Heteroaryl compounds as HPK1 inhibitors and methods of use thereof

Abstract

The present invention provides heteroaryl compounds of formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof, as HPK1 inhibitors, and methods of use thereof. # imgabs0 #

Description

[0001] Citation of Related Applications

[0002] This application claims priority to U.S. application No. 63 / 299,000 filed on January 12, 2022, International Application No. PCT / CN2022 / 112996 filed on August 17, 2022, and U.S. application No. 63 / 418,888 filed on October 24, 2022, the entire contents of which are incorporated herein by reference in their entirety. Background of the Invention

[0004] Progenitor cell kinase 1 (HPK1) is mainly expressed in hematopoietic cells and acts as a negative regulator in T cells and dendritic cells (DCs). Elimination of the kinase activity of HPK1 by genetic knockout of the kinase dead (KD) enzyme confirmed its involvement in anti-tumor immune responses (Hernandes et al., US2016 / 0158360). Mechanistically, HPK1 KD reduces phosphorylation of the downstream protein SLP76 in T cells and thereby increases the release of pro-immune cytokines IL-2 and IFNγ upon anti-CD3 and anti-CD28 stimulation. In a sarcoma model of mice expressing the KD enzyme, an increase in tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) and a decrease in tumor growth were observed (Liuet al., PLoS ONE 14(3): e0212670). In addition, in multiple cancer models, small molecule HPK1 inhibitors have shown anti-tumor activity as single agents or in combination with anti-PD1 antibodies (Chen et al., AACR Annual Meeting, June 2020, Poster 4513) or with anti-CTLA-4 antibodies (Ciccone et al., AACR Annual Meeting, June 2020, Poster 942).

[0005] HPK1 KD T cells have been shown to be resistant to immunosuppression produced by PGE2 and adenosine, supporting the study of synergistic anticancer effects with compounds that inhibit PGE2 and adenosine pathways. For example, the combination of HPK1 inhibitors with EP4 or A2a / b inhibitors may show excellent therapeutic benefits for cancer treatment (Liu et al., PLoS ONE 14(3):e0212670).

[0006] Given the role of HPK1 in regulating activity in immune cells, small molecule inhibitors could be used as single agents or in combination with existing immunotherapies, targeted therapies, or compounds that inhibit PGE2 or adenosine pathways for the treatment of cancer. SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0009]

[0010] in

[0011] R 1 is H, alkyl, cycloalkyl or substituted alkyl;

[0012] Ring A is a 5-membered or 6-membered aryl or heteroaryl group; wherein the 5-membered or 6-membered aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halogen or haloalkyl; wherein the 5-membered or 6-membered heteroaryl group has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms, each of which is independently N, O or S; the ring-forming N atom is optionally substituted by oxo to form N + _O - ; wherein the ring-forming carbon atoms of the 5- or 6-membered aryl or heteroaryl are optionally substituted with oxo to form a carbonyl group;

[0013] Ring B is a 5-membered or 6-membered monocyclic aryl or heteroaryl group, or an 8-membered to 12-membered fused bicyclic aryl or heteroaryl group; wherein the monocyclic aryl group or the fused bicyclic aryl or heteroaryl group is optionally substituted by 1-5 substituents, each of which is independently alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkyl-S(═O) 2 -alkyl, cyano, hydroxyalkylamino, amido, amino, alkylamino, -NR 10 R 11 , cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or polycyclic alkyl; wherein each substituent is optionally further substituted; wherein the ring-forming carbon atoms of the cycloalkyl or heterocycloalkyl are optionally substituted with oxo to form a carbonyl; wherein R 10 and R 11 each independently selected from H, alkyl, halogen, haloalkyl, cycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl or heterocycloalkyl, each of which is optionally further substituted;

[0014] Ring C is a 5- or 6-membered aryl or heteroaryl group, optionally substituted with one or more substituents each independently selected from alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkylamino, cyano, cycloalkyl, alkylcycloalkyl or heterocycloalkyl;

[0015] The heteroaryl groups each have at least one ring carbon atom and 1, 2 or 3 ring heteroatoms independently selected from N, O or S.

[0016] In certain embodiments, R 1 For H.

[0017] In certain embodiments, Ring A is

[0018]

[0019] Where R 2 is H, alkyl, halogen or haloalkyl. In certain preferred embodiments, R 2 is a halogen (eg, F).

[0020] In certain embodiments, Ring B in Formula (I) is

[0021]

[0022] Where R 3 is H, halogen, haloalkyl or alkyl; preferably, R 3 is H or halogen (e.g. F);

[0023] R 4 is cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, polycyclic alkyl, or -NR 10 R 11 ; wherein each substituent is optionally further substituted by one or more substituents; wherein R 10 and R 11 Each is independently selected from H, alkyl, halogen, haloalkyl, cycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl or heterocycloalkyl;

[0024] Each R 5 are independently H, alkyl, CD 3 , alkylthioalkyl, alkyl-S(=O) 2 -alkyl, cyano, amino, hydroxy, hydroxyalkyl, hydroxyalkylamino, amido, alkylamino, halogen, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spirocycloalkyl, polycycloalkyl, aryl or heteroaryl, wherein each substituent is optionally further substituted; wherein any hydrogen of the alkyl group can be optionally replaced by D; and

[0025] R 6 is H, halogen, haloalkyl or alkyl.

[0026] In certain embodiments, R 3 It is H or F.

[0027] In certain embodiments, R 6 It is H or F.

[0028] In certain embodiments, R 4 is cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or polycycloalkyl, each of which is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, alkyl, amino, alkylamino, dialkylamino, alkylamino, alkoxy, alkoxyalkyl, -NH-C(=O)-(CH 2 ) n -NH 2 , amido, cycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl or heterocycloalkyl; n is 0, 1, 2 or 3.

[0029] In certain embodiments, ring C in formula (I) is phenyl substituted by one or more substituents, each of which is independently -F, -Cl or alkoxy. In certain preferred embodiments, alkoxy is -O-CH 3 .

[0030] Specific examples of ring C in formula (I) are

[0031]

[0032] In certain embodiments, the compound has Formula (Ia) or Formula (Ib), or a stereoisomer or pharmaceutically acceptable salt thereof,

[0033]

[0034] Wherein ring A is

[0035]

[0036] and ring A is optionally further substituted with one or more R 2 replace;

[0037] X 1 , X 2 , X 3 and X 4 are each independently a carbon atom (C) or N, and are optionally replaced by R 2 replace;

[0038] R 2 is H, alkyl, halogen or haloalkyl;

[0039] Each R cis independently alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkylamino, cyano, cycloalkyl, alkylcycloalkyl, or heterocycloalkyl;

[0040] m is 0, 1, 2, 3, or 4;

[0041] X, Y and Z are each independently a carbon atom or a heteroatom selected from N or S;

[0042] Dashed bonds represent single or double bonds required to complete the valence of the atoms connected by the bond;

[0043] R 3 , R 4 , R 5 and R 6 Same as described above.

[0044] Examples of compounds of formula (I) include:

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] In certain embodiments, examples of compounds of Formula (I) include:

[0063]

[0064]

[0065]

[0066] Another aspect of the present invention includes a pharmaceutical composition, each of which comprises the compound and a pharmaceutically acceptable carrier or excipient. Such a pharmaceutical composition may include a second therapeutic agent, which may be an inhibitor such as an immune checkpoint inhibitor or PGE2 or adenosine pathway. Examples of suitable immune checkpoint inhibitors include ipilimumab, nivolumab and pembrolizumab.

[0067] Another aspect of the present invention provides a method for treating a condition mediated by HPK1 in an individual in need thereof. The method comprises administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition as described above. In certain embodiments, the condition is cancer. Cancers that can be treated (including reducing the likelihood of recurrence) by the methods of the present teachings include breast cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, prostate cancer, leukemia, lymphoma, brain cancer (including glioblastoma multiforme and neuroblastoma), head and neck cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, renal cancer, and soft tissue sarcoma.

[0068] definition

[0069] Unless the context indicates otherwise, references to formula (I) in all parts of this document (including uses, methods and other aspects of the invention) include references to all other subformulae, subgroups, preferences, embodiments and examples as defined herein.

[0070] Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below:

[0071] As used herein, the term "unsaturated" or "partially unsaturated" refers to a moiety containing at least one double or triple bond.

[0072] As used herein, the term "saturated" refers to a moiety that contains no double or triple bonds, ie, the moiety contains only single bonds.

[0073] As used herein, the term "alkyl" refers to a saturated straight chain (i.e., unbranched) or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having the stated number of carbon atoms (e.g., C 1 -C 10 or C1-10 Alkyl). Whenever it appears in this document, a numerical range such as "1 to 10" refers to each integer in the given range, for example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also covers the occurrence of the term "alkyl" in which no numerical range is specified. Examples include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl. Representative saturated straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc.; saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc.

[0074] As used herein, the term "substituted alkyl" refers to an alkyl group substituted with one or more substituents. Examples of substituents include, but are not limited to, halogen, hydroxy, cyano, amino, alkoxy, alkoxyalkyl, haloalkyl, alkoxy, amino, methylamino, dimethylamino, sulfone, sulfonamide, aryl, heteroaryl, heterocyclyl, trifluoroethyl, hydroxyethyl, cyanoethyl, methoxyethyl, and trifluoropropyl.

[0075] The term "alkylene" by itself or as part of another molecule refers to a divalent group derived from an alkane, which may be straight or branched. 1-4 , C 1-7 , C 1-20 , C 2-7 , C 3-7 , etc.) represents the number of carbon atoms or the range of the number of carbon atoms. For example, as used herein, the term "C 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0076] As used herein, the term "alkoxy" or "alkoxy" refers to a saturated straight or branched hydrocarbon attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc., preferably methoxy, ethoxy, propoxy or 2-propoxy. Representative saturated straight-chain alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, etc.; saturated branched alkoxy groups include isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, isopentyloxy, etc. Cycloalkoxy is referred to herein as "cycloalkoxy". "C 1-4 "Alkoxy" refers to an alkyl group having 1, 2, 3 or 4 carbon atoms. The alkoxy group can be attached to the molecule through one or two points of attachment.

[0077] The term "alkoxyalkyl" as used herein refers to an alkyl group substituted with one, two, or three alkoxy groups.

[0078] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain hydrocarbon. Examples include ethenyl and propenyl. The alkenyl group may also be substituted with one or more alkyl groups.

[0079] As used herein, the term "alkyl" (e.g., as a prefix in alkoxyalkyl and alkylthioalkyl) refers to a non-cyclic hydrocarbon group of an alkyl, alkenyl or alkynyl group. Unless otherwise indicated, the term "alkyl" includes "alkyl", "alkenyl" and "alkynyl".

[0080] As used herein, the term "carbonyl" refers to -C(=O)-.

[0081] As used herein, the term "cycloalkyl" by itself or as part of another substituent refers to a non-aromatic carbocyclic ring consisting of at least three carbon atoms. The term cycloalkyl includes monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, fused cycloalkyl, and spirocycloalkyl. In bridged cycloalkyl, the rings share at least two common non-adjacent atoms. In fused bicyclic cycloalkyl, two rings share a covalent bond. In spirocycloalkyl, one atom is common to two different rings.

[0082] The term "heterocycloalkyl" is a type of cycloalkyl as defined above, and is included within the meaning of the term "cycloalkyl" in which at least one of the carbon atoms of the ring is replaced by a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus. Cycloalkyl and heterocycloalkyl groups may be substituted or unsubstituted.

[0083] The term "polycycloalkyl" refers to a cycloalkyl group having multiple rings fused together.

[0084] As used herein, the term "halo" or "halogen" refers to fluorine (F, -F), chlorine (Cl, -Cl), bromine (Br, -Br) or iodine (I, -I). "Haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms have been replaced by a halogen independently selected from fluorine, chlorine, bromine and iodine. "Fluoroalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms have been replaced by a fluorine atom. Unless otherwise indicated, a haloalkyl group may include as many chemically possible halogen atoms as there are substituents on the alkyl group. For example, a fluoroethyl group may be -CH 2 CF 3 、-CHF-CH 3 or -CH 2 CH 2 F.

[0085] As used herein, the term "hydrogen" (or H) includes its deuterium (D or 2H) and tritium (3H) isotopes, meaning that a hydrogen atom or any hydrogen atom in the compounds of the present invention may be replaced by deuterium (D or 2H) and tritium (3H).

[0086] As used herein, the term "hydroxy" or "hydroxyl" refers to the group -OH.

[0087] The term "hydroxyalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more hydrogen atoms are replaced with a hydroxy substituent. Thus, the term "hydroxyalkyl" includes monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and the like.

[0088] As used herein, the term "cyano" refers to a -C≡N group. As used herein, the term "cyanoalkyl" refers to an alkyl group having at least one -CN substituent.

[0089] As used herein, the term "carbonyl" refers to a -C(=O)- group.

[0090] As used herein, the term "amino" or "amine" refers to -NH 2 The term "alkylamino" refers to a radical of the formula -NHR, and "dialkylamino" refers to a radical of the formula -NRR, wherein each R is independently alkyl.

[0091] The term "amido" or "amide" refers to a C-amido group, such as -C(=O)NR'R", or an N-amido group, such as -NR'C(=O)R", where R' or R" is a substituent group. Examples of R' and R" include, but are not limited to, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, hydroxyalkylamino, amino, alkylamino, cycloalkyl, alkylcycloalkyl, aryl, alkaryl, heterocycloalkyl, alkheterocycloalkyl, heteroaryl, and alkheteroaryl.

[0092] As used herein, the term "nitro" refers to -NO 2 .

[0093] As used herein, the term "alkylthioalkyl" or "alkylthioalkyl" refers to the group -alkyl-S-alkyl, where "alkyl (alk)" is alkylene. Typically, if a compound is attached to an "alkylthioalkyl" group, the alkylene portion of the "alkylthioalkyl" group is attached to the compound.

[0094] As used herein, the term "alkyl-S(=O) 2 -alkyl" or "alkyl-S(=O) 2 "-alkyl" refers to the group -alkyl-S(=O) 2 -alkyl, wherein "alk" is alkylene.

[0095] The term "alkylamino" as used herein refers to an amino group as described herein that is attached to an alkylene group. Typically, if a compound is attached to an alkylamino group, the alkylene portion of the alkylamino group is attached to the compound.

[0096] The term "alkyl-cycloalkyl" refers to a cycloalkyl group attached to an alkylene group. Typically, if a compound is attached to an alkanecycloalkyl group, the alkylene portion of the alkanecycloalkyl group is attached to the compound.

[0097] As used herein, the term "aromatic compound" or "aromatic ring" or similar terms refers to a planar ring with a delocalized π electron system containing 4n+2 π electrons, where n is a positive integer. The aromatic ring can be formed by five, six, seven, eight, nine, ten or more than ten atoms. Aromatic compounds are optionally substituted. The term "aromatic" includes carbocyclic aromatic groups ("aryls", such as phenyl) and "heteroaryl" (or "heteroaromatic") groups (such as pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0098] Dashed bonds represent single or double bonds, as required to complete the valence of the atoms connected by the bond. It will be understood that in some cases the bond has aromatic character.

[0099] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group of 6 to 12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aryl are phenyl, naphthyl, and anthracenyl.

[0100] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring (i.e., a ring that shares adjacent pairs of atoms) of 5 to 12 ring atoms, containing one, two, three or four heteroatoms selected from N, O or S, the remaining ring atoms being C, and otherwise having a completely conjugated π electron system. Non-limiting examples of unsubstituted heteroaryl are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzothiazole, indazole and quinazoline. Heteroaryl can be substituted or unsubstituted.

[0101] The groups defined above may include prefixes and / or suffixes that are commonly used in the art to produce additional recognized substituents. As an example, the term "haloalkoxy" or "haloalkoxy" refers to a haloalkyl group attached to the parent molecular moiety via an oxygen atom. The term "(haloalkyl)oxyalkyl" refers to an alkyl group substituted with one, two, or three (haloalkyl)oxy groups. As another example, the term "hydroxyalkylamino" refers to an amino group substituted with one or two hydroxyalkyl groups.

[0102] Stereoisomers are compounds that differ only in their arrangement in space. When a disclosed compound is named or depicted by a structure without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, geometric isomers, including substantially pure stereoisomers or geometric isomers and combinations thereof.

[0103] Combinations of substituents are permissible only if such combinations result in stable or chemically feasible compounds (ie, compounds that are not substantially altered when kept at 40°C or less for at least a week).

[0104] The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can but need not be present, and that the description includes instances where heterocyclyl is substituted with alkyl and instances where heterocyclyl is not substituted with alkyl.

[0105] "Pharmaceutically acceptable salts" prepared by acid addition are salts formed from acids which then form non-toxic acid anions, such as hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate. It should be understood that, as used herein, references to compounds of formula (I) also include pharmaceutically acceptable salts.

[0106] When the compound of the present invention has a carboxyl group, it can be reacted with a corresponding alcohol (e.g., C 1-6 Pharmaceutically acceptable esters can be prepared by reaction with 2-(4-(2-hydroxy-1-piperidin-2-yl)-2-ol.

[0107] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts or prodrugs with other chemical components (such as pharmaceutically acceptable excipients). The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0108] The term "pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0109] The term "therapeutically effective amount" refers to an amount of a compound administered that will alleviate to some extent one or more of the symptoms of the condition being treated. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reduces the size of a tumor; (2) inhibits tumor metastasis; (3) inhibits tumor growth; and / or (4) alleviates one or more symptoms associated with cancer.

[0110] As used herein, the terms "subject" or "patient" are used interchangeably and as used herein refer to any mammal, including but not limited to humans, including human patients or individuals to whom the compositions of the present invention can be administered. The term "mammal" includes human subjects and non-human primates, as well as experimental animals such as rabbits, rats and mice, and other animals.

[0111] As will be appreciated by those skilled in the art, the compounds taught herein can be given to patients in a variety of forms, depending on the route of administration selected. The compounds taught herein can be administered, for example, by oral, parenteral, oral, sublingual, nasal, rectal, patch, pump or transdermal administration, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical administration. Parenteral administration can be performed by continuous infusion over a selected time period.

[0112] Isomeric forms

[0113] The present invention provides compounds of formula (I) or pharmaceutically acceptable salts, esters or prodrugs thereof useful as HPK1 inhibitors and methods of using the same.

[0114]

[0115] Certain compounds of formula (I) (or salts, prodrugs or conjugates) may exist in isomeric forms and be separated in isomeric forms, including tautomeric forms, geometric isomers (i.e., cis or trans isomers), optical isomers (i.e., enantiomers and diastereomers), racemic forms, or any mixture of the above isomeric forms. It should be understood that the present invention includes compounds of formula (I) in any isomeric form or mixture thereof, such as active single enantiomers, racemic compounds, or any mixture thereof. The present invention is intended to include all such isomeric forms of compounds of formula (I).

[0116] Furthermore, the compounds of formula (I) (or their salts, prodrugs or conjugates) may exhibit polymorphism or may form solvates with water or organic solvents. The present invention also includes any such polymorphic forms, any solvates or any mixtures thereof.

[0117] Example 1: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0118]

[0119] plan

[0120]

[0121] Step 1: (1S,4S)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0122] At 60°C, 1,4-difluoro-2-nitrobenzene (0.85 g, 5.4 mmol, 1.00 eq), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 5.4 mmol, 1.00 eq), Et 3 The mixture was stirred in ACN (15 mL) solution of N (1 mL) for 10 h. TLC showed that the reaction was complete. The mixture was poured into 100 mL of water and extracted with 100 mL of EA (twice). The organic layer was washed with Na 2 SO 4 Drying and concentration to dryness in vacuo gave tert-butyl (1S,4S)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g).

[0123] LC-MS m / z: 338.3 (M+1) +

[0124] Step 2: (1S,4S)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0125] Pd / C 0.25 g was added to a solution of 2.5 g of tert-butyl (1S, 4S)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate in 30 mL of MeOH under hydrogen for 15 h. LCMS showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give tert-butyl (1S, 4S)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (1.32 g) as a white solid.

[0126] LC-MS m / z: 308.2 (M+1) +

[0127] Step 3: N-(2-((1S, 4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0128] To a solution of (1S,4S)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (95 mg, 0.36 mmol, 1.00 equiv) and DCM 5 mL was added 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (111 mg, 0.36 mmol, 1.00 equiv) and HATU (274 mg, 0.72 mmol, 2.00 equiv). Stir at room temperature (RT) for 4 hours. LCMS showed the target compound MS and the reaction was complete. The mixture was poured into 30 mL of water and extracted with EA 30 mL×2. The organic layer was purified by Na 2 SO 4 The residue was purified by column chromatography (EA:PE=1:1) to give 58 mg of a white solid, to which CF 3 COOH 1 mL and DCM 1 mL, stirred at room temperature for 2 h, concentrated to dryness in vacuo to give Example 1 (30 mg) as a white solid.

[0129] LC-MS m / z:455.6(M+1) +

[0130] 1 H NMR (400 MHz, CDCl 3 )δ10.05(s,1H),9.72(dd,J=29.5,13.0Hz,1H),8.79(d,J=4.9Hz,1H),8.46–8.34(m, 1H),8.15–8.04(m,1H),7.72–7.58(m,1H),7.50–7.39(m,1H),6.97–6.81(m,3H),4.33 (s,1H),3.87(s,1H),3.84(s,3H),3.78(dd,J=11.5,5.1Hz,1H),3.56(d,J=10.3Hz,1H ),3.43(t,J=10.7Hz,1H),3.13(s,1H),2.36(d,J=10.9Hz,1H),2.20(t,J=9.7Hz,1H).

