacuum. The crude product was purified by reverse flash evaporation (MeCN / H2O, 0.05% TFA) to give compound 15 (750 mg, 2.51 mmol, 53.42% yield) as a pale yellow solid.

[0347] 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),8.93(d,J=1.2Hz,1H),8.75(s,1H),8.29(s,1H),5. 17-4.76(m,1H),2.23-2.11(m,1H),1.67(tdd,J=3.3,6.9,19.9Hz,1H),1.25-1.13(m,1H).

[0348] Step 2) (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide 2TFA salt.

[0349] Under N2, Pd(dppf)Cl2 (12.23 mg, 16.72 μmol, 0.05 eq), compound 15 (100 mg, 334.34 μmol, 1 eq), and Na2CO3 (70.87 mg, 668.67 μmol, 2 eq) were added to a solution of (5-methyl-1H-indazol-4-yl)boric acid (58.84 mg, 334.34 μmol, 1 eq) in dioxane / H2O (3 mL). The mixture was stirred at 90 °C for 3 hours. Water (10 mL) was added and the aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2) and concentrated under vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 13%-43%, 10 min) to obtain Example 24 (38.2 mg, 62.74 μmol, 18.77% yield, 95% purity, 2 TFA) as a pale yellow solid.

[0350] 1 H NMR (400MHz, DMSO-d6) δ11.48-11.28(m,1H),9.06(s,1H),8.83(d,J=1.3Hz,1H),8.36(s,1H),7.91(d,J=0.9Hz,1H),7.52(d,J=8 .3Hz,1H),7.33(d,J=8.6Hz,1H),5.15-4.79(m,1H),2.43-2.35(m,3H),2.26-2.14(m,1H),1.78-1.62(m,1H),1.37-1.06(m,1H).

[0351] Synthesis method D

[0352] Example 25 (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- 2 TFA salt of 2-fluorocyclopropaneformamide.

[0353]

[0354] Step 1)(1S,2S)-2-fluoro-N-(6-(tributyltinyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropaneformamide.

[0355] Under N2, Pd(PPh3)4 (38.63 mg, 33.43 μmol, 0.05 eq) and TBAI (246.99 mg, 668.67 μmol, 1 eq) were added to a solution of tributyl(tributyltinyl)stanane (1.16 g, 2.01 mmol, 1.00 mL, 3 eq) and dioxane (3 mL) of compound 16 (200 mg, 668.67 μmol, 1 eq). The reaction mixture was stirred at 110 °C for 32 h. The reaction mixture was filtered and the filtrate was concentrated to give the product. The crude product was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to give compound 17 (130 mg, 255.28 μmol, 38.18% yield) as a white solid.

[0356] Step 2) (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropaneformamide 2TFA salt.

[0357] Under N2, Ad2n-BuP-Pd-G3 (11.98 mg, 16.46 μmol, 0.1 eq) was added to a solution of 4-bromo-5-ethyl-6-fluoro-1H-indazole (40 mg, 164.56 μmol, 1 eq) and compound 17 (92.18 mg, 181.01 μmol, 1.1 eq) in EtOH (2 mL). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 24%-54%, 10 min) to give Example 25 (10 mg, 16.22 μmol, 9.86% yield, 99% purity, 2 TFA) as a white solid.

[0358] 1 H NMR(400MHz METHANOL-d4)δ8.99(s,1H),8.71(s,1H),8.42(s,1H),7.83(s,1H),7.36(d,J=10.4Hz,1H),5.00-4.97 (m,1H),2.76-2.72(m,2H),2.16-2.15(m,1H),1.86-1.79(m,1H),1.26-1.24(m,1H),1.19-1.16(m,3H).

[0359] Synthesis Method E

[0360] Example 61 (1S, 2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0361]

[0362] To a solution of compound 17 (456 mg, 0.896 mmol, 1.3 eq) and intermediate 1E (269 mg, 0.689 mmol) in EtOH (3.44 mL), Ad2nBuP-Pd-G3 (50 mg, 0.0689 mmol, 0.1 eq) was added. The mixture was degassed and purged three times with N2, then stirred at 90 °C for 16 hours under N2 atmosphere. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (the product appears in ethyl acetate) to provide Example 61 (86 mg, 0.162 mmol, 24% yield) as a yellow solid.