[0131]

[0132]

[0133] Example 3: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxamide

[0134]

[0135] plan

[0136]

[0137] Step 1: 2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxylic acid

[0138] At 100°C, 3-bromo-2-fluorobenzoic acid (500 mg 2.27 mmol 1.00 equivalent), (2-fluoro-6-methoxyphenyl)boronic acid (772 mg 4.54 mmol 2.00 equivalent), Pd(PPh 3 ) 4 (127mg0.11mmol0.05equiv), K 2 CO 3 A mixture of (941 mg 6.81 mmol 3.00 equivalents), 1,4-dioxane 5 mL, EtOH 5 mL and water 1 mL was stirred in a microwave for 2 hours. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was poured into water 40 mL and AcOH 2 mL and extracted with EA 40 mL × 2. The organic layer was washed with MgSO 4 The mixture was dried and concentrated to dryness in vacuo. The residue was purified by column chromatography (EA:MeOH=3:1) to give 2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (135 mg, yield 23%) as a white solid.

[0139] LC-MS m / z: 263.2 (M-1) -

[0140] Step 2: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxamide

[0141] To a 10 mL toluene solution of 2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (50 mg, 0.19 mmol, 1.00 eq) was added SOCl 2 2 mL, stirred at 80 ° C for 2 h, and then concentrated to dryness in vacuo. DCM 5 mL, Et 3N 2mL and (1R, 4R) -5- (2-amino-4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (58mg 0.19mol 1.1 equivalents) were stirred at room temperature for 3h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was poured into 30mL of water and extracted with EA 30mL × 2. The organic layer was washed with Na 2 SO 4 The residue was purified by column chromatography (EA:PE=1:1) to give 30 mg of a white solid, and then CF 3 COOH and DCM, stirred at room temperature for 2 h, concentrated to dryness in vacuo, then added ammonium hydroxide 3 mL and water 10 mL, extracted with EA 10 mL, concentrated to dryness in vacuo to give Example 3 (7 mg, yield: 8%) as a white solid.

[0142] LC-MS m / z:454.5(M+1) +

[0143] 1 H NMR (400 MHz, CDCl 3 )δ9.79(dd,J=31.1,14.7Hz,1H),8.60(s,1H),8.41(ddd,J=10.6,7.8,2.9Hz,1H),8.31 –8.13(m,1H),7.63–7.54(m,1H),7.50(ddd,J=8.6,5.3,3.1Hz,1H),7.45–7.36(m,2H),6 .95–6.79(m,3H),4.13(s,1H),3.83(s,3H),3.81(s,1H),3.65(dd,J=10.6,3.5Hz,1H),3 .45–3.30(m,2H),3.01(d,J=10.9Hz,1H),2.24(d,J=10.3Hz,1H),2.05(t,J=9.9Hz,1H).

[0144] Example 4: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamide

[0145]

[0146] plan

[0147]

[0148] Step 1: (1R,4R)-5-(2-(2-bromo-3-fluoroisonicotinylamino)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0149] To 2-bromo-3-fluoroisonicotinic acid (429.45 mg, 1.95 mmol, 1.0 eq) in DCM (10 mL) was added HATU (1.11 g, 2.93 mmol, 1.5 eq) and DIEA (504 mg, 3.90 mmol, 2.0 eq). It was stirred at 26 °C for 30 min, then tert-butyl (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (600 mg, 1.9 5mmol, 1.0 equivalent). The reactant was stirred at 26 ° C overnight to give a brown solution. LCMS showed one of the main peaks with the desired mass, and the material was almost consumed. The reactant was washed with water and extracted with DCM. The organic phase was concentrated to dryness under reduced pressure to give the compound (1R, 4R)-5-(2-(2-bromo-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.71 g, yield: 71.4%) as a dark brown oily liquid.

[0150] LC-MS m / z: 509.1 (M+1) +

[0151] Step 2: (1R,4R)-5-(2-(2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0152] To a suspension of (1R,4R)-5-(2-(2-bromo-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 196.33 umol, 1.0 equiv) in toluene (2 mL) was added (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (120.38 mg, 588.98 μmol, 3.0 equiv), K3PO4 (83.35 mg, 392.66 μmol, 2.0 equiv) and xphos Pd G2 (15.43 mg, 19.633 μmol, 0.1 equiv). The reaction was stirred at 100 °C for 2 hours to give a brown suspension. LCMS showed a major peak with the desired mass and the material was still retained. The reaction was washed with water and extracted with DCM. The organic phase was concentrated to dryness under reduced pressure and purified by flash column (SiO 2, eluted with 0-30% EA / PE, COMBIFLASH NEXTAGEN 300) to give (1R,4R)-5-(2-(2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (102 mg, 5%) as a pale yellow oil. Yield: 88%).

[0153] LC-MS m / z:589.2(M+1) +

[0154] Step 3: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamide

[0155] A mixture of (1R,4R)-tert-butyl 5-(2-(2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (102 mg, 173.17 μmol, 1.0 equiv) in 4M HCl in dioxane (2 mL) was stirred overnight at 25°C to give a yellow solution. LCMS showed one of the peaks with the desired mass and the material was almost consumed. The reaction was concentrated to dryness under reduced pressure and purified by flash column (C18, peak time = 50% ACN / H 2 The reaction mixture was purified by HPLC-MS / MS (MS / MS: HPLC- ...

[0156] LC-MS m / z:489.1(M+1) +

[0157] 1 H NMR (400MHz, CD 3OD): δ8.70(d,J=4.9Hz,1H),7.99(m,J=10.0,5.0Hz,1H),7.88(m,J=10.0,3.3Hz, 1H),7.64(t,J=8.8Hz,1H),7.24(m,J=9.0,5.3Hz,1H),7.11–6.96(m,2H),4.43(s ,1H),4.19(s,1H),3.84(s,3H),3.55(m,J=23.1,11.3Hz,2H),3.40(d,J=11.5Hz, 1H), 3.28 (m, J=11.5, 2.2Hz, 1H), 2.34 (d, J=11.4Hz, 1H), 2.00 (d, J=11.5Hz, 1H).

[0158]

[0159]

[0160] Example 7: N-(4-((1S,4S)-2-azabicyclo[2.2.1]hept-5-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0161]

[0162] plan

[0163]

[0164] Step 1: N-(2-chloro-6-fluorophenyl)acetamide

[0165] To a solution of 2-chloro-6-fluoroaniline (10 g, 68.7 mmol, 1 equivalent) in AcOH (40 mL) was added acetic anhydride. The reactants were stirred at 90 ° C for 2 hours. LCMS analysis of the reaction mixture showed complete conversion to the desired product. After cooling to room temperature, water was added, and the solid precipitate was collected by filtration, washed with water, and air-dried to give N-(2-chloro-6-fluorophenyl)acetamide (9.28 g, yield: 72.01%) as a white solid.

[0166] LC-MS m / z:188.1(M+1) +

[0167] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide

[0168] N-(2-chloro-6-fluorophenyl)acetamide (9.28 g, 49.47 mmol, 1 eq.) was added to the 2SO 4 The (43 mL) solution was cooled to -78 °C in a reaction bath and HNO was added dropwise 3 (2.67 mL, 64.31 mmol, 1.3 eq). The mixture was stirred for 2 hours. LCMS analysis showed that the desired mass was detected and the reaction was complete. It was then carefully poured into an ice / water mixture and the solid precipitate was collected by filtration, washed with water, and air-dried to give N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (16.09 g, yield: 139.8%) as an off-white solid.

[0169] LC-MS m / z: 233.1 (M+1) +

[0170] Step 3: 4-Chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole

[0171] N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (5.0 g, 21.5 mmol, 1 equivalent), 33% CH 3 NH 2 A mixture of EtOH solution (3.37 mL, 21.5 mmol, 1 eq.) and TEA (6 mL, 43 mmol, 1 eq.) in DMSO (20 mL) was stirred at room temperature for 2 h. The mixture was then washed with N 2 Bubble for 30 minutes, then add TEA (6 mL, 43 mmol, 1 eq.). Add), and heat the reaction mixture to 120 ° C for 4 hours. LCMS analysis shows that the desired mass is detected and the reaction is complete. After cooling to room temperature. Water is added, the solid precipitate is collected by filtration, washed with water, and air-dried to obtain 4-chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole (1.25 g, yield: 25.8%) as a light yellow solid.

[0172] LC-MS m / z: 226.1 (M+1) +

[0173] Step 4: (1R,4R)-5-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0174] A solution of (1R,4R)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200.0 mg, 1.01 mmol, 1 eq) and 4-chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole (250.6 mg, 1.11 mmol, 1.1 eq) in DMSO (2 mL) was treated with TEA (0.21 mL). The reaction was then heated to 80 °C for 3 h. LCMS analysis showed the desired mass was detected and the reaction was complete. After cooling to room temperature, the solid precipitate was collected by filtration, washed with water, and air-dried to give (1R,4R)-5-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (241.3 mg, yield: 61.66%) as an orange solid.

[0175] LC-MS m / z: 388.3 (M+1) +

[0176] Step 5: (1R,4R)-5-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0177] A solution of tert-butyl (1R,4R)-5-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (241.3 mg, 0.623 mmol, 1 eq) and Pd / C (100.0 mg) in MeOH (5 mL) was stirred at room temperature in H 2 Atmosphere (60psi) was stirred for 16h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was filtered and concentrated to give (1R, 4R)-5-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (239.5mg, yield: 101.6%) as a dark purple solid.

[0178] LC-MS m / z: 358.2 (M+1) +

[0179] Step 6: (1R,4R)-5-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0180] To a solution of (1R,4R)-tert-butyl 5-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (149.0 mg, 0.417 mmol, 1 eq), 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (121.6 mg, 0.459 mmol, 1.1 eq) and DIPEA (0.15 mL, 0.459 mmol, 2 eq) in DMF (2 mL) was added HATU (237.74 mg, 0.625 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 16 hours. LCMS analysis showed that the desired mass was detected and the reaction was complete. The mixture was then treated with water. The precipitated product was collected by filtration, washed with water and dried by oil pump to give (1R,4R)-5-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (235.1 mg, 4%) as a green solid, yield: 93.28%).

[0181] LC-MS m / z:605.3(M+1) +

[0182] Step 7: N-(4-((1S,4S)-2-azabicyclo[2.2.1]hept-5-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0183] A solution of (1R,4R)-tert-butyl 5-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (235.1 mg, 0.389 mmol, 1 eq) in TFA (2 mL) was stirred at room temperature for 1 hour to give a dark brown solution. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was then poured into 20 mL of water and DCM, and the organic layer was separated. The water was basified with NaOH to pH = 11, and the solid precipitate was collected by filtration, washed with water, and freeze-dried to give Example 7 (62.5 mg, yield: 50.27%) as a yellow solid.

[0184] LC-MS m / z:504.2(M+1) +

[0185] 1 H NMR (400MHz, CD 3OD): δ8.66(d,J=5.0Hz,1H),8.03(dt,J=5.1,2.6Hz,1H),8.00(t,J=5.3Hz,1H),7.55(td,J=8 .5,6.8Hz,1H),7.19(d,J=8.7Hz,1H),7.04(d,J=8.5Hz,1H),6.93(t,J=8.7Hz,1H),4.21(s,1H ),4.12(t,J=8.3Hz,1H),3.86(s,3H),3.81(s,1H),3.77(s,3H),3.63–3.53(m,1H),3.17(d,J= 8.8Hz,1H),2.79(d,J=10.3Hz,1H),2.60(s,3H),2.15(d,J=9.5Hz,1H),1.84(d,J=9.6Hz,1H).

[0186]

[0187]

[0188]

[0189] Example 11: N-(4-((S)-3-aminopyrrolidin-1-yl)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-5-yl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0190]

[0191] plan

[0192]

[0193] Step 1: N-(2-chloro-6-((2-methoxyethyl)amino)-3-nitrophenyl)acetamide

[0194] At 25 ° C, a mixture of N-(2-chloro-6-((2-methoxyethyl)amino)-3-nitrophenyl)acetamide (500 mg, 2.15 mmol, 1 eq), methylamine in THF (1.6 mL, 2M) and triethylamine (0.45 mL, 3.22 mmol, 1.5 eq) in DMSO (5 mL) was stirred for 2 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4Drying, filtration and concentration under reduced pressure gave N-(2-chloro-6-((2-methoxyethyl)amino)-3-nitrophenyl)acetamide (400 mg, yield: 38.8%) as a brown solid, which was not further purified.

[0195] LC-MS m / z: 288.0 (M+1) +

[0196] Step 2: 4-Chloro-1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazole

[0197] A mixture of N-(2-chloro-6-((2-methoxyethyl)amino)-3-nitrophenyl)acetamide (400 mg, 1.39 mmol, 1 eq.) and triethylamine (0.58 mL, 4.17 mmol, 3 eq.) in DMSO (5 mL) was stirred at 120 °C for 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×3) and purified by Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=1 / 1) to give 4-chloro-1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazole (300 mg, yield: 76.0%) as a gray solid.

[0198] LC-MS m / z: 270.1 (M+1) +

[0199] Step 3: (S)-tert-butyl (1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0200] At 100 ° C, a DMSO solution of a mixture of (S)-(1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (100 mg, 0.37 mmol, 1 eq.), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (104 mg, 0.56 mmol, 1.5 eq.) and diisopropylethylamine (0.13 mL, 0.74 mmol, 2 eq.) was stirred for 3 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc (= 1 / 1)) to give (S)-tert-butyl (1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (145 mg, yield: 93.2%) as a yellow solid.

[0201] LC-MS m / z: 420.2 (M+1) +

[0202] Step 4: (S)-tert-butyl (1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0203] A mixture of Pd / C (72 mg, 10%) and (S)-tert-butyl (1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (145 mg, 0.35 mmol) in methanol (3 mL) was hydrogenated at 15 psi for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (S)-tert-butyl (1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (113 mg, yield: 71.3%) as a light yellow solid.

[0204] LC-MS m / z: 390.1 (M+1) +

[0205] Step 5: tert-Butyl ((3S)-1-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0206] To a solution of (S)-tert-butyl (1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (109 mg, 0.28 mmol, 1.0 equiv) and 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (74 mg, 0.28 mmol, 1.0 equiv) in DMF (3 mL) was added HATU (128 mg, 0.34 mmol, 1.2 equiv) and DIPEA (0.24 mL, 1.40 mmol, 5.0 equiv). The reaction mixture was stirred at 50 °C for 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×3) and purified by anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=97 / 3) to give ((3S)-1-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazole).4-(pyrrolidin-3-yl)carbamate (112 mg, yield: 59.7%) as a pale yellow solid.

[0207] LC-MS m / z:637.2(M+1) +

[0208] Step 6: N-(4-((S)-3-aminopyrrolidin-1-yl)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-5-yl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0209] To a solution of tert-butyl ((3S)-1-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (97 mg, 0.15 mmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated to give the trifluoroacetate salt of Example 11 (33.7 mg, yield: 39.1%) as a yellow solid.

[0210] LC-MS m / z:537.2(M+1) +

[0211] 1H NMR (400MHz, CD 3OD)δ8.67(d,J=4.9Hz,1H),8.05(d,J=8.9Hz,1H),7.94(t,J=5.1Hz,1H),7.66 (d,J=8.9Hz,1H),7.54(m,1H),7.03(d,J=8.5Hz,1H),6.92(m,1H),4.62(t,J= 4.5Hz,2H),4.02(m,1H),3.84(s,3H),3.82–3.79(m,2H),3.68(m,1H),3.50-3 .44(m,2H),3.33(s,1H),3.32(s,3H),2.91(s,3H),2.50(m,1H),2.17(m,1H).

[0212] Example 12: N-(2-((S)-3-aminopyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0213]

[0214] plan

[0215]

[0216] Step 1: (S)-tert-butyl (1-(5-bromo-2-nitrophenyl)pyrrolidin-3-yl)carbamate

[0217] To a DMSO solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol, 1.0 equiv) was added tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (508 mg, 2.72 mmol, 1.2 equiv) and diisopropylethylamine (587 mg, 4.54 mmol, 2.0 equiv). The reaction mixture was stirred at 60 ° C for 2 hours under nitrogen. The mixture was then diluted with water and extracted with EtOAc (3×30 mL). The organic layer was washed with Na 2 SO 4 Drying and evaporation in vacuo afforded a crude product. The residue was purified by flash chromatography eluting with petroleum ether / EtOAc (=10:1) to afford (S)-tert-butyl(1-(5-bromo-2-nitrophenyl)pyrrolidin-3-yl)carbamate (660 mg, yield: 72.3%) as a yellow solid.

[0218] LC-MS m / z: 387.2 (M+1) +

[0219] Step 2: (S)-tert-butyl (1-(2-amino-5-bromophenyl)pyrrolidin-3-yl)carbamate

[0220] To a mixture of tert-butyl N-[(3S)-1-(5-bromo-2-nitrophenyl)pyrrolidin-3-yl]carbamate [300 mg, 0.77 mmol, 1.0 equiv] and iron [217 mg, 3.88 mmol, 5.0 equiv] in EtOH [8.0 mL] was added dropwise ammonium chloride [210 mg, 3.88 mmol, 5.0 equiv] in H 2 The product was stirred for 2 hours at 4 ℃ for 10 minutes at 4 ℃ for 30 minutes.Then add 4-(4-bromo-2-phenyl)-1-(2-amino-5-bromophenyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (200mg, yield: 70.3%) by flash chromatography purification of the residue, eluted with petroleum ether / EtOAc.

[0221] LC-MS m / z: 357.2 (M+1) +

[0222] Step 3: tert-butyl ((3S)-1-(5-bromo-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)phenyl)pyrrolidin-3-yl)carbamate

[0223] To a solution of 3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxylic acid (45 mg, 0.16 mmol, 1.0 eq) in DMF was added tert-butyl N-[(3S)-1-(2-amino-5-bromophenyl)pyrrolidin-3-yl]carbamate [60 mg, 0.16 mmol, 1.0 eq], 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate [77 mg, 0.20 mmol, 1.3 eq] and diisopropylethylamine [87 mg, 0.67 mmol, 4.2 eq]. The reaction mixture was stirred at 50 °C for 3 hours. The mixture was diluted with brine solution [5.0 mL] and extracted with EtOAc (3 x 10 mL). The organic layer was washed with Na 2 SO 4 Drying and evaporation in vacuo gave a crude product. The residue was purified by flash chromatography using petroleum ether / EtOAc=5:1 as eluent to give tert-butyl ((3S)-1-(5-bromo-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)phenyl)pyrrolidin-3-yl)carbamate (60 mg, yield: 54.4%).

[0224] LC-MS m / z:604.1(M+1) +

[0225] Step 4: tert-butyl ((3S)-1-(5-(4-cyanopyridin-3-yl)-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)phenyl)pyrrolidin-3-yl)carbamate

[0226] To a solution of tert-butyl N-[(3S)-1-{5-bromo-2-[3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridin-4-amido]phenyl}pyrrolidin-3-yl]carbamate [60 mg, 0.09 mmol, 1.0 equiv] in dioxane was added 4-cyanopyridine-3-boronate [46 mg, 0.19 mmol, 2.1 equiv], anhydrous potassium phosphate [42.2 mg, 0.19 mmol, 2.1 equiv] and XPhosPdG2 [7.81 mg, 0.01 mmol, 0.11 equiv]. The reaction mixture was stirred at 80° C. for 12 hours under nitrogen. The reaction mixture was concentrated under reduced pressure at 40° C. The residue was purified by flash chromatography eluting with DCM / MeOH=20:1 to give tert-butyl ((3S)-1-(5-(4-cyanopyridin-3-yl)-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)phenyl)pyrrolidin-3-yl)carbamate (50 mg, yield: 74.5%) as a yellow solid.

[0227] LC-MS m / z:627.2(M+1) +

[0228] Step 5: N-(2-((S)-3-aminopyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0229] To a solution of tert-butyl N-[(3S)-1-[5-(4-cyanopyridin-3-yl)-2-[3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-amido]phenyl]pyrrolidin-3-yl]carbamate (40 mg, 0.06 mmol) in DCM [1.5 mL] was added a solution of hydrogen chloride in 1,4-dioxane [1.5 mL, 4 M]. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated and washed with DCM. The solid was collected and then freeze-dried to give Example 12 (25 mg, yield: 66.4%) as a yellow solid.

[0230] LC-MS m / z:527.2(M+1) +

[0231] 1 H NMR (400MHz, CD 3OD)δ9.21(s,1H),8.99(d,J=5.6Hz,1H),8.85(d,J=5.3Hz,1H),8.33(d,J=5.6Hz,1H),8.29–8.18(m,2H),7.66(m,2H),7.49(d,J=8.4Hz,1H ),7.12(d,J=8.5Hz,1H),7.00(t,J=8.8Hz,1H),4.01(s,1H),3.90(s,3H),3.69(m,2H),3.37(m,1H),3.19(m,1H),2.51(m,1H),2.09(m,1H).

[0232]

[0233]

[0234] Example 14: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-5-yl}-3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide

[0235]

[0236] plan

[0237]

[0238] Step 1: tert-Butyl N-[(3S)-1-[2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate

[0239] To a solution of 4-chloro-2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazole (100 mg, 0.39 mmol, 1.0 equiv) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (73 mg, 0.39 mmol, 1 equiv) in DMSO (1.5 mL) was added DIPEA (0.16 mL, 0.78 mmol, 2 equiv) at room temperature. The reaction mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction was quenched with EtOAc (10 mL×3) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure to give a crude product, which was purified by SGC (UV254, petroleum ether:EtOAc=1:1) to give tert-butyl N-[(3S)-1-[2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (80 mg, yield: 46.2%) as a yellow solid.

[0240] LC-MS m / z:457.2(M+1) +

[0241] Step 2: tert-butyl N-[(3S)-1-[5-amino-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate

[0242] A solution of a mixture of Pd / C (32 mg, 0.29 mmol) and tert-butyl N-[(3S)-1-[2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (80 mg, 0.15 mmol) in methanol (6 mL) was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-[(3S)-1-[5-amino-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (90 mg, yield: 96.3%) as a yellow solid.

[0243] LC-MS m / z:427.1(M+1) +

[0244] Step 3: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-5-yl}-3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide

[0245] To a solution of (S)-tert-butyl (1-(5-amino-2-(3-fluoropyridin-4-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.18 mmol, 1.0 equiv) and 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (49.75 mg, 0.18 mmol, 1. equiv) in DMF (15 mL) at room temperature was added HATU (85.6 mg, 0.22 mmol, 1.2 equiv) and DIPEA (0.12 mL, 0.75 mmol, 4.0 equiv). The reaction temperature was raised to 50 °C and the reaction was stirred at 50 °C for 4 hours. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=40 / 1) to give N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-5-yl}-3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (35 mg, yield: 26.3%) as a yellow solid.

[0246] LC-MS m / z:674.3(M+1) +

[0247] Step 4: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0248] To a solution of N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-5-yl}-3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (35 mg, 0.052 mmol, 1.0 equiv) in DCM (0.5 mL) was added trifluoroacetic acid in DCM (0.3 mL, 0.052 mmol, 1.0 equiv) at 25° C. The reaction mixture was stirred for 2 hours at 25° C. The reaction mixture was concentrated and washed with MTBE to give Example 14 (8.7 mg, yield: 23.3%) as a yellow solid.

[0249] LC-MS m / z:574.2(M+1) +

[0250] 1 H NMR (400MHz, CD 3 OD)δ8.70(d,J=1.6Hz,1H),8.58(d,J=4.8Hz,2H),8.22(d,J=8.3Hz,1H),7.89(s,1H),7.77–7.6 5(m,1H),7.45(dd,J=15.3,8.5Hz,2H),6.94(d,J=8.4Hz,1H),6.82(t,J=8.7Hz,1H),3.90(d,J=1 6.2Hz,1H),3.85(dd,J=12.2,6.4Hz,1H),3.80(d,J=1.1Hz,3H),3.74(s,3H),3.61(dd,J=17.1,8 .6Hz,1H),3.52(d,J=11.9Hz,1H),3.47–3.38(m,1H),2.34(dt,J=15.5,7.6Hz,1H),2.11(s,1H).

[0251] Example 15: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(methoxymethyl)-1-methyl-1,3-benzodiazol-5-yl}-3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide

[0252]

[0253] plan

[0254]

[0255]

[0256] Step 1: N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide

[0257] At 0 ° C, 2-chloro-6-fluoroaniline (2.0 g, 13.7 mmol, 1.0 equiv) and DIPEA (2.66 g, 20.6 mmol, 1.5 equiv) in DCM (20 mL) solution was added dropwise. 2-methoxyacetyl chloride (1.75 g, 16.4 mmol, 1.2 equiv) in DCM (10 ml) solution. The mixture was stirred at 20 ° C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure at 35 ° C. The residue was purified by flash chromatography and eluted with petroleum ether / EtOAc=5:1 to give N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, yield: 57.7%) as a white solid.

[0258] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide

[0259] To a stirred solution of N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, 8.3 mmol, 1.0 equiv) at -55 °C was added H 2 SO 4 Concentrated nitric acid (0.6 mL, 11.6 mmol, 1.4 equiv) was added dropwise to the H 2 SO 4 (2 mL) solution. The reaction mixture was stirred at -55 °C for 2 h. The resulting mixture was warmed to room temperature and poured into ice water (30 mL) and the resulting precipitate was filtered. The filter cake was dissolved in DCM (80 mL) and washed with Na 2 SO 4 Drying and concentration gave N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide (1.2 g, yield: 49.4%).

[0260] LC-MS m / z: 263.1 (M+1) +

[0261] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2,2-trifluoroacetamide

[0262] A solution of compound N-(2-chloro-6-fluorophenyl)-2,2,2-trifluoroacetamide (2.82 g, 11.7 mmol, 1.0 equiv) in sulfuric acid (25 mL) was cooled to 0°C, and potassium nitrate (1.3 g, 12.8 mmol, 1.1 equiv) was added in portions. The resulting mixture was stirred at 0°C for 20 minutes. After completion, the mixture was poured into ice water (30 mL) and the resulting precipitate was filtered. The filter cake was dissolved in DCM (80 mL) and washed with Na 2 SO 4 The residue was dried and concentrated to give compound N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2,2-trifluoroacetamide (2.94 g, yield: 78.6%).

[0263] 1 H NMR (400MHz, d 6 -DMSO) δ11.91(s,1H),8.30(dd,J=8.8,5.2Hz,1H),7.76(t,J=8.8Hz,1H).

[0264] Step 3: 4-Chloro-1-methyl-5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0265] At 25°C, a mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2,2-trifluoroacetamide (2.94 g, 10.3 mmol, 1.0 equivalent), CH 3 NH 2 A solution of (320 mg, 10.3 mmol, 33%, 1.0 eq.) in THF (5.15 ml, 2 M) and TEA (1.43 mL, 10.3 mmol, 1.0 eq.) in DMSO (2 mL) was stirred for 2 h. The mixture was then heated to N 2 After bubbling for 30 minutes, additional TEA (1.43 mL, 10.3 mmol, 1 eq.) was added, and the reaction mixture was heated to 120°C and stirred at the same temperature for 4 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (50 mL x 2). The organic phase was washed with brine (50 mL x 3) and purified by Na 2 SO 4 Drying, filtration and concentration in vacuo gave a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=10:1) to give 4-chloro-1-methyl-5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (490 mg, yield: 16.5%) as a yellow solid.

[0266] 1 H NMR (400MHz, d 6 -DMSO): δ8.22(d,J=9.2Hz,1H), 8.05(d,J=9.2Hz,1H), 4.06(d,J=0.2Hz,3H).

[0267] Step 4: (S)-tert-butyl (1-(1,5-dimethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0268] To a DMSO (5 mL) solution of compound 4-chloro-1-methyl-5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (300 mg, 1.08 mmol, 1.0 eq) and compound (S)-tert-butyl pyrrolidin-3-ylcarbamate (300 mg, 1.61 mmol, 1.5 eq) was added DIPEA (555 mg, 4.30 mmol, 4 equivalents). The mixture was stirred at 100 ° C for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (10 mL×2). The organic phase was washed with brine (10 mL×3) and purified by Na 2 SO 4Dry, filter, and concentrate in vacuo to give a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=10:1) to give (S)-tert-butyl(1-(1,5-dimethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (450 mg, yield: 97.6%) as a yellow solid.

[0269] 1 H NMR (400MHz, d 6 -DMSO) δ7.86(d,J=9.2Hz,1H),7.25(d,J=4.8Hz,1H),7.05(d,J=9.2Hz,1H),4.10(d,J=3.6Hz,1H) ,3.94(s,4H),3.82–3.64(m,2H),3.32–3.27(s,1H),2.15–2.07(m,1H),1.94(m,1H),1.37(s,9H).

[0270] Step 5: (S)-tert-butyl (1-(5-amino-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0271] 10% Pd / C (50 mg, 0.47 mmol) was added to a solution of compound (S)-tert-butyl (1-(1,5-dimethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (450 mg, 1.06 mmol) in methanol (8 mL), and the reaction mixture was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated to give compound (S)-tert-butyl (1-(5-amino-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (300 mg, yield: 71.7%) as a dark purple solid.

[0272] 1 H NMR (400MHz, d 6 -DMSO) δ7.48(d,J=7.6Hz,1H),7.23(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.88(s,2H),4.15(s,1H),3.85(s,3 H),3.61–3.54(m,1H),3.30–3.22(m,2H),3.13-3.10(m,1H),2.28–2.09(m,1H),1.86–1.71(m,1H),1.39(s,9H).

[0273] Step 6: (S)-tert-butyl (1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0274] To a solution of (S)-tert-butyl(1-(5-amino-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (140 mg, 0.35 mmol, 1.0 eq) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (88 mg, 0.35 mmol, 1.0 eq) in DMF (2 mL) were added HATU (200 mg, 0.53 mmol, 1.5 eq) and DIPEA (0.23 mL, 1.4 mmol, 4.0 eq). The mixture was stirred at 50 °C for 16 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (5 mL×3). The organic phase was washed with brine (10 mL×3), purified by chromatography on agarose gel. 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=10:1) to give (S)-tert-butyl(1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-pyrrolidin-3-yl)carbamate (180 mg, yield: 92.4%) as a yellow solid.

[0275] 1 H NMR (400MHz, d 6 -DMSO)δ11.62(s,1H),8.48(d,J=4.4Hz,1H),8.38(d,J=4.4Hz,1H),8.35(s,1H),7.79–7.63(m,1H),7.53–7.33(m,3H),7.01(d,J=6.8Hz,1H), 4.10(s,1H),3.95(s,3H),3.78–3.70(m,1H),3.49–3.40(m,1H),3.34( s,1H),2.69(s,1H),2.16–2.04(m,1H),1.81–1.71(m,1H),1.34(s,9H).

[0276] Step 7: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0277] To a solution of (S)-tert-butyl(1-(5-amino-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.13 mmol, 1.0 equiv) in DCM (1.5 mL) was added a solution of HCl in 1,4-dioxane (1 mL, 4 M, 30.0 equiv). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to give Example 39 (57 mg, yield: 85.6%) as a yellow solid.

[0278] LC-MS m / z:534.1(M+1) +

[0279] 1HNMR (400MHz, d 6 -DMSO) δ11.59(s,1H),8.51(d,J=4.0Hz,1H),8.46(d,J=9.2Hz,1H),8.40(d,J=4.0Hz,1H),7.98(s,2H),7.80–7.69(m,1H),7.58(d,J=8.8Hz ,1H),7.45(t,J=7.6Hz,2H),3.97(s,3H),3.86(d,J=6.8Hz,2H),3.59– 3.46(m,2H),3.46–3.37(m,1H),2.36–2.23(m,1H),1.94–1.83(m,1H).

[0280]

[0281]

[0282] Example 42: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-5-yl}-2-(2,6-difluorophenyl)-3-oxopyridazine-4-carboxamide

[0283]

[0284] plan

[0285]

[0286]

[0287] Step 1: tert-Butyl N-[(3S)-1-[2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate

[0288] To a solution of 4-chloro-2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazole (100 mg, 0.39 mmol, 1.0 equiv) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (73 mg, 0.39 mmol, 1 equiv) in DMSO (1.5 mL) was added DIPEA (0.16 mL, 0.78 mmol, 2 equiv) at room temperature. The reaction mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction was quenched with EtOAc (10 mL×3) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a crude product, which was purified by SGC (UV254, petroleum ether:EtOAc=1:1) to give tert-butyl N-[(3S)-1-[2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (80 mg, yield: 46.2%) as a yellow solid.

[0289] LC-MS m / z:457.2(M+1) +

[0290] Step 2: tert-butyl N-[(3S)-1-[5-amino-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate

[0291] A solution of a mixture of Pd / C (32 mg, 0.29 mmol) and tert-butyl N-[(3S)-1-[2-(3-fluoropyridin-4-yl)-1-methyl-5-nitro-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (80 mg, 0.15 mmol) in methanol (6 mL) was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-[(3S)-1-[5-amino-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (90 mg, yield: 96.3%) as a yellow solid.

[0292] LC-MS m / z:427.1(M+1) +

[0293] Step 3: tert-Butyl N-[(3S)-1-{5-[2-(2,6-difluorophenyl)-3-oxopyridazine-4-amino]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0294] To a solution of tert-butyl N-[(3S)-1-[5-amino-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl]pyrrolidin-3-yl]carbamate (50 mg, 0.12 mmol, 1.0 equiv) and 2-(2,6-difluorophenyl)-3-oxopyridazine-4-carboxylic acid (30 mg, 0.12 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (54 mg, 0.14 mmol, 1.2 equiv) and DIPEA (0.4 mL, 0.48 mmol, 4.0 equiv). The reaction mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (50 mL) and purified by Na 2 SO 4 The reaction mixture was dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by SGC (UV254, petroleum ether: EtOAc = 3:1) to give tert-butyl N-[(3S)-1-{5-[2-(2,6-difluorophenyl)-3-oxo-pyridazin-4-ylamino]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzotriazole-4-pyrrolidin-3-yl]carbamate (40 mg, yield: 49.1%) as a yellow solid.

[0295] 1 H NMR (400MHz, CD 3 OD)δ8.64(s,1H),8.52-8.50(m,2H),8.32(d,J=4.2Hz,1H),8.25(d,J=4. 2Hz,1H),7.73(d,J=5.1Hz,1H),7.61–7.47(m,1H),7.34(d,J=8.8Hz,1H) ,7.17(t,J=8.6Hz,2H),4.12(s,1H),3.75-3.73(m,4H),3.32-3.31(m,2H ),2.21–2.04(m,1H),1.82-1.79(m,1H),1.43–1.26(m,2H),1.19(s,9H).

[0296] Step 3: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-5-yl}-2-(2,6-difluorophenyl)-3-oxopyridazine-4-carboxamide

[0297] To a solution of tert-butyl N-[(3S)-1-{5-[2-(2,6-difluorophenyl)-3-oxopyridazin-4-amine]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (30 mg, 0.045 mmol, 1.0 equiv) in DCM (3 mL) was added HCl in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 42 (14 mg, yield: 49.6%) as a yellow solid.

[0298] LC-MS m / z:561.2(M+1) +

[0299] 1 H NMR (400MHz, CD 3 OD)δ8.66(s,1H),8.60(d,J=9.0Hz,1H),8.55(d,J=4.7Hz,1H),8.35-8.34( m,1H),8.32-8.31(m,1H),7.70(s,1H),7.65–7.52(m,1H),7.44(d,J=9.0Hz, 1H),7.20-7.17(m,2H),3.99–3.90(m,1H),3.80-3.79(m,1H),3.74(s,3H), 3.43-3.39(m,2H),3.25-3.24(m,2H),2.42-2.40(m,1H),1.90-1.88(m,1H).

[0300]

[0301]

[0302] Example 44: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0303]

[0304] plan

[0305]

[0306] Step 1: N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide

[0307] To a stirred solution of 2-chloro-6-fluoroaniline (2.0 g, 13.7 mmol, 1.0 equiv) and DIPEA (2.66 g, 20.6 mmol, 1.5 equiv) in DCM (20 mL) at 0 ° C., a solution of 2-methoxyacetyl chloride (1.75 g, 16.4 mmol, 1.2 equiv) in DCM (10 ml) was added dropwise. The mixture was stirred at 20 ° C. for 2 h. After completion, the reaction mixture was concentrated under reduced pressure at 35 ° C. The residue was purified by flash chromatography and eluted with petroleum ether / EtOAc=5:1 to give N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, yield: 57.7%) as a white solid.

[0308] LC-MS m / z: 218.1 (M+1) +

[0309] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide

[0310] At -55 °C, N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, 8.3 mmol, 1.0 equiv) was stirred in H 2 SO 4 Concentrated nitric acid (0.6 mL, 11.6 mmol, 1.4 equiv) was added dropwise to the H 2 SO 4 (2 mL) solution. The reaction mixture was stirred at -55 °C for 2 h. The resulting mixture was warmed to room temperature and poured into ice water (30 mL) and the resulting precipitate was filtered. The filter cake was dissolved in DCM (80 mL) and washed with Na 2 SO 4 Drying and concentration gave N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide (1.2 g, yield: 49.4%).

[0311] LC-MS m / z: 263.1 (M+1) +

[0312] Step 3: 4-chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole

[0313] At room temperature, N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide (500 mg, 1.92 mmol, 1 equivalent), CH3 NH 2 A mixture of a solution of THF [2M] (1.5 mL, 2.85 mmol, 1.5 eq.) and a solution of TEA (289 mg, 2.85 mmol, 1.5 eq.) in DMSO (2 mL) was stirred for 2 hours. The mixture was then extracted with water and ethyl acetate. The organic phase was concentrated and the residue was dissolved in DMSO. Additional TEA was added and the mixture was stirred at 100 ° C for 4 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (50 mL×2). The organic phase was washed with brine (50 mL×3) and purified by Na 2 SO 4 Drying, filtration and concentration in vacuo gave a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=1:1) to give 4-chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole (300 mg, yield: 59.2%) as a yellow solid.

[0314] LC-MS m / z: 255.2 (M+1) +

[0315] Step 4: (S)-tert-butyl (1-(2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0316] To a solution of 4-chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole (120 mg, 0.47 mmol, 1.0 equiv) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (105 mg, 0.56 mmol, 1.2 equiv) in DMSO (1.5 mL) was added diisopropylethylamine (121 mg, 0.94 mmol, 2 equiv). The mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (10 mL×2). The organic phase was washed with brine (10 mL×3) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=3:1) to give (S)-tert-butyl(1-(2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, yield: 50.5%) as a yellow solid.

[0317] LC-MS m / z:405.2(M+1) +

[0318] Step 5: (S)-tert-butyl (1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0319] To a solution of (S)-tert-butyl (1-(2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (548 mg, 1.0 equiv) in MeOH (10 mL) was added 10% Pd / C (60 mg). The reaction was stirred for 16 hours. Filtered through a pad of celite. The organic phase was washed with brine (20 mL x 3) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=1:1) to give compound (S)-tert-butyl(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (300 mg, yield: 59.2%) as a yellow solid.

[0320] LC-MS m / z: 376.2 (M+1) +

[0321] Step 6: (S)-tert-butyl (1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0322] To a solution of (S)-tert-butyl (1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.45 mmol, 1.0 equiv) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.18 mmol, 1 equiv) in DMF (2 ml) was added HATU (85.6 mg, 0.22 mmol, 1.5 equiv) and DIPEA (0.29 mL, 1.35 mmol, 3.0 equiv). The resulting mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (50 mL) and purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure to give a crude product, which was purified by SGC (UV254, petroleum ether: EtOAc = 3:1) to give (S)-(1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole. 4-(pyrrolidin-3-yl)carbamic acid tert-butyl ester (100 mg, yield: 69.3%) as a yellow solid.

[0323] LC-MS m / z:610.3(M+1) +

[0324] Step 7: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0325] To a solution of tert-butyl (S)-(1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (50 mg, 0.082 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (0.3 mL, 4 M, 30.0 equiv) at room temperature. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 44 as a yellow solid.

[0326] LC-MS m / z: 510.2 (M+1) +

[0327] 1 H NMR (400MHz, CD 3 OD)δ8.56(d,J=8.9Hz,1H),8.39(d,J=4.2Hz,1H),8.33(d,J=4.2Hz,1H),7.66–7.48(m,1H),7.42-7.37(m,1H),7.28–7.11(m,2H) ,4.71-4.69(m,2H),3.95–3.83(m,2H),3.79(s,3H),3.50–3.34(m,5H),3.29-3.27(m,1H),2.50-2.40(s,1H),2.03–1.96(m,1H).

[0328] Example 45: N-(4-((S)-3-aminopyrrolidin-1-yl)-1-methyl-2-(trifluoromethyl)-5,6-dihydro-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0329]

[0330] plan

[0331]

[0332] Step 1: (S)-tert-butyl ((1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate

[0333] At 100 ° C, a mixture of 4-chloro-1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazole (270 mg, 1.00 mmol, 1.0 equiv), (S)-tert-butyl (pyrrolidin-2-ylmethyl)carbamate (305 mg, 1.50 mmol, 1.5 equiv) and diisopropylethylamine (518 mg, 4.00 mmol, 4 equiv) in DMSO (8 mL) was stirred for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (5.0 mL) and extracted with EtOAc (10 mL×3). The combined organic phase was washed with brine (10 mL×3) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=10 / 1) to give (S)-tert-butyl((1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate (315 mg, yield: 61.7%) as a yellow solid.

[0334] LC-MS m / z: 434.3 (M+1) +

[0335] Step 2: (S)-tert-butyl ((1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate

[0336] A mixture of Pd / C (40 mg, 10%) and (S)-tert-butyl ((1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate (100 mg, 0.35 mmol) in methanol (10 mL) was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (S)-tert-butyl ((1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate (252 mg, yield: 77.4%) as a white solid.