[0363] Synthesis method F

[0364] Implementation Example 64 (1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine (2-azine-2-yl)-2-fluorocyclopropane-1-carboxamide

[0365]

[0366] Step 1) 4-Bromo-5-chloro-6-fluoro-7-(prop-1-en-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

[0367] Under a nitrogen atmosphere, Na₂CO₃ (922.69 mg, 8.71 mmol, 2 eq) and Pd(dppf)Cl₂ (159.25 mg, 217.64 μmol, 0.05 eq) were added to a solution of intermediate 1B (2 g, 4.35 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoborane (877.73 mg, 5.22 mmol, 1.2 eq) in dioxane (0.4 mL) and H₂O (0.1 mL). The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with 100 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0-20:1). Compound 18 (870 mg, 2.33 mmol, 53.49% yield) was given as a yellow oil.

[0368] Step 2) 4-Bromo-5-chloro-6-fluoro-7-isopropyl-1H-indazole

[0369] Under N2, PtO2 (40.00 mg, 176.15 μmol, 1.65 e⁻¹ eq) was added to a MeOH (0.5 mL) solution of compound 18 (400 mg, 1.07 mmol, 1 eq). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25 °C for 1 hour under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0–4:1). Compound 19 (240 mg, 823.19 μmol, 76.90% yield) was given as a yellow solid.

[0370] 1 H NMR (400MHz, DMSO-d6) δ13.73 (br s, 1H), 8.09 (s, 1H), 3.59-3.49 (m, 1H), 1.39 (d, J = 6.9Hz, 6H).

[0371] Step 3)(1S,2S)-N-(6-(5-chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

[0372] Under a nitrogen atmosphere, Ad2nBuP-Pd-G3 (17.49 mg, 24.01 μmol, 0.1 eq) was added to a solution of compound 19 (70 mg, 240.10 μmol, 1 eq) and compound 17 (134.50 mg, 264.11 μmol, 1.1 eq) in EtOH (1 mL). The mixture was stirred at 80 °C for 12 hours under a nitrogen atmosphere. 5 mL of saturated KF aqueous solution was added to quench the reaction mixture. The mixture was dissolved in water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-60%, 10 min) and lyophilized. Example 64 (15 mg, 34.12 μmol, 14.21% yield, 98% purity) was obtained as a white solid.

[0373] 1¹H NMR (400MHz, DMSO-d⁶) δ 13.52 (br s, 1H), 11.40 (s, 1H), 9.14–8.87 (m, 2H), 8.38 (s, 1H), 8.04 (br s, 1H), 5.17–4.75 (m, 1H), 3.66–3.59 (m, 1H), 2.19 (td, J = 7.0, 13.6 Hz, 1H), 1.75–1.62 (m, 1H), 1.45 (br d, J = 7.0 Hz, 6H), 1.20 (tdd, J = 6.3, 8.9, 12.3 Hz, 1H); LCMS (electrospray) m / z 431.2 (M+H+).

[0374] Table 1 below shows the compounds of the examples, as well as the general synthetic methods and characterization data used to prepare the compounds.

[0375] Table 1. Compounds from the Examples

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[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] Evaluation of compounds

[0444] HPK1 kinase assay

[0445] Through Promega's ADP-Glo TM HPK1 kinase activity was measured using a kinase assay. In this assay, 5 ng of recombinant human HPK1 (signalchem) was incubated with 5 μL of the compound (0.5% DMSO), 5 μL of MBP (0.5 μg / μl), and 5 μL of ATP (25 μM) buffer (40 mM Tris, 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 μM DTT). The assay was initiated by incubating the reaction mixture in a 96-well plate at 30 °C for 40 min. After incubation, 25 μL of ADP-Glo ​​reagent was added, and the plate was incubated at room temperature for 40 min to stop the reaction and degrade residual ATP. The ADP product was then converted to ATP by adding 50 μL of the assay reagent to each well. Cold light was detected after incubation at room temperature for 30 min using a Molecular device I3X plate reader. The IC50 was calculated from a series of inhibition percentage values ​​determined within the inhibitor concentration range using software programs executed in GraphPad Prism 7 and SigmaPlot 13.0. 50 value.