[0337] LC-MS m / z: 404.2 (M+1) +

[0338] 1 H NMR (400MHz, d 6 -DMSO) δ6.99(d,J=8.4Hz,1H),6.66(t,J=5.2Hz,1H),6.59(d,J=8.8Hz,1H),4.58(s,2H),4.20(t,J=5.2Hz,2H),3.97(s,1H) ,3.58(t,J=5.2Hz,2H),3.21(s,4H),3.17(d,J=5.2Hz,1H),2.95–2.83(m,1H),2.79–2.61(m,1H),2.44(s,3H),2.11(dd,J=1

[0339] Step 3: (S)-tert-butyl ((1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate

[0340] To a solution of (S)-tert-butyl((1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate (139 mg, 0.35 mmol, 1.0 equiv) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (87 mg, 0.35 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (197 mg, 0.52 mmol, 1.5 equiv) and DIPEA (0.23 mL, 1.38 mmol, 4.0 equiv). The mixture was stirred at 50 °C for 16 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (5 mL×3). The organic phase was washed with brine (10 mL×3) and purified by Na2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=1:1) to give (S)-tert-butyl((1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate (160 mg, yield: 69.1%) as a yellow solid.

[0341] 1 H NMR (400MHz, d 6 -DMSO) δ11.99(s,1H),8.45(d,J=4.4Hz,1H),8.39(s,1H),8.37(d,J=4.8Hz,1H),7.71(t,J =8.0Hz,1H),7.44(t,J=8.8Hz,2H),7.34(d,J=8.8Hz,1H), δ6.39(s,1H),4.33(t,J=4.8Hz, 2H),4.14(s,1H),3.64(s,2H),3.27(s,1H),3.22(s,3H),3.09(q,J=7.8Hz,1H),2.82–2.71 (m,2H),2.52(s,3H),2.16–2.05(m,1H),1.91–1.82(m,2H),1.76–1.66(m,1H),1.21(s,9H).

[0342] Step 4: N-(4-((S)-3-aminopyrrolidin-1-yl)-1-methyl-2-(trifluoromethyl)-5,6-dihydro-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0343] To a solution of N-(4-((S)-3-aminopyrrolidin-1-yl)-1-methyl-2-(trifluoromethyl)-5,6-dihydro-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (80 mg, 0.13 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated to give Example 45 as a yellow solid.

[0344] LC-MS m / z:538.2(M+1) +

[0345] 1H NMR (400MHz, d 6 -DMSO) δ11.93(s,1H),8.50(d,J=4.0Hz,1H),8.46(d,J=7.2Hz,1H),8.40(d,J=4.0Hz,1H),7.74(m,1H),7.59(br,3H),7.46(m,2H),4.47(s, 2H),4.25(s,1H),3.68(s,2H),3.26(m,1H),3.23(s,3H),3.13–3.05(m ,1H),2.66(s,3H),2.60(m,2H),2.37–2.23(m,1H),1.99–1.74(m,3H).

[0346] Example 46: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0347]

[0348] plan

[0349]

[0350] Step 1: tert-Butyl N-[(3S)-1-(2-isopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0351] At 100 ° C, a mixture of 4-chloro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (100 mg, 0.39 mmol, 1.0 equiv), diisopropylethylamine (130 mL, 0.79 mmol, 2 equiv) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (88 mg, 0.43 mmol, 1.2 equiv) in DMSO was stirred for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL×3) and washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue, which was purified by SGC (UV254, petroleum ether:EtOAc=3:1) to give tert-butyl N-[(3S)-1-(2-isopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (150 mg, yield: 89.6%) as a yellow solid.

[0352] LC-MS m / z:404.1(M+1) +

[0353] Step 2: (S)-tert-butyl (1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0354] A mixture of Pd / C (79 mg, 0.25 mmol, 10%) and tert-butyl N-[(3S)-1-(2-isopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (150 mg, 0.37 mmol) in methanol (5 mL) was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated to give tert-butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, yield: 46.1%) as a white solid.

[0355] LC-MS m / z: 374.2 (M+1) +

[0356] Step 3: (S)-tert-butyl (1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0357] To a solution of (S)-tert-butyl (1-(5-amino-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.19 mmol) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (67 mg, 0.27 mmol, 1.0 equiv) in DMF (2.0 mL) was added HATU (122 mg, 0.32 mmol, 1.2 equiv) and DIPEA (0.2 mL, 1.33 mmol, 5.0 equiv). The reaction mixture was stirred at 50 °C for 10 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=25 / 1) to give (S)-tert-butyl(1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate as a yellow solid (100 mg, yield: 58.4%).

[0358] LC-MS m / z:608.7(M+1) +

[0359] Step 4: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0360] To a solution of tert-butyl (S)-(1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.16 mmol) in DCM (2.0 mL) was added a solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4 M) at 25 °C. The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 46 hydrochloride (40 mg, yield: 42.9%) as a yellow solid.

[0361] LC-MS m / z: 508.7 (M+1) +

[0362] 1 H NMR: (400MHz, CD 3 OD)δ8.60(br,1H),8.38(s,1H),8.32(s,1H),7.64–7.53(m,1H),7.47(br,1H),7.20(t,J=8.8Hz,2H),3.93(s,1H ),3.83(s,3H),3.80–3.74(m,1H),3.44(s,1H),3.40(s,2H),3.26(s,1H),2.47(s,1H),2.07(s,1H),1.41(s,6H).

[0363] Example 47: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide trifluoroacetate

[0364]

[0365] plan

[0366]

[0367] Step 1: N-(2-chloro-3-nitro-6-((tetrahydro-2H-pyran-4-yl)amino)phenyl)acetamide

[0368] At 25 ° C, a mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (500 mg, 2.15 mmol, 1 eq.), tetrahydro-2H-pyran-4-amine (326 mg, 3.22 mmol, 1.5 eq.) and triethylamine (0.45 mL, 3.22 mmol, 1.5 eq.) in DMSO (3 mL) was stirred for 2 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave N-(2-chloro-3-nitro-6-((tetrahydro-2H-pyran-4-yl)amino)phenyl)acetamide (370 mg, yield: 54.9%) as a yellow solid, which was not further purified.

[0369] LC-MS m / z: 313.9 (M+1) +

[0370] Step 2: 4-chloro-2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole

[0371] At 120 ° C, a mixture of N-(2-chloro-3-nitro-6-((tetrahydro-2H-pyran-4-yl)amino)phenyl)acetamide (370 mg, 1.19 mmol, 1 eq) and triethylamine (0.25 mL, 1.77 mmol, 1.5 eq) in DMSO (3 mL) was stirred for 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4Drying, filtration and concentration under reduced pressure gave a residue, which was purified by flash column chromatography (eluted with DCM / MeOH=19 / 1) to give 4-chloro-2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole (320 mg, yield: 40.3%) as a yellow solid.

[0372] LC-MS m / z: 295.9 (M+1) +

[0373] Step 3: (S)-tert-butyl (1-(2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0374] At 100 ° C, a mixture of 4-chloro-2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole (320 mg, 1.08 mmol, 1 eq.), (S)-tert-butyl pyrrolidin-3-ylcarbamate (302 mg, 1.62 mmol, 1.5 eq.) and diisopropylethylamine (0.28 mL, 1.62 mmol, 1.5 eq.) in DMSO (3 mL) was stirred for 3 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=13 / 7) to give (S)-tert-butyl(1-(2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate as a yellow solid (345 mg, yield: 68.0%).

[0375] LC-MS m / z:446.1(M+1) +

[0376] Step 4: (S)-tert-butyl (1-(5-amino-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0377] A mixture of Pd / C (170 mg, 10%) and (S)-tert-butyl (1-(2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (345 mg, 0.77 mmol) in methanol (3 mL) was hydrogenated at 15 psi for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (S)-tert-butyl (1-(5-amino-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (337.0 mg, yield: 94.3%) as a gray solid.

[0378] LC-MS m / z: 416.2 (M+1) +

[0379] Step 5: (S)-tert-butyl (1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0380] To a solution of (S)-tert-butyl (1-(5-amino-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.24 mmol, 1.0 equiv) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (61 mg, 0.24 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (110 mg, 0.29 mmol, 1.2 equiv) and DIPEA (0.21 mL, 1.20 mmol, 5.0 equiv). The reaction mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×3) and purified by anhydrous Na 2 SO 4 The reaction mixture was dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=19 / 1) to give (S)-tert-butyl (1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (85 mg, yield: 51.6%) as an orange solid.

[0381] LC-MS m / z:650.3(M+1) +

[0382] Step 6: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0383] To a solution of (S)-tert-butyl(1-(5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (85 mg, 0.14 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25 °C for 3 hours. Water (5 mL) was added and extracted with DCM (5 mL). The combined organic phases were concentrated under reduced pressure to give Example 47 (80.9 mg, yield: 90%) as a yellow solid.

[0384] LC-MS m / z: 550.2 (M+1) +

[0385] 1 H NMR (400MHz, CD 3 OD)δ8.66(d,J=9.1Hz,1H),8.50(d,J=4.2Hz,1H),8.44(d,J=4.2Hz,1H),7.77(d,J=9.2 Hz,1H),7.75–7.67(m,1H),7.36-7.30(m,2H),4.75-4.73(m,1H),4.16-4.14(m,2H),4. 01-3.99(m,1H),3.88(dd,J=11.0,5.3Hz,1H),3.67-3.65(m,2H),3.51-3.46(m,2H),3. 28–3.26(m,1H),2.79(s,3H),2.62-2.58(m,3H),2.13–2.04(m,1H),1.91-1.89(m,2H).

[0386] Example 48: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-1-cyclopropyl-2-methyl-1,3-benzodiazol-5-yl}-2-(2,6-difluorophenyl)-3-oxopyridazine-4-carboxamide Scheme

[0387]

[0388] Step 1: N-(2-chloro-6-(cyclopropylamino)-3-nitrophenyl)acetamide

[0389] At 25 ° C, a mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (500 mg, 2.15 mmol, 1.0 equivalent), cyclopropylamine (184 mg, 3.22 mmol, 1.5 equivalents) and triethylamine (0.45 mL, 3.22 mmol, 1.5 equivalents) in DMSO (3 mL) was stirred for 2 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3) and washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave N-(2-chloro-6-(cyclopropylamino)-3-nitrophenyl)acetamide (451 mg, yield: 78%) as a yellow solid, which was not further purified.

[0390] LC-MS m / z: 270.0 (M+1) +

[0391] Step 2: 4-chloro-1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazole

[0392] At 120 ° C, a mixture of N-(2-chloro-6-(cyclopropylamino)-3-nitrophenyl)acetamide (451 mg, 1.67 mmol, 1.0 eq) and triethylamine (0.35 mL, 2.50 mmol, 1.5 eq) in DMSO (3 mL) was stirred for 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc (=97 / 3)) to give 4-chloro-1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazole (294 mg, 5%) as a pale yellow solid. Yield: 48.9%).

[0393] LC-MS m / z: 251.9 (M+1) +

[0394] Step 3: (S)-tert-butyl (1-(1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0395] At 100 ° C, a mixture of 4-chloro-1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazole (150 mg, 0.60 mmol, 1.0 equiv), (S)-tert-butyl pyrrolidin-3-ylcarbamate (167 mg, 0.89 mmol, 1.48 equiv) and diisopropylethylamine (0.16 mL, 0.89 mmol, 1.48 equiv) in DMSO (3 mL) was stirred for 3 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×3) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=4 / 1) to give (S)-tert-butyl(1-(1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (110 mg, yield: 30.7%) as a yellow solid.

[0396] LC-MS m / z:402.0(M+1) +

[0397] Step 4: (S)-tert-butyl (1-(5-amino-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0398] A mixture of Pd / C (55 mg, 10%) and (S)-tert-butyl (1-(1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (110 mg, 0.27 mmol) in methanol (3 mL) was hydrogenated at 15 psi for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (S)-tert-butyl (1-(5-amino-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (82 mg, yield: 72.5%) as a gray solid.

[0399] LC-MS m / z: 372.2 (M+1) +

[0400] Step 4: (S)-tert-butyl (1-(1-cyclopropyl-5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0401] To a solution of (S)-tert-butyl (1-(5-amino-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (82 mg, 0.22 mmol, 1.0 equiv) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (82 mg, 0.22 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (101 mg, 0.26 mmol, 1.18 equiv) and DIPEA (0.19 mL, 1.10 mmol, 5.0 equiv) at room temperature. The reaction temperature was raised to 50 °C, and the reaction was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=7 / 3) to give (S)-tert-butyl (1-(1-cyclopropyl-5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (92 mg, yield: 65.4%) as a yellow solid.

[0402] LC-MS m / z:606.2(M+1) +

[0403] Step 5: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)-2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0404] To a solution of (S)-tert-butyl (1-(1-cyclopropyl-5-(2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (87 mg, 0.14 mmol) in DCM (2 mL) at 25°C was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 3 hours. Water (5 mL) was added and the mixture was extracted with DCM (5 mL). The aqueous phase was freeze dried to give Example 48 as a yellow solid.

[0405] LC-MS m / z: 506.2 (M+1) +

[0406] 1 H NMR (400MHz, CD3 OD)δ8.74(d,J=9.1Hz,1H),8.51-8.32(m,2H),7.72(d,J=8.9Hz,1H),7.66–7.53(m,1H),7.22(m,2H),3.94(s,1H),3. 69(m,1H),3.52–3.32(m,2H),3.37(m,2H),2.91(s,3H),2.64(m,1H),2.09(m,1H),1.42(d,J=6.0Hz,2H),1.23(s,2H).

[0407] Example 49: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-2-(2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0408]

[0409] plan

[0410]

[0411] Step 1: (Z)-2-(2-(2,6-dichlorophenyl)hydrazono)acetaldehyde

[0412] To a mixture of glyoxal (80 mL, 40% in water) and THF (40 mL) was added dropwise a solution of (2,6-dichlorophenyl)hydrazine hydrochloride (8.0 g, 38 mmol, 1 eq.) at 25 °C. 2 O / HOAc (volume ratio = 5 / 1, 48 mL) solution. LCMS analysis of the reaction mixture showed complete conversion to the desired product. By adding saturated NaHCO 3 The mixture was quenched and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (300 mL) and purified by Na 2 SO 4 The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0 to 9%) to give (Z)-2-(2-(2,6-dichlorophenyl)hydrazono)acetaldehyde (4 g, yield: 44.3%) as a yellow solid.

[0413] LC-MS m / z: 218.9 (M+1) +

[0414] Step 2: (Z)-5-(2-(2-(2,6-dichlorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0415] To a solution of (Z)-2-(2-(2,6-dichlorophenyl)hydrazono)acetaldehyde (2 g, 9.2 mmol, 1 eq) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.46 g, 10 mmol, 1.1 eq) in THF (30 mL) was added diallylamine (2 mL) dropwise at 25°C. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was concentrated under reduced pressure to remove most of the solvent and then washed with H 2 O and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (100 mL) and purified by Na 2 SO 4 Drying and concentration gave (Z)-5-(2-(2-(2,6-dichlorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.5 g, yield: 47.8%) as a black solid, which was used directly in the next step.

[0416] Step 3: 2-(2,6-dichlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0417] In N 2 To a solution of (Z)-5-(2-(2-(2,6-dichlorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.5 g, 7.3 mmol, 1 eq) in MeOH (50 mL) was added NaOMe (0.59 g, 10.9 mmol, 1.5 eq). The reaction mixture was stirred at 70 °C. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was concentrated under reduced pressure to remove most of the solvent and washed with H 2 O (100 mL) and washed with ethyl acetate (200 mL). The aqueous phase was adjusted to pH = 3 with citric acid and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (100 mL) and purified by Na 2 SO 4 The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH, from 0 to 1%) to give 2-(2,6-dichlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.6 g, yield: 26.0%) as a yellow solid.

[0418] LC-MS m / z:283(M-1) -

[0419] 1 H NMR (400MHz, d 6-DMSO): δ13.77(s,1H),8.27(d,J=4.0Hz,1H),7.95(d,J=4.0Hz,1H),7.72(d,J=8.4Hz,2H),7.61-7.57(m,1H).

[0420] Step 4: tert-butyl N-[(3S)-1-{5-[2-(2,6-dichlorophenyl)-3-oxopyridazine-4-amido]-2,3-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0421] To a solution of tert-butyl N-[(3S)-1-(5-amino-1,2-dimethyl-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (50 mg, 0.14 mmol, 1.0 equiv) and 2-(2,6-dichlorophenyl)-3-oxopyridazine-4-carboxylic acid (41 mg, 0.14 mmol, 1.0 equiv) in DMF (0.5 mL) was added HATU (66 mg, 0.17 mmol, 1.2 equiv) and DIPEA (0.12 mL, 0.72 mmol, 5.0 equiv). The reaction mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=97 / 3) to give N-[(3S)-1-{5-[2-(2,6-dichlorophenyl)-3-oxopyridazin-4-ylamino]-1,3-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (76 mg, yield: 85.7%) as an orange solid.

[0422] LC-MSm / z:612.18(M+1) +

[0423] Step 5: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-1,2-dimethyl-1,3-benzodiazol-5-yl}-2-(2,6-dichlorophenyl)-3-oxopyridazine-4-carboxamide hydrochloride

[0424] To a solution of tert-butyl N-[(3S)-1-{5-[2-(2,6-dichlorophenyl)-3-oxopyridazine-4-amido]-1,3-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (76 mg, 0.12 mmol) in DCM (2.0 mL) was added a solution of hydrogen chloride in 1,4-dioxane (0.2 mL, 4 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give the hydrochloride salt of Example 49 (41.5 mg, yield: 55.9%) as a yellow solid.

[0425] LC-MS m / z:512.1(M+1) +

[0426] 1 H NMR (400MHz, CD 3 OD)δ8.89(d,J=5.5Hz,1H),8.61(d,J=4.2Hz,1H),8.56(d,J=4.2Hz,1H),7.80(d,J=9.0Hz,1H),7.75-7.72(m,2H),7.69-7.61(m,1H),4.1 0-4.07(m,1H),4.01(s,3H),3.87-3.83(m,1H),3.56-3,52(m,1H),3.44–3.36(m,1H),2.93(s,3H),2.74-2.70(m,1H),2.17–1.97(m,1H).

[0427] Example 50: tert-Butyl N-[(3S)-1-{5-[2-(5-fluoro-2-methoxyphenyl)-3-oxopyridazine-4-amido]-1,2-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate hydrochloride

[0428]

[0429] plan

[0430]

[0431] Step 1: (5-Fluoro-2-methoxyphenyl)hydrazine

[0432] To a solution of 5-fluoro-2-methoxyaniline (1 g, 7.7 mmol, 1 eq.) in 5 M HCl (10 mL) was slowly added NaNO 2 (0.64 g, 9.2 mmol, 1.3 equiv.) After stirring at 0-5°C for 2 hours, SnCl was added to the reaction mixture at 0-5°C. 2(3.37 g, 17.7 mmol, 2.5 equiv.). LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was quenched by adding 1 M NaOH and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine 50 mL and purified by Na 2 SO 4 The solution was dried and filtered. The filtrate was concentrated to give (5-fluoro-2-methoxyphenyl)hydrazine (0.8 g, yield: 57.8%) as a black solid.

[0433] LC-MS m / z:157.1(M+1) +

[0434] Step 2: (Z)-2-(2-(5-fluoro-2-methoxyphenyl)hydrazono)acetaldehyde

[0435] To a mixture of glyoxal (10 mL, 40% in water) and THF (5 mL) was added a solution of (5-fluoro-2-methoxyphenyl)hydrazine (0.8 g, 5.1 mmol, 1 eq.) at 25 °C. 2 O / HOAc (volume ratio = 1 / 1, 10 mL) solution. LCMS analysis of the reaction mixture showed complete conversion to the desired product. By adding saturated NaHCO 3 The mixture was quenched and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate, from 0% to 10%) to give (Z)-2-(2-(5-fluoro-2-methoxyphenyl)hydrazono)acetaldehyde (0.8 g, yield: 72.6%) as a yellow solid.

[0436] LC-MS m / z: 197.1 (M+1) +

[0437] Step 3: (Z)-5-(2-(2-(5-fluoro-2-methoxyphenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0438] To a solution of (Z)-2-(2-(5-fluoro-2-methoxyphenyl)hydrazono)acetaldehyde (0.8 g, 4.1 mmol, 1 eq.) and 2,2-dimethyl-1,3-dioxane-4,6-dione (0.65 g, 4.5 mmol, 1.1 eq.) in THF (20 mL) was added diallylamine (0.8 mL) dropwise at 25 °C. The reaction mixture was stirred at the same temperature for 1 hour. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was concentrated under reduced pressure to remove most of the solvent and then washed with H 2 O and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give (Z)-5-(2-(2-(5-fluoro-2-methoxyphenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1 g, yield: 53.7%) as a black solid, which was used directly in the next step.

[0439] MS (ES-API negative): 321.0 (M-1) -

[0440] Step 4: 2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0441] In N 2 To a solution of (Z)-5-(2-(2-(5-fluoro-2-methoxyphenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1 g, 3.1 mmol, 1 eq) in MeOH (20 mL) was added NaOMe (0.25 g, 4.6 mmol, 1.5 eq). The reaction mixture was stirred at 70 °C for 3 h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was concentrated under reduced pressure to remove most of the solvent and washed with H 2 O and washed with ethyl acetate (20 mL). The aqueous phase was adjusted to pH = 3 with citric acid and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH, from 0 to 1%) to give 2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.3 g, yield: 32.3%) as a light brown solid.

[0442] LC-MS m / z: 264.9 (M+1) +

[0443] 1 HNMR (400MHz, d 6 -DMSO) δ13.66(s,1H),8.20(d,J=4.0Hz,1H),7.95(d,J=4.0Hz,1H),7.42-7.35(m,2H),7.25(dd,J=9.2,4.8Hz,1H),3.75(s,3H).

[0444] Step 5: (S)-tert-butyl (1-(5-(2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0445] To a solution of (S)-tert-butyl (1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (157 mg, 0.45 mmol, 1.2 equiv) and 2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.38 mmol, 1 equiv) in DMF (2 mL) was added HATU (216 mg, 0.57 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.19 mL, 1.14 mmol, 3.0 equiv). The reaction was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (100 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a crude product, which was purified by SGC (UV254, DCM:MeOH=20:1) to give (S)-tert-butyl(1-(5-(2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (200 mg, yield: 67.0%) as a light brown solid.

[0446] LC-MS m / z:592.3(M+1) +

[0447] Step 6: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0448] To a solution of (S)-tert-butyl(1-(5-(2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (70 mg, 0.12 mmol, 1.0 equiv) in DCM (5 mL) was added HCl in 1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated and washed with DCM to give Example 50 hydrochloride (26.6 mg, yield: 42.3%) as a yellow solid.

[0449] LC-MS m / z:492.1(M+1) +

[0450] 1 H NMR (400MHz, d 6 -DMSO) δ12.17(s,1H),8.55(s,1H),8.41(d,J=4.4Hz,1H),8.36(d,J=4.4Hz,1H),8.19(s,2H),7.77(br,1H),7.45-7.43(m,2H),7 .32-7.30(m,1H),3.87(s,3H),3.80(s,3H),3.76-3.74(m,1H),3.28(s,2H),2.82(s,2H),2.51(s,3H),2.43(s,1H),1.99(s,1H).

[0451] Example 51: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0452]

[0453] plan

[0454]

[0455] Step 1: 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0456] At 0°C. To a solution of 3-(methoxycarbonyl)-2-oxo-1,2-dihydropyran (1 g, 6.49 mmol, 1 eq) in DMF (5 mL) was added 2-fluoro-6-methoxyaniline (0.92 g, 6.49 mmol, 1 eq). After stirring for 7 hours, EDCI (2.1 g, 8.43 mmol, 1.3 eq) and DMAP (0.2 g, 1.62 mmol, 0.25 eq) were added to the reaction. The reaction was stirred at 26°C for 16 hours to give a brown solution. LCMS showed that the reaction was turbid and the starting material was consumed. The reaction was washed with H 2 O and extracted with EA (20 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was triturated with i-PrOH and filtered, and the filtrate was concentrated to give methyl 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (2.3 g, crude) as a brown oil, which was used directly in the next step.

[0457] LC-MS m / z: 278.1 (M+1) +

[0458] Step 2: 1-(2-Fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0459] To a solution of methyl 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (6.49 mmol, 1 eq.) in MeOH (20 mL) was added NaOH solution (2.08 g, 51.92 mmol, 8 eq.) and H 2 O (30 mL) solution. The reactant was stirred at 65 °C for 1 hour to obtain a dark brown solution. LCMS showed that the starting material was completely consumed and a peak with the desired mass was detected. The reactant was washed with H 2 O and washed with EA (30 mL x 3). The aqueous layer was acidified to pH = 1-2 with 1N HCl and extracted with EA (30 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (523 mg, yield: 30.58%) as a brown solid.

[0460] LC-MS m / z: 262.1 (M-1) -

[0461] Step 3: (1R,4R)-5-(4-fluoro-2-(1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0462] To a solution of 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (79.35 mg, 301.47 μmol, 1.5 eq.) and (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (65 mg, 200.98 μmol, 1 eq.) in DMF (2 mL) was added HATU (152.84 mg, 401.96 μmol, 2 eq.) and DIEA (77.93 mg, 602.95 μmol, 3 eq.). The reaction was stirred at 26 °C for 16 h to give a dark brown solution. LCMS showed that the starting material was consumed and a peak with the desired mass was detected. The reaction was treated with H2O and acidified to pH = 4-5 with 1N HCl. The mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness and use it directly in the next step.

[0463] LC-MS m / z:553.2(M+1) +

[0464] Step 4: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0465] A solution of (1R,4R)-tert-butyl 5-(4-fluoro-2-(1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200.98 μmol, 1 eq) in TFA (3 mL) was stirred for 15 min to give a dark brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was basified with concentrated hydrochloric acid. Na 2 CO 3 The aqueous solution was adjusted to pH = 10-11 and extracted with EA (10 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4Dry, filter and concentrate to dryness. The residue was purified by flash column (C18, eluted with 70% ACN / H2O, 0.01% TFA). The collected stream was concentrated and lyophilized to give Example 51 (38.5 mg, yield: 42.34%) as an off-white solid.

[0466] LC-MS m / z:453.2(M+1) +

[0467] 1 H NMR (400MHz, CD 3 OD)δ12.17(d,J=10.5Hz,1H),8.74(dt,J=7.3,2.0Hz,1H),8.26(ddd,J=11.1,3.1,1.9Hz,1H),7.85(dd,J=6.6,2. 2Hz,1H),7.57(td,J=8.6,6.5Hz,1H),7.26(ddd,J=8.4,5.5,2.5Hz,1H),7.16–7.07(m,1H),7.04–6.94(m,1H),6.8 7(tdd,J=9.1,3.1,1.3Hz,1H),6.76(ddd,J=7.5,6.6,1.0Hz,1H),4.38(s,1H),3.94–3.90(m,1H),3.88(d,J=2.5H z,3H),3.70–3.56(m,1H),3.47–3.38(m,2H),3.20–3.13(m,1H),2.38(dd,J=16.1,11.4Hz,1H),1.91–1.82(m,1H).

[0468]

[0469]

[0470]

[0471] Example 55: 2-((2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0472]

[0473] plan

[0474]

[0475] Step 1: 6-(2-Fluoro-6-methoxyphenyl)picolinic acid

[0476] In N 2 6-Bromopicolinic acid (1 g, 4.95 mmol, 1 eq.) and (2-fluoro-6-methoxyphenyl)boronic acid (0.84 g, 4.95 mmol, 1 eq.) in dioxane (15 mL) and H 2 Add K into the O (3 mL) solution 3 PO 4 (2.1 g, 9.9 mmol, 2 eq) and XPhos Pd G2 (0.19 g, 0.25 mmol, 0.05 eq). The reaction was warmed to 80 °C and stirred for 2 hours to give a yellow suspension. LCMS showed that most of the starting material was consumed and a major peak with the desired mass was detected. The reaction was acidified to pH = 3-4 with 1N HCl and extracted with EA (20 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The resulting product is triturated with ACN and filtered. The filtrate is concentrated and lyophilized to give 6-(2-fluoro-6-methoxyphenyl)picolinic acid (1.09 g, yield: 89.34%) as an off-white solid.

[0477] LC-MS m / z: 246.2 (M-1) -

[0478] Step 2: 2-Carboxy-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0479] To a solution of 6-(2-fluoro-6-methoxyphenyl)picolinic acid (1 g, 4.04 mmol, 1 eq.) in DCE (80 mL) was added K 2 HPO 4 (3.52 g, 20.22 mmol, 5 eq.) and m-CPBA (4.11 g, 20.22 mmol, 5 eq.). The reaction was warmed to 70 °C and stirred for 5 hours to give a light yellow suspension. LCMS showed that about half of the starting material remained and a main peak with the desired mass was detected. The reaction was stirred at 70 °C for another 5 hours to give a light yellow suspension. LCMS showed that most of the starting material was consumed and a main peak with the desired mass was detected. The reaction was heated to 40 °C and stirred for 5 hours. 2 O and extracted with IPA / DCM=1 / 3 (30 mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave 2-carboxy-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (1.2 g) as a brown oil.

[0480] LC-MS m / z: 264.2 (M+1) +

[0481] Step 3: 2-((2-((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0482] To a solution of 2-carboxy-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (256.91 mg, 976.02 μmol, 3 eq) and (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 325.34 μmol, 1 eq) in DMF (3 mL) was added HATU (371.12 mg, 976.02 μmol, 3 eq) and DIEA (210.25 mg, 1.63 mmol, 5 eq). The reaction was stirred at 26 °C for 1 hour to give a dark brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was purified by H 2 O and acidified with 1N HCl to pH = 4-5. The mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration gave 2-((2-((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (450 mg, crude) as a brown oil.

[0483] LC-MS m / z: 553.3 (M+1) +

[0484] Step 4: 2-((2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0485] A solution of 2-((2-((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (325.34 μmol, 1 eq) in TFA (5 mL) was stirred at 26°C for 30 min to give a dark brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was purified by HPLC with H 2 O and diluted with NaHCO 3 Alkalization. 2 CO 3 The aqueous solution was adjusted to pH = 10-11. The mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was purified by flash column (C18, 70% ACN in H2O containing TFA). 2 The collected fractions were concentrated and lyophilized to give Example 55 (104.4 mg, yield: 70.92%) as an off-white foam.

[0486] LC-MS m / z:453.2(M+1) +

[0487] 1 H NMR (400MHz, d 6 -DMSO) δ13.81(s,1H),8.74(s,2H),8.47(ddd,J=8.0,2.2,0.8Hz,1H),8.18(ddd,J=11.2,8.4,3.1Hz,1H),7.93–7.83(m,1H),7.86 –7.70(m,1H),7.62–7.47(m,1H),7.36(dd,J=8.9,5.6Hz,1H),7.11–6.94(m,3H),4.36(s,1H),3.96(d,J=4.4Hz,1H),3.79(d,J=1.3 Hz,3H),3.48(t,J=10.1 Hz,1H),3.04(d,J=8.9 Hz,1H),2.14–2.03(m,1H),1.74(t,J=10.5 Hz,1H).

[0488]

[0489]

[0490]

[0491]

[0492]

[0493] Example 64: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxamide

[0494]

[0495] plan

[0496]

[0497] Step 1: 2-(2-Fluoro-6-methoxyphenyl)thiazole-4-carboxylic acid

[0498] In N 2 4-bromothiazole-2-carboxylic acid (1 g, 4.81 mmol, 1 eq.) and (2-fluoro-6-methoxyphenyl)boronic acid (0.98 g, 5.77 mmol, 1.2 eq.) in dioxane (15 mL) and H 2 Add K into the O (3 mL) solution 3 PO 4 The mixture was stirred for 1 h at 4 °C for 2 h at 4 °C for 3 hours. The mixture was stirred for 2 h at 4 °C for 3 hours. The mixture was stirred for 1 h at 4 °C for 2 hours. The mixture was stirred for 2 h at 4 °C for 3 ...

[0499] LC-MS m / z:252.1(M-1) -

[0500] Step 2: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxamide

[0501] In N 2HATU (911.10 mg, 2.40 mmol, 1.5 eq) and DIEA (412.93 mg, 3.19 mmol, 2 eq) were added to a solution of 2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxylic acid (404.54 mg, 1.60 mmol, 1 eq) in DMF (5 mL) under 4% CO 2 0.5% CO 2 0.5% CO 2 0.6% CO 2 0.7% CO 2 0.8% CO 2 0.9% CO 2 0.9% CO 2 0.8 ... 2 O and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The resulting product was dissolved in TFA (3 mL) and stirred at 45° C. for 3 hours to obtain a black eyebrow solution. LCMS showed that two peaks with the desired mass were detected. The reaction was concentrated to remove most of the solvent and filtered through a flash column (C18, 90% ACN in H2O containing TFA). 2 The collected fractions were concentrated and lyophilized to give Example 64 (9.9 mg) as a grey solid.

[0502] LC-MS m / z: 443.2 (M+1) +

[0503] 1 H NMR (400MHz, d 6 -DMSO): δ10.05(s,1H),8.87(s,1H),8.78(s,1H),8.71(s,1H),8.11(dd,J=1 0.6,3.0Hz,1H),7.64–7.54(m,1H),7.39(dd,J=9.0,5.6Hz,1H),7.15(d,J=8 .5Hz,1H),7.11–6.98(m,2H),4.43(s,1H),4.01(s,1H),3.97(s,3H),3.52(d ,J=11.1Hz,1H),3.10(s,1H),2.21(d,J=11.2Hz,1H),1.88(d,J=10.8Hz,1H).

[0504] Example 65: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxamide

[0505]

[0506] plan

[0507]

[0508] Step 1: 4-(2-Fluoro-6-methoxyphenyl)thiazole-2-carboxylic acid

[0509] In N 2 4-bromothiazole-2-carboxylic acid (1 g, 4.81 mmol, 1 eq.) and (2-fluoro-6-methoxyphenyl)boronic acid (0.98 g, 5.77 mmol, 1.2 eq.) in dioxane (15 mL) and H 2 Add K into the O (3 mL) solution 3 PO 4 The reaction mixture was heated to 80 ° C in a microwave and stirred for 1.5 hours to give an off-white suspension. LCMS showed that a peak with the desired mass was detected and the starting material was exhausted. The reactant was diluted with DCM / MeOH=10 / 1 and filtered through a celite pad. The solution was concentrated to dryness. The residue was ground with EA, filtered and dried in air to give 4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxylic acid (0.57 g, yield: 46.72%) as an off-white solid.

[0510] LC-MS m / z:252.1(M-1) -

[0511] Step 2: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxamide

[0512] In N 2 HATU (556.68 mg, 1.46 mmol, 1.5 eq) and DIEA (252.30 mg, 1.95 mmol, 2 eq) were added to a solution of 4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxylic acid (247.18 mg, 0.98 mmol, 1 eq) in DMF (3 mL) under 4% CO 2 0 4 0 0 0 0 0 1 0 1 0 2 0 3 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 2 O and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO4 The reaction mixture was dried, filtered and concentrated to dryness. The obtained product was dissolved in TFA (3 mL) and stirred for 16 hours to give a dark brown solution. LCMS showed that a main peak with the desired mass was detected. The reaction was concentrated to remove most of the solvent and passed through a flash column (C18, 90% ACN in H2O containing TFA). 2 The collected fractions were concentrated and lyophilized to give Example 65 (141.5 mg, yield: 32.76%) as an off-white solid.

[0513] LC-MS m / z: 443.2 (M+1) +

[0514] 1 H NMR (400MHz, d 6 -DMSO): δ10.13(s,1H),8.99(s,1H),8.78(s,1H),8.22(s,1H),7.82(dd,J=10.3,3.0H z,1H),7.55–7.45(m,1H),7.30(dd,J=9.3,5.4Hz,1H),7.05(t,J=7.6Hz,2H),6.97(t, J=8.9Hz,1H),4.41(d,J=3.3Hz,1H),4.08(s,1H),3.81(s,3H),3.55(d,J=11.0Hz,1H) ,3.30(d,J=11.4Hz,1H),3.12(s,1H),2.09(d,J=11.0Hz,1H),1.84(d,J=10.9Hz,1H).

[0515] Example 66: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-tert-butyl (S)-N-(4-(3-aminopyrrolidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0516]

[0517] plan

[0518]

[0519] Step 1: 2H-pyran-2,6(3H)-dione

[0520] A solution of (E)-pent-2-enedioic acid (3 g, 23.06 mmol, 1 eq) in acetic anhydride (9.42 g, 92.24 mmol, 4 eq) was stirred at 150 °C for 1 hour to give a dark brown solution. No monitoring was performed. The reaction was concentrated to give 2H-pyran-2,6(3H)-dione (2.6 g, yield: 100.78%) as a black solid.

[0521] Step 2: (Z)-3-(2-(2-fluoro-6-methoxyphenyl)hydrazono)-2H-pyran-2,6(3H)-dione

[0522] At 0 °C, 2-fluoro-6-methoxyaniline (1.5 g, 10.63 mmol, 1 eq.) was added in portions to a solution of H 2 O (40 mL) and 12N HCl (12 mL) solution was added with NaNO 2 (0.95 g, 13.82 mmol, 1.3 equivalents). After stirring at 0°C for 1 hour, 2H-pyran-2,6(3H)-dione (1.19 g, 10.63 mmol, 1 equivalent) and Na 2 CO 3 (0.56 g, 5.31 mmol, 0.5 eq) 2 O (40 mL) solution was added dropwise to the reaction. The reaction was stirred for 16 hours to give a brown suspension. LCMS showed that the reaction was turbid and a peak with the desired mass was detected. The reaction was filtered and the filter cake was washed with H 2 O and dried by oil pump to give (Z)-3-(2-(2-fluoro-6-methoxyphenyl)hydrazono)-2H-pyran-2,6(3H)-dione (1 g, yield: 35.59%) as a brown solid.

[0523] LC-MS m / z: 265.1 (M+1) +

[0524] Step 3: 1-(2-Fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0525] To (Z)-3-(2-(2-fluoro-6-methoxyphenyl)hydrazono)-2H-pyran-2,6(3H)-dione (1 g, 3.78 mmol, 1 eq.) 2O (30mL) solution was added with KOH (1.06 g, 18.92 mmol, 5 equivalents). The reaction was stirred at 100 ° C for 3 hours to obtain a dark brown solution. LCMS showed that the starting material was consumed and a new peak with the desired mass was detected. The reaction was acidified with 1N HCl to pH = 2-3 and extracted with EA (20 mL × 3). The combined organic layer was washed with brine and purified by Na 2 SO 4 The residue was purified by flash column (C18, eluted with 62% ACN in H 2 The collected stream was acidified to pH = 2-3 with 1N HCl and extracted with EA (20 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness. The obtained product was lyophilized to give 1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (103 mg, yield: 10.3%) as a light brown solid.

[0526] LC-MS m / z: 263.1 (M-1) -

[0527] Step 4: (S)-tert-butyl (1-(5-(1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0528] To a solution of 1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (70 mg, 264.94 μmol, 1 eq) and (S)-tert-butyl (1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100.67 mg, 291.43 μmol, 1.1 eq) in DMF (2 mL) was added HATU (151.11 mg, 397.41 μmol, 1.5 eq) and DIEA (102.73 mg, 794.82 μmol, 3 eq). The reaction was stirred at 18 °C for 16 h to give a dark brown solution. LCMS showed that the starting material was consumed and one peak with the desired mass was detected. The reaction was treated with H2O and extracted with EA (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl(1-(5-(1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (205 mg, 95%) as a light brown solid. Yield: 130.78%).

[0529] LC-MS m / z:592.3(M+1) +

[0530] Step 5: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0531] To a solution of (S)-tert-butyl(1-(5-(1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (264.94 μmol, 1 eq.) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred for 30 minutes to give a dark brown solution. LCMS showed that the starting material was exhausted and one major peak with the desired mass was detected. The reaction was basified with concentrated hydrochloric acid. NaHCO3 aqueous solution was adjusted to pH = 9-10 and extracted with DCM / i-PrOH = 3 / 1 (10 mL×3). The combined organic layers were washed with brine and purified by MgSO 4 Dried, filtered and concentrated to dryness.The residue was purified by flash column (C18, eluted with 48% ACN / H2O, containing 0.1% HCOOH) and the stream was lyophilized to give Example 66 (32.18 mg, yield: 24.72%) as a light yellow solid.

[0532] LC-MS m / z:492.2(M+1) +

[0533] 1 H NMR (400MHz, CD 3 OD): δ8.27(dd,J=8.8,3.4Hz,1H),8.20(d,J=9.8Hz,1H),7.59(td,J=8.6,6 .5Hz,1H),7.37(dd,J=8.8,1.6Hz,1H),7.27(d,J=9.8Hz,1H),7.15–7.08(m, 1H),7.02(tt,J=8.5,1.1Hz,1H),3.89(d,J=1.5Hz,3H),3.79(s,3H),3.65–3 .37(m,3H),3.35(s,1H),3.28–3.11(m,1H),2.62(s,3H),2.13–1.93(m,2H).

[0534] Example 67: (R)-N-(4-(3-aminopiperidin-1-yl)-1,6-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0535]

[0536] plan

[0537]

[0538] Step 1: 2H-pyran-2,6(3H)-dione

[0539] A solution of (E)-pent-2-enedioic acid (15 g, 115.3 mmol, 1 eq) in acetic anhydride (47.08 g, 461.19 mmol, 4 eq) was stirred at 150° C. for 1 hour to give a dark brown solution. The reaction was concentrated to give 2H-pyran-2,6(3H)-dione (14.3 g, 110.7%) as a black solid.

[0540] Step 2: (Z)-3-(2-(2,6-difluorophenyl)hydrazono)-2H-pyran-2,6(3H)-dione

[0541] At 0 °C, 2,6-difluoroaniline (22.33 g, 172.95 mmol, 1.5 eq.) was reacted with H 2 O (300 mL) and 12N HCl (80 mL) solution were added with NaNO in batches.2 (11.93 g, 172.95 mmol, 1.5 equivalents) to obtain a light brown solution. After stirring at 0°C for 1 hour, 2H-pyran-2,6(3H)-dione (115.3 mmol, 1 equivalent) and Na 2 CO 3 (7.33 g, 69.18 mmol, 0.6 eq) of H 2 O (100 mL) and THF (50 mL) solution were added dropwise to the reaction. The reaction was stirred at room temperature for 16 hours to give a brown suspension. LCMS showed that the starting material was exhausted and a peak with the desired mass was detected. The reaction was filtered and the filter cake was washed with H 2 O and dried by oil pump to give (Z)-3-(2-(2,6-difluorophenyl)hydrazono)-2H-pyran-2,6(3H)-dione (23 g, yield: 79.3%) as a brown solid.