[0446] Table 2 shows the IC50 of the compounds of the present invention. 50 The values ​​are denoted as follows: + indicates >1000nM, ++ indicates 501-1000nM, +++ indicates 101-500nM, and ++++ indicates <100nM.

[0447] Table 2. In vitro activity based on HPK1 data

[0448]

[0449]

[0450]

[0451] Analysis of IFNγ and IL-2 in human peripheral pan-T cells

[0452] 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 4T cells were seeded in 96-well plates and cultured for 1 hour with different concentrations of the compound and 100 nM prostaglandin E2. T cells were stimulated with Dynabeads human T-activator CD3 / CD28 (Life Technologies) at a cell:bead ratio of 1:3. Cytokine secretion was measured 24 hours post-stimulation using the MSD V-PLEX Human Cytokine Kit, as recommended by the manufacturer. Data were analyzed using a MESO Quickplex SQ120 (Mesoscale Discovery).

[0453] In Table 3, the value + indicates >1000nM, ++ indicates 200-1000nM, +++ indicates <200nM and – indicates unmeasured.

[0454] Table 3. IFNγ and IL-2 secretion by the compounds of the present invention in human peripheral blood pan-T cells.

[0455]

[0456]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: Compound 2: Compound 3: Compound 4: Compound 5: Compound 6: Compound 7: Compound 8: Compound 9: Compound 10: Compound 12: Compound 13: Compound 14: Compound 15: Compound 16: Compound 17: Compound 18: Compound 19: Compound 20: Compound 21: Compound 22: Compound 23: Compound 25: Compound 26: Compound 27: Compound 28: Compound 29: Compound 30: Compound 31: Compound 32: Compound 33: Compound 34: Compound 35: Compound 36: Compound 37: Compound 38: Compound 39: Compound 40: Compound 41: Compound 42: Compound 43: Compound 44: Compound 45: Compound 46: Compound 47: Compound 48: Compound 49: Compound 50: Compound 51: Compound 52: Compound 53: Compound 54: Compound 55: Compound 56: Compound 57: Compound 58: Compound 59: Compound 60: 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 121: Compound 122: Compound 123: Compound 124: Compound 125: Compound 126: Compound 127: Compound 128: Compound 129: Compound 130: Compound 131: Compound 132: Compound 133: Compound 134: Compound 136: Compound 138: Compound 139: Compound 140: Compound 141: Compound 142: Compound 143: Compound 144: Compound 145: Compound 146: Compound 147: Compound 148: Compound 149: Compound 150: Compound 151: 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 164: Compound 165: Compound 166: Compound 167: Compound 168: Compound 169: Compound 170: Compound 171: Compound 172: Compound 173: Compound 174: Compound 175: Compound 176: Compound 177: Compound 178: Compound 179: Compound 180: Compound 181: Compound 182: Compound 183: Compound 184: Compound 185: Compound 186: Compound 187: Compound 188: 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 201: Compound 202: Compound 203: Compound 204: Compound 205: Compound 206: Compound 207: Compound 208: Compound 209: Compound 210: Compound 211: Compound 212: Compound 213: Compound 214: Compound 215: Compound 216: Compound 217: Compound 218: Compound 219: Compound 220: Compound 221: Compound 222: Compound 223: Compound 224: Compound 225: Compound 226: Compound 227: Compound 228: Compound 229: Compound 230: Compound 231: Compound 232: Compound 233: Compound 234: Compound 235: Compound 236: Compound 237: Compound 238: Compound 239: Compound 240: Compound 241: Compound 242: Compound 243: Compound 244: Compound 245: Compound 246: Compound 247: Compound 248: Compound 249: Compound 250: Compound 251: Compound 252: Compound 253: Compound 254: Compound 255: Compound 256: Compound 257: Compound 258: Compound 259: 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 282: Compound 283: Compound 284: Compound 285: Compound 286: Compound 287: Compound 288: Compound 289: 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:

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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