[0542] LC-MS m / z: 253.1 (M+1) +

[0543] Step 3: 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0544] To (Z)-3-(2-(2,6-difluorophenyl)hydrazono)-2H-pyran-2,6(3H)-dione (23 g, 91.21 mmol, 1 equivalent) 2 O (300mL) solution was added with KOH (10.23g, 182.41mmol, 2 equivalents). The reaction was stirred at 100°C for 3 hours to obtain a dark brown solution. LCMS showed that the starting material was consumed and a new peak with the desired mass was detected. The reaction was acidified with 1N HCl to pH = 2-3 and extracted with EA (20mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness.The residue was purified by flash column (silica gel column, eluted with 30% to 50% EA / PE) to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (5 g) as a light red solid.

[0545] LC-MS m / z: 253.1 (M+1) +

[0546] Step 4: (R)-tert-butyl (1-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate

[0547] To a solution of 4-chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole (300 mg, 1.33 mmol, 1.0 equiv) in DMSO (5 mL) was added TEA (269.09 mg, 2.66 mmol, 2.0 equiv) and (R)-tert-butyl piperidin-3-ylcarbamate (532.59 mg, 2.66 mmol, 2.0 equiv). The reactants were stirred at 100 °C for 2 hours to give a yellow solution. LCMS showed a major peak with the desired mass and the material was almost consumed. The reactants were poured into water and filtered. The filter cake was dried to give compound (R)-tert-butyl (1-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazole-4-yl)piperidin-3-yl)carbamate (517.8 mg, yield: 100%) as a yellow solid.

[0548] LC-MS m / z: 390.2 (M+1) +

[0549] Step 5: (R)-tert-butyl (1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate

[0550] Pd / C (26 mg) was added to a solution of (R)-(1-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamic acid tert-butyl ester (517.82 mg, 1.33 mmol, 1.0 equiv) in MeOH (5 mL). The reactant was stirred overnight at 20 ° C to give a brown green suspension. LCMS showed a main peak with the desired mass, and the material was almost consumed. The reactant was diluted with DCM:MeOH=10:1 and filtered through a celite pad. The filtrate was concentrated to dryness to give compound (R)-(1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamic acid tert-butyl ester (532 mg, yield: 111%) as a brown solid.

[0551] LC-MS m / z: 360.23 (M+1) +

[0552] Step 6: (R)-N-(4-(3-aminopiperidin-1-yl)-1,6-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0553] HATU (113.09 mg, 297.41 μmol, 1.5 eq) and DIEA (0.065 mL) were added to a solution of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 198.27 μmol, 1.0 eq) in DMF (1 mL) and stirred at 20 °C for 40 minutes. Then (R)-tert-butyl (1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate (71.27 mg, 198.27 μmol, 1.0 eq) was added. The reaction was stirred at 20 °C overnight to give a brown suspension. LCMS showed one of the main peaks with the desired mass and the material was almost consumed. The reaction was washed with water and extracted with DCM (3X), the organic phase was concentrated to dryness under reduced pressure and TFA (1 mL) was added and stirred for 10 min. The mixture was washed with NaHCO 3 Adjust to pH 7-8, extract with DCM (3X), and concentrate the organic phase to dryness under reduced pressure. The crude product is purified by flash column (C18, peak time = 30% ACN / H 2 O, COMBI FLASH NEXTAGEN 300) to give Example 67 (57.83 mg, yield: 49%) as a yellow solid.

[0554] LC-MS m / z:494.20(M+1) +

[0555] 1 H NMR (400MHz, CD 3 OD)δ8.40(d,J=8.8Hz,1H),8.24(d,J=9.8Hz,1H),7.74(m,J=8.6,6.3Hz,1 H),7.43–7.31(m,4H),3.79(s,3H),3.60(t,J=10.7Hz,1H),3.37(m,J=11. 7,2.5Hz,1H),3.22–3.11(m,1H),3.00–2.79(m,2H),2.63(s,3H),1.90–1. 69(m,2H),1.52(m,J=23.9,12.2,3.7Hz,1H),1.32(m,J=16.3,8.6Hz,1H).

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572] Example 97: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-cyclopropyl-1-methyl-1,3-benzodiazol-5-yl}-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0573]

[0574] plan

[0575]

[0576]

[0577] Step 1: N-(2-chloro-6-fluorophenyl)cyclopropanecarboxamide

[0578] At 0 ° C, to 2-chloro-6-fluoroaniline (2.0 g, 13.7 mmol, 1.0 eq.) and DIPEA (3.4 mL, 20.55 mmol, 1.5 eq.) in DCM (20 mL) solution was added dropwise cyclopropanecarbonyl chloride (1.48 mL, 16.44 mmol, 1.2 eq.) in DCM (10 mL). The reaction mixture was stirred at the same temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluted with petroleum ether / EtOAc=1 / 1) to give N-(2-chloro-6-fluorophenyl)cyclopropanecarboxamide (2.2 g, yield: 71.5%) as a white solid.

[0579] LC-MS m / z: 214.1 (M+1) +

[0580] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)cyclopropanecarboxamide

[0581] At -55 °C, H 2 SO 4 A solution of concentrated nitric acid (0.6 mL, 11.6 mmol, 1.13 equivalents) was added dropwise to the solution (10 mL). The reaction mixture was stirred for 2 hours at the same temperature. The resulting mixture was warmed to room temperature and then quenched with ice water (30 mL) to give N-(2-chloro-6-fluoro-3-nitrophenyl)cyclopropanecarboxamide (2 g, yield: 70.9%) as a yellow solid.

[0582] LC-MS m / z: 259.1 (M+1) +

[0583] Step 3: 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole

[0584] To a solution of N-(2-chloro-6-fluoro-3-nitrophenyl)cyclopropanecarboxamide (500 mg, 1.93 mmol, 1 eq.) and TEA (1 mL) in DMSO (5 mL) was added CH 3 NH 2 The reaction was stirred at room temperature for 4 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine (50 mL × 3) and then purified by Na 2 SO 4Drying, filtration and concentration under reduced pressure gave a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=2 / 1) to give 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole (210 mg, yield: 42.8%) as a yellow solid.

[0585] LC-MS m / z:252.0(M+1) +

[0586] Step 4: tert-Butyl N-[(3S)-1-(2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0587] To a solution of 4-chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole (100 mg, 0.40 mmol, 1.0 equiv) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (89 mg, 0.48 mmol, 1.2 equiv) in DMSO (1.5 mL) was added diisopropylethylamine (103 mg, 0.79 mmol, 2 equiv). The reaction mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL×3) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=3 / 1) to give tert-butyl N-[(3S)-1-(2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (130 mg, yield: 77.4%) as a yellow solid.

[0588] LC-MS m / z:402.1(M+1) +

[0589] Step 5: (S)-tert-butyl (1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0590] A mixture of Pd / C (60 mg, 10%) and tert-butyl N-[(3S)-1-(2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (100 mg, 0.25 mmol) in methanol (5 mL) was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, yield: 70.7%) as a white solid.

[0591] LC-MS m / z: 372.3 (M+1) +

[0592] Step 6: tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazine-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0593] To a solution of (S)-tert-butyl (1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.21 mmol, 1.2 equiv) and 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.18 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (86 mg, 0.22 mmol, 1.5 equiv) and DIPEA (0.14 mL, 0.63 mmol, 3.0 equiv). The reaction mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a crude product, which was purified by SGC (UV254, petroleum ether: EtOAc = 3: 1) to give tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazine-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (55 mg, yield: 40.1%) as a yellow solid.

[0594] LC-MS m / z:606.3(M+1) +

[0595] Step 7: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-cyclopropyl-1-methyl-1,3-benzodiazol-5-yl}-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0596] To a solution of tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazine-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (35 mg, 0.052 mmol, 1.0 equiv) in DCM (3 mL) was added HCl in EtOAC (0.5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 97 (29.7 mg, yield: 59.5%) as a yellow solid.

[0597] LC-MS m / z: 506.3 (M+1) +

[0598] 1 H NMR (400MHz, CD 3 OD)δ8.22(d,J=9.9Hz,1H),8.11(d,J=8.6Hz,1H),7.73-7.64(m,2H),7.36-7.32(m,3H),4.08(s,3H),3.84-3.70(m ,3H),3.46–3.37(m,1H),3.29-3.26(m,1H),2.50-2.40(m,1H),2.28-2.13(m,2H),1.58(m,2H),1.47-1.45(m,2H).

[0599] Example 98: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-tert-butyl-1-methyl-1,3-benzodiazol-5-yl}-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0600]

[0601] plan

[0602]

[0603]

[0604] Step 1: N-(2-chloro-6-fluorophenyl)-2,2-dimethylpropionamide

[0605] To a solution of 2-chloro-6-fluoroaniline (2.0 g, 13.7 mmol, 1.0 equiv) and DIPEA (3.4 mL, 20.55 mmol, 1.5 equiv) in DCM (20 mL) was added a solution of 2,2-dimethylpropanoyl chloride (1.98 g, 16.44 mmol, 1.2 equiv) in DCM (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=3 / 1) to give N-(2-chloro-6-fluorophenyl)pivalamide (2.4 g, yield: 55.3%) as a white solid.

[0606] LC-MS m / z: 230.2 (M+1) +

[0607] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2-dimethylpropionamide

[0608] At -55 °C, N-(2-chloro-6-fluorophenyl)-2,2-dimethylpropanamide (2.4 g, 10.4 mmol, 1.0 equiv) was reacted with H 2 SO 4 Concentrated nitric acid (0.6 mL, 11.6 mmol, 1.12 equivalents) was added dropwise to the H 2 SO 4 (2mL) solution. The reaction mixture was stirred for 2 hours at the same temperature. The resulting mixture was warmed to room temperature and then quenched with ice water (30mL) to give N-(2-chloro-6-fluoro-3-nitrophenyl)-pivalamide (2.8 g, yield: 88.5%) as a yellow solid.

[0609] LC-MS m / z: 275.1 (M+1) +

[0610] Step 3: 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole

[0611] To a solution of a mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2-dimethylpropanamide (500 mg, 1.82 mmol, 1 eq.) and TEA (388 mg, 3.83 mmol, 2 eq.) in DMSO (5 mL) was added CH 3 NH 2 THF solution (2M, 113 mg, 3.64 mmol, 2 equivalents). Continue stirring the reaction for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (50 mL×3) and washed with Na2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue, which was purified by flash column chromatography (eluted with petroleum ether / EtOAc=3 / 1) to give 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole (150 mg, yield: 43.6%) as a yellow solid.

[0612] LC-MS m / z: 268.0 (M+1) +

[0613] Step 4: tert-butyl N-[(3S)-1-(2-tert-butyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0614] At 100°C, a mixture of 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole (150 mg, 0.56 mmol, 1.0 equiv), diisopropylethylamine (290 mg, 2.24 mmol, 4 equiv) and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (88 mg, 0.43 mmol, 1.2 equiv) was stirred in a DMSO solution for 4 hours. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL×3) and purified by Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to give a residue, which was purified by SGC (UV254, petroleum ether: EtOAc = 3: 1) to give tert-butyl N-[(3S)-1-(2-tert-butyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (190 mg, 95%) as a yellow solid. Yield: 77.2%).

[0615] LC-MS m / z:418.2(M+1) +

[0616] Step 5: tert-butyl N-[(3S)-1-(5-amino-2-tert-butyl-1-methyl-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0617] A mixture of Pd / C (79 mg, 0.25 mmol, 10%) and tert-butyl N-[(3S)-1-(2-tert-butyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (190 mg, 0.46 mmol) in methanol (5 mL) was hydrogenated at 15 psi for 2 hours. The reaction mixture was filtered and concentrated to give tert-butyl N-[(3S)-1-(5-amino-2-tert-butyl-1-methyl-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (120 mg, yield: 54.4%) as a white solid.

[0618] LC-MS m / z: 388.2 (M+1) +

[0619] Step 6: tert-butyl N-[(3S)-1-{2-tert-butyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazine-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0620] To a solution of a mixture of tert-butyl N-[(3S)-1-(5-amino-2-tert-butyl-1-methyl-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate (80 mg, 0.20 mmol, 1.0 equiv) and 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.20 mmol, 1 equiv) in DMF (2 mL) was added HATU (86 mg, 0.22 mmol, 1.5 equiv) and DIPEA (0.12 mL, 0.60 mmol, 3.0 equiv). The mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (50 mL) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by SGC (UV254, petroleum ether: EtOAc = 3: 1) to give tert-butyl N-[(3S)-1-{2-tert-butyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazine-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidine-3-carbamic acid ester (60 mg, yield: 44.4%) as a yellow solid.

[0621] LC-MS m / z: 622.4 (M+1) +

[0622] Step 7: N-{4-[(3S)-3-aminopyrrolidin-1-yl]-2-tert-butyl-1-methyl-1,3-benzodiazol-5-yl}-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0623] To a solution of tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazine-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (35 mg, 0.052 mmol, 1.0 equiv) in DCM (3 mL) was added HCl in EtOAc (0.5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 98 as a yellow solid.

[0624] LC-MS m / z: 522.4 (M+1) +

[0625] 1 H NMR (400MHz, CD 3 OD)δ8.39(d,J=8.8Hz,1H),8.23(d,J=9.8Hz,1H),7.80–7.63(m,1H),7.43(d,J=8.9Hz,1H),7.35-7.31(m,3H),4.01 (s,3H),4.00-3.99(m,1H),3.68-3.64(m,1H),3.52-3.38(m,3H),2.35-2.30(m,1H),2.17-2.09(m,1H),1.58(s,9H).

[0626]

[0627]

[0628]

[0629]

[0630]

[0631] Example 106: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0632]

[0633] plan

[0634]

[0635]

[0636] Step 1: N-(2-chloro-6-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)acetamide

[0637] A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (200 mg, 0.86 mmol, 1 eq.), 1-methylpiperidin-4-amine (147 mg, 1.28 mmol, 1.5 eq.) and TEA (0.2 mL, 1.72 mmol, 2.0 eq.) in DMSO (3 mL) was stirred at 50 °C for 12 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL×3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography to give N-(2-chloro-6-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)acetamide (300 mg, yield: 64.1%) as a dark brown solid.

[0638] LC-MS m / z: 327.8 (M+1) +

[0639] Step 2: 4-chloro-2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazole

[0640] A solution of N-(2-chloro-6-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)acetamide (300 mg, 0.92 mmol, 1.0 equiv) and TEA (186 mg, 1.84 mmol, 2.0 equiv) in DMSO (5 mL) was stirred at 100 °C for 12 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and evaporate to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, from 0% to 2%) to give 4-chloro-2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazole (120 mg, yield: 41.1%) as a dark brown solid.

[0641] LC-MS m / z: 308.8 (M+1) +

[0642] Step 3: (S)-tert-butyl (1-(2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0643] At 100 ° C, a DMSO solution of 4-chloro-2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazole (120 mg, 0.88 mmol, 1.9 equiv), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (87 mg, 0.47 mmol, 1.0 equiv) and DIPEA (0.15 mL, 0.78 mmol, 1.7 equiv) was stirred under nitrogen for 4 hours. After cooling to room temperature, the reaction was quenched with water (5.0 mL) and extracted with EtOAc (10 mL×3). The combined organic phase was washed with Na 2 SO 4 Drying and concentration under reduced pressure gave a crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=50 / 1) to give (S)-tert-butyl(1-(2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate as a red solid (150 mg, yield: 80.1%).

[0644] LC-MS m / z:459.9(M+1) +

[0645] Step 4: (S)-tert-butyl (1-(5-amino-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0646] A mixture of Pd / C (78 mg, 10%) and (S)-tert-butyl (1-(2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (150 mg, 0.33 mmol) in methanol (10 mL) was hydrogenated at 15 psi for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (S)-tert-butyl (1-(5-amino-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (120 mg, yield: 81.3%) as a white solid.

[0647] LC-MS m / z:429.3(M+1) +

[0648] Step 5: (S)-tert-butyl (1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0649] To a solution of (S)-tert-butyl (1-(5-amino-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (60 mg, 0.16 mmol, 1.0 equiv) and 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.16 mmol, 1.0 equiv) in DMF (2.0 mL) was added HATU (80 mg, 0.21 mmol, 1.3 equiv) and DIPEA (0.1 mL, 0.65 mmol, 4.1 equiv). The reaction mixture was stirred at 50 °C for 10 hours. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=25 / 1) to give tert-butyl (S)-(1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-2-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, yield: 77.7%) as a yellow solid.

[0650] LC-MS m / z: 663.7 (M+1) +

[0651] Step 6: (S)-N-(4-(3-aminopyrrolidin-1-yl)-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0652] To a solution of tert-butyl (S)-(1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.13 mmol) in DCM (2.0 mL) was added a solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 106 (60 mg, yield: 79.6%) as a yellow solid.

[0653] LC-MS m / z: 563.6 (M+1) +

[0654] 1 H NMR (400MHz, CD 3 OD)δ8.22(d,J=9.9Hz,1H),8.17(d,J=9.0Hz,1H),7.99(br,1H),7.70(m,1H),7.36-7.32(m,3H),5.00(m,1H),3. 88(m,1H),3.82–3.67(m,4H),3.52–3.35(m,4H),3.01(s,3H),2.98(m,5H),2.35-2.31(m,2H),2.30–2.12(m,2H).

[0655] Example 107: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1,6-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0656]

[0657] plan

[0658]

[0659] Step 1: 6-Hydroxy-2H-pyran-2-one

[0660] At 150°C, (2E)-pent-2-enedioic acid (3 g, 23.1 mmol, 1 eq.) was dissolved in Ac 2 A solution of 6-hydroxy-2H-pyran-2-one (9.4 g, 92.4 mmol, 4 equivalents) was stirred for 1 hour to obtain a dark brown solution. The reaction mixture was concentrated to obtain 6-hydroxy-2H-pyran-2-one (3.0 g, yield: 94.0%) as a black solid.

[0661] 1H NMR (400 MHz, CDCl 3 )δ6.99(dd,J=6.0,4.0Hz,1H),6.31(d,J=9.8Hz,1H).

[0662] Step 2: (Z)-5-(2-(2,6-dichlorophenyl)hydrazono)-6-hydroxy-5,6-dihydro-2H-pyran-2-one

[0663] To a solution of 2,6-dichloroaniline (5.78 g, 35.7 mol) in 3M HCl (120 mL) was added NaNO in portions at 0°C. 2 (3.2 g, 46.4 mmol). After stirring at 0°C for 1 hour, 6-hydroxypyran-2-one (4 g, 26.8 mmol) and Na 2 CO 3 (1.89 g, 17.8 mmol) 2 O (50mL) solution was added dropwise to the reaction mixture. The reaction mixture was stirred for 16 hours to obtain a brown suspension. The reaction was filtered and the filter cake was washed with H 2 O, and dried under vacuum to obtain (Z)-5-(2-(2,6-dichlorophenyl)hydrazono)-6-hydroxy-5,6-dihydro-2H-pyran-2-one (3 g, yield: 23.5%) as a brown solid.

[0664] Step 3: 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0665] Compound (Z)-5-(2-(2,6-dichlorophenyl)hydrazono)-6-hydroxy-5,6-dihydro-2H-pyran-2-one (3.0 g, 10.4 mmol, 1 equivalent) was reacted with H 2 O (50mL) solution was added with KOH (2.2 g, 39.5 mmol, 5 equivalents). The reaction mixture was stirred at 100°C for 3 hours to obtain a dark brown solution. The reactant was acidified to pH = 2-3 with 1N HCl and extracted with EtOAc (30 mL×3). The organic phase was washed with brine (20 mL×3) and washed with Na 2 SO 4 Dry, filter and concentrate in vacuo to give 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.6 g, yield: 19.7%) as a black solid.

[0666] LC-MS m / z: 285.0 (M+1) +

[0667] Step 4: (S)-tert-butyl (1-(5-(1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0668] To a solution of (S)-tert-butyl (1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (69 mg, 0.20 mmol, 1.0 equiv) and 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.20 mmol, 1.0 equiv) in DMF (2.0 mL) was added HATU (113 mg, 0.20 mmol, 0.30 mmol, 1.5 equiv) and DIPEA (0.15 ml, 0.79 mmol, 4.0 equiv). The reaction mixture was stirred at 50 °C for 10 hours. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3) and purified by anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=25 / 1) to give (S)-tert-butyl(1-(5-(1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl))pyrrolidin-3-yl)carbamate as a yellow solid (20 mg, yield: 15.8%).

[0669] LC-MS m / z:613.5(M+1) +

[0670] Step 5: N-(4-(3-aminoazetidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0671] To a solution of tert-butyl (S)-(1-(5-(1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (20 mg, 0.03 mmol) in DCM (2.0 mL) was added a solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 107 (10 mg, yield: 23.5%) as a yellow solid.

[0672] LC-MS m / z: 513.5 (M+1) +

[0673] 1 H NMR: (400MHz, CD 3 OD)δ8.15(d,J=9.9Hz,1H),8.09(d,J=8.9Hz,1H),7.62(d,J=8.3Hz,2H),7.56–7.48(m,2H),7.24(d,J=9.9Hz,1H), 3.84(s,3H),3.66(m,2H),3.61–3.52(m,1H),3.39–3.30(m,1H),3.19–3.10(m,1H),2.78(s,3H),2.06–1.97(m,2H).

[0674]

[0675] Example 109: (R)-N-(4-(3-aminopyrrolidin-1-yl)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0676]

[0677] plan

[0678]

[0679] Step 1: N-(2-chloro-6-fluorophenyl)isobutyramide

[0680] 2-Chloro-6-fluoroaniline (6.5 g, 44.65 mmol, 1 eq.) in isobutyric anhydride (8.48 g, 53.59 mmol, 1.2 eq.) and Py (4.24 g, 53.59 mmol, 1.2 eq.). The reaction was stirred at 155 ° C for 2 hours by microwave to obtain a light brown solution. LCMS showed that the starting material was completely consumed and a main peak with the required mass was detected. Two reactions were carried out in parallel and combined for post-processing. The reactants were poured into water and a large amount of solids precipitated. Filtering and drying the filter cake by oil pump gave N-(2-chloro-6-fluorophenyl)isobutyramide (19.8 g, yield: 103%) as a light brown solid.

[0681] LC-MS m / z: 216.1 (M+1) +

[0682] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)isobutyramide

[0683] At 0°C, 98% H2O2 was added to N-(2-chloro-6-fluorophenyl)isobutyramide (89.31 mmol, 1 eq.). 2 SO 4 66% HNO (40 ml) was added dropwise to the solution 3 (7.34 mL, 107.17 mmol, 1.2 eq.). The ice bath was removed and the reaction was stirred at room temperature for 30 minutes. The reaction was then warmed to 50°C and stirred for another hour to give a dark brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The mixture was then poured into ice water and washed with Na 2 CO 3 The mixture was basified to pH = 2-3 and then extracted with EA (50 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness.The residue was purified by flash column (silica gel column, eluted with 5% to 15% EA / PE) to give N-(2-chloro-6-fluoro-3-nitrophenyl)isobutyramide (9.5 g, yield: 41%) as a brown solid.

[0684] LC-MS m / z: 261.1 (M+1) +

[0685] Step 3: 4-Chloro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole

[0686] To a solution of N-(2-chloro-6-fluoro-3-nitrophenyl)isobutyramide (9.5 g, 36.45 mmol, 1 eq.) in DMSO (100 ml) was added TEA (7.38 g, 72.89 mmol, 2 eq.) and 33% methylamine (7.77 mL, 54.67 mmol, 1.5 eq.) in EtOH. The reaction was stirred at room temperature for 1 hour, then warmed to 130 °C and stirred for another 10 hours to give a dark brown solution. LCMS showed that the starting material was consumed and two new peaks were detected. The mixture was purified by H 2 O and extracted with EA (80 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash column (silica gel column, eluted with 10% to 20% EA / PE) to give 4-chloro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (7.5 g, yield: 81.1%) as a brown solid.

[0687] LC-MS m / z: 254.1 (M+1) +

[0688] Step 4: (R)-tert-butyl (1-(2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0689] To a solution of 4-chloro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (3 g, 11.83 mmol, 1 eq) in DMSO (30 ml) was added TEA (3.59 g, 35.48 mmol, 3 eq) and (R)-tert-butyl pyrrolidin-3-ylcarbamate (2.2 g, 11.83 mmol, 1 eq). The reaction was stirred at 100 °C for 6 hours to give a dark brown solution. LCMS showed that the starting material was exhausted and one major peak with the desired mass was detected. The reaction was concentrated with H 2 O and extracted with EA (30 mL x 3). The combined organic layers were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration gave tert-butyl (R)-(1-(2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (4.7 g, yield: 98.5%) as a brown solid.

[0690] LC-MS m / z: 404.3 (M+1) +

[0691] Step 5: (R)-tert-butyl (1-(5-amino-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0692] In N 2 Pd / C (0.4 g) was added to a solution of (R)-tert-butyl (1-(2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (4.7 g, 11.65 mmol, 1 eq.) in MeOH (50 mL). The reactants were treated with H 2 The mixture was degassed for several times and stirred at room temperature for 3 hours at 45 psi to obtain a dark brown suspension. LCMS showed that the starting material was exhausted and a main peak with the required mass was detected. The reactant was filtered through a diatomaceous earth pad and the filter cake was washed with MeOH. The concentrated filtrate obtained brown colloid (R)-(1-(5-amino-2-isopropyl-1-methyl-1H-benzo [d] imidazoles-4-yl) pyrrolidin-3-yl) tert-butyl carbamate (4.2 g, yield: 97.7%).

[0693] LC-MS m / z: 374.3 (M+1) +

[0694] Step 6: (R)-tert-butyl (1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0695] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.3 g, 5.16 mmol, 1 eq) and (R)-tert-butyl(1-(5-amino-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (2.12 g, 5.67 mmol, 1.1 eq) in DMF (20 mL) was added HATU (2.55 g, 6.7 mmol, 1.3 eq) and DIEA (2 g, 15.47 mmol, 3 eq). The reaction was stirred at room temperature for 2 hours to give a dark brown solution. LCMS showed that the starting material was exhausted and one major peak with the desired mass was detected. The reaction was treated with water and the precipitated solid was collected by filtration. The filter cake was washed with water and dried to dryness by oil pump. The product was triturated with MTBE / hexanes to give tert-butyl (R)-(1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (2.7 g, yield: 86%) as a yellow solid.

[0696] LC-MS m / z:608.3(M+1) +

[0697] Step 7: (R)-N-(4-(3-aminopyrrolidin-1-yl)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0698] To a solution of (R)-tert-butyl(1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (2.7 g, 4.44 mmol, 1 eq) in DCM (10 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 1 hour to give a brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was concentrated with NaHCO 3 The aqueous solution was basified to pH = 9 and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried, filtered and concentrated to dryness.The product was triturated with EA / MTBE, filtered and the filter cake was lyophilized from 3M aqueous HCl to give Example 109 (1489.32 mg) as a yellow solid.

[0699] LC-MS m / z: 508.3 (M+1) +

[0700] 1 H NMR (400MHz, CD 3 OD)δ8.21(d,J=9.8Hz,1H),8.13(d,J=8.9Hz,1H),7.68(t,J=8.0Hz,2H),7.31(d,J=9.7Hz,3H),4.04(s,3H),3.94–3. 78(m,2H),3.73(t,J=8.8Hz,2H),3.47(d,J=10.2Hz,1H),2.21(dd,J=15.5,7.8Hz,2H),1.63(dd,J=10.7,7.0Hz,6H).

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] Example 143: (R)-N-(4-(3-aminopyrrolidin-1-yl)-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0727]

[0728] plan

[0729]

[0730] Step 1: 4-bromo-6-chloro-2,3-difluoroaniline

[0731] At 70°C, NCS (7.06 g, 52.88 mmol, 1.1 eq.) was added in batches to a solution of 4-bromo-2,3-difluoroaniline (10 g, 48.08 mmol, 1 eq.) in ACN (80 mL). The reactants were stirred at 70°C for 1 hour to obtain a dark brown solution. LCMS showed that the starting material was consumed and a new main peak was detected. The reactants were diluted with water and extracted with EA (80 mL × 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave 4-bromo-6-chloro-2,3-difluoroaniline (12.21 g, yield: 104.7%) as a dark oil.

[0732] LC-MS m / z: 242.1 (M+1) +

[0733] Step 2: 6-Chloro-2,3-difluoroaniline

[0734] To a solution of 4-bromo-6-chloro-2,3-difluoroaniline (48.08 mmol, 1 eq.) in THF (100 mL) was added n-BuLi (54.09 mL, 86.54 mmol, 1.8 eq.) dropwise at -78 °C. The reaction was stirred at -78 °C for 2 h to obtain a dark brown solution. 2 O quenched the reaction, LCMS showed that the reaction starting material was exhausted and a new main peak was detected. 2 O and extracted with EA (100 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave 6-chloro-2,3-difluoroaniline (7 g, yield: 89%) as a black oil.

[0735] LC-MS m / z:164.1(M+1) +

[0736] Step 3: N-(6-chloro-2,3-difluorophenyl)isobutyramide

[0737] A solution of 6-chloro-2,3-difluoroaniline (7 g, 42.8 mmol, 1 eq.) in isobutyric anhydride (8.12 g, 51.36 mmol, 1.2 eq.) and Py (4.06 g, 51.36 mmol, 1.2 eq.) was prepared by microwave stirring at 150 °C for 2 hours to obtain a dark brown solution. LCMS showed that the starting material was exhausted and a main peak with the desired mass was detected. The reactants were purified by H 2 O and extracted with EA (50 mL x 3). The combined organic layers were washed with brine and purified by Na2 SO 4 Dry, filter and concentrate to dryness.The residue was purified by flash column (silica gel column, eluted with 5% to 10% EA / PE) to give N-(6-chloro-2,3-difluorophenyl)isobutyramide (2.7 g, yield: 27%) as off-white solid.

[0738] LC-MS m / z: 234.1 (M+1) +

[0739] Step 4: N-(2-chloro-5,6-difluoro-3-nitrophenyl)isobutyramide

[0740] At 0°C, N-(6-chloro-2,3-difluorophenyl)isobutyramide (2.1 g, 8.99 mmol, 1 eq.) was added to 98% H 2 SO 4 66% HNO (8 ml) was added dropwise to the solution 3 (0.68 mL, 9.89 mmol, 1.1 eq.). The ice bath was removed and the reaction was stirred at room temperature for 1 hour to give a dark brown solution. LCMS showed that the starting material was consumed and a major peak with the desired mass was detected. The mixture was then poured into ice water and washed with Na 2 CO 3 The mixture was basified to pH = 1-2 and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was dried, filtered and concentrated to give N-(2-chloro-5,6-difluoro-3-nitrophenyl)isobutyramide (1.8 g, yield: 72%) as a dark brown solid.

[0741] LC-MS m / z: 279.1 (M+1) +

[0742] Step 5: 4-Chloro-7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole

[0743] To a solution of N-(2-chloro-5,6-difluoro-3-nitrophenyl)isobutyramide (1.8 g, 6.46 mmol, 1 eq.) and TEA (2.61 g, 25.84 mmol, 4 eq.) in DMSO (20 mL) was added methylamine hydrochloride (0.43 g, 6.46 mmol, 1 eq.). The reaction was stirred at room temperature for 1 hour, then warmed to 100 °C and stirred for another 10 hours to give a dark brown solution. LCMS showed that the starting material was consumed and a small peak with the desired mass was detected. The mixture was purified by HPLC with H 2O and extracted with EA (20 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave 4-chloro-7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (1.3 g, yield: 74%) as a brown solid.

[0744] LC-MS m / z: 272.1 (M+1) +

[0745] Step 6: (R)-tert-butyl (1-(7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0746] To a solution of 4-chloro-7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (500 mg, 1.84 mmol, 1 eq.) in DMSO (5 ml) was added TEA (558.71 mg, 5.52 mmol, 3 eq.) and (R)-tert-butyl pyrrolidin-3-ylcarbamate (342.79 mg, 1.84 mmol, 1 eq.). The reaction was stirred at 90 °C for 3 hours to give a dark brown solution. LCMS showed that the starting material was exhausted and a major peak with the desired mass was detected. The reaction was diluted with H2O and extracted with EA (10 mL×3). The combined organic layers were washed with brine and washed with Na 2 SO 4 Drying, filtration and concentration gave tert-butyl (R)-(1-(7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (0.8 g, crude) as a brown solid.

[0747] LC-MS m / z: 422.3 (M+1) +

[0748] Step 7: (R)-tert-butyl (1-(5-amino-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0749] In N 2 To a solution of (R)-tert-butyl(1-(7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (1.84 mmol, 1 eq.) in MeOH (8 mL) was added Pd / C (100 mg). The reactants were heated with H 2The mixture was degassed for several times and stirred at room temperature for 3 hours at 45 psi to obtain a dark brown suspension. LCMS showed that the starting material was exhausted and a main peak with the required mass was detected. The reactant was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH. The concentrated filtrate obtained (R)-(1-(5-amino-7-fluoro-2-isopropyl-1-methyl-1H-benzo [d] imidazoles-4-yl) pyrrolidin-3-yl) tert-butyl carbamate (0.7 g, yield: 97.2%) of a dark brown solid.

[0750] LC-MS m / z: 392.3 (M+1) +

[0751] Step 8: (R)-tert-butyl (1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0752] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (200 mg, 60% purity, 475.86 μmol, 1 eq) and (R)-tert-butyl(1-(5-amino-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (223.55 mg, 571.03 μmol, 1.2 eq) in DMF (5 mL) was added HATU (271.41 mg, 713.78 μmol, 1.5 eq) and DIEA (184.51 mg, 1.43 mmol, 3 eq). The reaction was stirred at room temperature for 1 hour to give a dark brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was diluted with H2O and extracted with EA (10 mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave tert-butyl (R)-(1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (450 mg, crude) as a brown oil.

[0753] LC-MS m / z:626.3(M+1) +

[0754] Step 9: (R)-N-(4-(3-aminopyrrolidin-1-yl)-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0755] To a solution of (R)-tert-butyl(1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (475.86 μmol, 1 eq) in DCM (6 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 1 hour to give a brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was concentrated with Na 2 CO 3 The aqueous solution was basified to pH = 10-11 and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. Pass through a flash column (C18 column, elute with ACN / H containing 0.1% HCOOH) 2 The residue was purified by purifying with a gradient of 10% O at a flow rate of 30 mL / min. The collected stream was washed with concentrated Na 2 CO 3 The aqueous solution was basified to pH = 10-11 and extracted with EA (30 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried, filtered and concentrated to dryness. The residue was purified by flash column (silica gel column, eluted with 10% MeOH in DCMo). The collected stream was concentrated and lyophilized with 2M HCl solution (3 drops) to give Example 143 (43 mg, 17.2%) as a brown solid.

[0756] LC-MS m / z: 526.3 (M+1) +

[0757] 1 H NMR (400 MHz, CD 3OD)δ8.27–8.17(m,2H),7.69(tt,J=8.6,6.2 Hz,1H),7.38–7.29(m,3H),4.01(d,J=0.9 Hz,3H),4.01–3.96(m,1H),3.64(dd,J=12.6,4.9 Hz,1H),3.49–3.33(m,3H),2.35–2.24(m,1H),2.20–2.07(m,1H),1.42(dd,J=6.8,3.2 Hz,6H).

[0758]

[0759]

[0760] Example 146: (R)-N-(4-(3-aminopyrrolidin-1-yl)-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0761]

[0762] plan

[0763]

[0764]

[0765] Step 1: N-(2-chloro-6-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide

[0766] To a mixture of 2-chloro-6-fluoroaniline (1.46 g, 10.03 mmol, 1.0 equiv) and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (1.54 g, 10.03 mmol, 1.00 equiv) in 10 M pyridine was added POCl 3 (2.50 g, 16.33 mmol, 1.60 equiv.). The mixture was stirred at 25 °C for 1 h to give a black solution. LCMS analysis of the reaction mixture showed that the reaction was complete. The mixture was poured into 100 mL of water and then filtered, and the filter cake was dried in vacuo to give N-(2-chloro-6-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.20 g) as a white solid.

[0767] LC-MS m / z: 282.6 (M+1) +

[0768] Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide

[0769] At 0°C, fuming nitric acid 0.6 mL was added to a solution of N-(2-chloro-6-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.20 g, 7.82 mol, 1.00 equivalent) in concentrated sulfuric acid 7 mL, and stirred at 0°C for 1 h to give a brown solution. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The residue was poured into 100 ml of water, then filtered, and the filter cake was dried in vacuo to give N-(2-chloro-6-fluoro-3-nitrophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.30 g) as a pale yellow solid.

[0770] LC-MS m / z: 327.6 (M+1) +

[0771] Step 3: 4-Chloro-1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazole

[0772] At 120°C, N-(2-chloro-6-fluoro-3-nitrophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.30 g 7.18 mmol 1.0 equivalent), CH 3 NH 2 HCl (0.53 g 7.90 mmol 1.10 equiv), Et 3 A mixture of 2 mL of N and 20 mL of DMSO was stirred for 3 h to give a brown suspension. The target compound MS was detected by LC-MS. The mixture was poured into 100 mL of water and extracted with DCM (30 mL×2). The reaction mixture was concentrated to dryness in vacuo. The resulting residue was passed through a column (SiO 2 , eluted with 80%-90% EA / PE, COMBI FLASH NEXTAGEN 300) to give 4-chloro-1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazole (1.2 g) as a yellow solid.

[0773] LC-MS m / z: 320.7 (M+1) +

[0774] Step 4: (R)-tert-butyl (1-(1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0775] 4-Chloro-1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazole (2.20 g, 6.88 mmol, 1.0 equiv), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.67 g, 8.95 mmol, 1.30 equiv) and 20 mL of dioxane and Et 3 N 2mL mixture. The reaction mixture was stirred at 100°C for 4h to obtain a brown suspension. The target compound MS was detected by LC-MS. The reaction mixture was concentrated to dryness in vacuo. 2 , eluted with 50%-60% EA / PE, COMBIFLASH NEXTAGEN 300) to give tert-butyl (R)-(1-(1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (1.4 g) as a yellow solid.

[0776] LC-MS m / z:470.5(M+1) +

[0777] Step 5: (R)-tert-butyl (1-(5-amino-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0778] To a solution of (R)-tert-butyl(1-(1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (0.40 g, 0.85 mmol, 1.00 equiv) in 10 mL of EtOH was added Fe (0.24 g, 4.25 mmol, 5.00 equiv) and AcOH (1 mL). The mixture was placed at 25° C. in the form of a black suspension for 5 hours. The target compound MS was detected by LC-MS, and no SM remained. The reaction mixture was filtered, the filtrate was concentrated, and NaHCO was added. 3 The solution was adjusted to pH = 8, extracted with EA 30 mL, and then dried in vacuo to give (R)-tert-butyl(1-(5-amino-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (0.40 g) as a red solid, which was directly used in the next reaction.

[0779] LC-MS m / z:440.5(M+1) +

[0780] Step 6: (R)-N-(4-(3-aminopyrrolidin-1-yl)-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0781] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (150 mg, 0.43 mmol, 1.00 equiv) and (R)-tert-butyl(1-(5-amino-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (251 mg, 57 mmol, 1.34 equiv) in ACN (10 mL) was added DIEA 0.3 mL, followed by HATU (245 mg, 0.65 mmol, 1.5 equiv) and stirred for 3 hours to give a black suspension. LC-MS showed that most of the starting material was consumed and one peak was detected. The reactant was purified by H 2 O and extracted with EA. The combined organic layers were washed with Na 2 SO 4 The product was dried, filtered and concentrated. The residue was purified by FLASH column (EA in PE 50%-60%, COMBI FLASHNEXTAGEN 300) to obtain the intermediate 170mg of yellow solid. 10mL dioxane and 10mL HCl / dioxane (4mol / L) were added to the intermediate, and stirred for 4h to obtain a yellow suspension. The reaction mixture was concentrated to obtain Example 146 (78mg) of a yellow solid.

[0782] LC-MS m / z: 574.5 (M+1) +

[0783] 1 H NMR (400MHz, CD 3 OD)δ8.35(d,J=8.9Hz,1H),8.24(d,J=9.8Hz,1H),7.70(td,J=8.7,4.2Hz,1H),7.50(d,J=9.0Hz,1H),7.34(dd,J=9.2,6.1 Hz,3H),4.08–3.89(m,4H),3.71(dd,J=12.0,5.9Hz,1H),3.65–3.48(m,3H),2.28–2.13(m,2H),1.71(s,2H),1.52(s,2H).

[0784]

[0785]

[0786]

[0787] Similar synthesis method as before:

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797] Example 166: N-[4-[(3R,4R)-3-amino-4-methyl-pyrrolidin-1-yl]-1-methyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0798]

[0799] plan

[0800]

[0801] Step 1: 4-Bromo-1-methyl-5-nitro-indazole

[0802] To a solution of 4-bromo-5-nitro-1H-indazole (500 mg, 2.07 mmol, 1 eq.) in DMF (2 mL) was added K 2 CO 3 (856.54 mg, 6.20 mmol, 3 eq.) and MeI (439.84 mg, 3.10 mmol, 192.91 uL, 1.5 eq.). The mixture was stirred at 20 °C for 1 hour. LCMS showed that the starting material was consumed and the desired compound was observed. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4The residue was purified by flash silica gel chromatography ( 10g Silica flash column, eluting with 0-50% ethyl acetate / petroleum ether gradient). The compound 4-bromo-1-methyl-5-nitro-indazole (205 mg, yield: 38.75%) was obtained as a yellow solid.

[0803] LC-MS m / z: 258.1 (M+1) +

[0804] Step 2: tert-Butyl N-[(3R,4R)-4-methyl-1-(1-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate

[0805] TEA (118.55 mg, 1.17 mmol, 163.07 uL, 3 equiv) and 4-bromo-1-methyl-5-nitro-indazole (100 mg, 390.54 umol, 1 equiv) were added to a solution of tert-butyl N-[(3R, 4R)-4-methylpyrrolidin-3-yl]carbamate (78.22 mg, 390.54 umol, 1 equiv) in DMSO (3 mL). The mixture was stirred at 110 ° C for 2 hours. LCMS showed that the starting material was exhausted and the desired compound was observed. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (40 mL×3). The combined organic layer was washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a residue. The crude product was used in the next step without further purification. The compound N-[(3R,4R)-4-methyl-1-(1-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (140 mg, yield: 95.49%) was obtained as a yellow oil.

[0806] LC-MS m / z: 376.3 (M+1) +

[0807] Step 3: N-[(3R,4R)-1-(5-amino-1-methyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[0808] To a solution of tert-butyl N-[(3R,4R)-4-methyl-1-(1-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate (130 mg, 346.28 umol, 1 eq.) in DMF (2 mL) was added boronic acid (93.13 mg, 1.04 mmol, 3 eq.) and 4-(4-pyridyl)pyridine (5.41 mg, 34.63 μmol, 0.1 eq.). The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the starting material was consumed and the desired compound was observed. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a residue. The residue was used in the next step without further purification. The compound N-[(3R,4R)-1-(5-amino-1-methyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (100 mg, yield: 83.60%) was obtained as a yellow oil.

[0809] LC-MS m / z: 346.3 (M+1) +

[0810] Step 4: N-[(3R, 4R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-methyl-indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[0811] To a solution of tert-butyl N-[(3R,4R)-1-(5-amino-1-methyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (100 mg, 289.49 μmol, 1 eq.) in DMF (3 mL) was added T 3 P (552.66 mg, 868.46 μmol, 516.50 uL, 50% purity, 3 equiv) and 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (73.00 mg, 289.49 μmol, 1 equiv) and TEA (146.46 mg, 1.45 mmol, 201.46 uL, 5 equiv). The mixture was stirred at 20 ° C for 1 hour. LCMS showed that most of the starting material was consumed and the desired compound was observed. The reaction mixture was poured into water (80 ml) and extracted with EtOAc (40 mL×3). The combined organic layer was washed with brine and purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure to obtain a residue. The residue is used in the next step without further purification. The compound N-[(3R, 4R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-methyl-indazole-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (120 mg, yield: 71.52%) is obtained as a brown oil.

[0812] LC-MS m / z: 580.4 (M+1) +

[0813] Step 5: N-[4-[(3R,4R)-3-amino-4-methyl-pyrrolidin-1-yl]-1-methyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0814] To a solution of tert-butyl N-[(3R,4R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-methyl-indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (120 mg, 207.04 μmol, 1 eq) in dioxane (0.5 mL) was added HCl / dioxane (4 M, 1 eq). The mixture was stirred at 20°C for 0.5 hours. LCMS showed that the starting material was consumed and the desired compound was observed. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Boston Green ODS 150x30mm×5mm; mobile phase: [water (HCl)-ACN]; B%: 23%-43%, 10 minutes). Example 166 (13.22 mg, yield: 13.32%) was obtained as a brown solid.

[0815] 1 H NMR (400 MHz, CD 3OD)δ8.33-8.14(m,2H),7.72-7.54(m,1H),7.73-7.53(m,1H),7.74-7.51(m,1H),7.37-7.22(m,1H),7.38-7.21(m,1H),7.13(d,J=8.9 Hz,1H),7.34-7.06(m,1H),4.90(s,21H),4.10(dd,J=5.9,10.7 Hz,1H),4.02(s,3H),3.84(br d,J=3.3Hz,1H),3.70(br t,J=8.5 Hz,1H),3.61(br dd,J=3.0,10.7 Hz,1H),3.51(br t,J=9.0Hz,1H),2.68-2.55(m,1H),1.17-1.11(m,1H),1.17-1.11(m,1H),1.15(d,J=7.0Hz,1H).

[0816] LC-MS m / z:480.1(M+1) +

[0817]

[0818]

[0819]

[0820]

[0821] Example 175: (R)-N-(4-(3-aminopyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0822]

[0823] plan

[0824]

[0825] Step 1: (R)-tert-butyl (1-(2-methyl-5-nitro-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

[0826] To a solution of 4-bromo-2-methyl-5-nitro-indazole (300 mg, 1.17 mmol, 1 eq.) in DMSO (6 mL) was added tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (327.32 mg, 1.76 mmol, 1.5 eq.) and TEA (237.11 mg, 2.34 mmol, 326.15 uL, 2 eq.). The mixture was stirred at 110 ° C for 2 hours. LCMS showed the formation of the desired mass. TLC showed the generation of new spots. The reaction mixture was quenched by the addition of water (10 mL) at 25 ° C. The combined organic layers were extracted with EtOAc 30 mL (10 mL×3) and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 4g Silica flash column, 0-60% ethyl acetate / petroleum ether gradient eluent). Compound N-[(3R)-1-(2-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (400 mg, yield: 94.47%) was obtained as a brown oil.

[0827] LC-MS m / z: 362.2 (M+1) +

[0828] Step 2: (R)-tert-butyl (1-(5-amino-2-methyl-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

[0829] To a solution of tert-butyl N-[(3R)-1-(2-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate (300 mg, 830.12 μmol, 1 eq) in MeOH (5 mL) was added Pd / C (87.99 mg, 83.01 μmol, 10%, w%, 0.1 eq). The mixture was washed with H 2 The balloon was stirred at 25°C for 2 hours. LCMS showed the desired mass formed and the starting material was consumed. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was used directly in the next step without further purification. Compound N-[(3R)-1-(5-amino-2-methyl-indazole-4-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (250 mg, yield: 90.87%) was obtained as a blue solid.

[0830] LC-MS m / z: 332.2 (M+1) +

[0831] Step 3: (R)-tert-butyl (1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-2-methyl-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

[0832] To a solution of tert-butyl N-[(3R)-1-(5-amino-2-methyl-indazol-4-yl)pyrrolidin-3-yl]carbamate (197.13 mg, 594.83 μmol, 1 eq.) in DMF (3 mL) was added 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (150 mg, 594.83 μmol, 1 eq.). The mixture was stirred at 25 °C for 2 hours. LCMS showed the desired mass formed. TLC showed the generation of new spots. The reaction mixture was quenched by the addition of water (15 mL) at 25 °C. The combined organic layers were extracted with EtOAc (15 mL×3) and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 4g Silica flash column, 0-67% ethyl acetate / petroleum ether gradient eluent). The brown solid product N-[(3R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-2-methyl-indazol-4-yl]pyrrolidin-3-yl]carbamic acid tert-butyl ester (250 mg, yield: 74.31%) was obtained.

[0833] LC-MS m / z: 566.2 (M+1) +

[0834] Step 4: (R)-N-(4-(3-aminopyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0835] To a solution of tert-butyl N-[(3R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-2-methyl-indazol-4-yl]pyrrolidin-3-yl]carbamate (250 mg, 442.03 μmol, 1 eq) in DCM (2 mL) was added TFA (5.13 g, 45.02 mmol, 3.33 mL, 101.85 eq). The mixture was stirred at 25 °C for 2 hours. LCMS showed the desired mass formed. The combined organic phases were concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150×30 mm×5 um, water (FA)-ACN, start B 6, end B 36, gradient time (min) 12, 100% B hold time (min) 2, flow rate (ml / min) 25). Example 175 (133.76 mg, yield: 65.01%) was obtained as a yellow solid.

[0836] LC-MS m / z:466.2(M+1) +

[0837] 1 H NMR (500MHz, CD 3 OD)δ8.44(s,1H),8.22(d,J=9.92Hz,1H),7.64-7.74(m,2H),7.26-7.38(m,4H),4.17-4.25(m,3H ),3.75-3.86(m,2H),3.64-3.71(m,1H),3.37-3.47(m,2H),2.25-2.37(m,1H),1.91-2.01(m,1H).

[0838]

[0839]

[0840] Example 179: N-[4-[(3R)-3-aminopyrrolidin-1-yl]-1-isopropyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0841]

[0842] plan

[0843]

[0844] Step 1: 4-bromo-1-isopropyl-5-nitro-1H-indazole

[0845] To a solution of 4-bromo-5-nitro-1H-indazole (5 g, 20.659 mmol) and 2-iodopropane (5.27 g, 30.988 mmol) in DMF (50 mL) was added NaH (1.07 g, 26.856 mmol) in portions at 0-5 °C. The reaction was stirred at room temperature for 2 hours to give a dark brown solution. LCMS showed that the starting material was consumed and two peaks with the desired mass were detected. The reaction was heated to 40 °C with H 2 O and extracted with EA (60 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness.The residue was purified by flash column (SiO2, eluted with PE to 5% EA / PE) to give 4-bromo-5-nitro-1-(propan-2-yl)indazole (2.6 g, yield: 44.29%) as a yellow solid.

[0846] LC-MS m / z: 284.1 (M+1) +

[0847] Step 2: tert-Butyl N-[(3R)-1-(1-isopropyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate

[0848] To a solution of 4-bromo-1-isopropyl-5-nitro-indazole (300 mg, 1.06 mmol, 1 eq) in DMSO (4 mL) was added TEA (213.70 mg, 2.11 mmol, 293.94 uL, 2 eq) and tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (295.00 mg, 1.58 mmol, 1.5 eq). The mixture was stirred at 120 ° C for 2 hours. TLC showed that the starting material was consumed and a new spot was formed. LCMS showed the desired mass formed. The reaction mixture was poured into H 2 O (40 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue is purified by flash silica gel chromatography ( 20g Silica flash column, [0-30]% petroleum ether / ethyl acetate gradient eluent). The compound N-[(3R)-1-(1-isopropyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (395 mg, yield: 96.05%) was obtained as a red solid.

[0849] LC-MS m / z: 390.2 (M+1) +

[0850] Step 3: tert-Butyl N-[(3R)-1-(5-amino-1-isopropyl-indazol-4-yl)pyrrolidin-3-yl]carbamate

[0851] To a solution of tert-butyl N-[(3R)-1-(1-isopropyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate (395 mg, 1.01 mmol, 1 eq.) in MeOH (10 mL) was added Pd / C (119.58 mg, 101.43 umol, 10%, w%, 0.1 eq.). The reaction mixture was heated at 25 °C using H 2 Balloon stirring for 1 hour.LCMS shows that starting material is consumed and required mass is detected.The mixture is filtered and the filtrate is concentrated under reduced pressure.Compound N-[(3R)-1-(5-amino-1-isopropyl-indazole-4-yl)pyrrolidin-3-yl] tert-butyl carbamate (305mg, yield: 83.66%) of brown oil is obtained.

[0852] LC-MS m / z: 360.2 (M+1) +

[0853] Step 4: N-[(3R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-isopropyl-indazol-4-yl]pyrrolidin-3-yl]carbamic acid tert-butyl ester

[0854] To a solution of tert-butyl N-[(3R)-1-(5-amino-1-isopropyl-indazol-4-yl)pyrrolidin-3-yl]carbamate (160 mg, 445.11 μmol, 1 eq) in DMF (5.5 mL) was added 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (112.24 mg, 445.11 μmol, 1 eq), TEA (90.08 mg, 890.21 μmol, 123.91 μL, 2 eq) and HATU (253.86 mg, 667.66 μmol, 1.5 eq). The mixture was stirred at 25 °C for 1 hour. LCMS showed the desired mass formed. TLC showed consumption of starting material and formation of a new spot. The reaction mixture was poured into H 2 O (30 mL) and extracted with EtOAc (10×3 mL). The combined organic phases were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue is purified by flash silica gel chromatography ( 12g Silica flash column, [0-30]% petroleum ether / ethyl acetate gradient eluent). A brown solid N-[(3R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-isopropyl-indazol-4-yl]pyrrolidin-3-yl]carbamic acid tert-butyl ester (240 mg, yield: 90.83%) was obtained.

[0855] LC-MS m / z: 594.2 (M+1) +

[0856] Step 5: N-[4-[(3R)-3-aminopyrrolidin-1-yl]-1-isopropyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0857] To a solution of tert-butyl N-[(3R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-isopropyl-indazol-4-yl]pyrrolidin-3-yl]carbamate (240 mg, 404.30 μmol, 1 equivalent) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at 25 ° C for 1 hour. LCMS showed that the desired mass was formed and the starting material was consumed. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, water (FA)-ACN, start B15, end B 35, gradient time (min) 12, 100% B hold time (min) 2, flow rate (ml / min) 25). Example 179 (116.33 mg, yield: 58.30%, FA) was obtained as a yellow solid.

[0858] LC-MS m / z: 494.3 (M+1) +

[0859] 1 H NMR (400MHz, CD 3 OD)δ8.24-8.19(m,2H),7.77(d,J=8.9Hz,1H),7.71-7.62(m,1H),7.35-7.25(m,4H), 4.96-4.92(m,1H),3.89-3.83(m,1H),3.82-3.75(m,1H),3.75-3.69(m,1H),3.49(br dd,J=4.2,10.3Hz,2H),2.30(qd,J=7.2,14.0Hz,1H),2.01-1.91(m,1H),1.53(d,J=6.7Hz,6H).

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881] Example 220: (R)-N-(4-(3-amino-3-methylpyrrolidin-1-yl)-2-isopropyl-2H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0882]

[0883] plan

[0884]

[0885] Step 1: (R)-tert-butyl (1-(2-isopropyl-5-nitro-2H-indazol-4-yl)-3-methylpyrrolidin-3-yl)carbamate

[0886] To a solution of 4-chloro-5-nitro-2-(propan-2-yl)indazole (240 mg, 1.001 mmol) in dioxane (10 mL) was added 2-methylpropan-2-yl {[(3R)-3-methyltetrahydro-1H-pyrrol-3-yl]amino}carboxylate (200.56 mg, 1.001 mmol) and Et 3 To the mixture was added 4-(2-isopropyl-5-nitro-2H-indazole-4-yl)-3-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester (405 mg) of 1-(2-isopropyl-5-nitro-2H-indazole-4-yl)-3-methylpyrrolidin-3-yl)carbamate (0.418 mL, 1.001 mmol). The reaction mixture was stirred at 100 ° C for 5 hours to give a brown suspension. LCMS showed that the reaction was complete. The reaction mixture was concentrated in vacuo to give tert-butyl (R)-(1-(2-isopropyl-5-nitro-2H-indazole-4-yl)-3-methylpyrrolidin-3-yl)carbamate (405 mg) as a yellow solid.

[0887] LC-MS m / z:404.5(M+1) +

[0888] Step 2: (R)-tert-butyl (1-(5-amino-2-isopropyl-2H-indazol-4-yl)-3-methylpyrrolidin-3-yl)carbamate

[0889] Pd / C 10% (100 mg, 0.940 mmol) was added to a solution of 2-methylpropan-2-yl {[(3R)-3-methyl-1-[5-nitro-2-(propan-2-yl)indazol-4-yl]tetrahydro-1H-pyrrol-3-yl]amino}carbamate (405 mg, 1.004 mmol) in MeOH 20 mL, and the mixture was kept at room temperature under hydrogen for 15 hours (60 Psi) to obtain a black suspension, and the target compound MS was detected by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo to give tert-butyl (R)-(1-(5-amino-2-isopropyl-2H-indazol-4-yl)-3-methylpyrrolidin-3-yl)carbamate (353 mg) as a yellow solid, which was used directly in the next reaction.

[0890] LC-MS m / z: 374.5 (M+1) +

[0891] Step 3: (R)-N-(4-(3-amino-3-methylpyrrolidin-1-yl)-2-isopropyl-2H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0892] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-carboxylic acid (150 mg, 0.595 mmol) (150 mg, 0.43 mmol, 1.00 equiv), 2-methylpropan-2-yl {[(3R)-1-[5-amino-2-(propan-2-yl)indazol-4-yl]-3-methyltetrahydro-1H-pyrrol-3-yl]amino}carboxylate (244.38 mg, 0.654 mmol) in ACN (10 mL) was added ethyl diisopropylamine (0.3 mL, 1.815 mmol). Then HATU (339.17 mg, 0.892 mmol) was added and stirred for 2 hours to give a black suspension. LC-MS showed that most of the starting material was consumed and one peak was detected. The reactant was purified by H 2 O 50mL diluted and extracted with EA 30mL * 2. The combined organic layer was purified by Na 2 SO 4 Dry, filter and concentrate. The residue is passed through a FLASH column (SiO 2 , EA in PE 60%, COMBI FLASH NEXTAGEN 300) was purified to give the intermediate 120 mg as a yellow solid. 10 mL HCl / dioxane (4 mol / L) was added to the intermediate and stirred for 3 h to give a yellow suspension. The reaction mixture was concentrated to give Example 220 (22.32 mg) as a yellow solid.

[0893] LC-MS m / z:508.5(M+1) +

[0894] 1 H NMR (400MHz, CD 3 OD)δ8.47(s,1H),8.25(d,J=9.8Hz,1H),7.90(d,J=9.2Hz,1H),7.69(dd,J=10.6,4.2Hz,1H),7.32(q,J=8.9Hz,4H),3.63(dd, J=16.5,8.1Hz,2H),3.45(dd,J=20.6,11.4Hz,4H),2.02(s,1H),1.94(s,1H),1.64(t,J=8.8Hz,6H),1.31(s,2H),1.27(s,3H).

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902] Example 234: N-[4-[(3R,4R)-3-amino-4-methyl-pyrrolidin-1-yl]-2-tert-butyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0903]

[0904] plan

[0905]

[0906] Step 1: 4-bromo-2-tert-butyl-5-nitro-indazole

[0907] To a solution of 4-bromo-5-nitro-2H-indazole (10 g, 41.32 mmol, 1 eq) in toluene (30 mL) was added tert-butyl acetate (95.99 g, 826.35 mmol, 110.84 mL, 20 eq) and MSA (3.97 g, 41.32 mmol, 2.94 mL, 1 eq). The mixture was stirred at 70 °C for 48 hours. LCMS showed that the desired product was formed as a major peak. The reaction mixture was poured into saturated NaHCO 3 (50 mL) and extracted with EA (40 mL × 3). The combined organic phases were purified by Na 2 SO 4 Dry and filter. The filtrate was concentrated in vacuo. The residue was used directly in the next step without further purification. 4-Bromo-2-tert-butyl-5-nitro-indazole (12 g, yield: 97.42%) was obtained as a white solid.

[0908] LC-MS m / z: 298.0 (M+1) +

[0909] Step 2: N-[(3R,4R)-1-(2-tert-butyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[0910] To a solution of 4-bromo-2-tert-butyl-5-nitro-indazole (9 g, 30.19 mmol, 1 eq.) in DMSO (90 mL) was added TEA (9.16 g, 90.56 mmol, 12.61 mL, 3 eq.) and tert-butyl N-[(3R, 4R)-4-methylpyrrolidin-3-yl]carbamate (6.05 g, 30.19 mmol, 1 eq.). The mixture was stirred at 100 °C for 2 hours. LCMS showed that the desired product was formed as a major peak. The reaction mixture was poured into water (400 mL), filtered and the formed solid was collected. The solid was dissolved in EA (500 mL) and purified by Na 2 SO 4 Dry and filter. The filtrate was concentrated in vacuo. The residue was used directly in the next step without further purification. N-[(3R,4R)-1-(2-tert-butyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (11 g, yield: 87.28%) was obtained as a yellow solid.

[0911] LC-MS m / z: 418.4 (M+1) +

[0912] Step 3: N-[(3R, 4R)-1-(5-amino-2-tert-butyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[0913] To a solution of tert-butyl N-[(3R,4R)-1-(2-tert-butyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (11 g, 26.35 mmol, 1 eq) in THF (120 mL) and H 2 O (60 mL) solution was added in portions with NH 4 Cl (11.27 g, 210.78 mmol, 8 eq.) and Zn (13.89 g, 212.42 mmol, 8.06 eq.) were added and the temperature was kept below 25 °C using ice water. The mixture was stirred at 25 °C for 1 hour. LCMS showed that the desired product was formed as the main peak. The reaction mixture was filtered. The filtrate was poured into water (60 mL) and extracted with EA (60 mL×3). The combined organic phase was purified by Na 2 SO 4 The mixture was dried and filtered. The filtrate was concentrated in vacuo. The remaining Zn was treated with 1N HCl, then neutralized with 1N NaOH and discarded. The residue was used directly in the next step without further purification. N-[(3R,4R)-1-(5-amino-2-tert-butyl-indazole-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (10 g, yield: 97.94%) was obtained as a green solid.

[0914] LC-MS m / z: 388.3 (M+1) +

[0915] Step 4: N-[(3R,4R)-1-[2-tert-butyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[0916] To a CH 4 solution of N-[(3R,4R)-1-(5-amino-2-tert-butyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (10 g, 25.81 mmol, 1 eq) and 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (6.51 g, 25.81 mmol, 1 eq) was added. 3 NMI (6.36 g, 77.42 mmol, 6.17 mL, 3 eq.) and TCFH (8.69 g, 30.97 mmol, 1.2 eq.) were added to a CN (200 mL) solution. The mixture was stirred at 25 °C for 3 hours. LCMS showed that the desired product was formed as a major peak. The reaction mixture was poured into water (400 mL) and extracted with EA (100 mL×3). The combined organic phases were purified by Na 2 SO 4 Dry and filter. The filtrate is concentrated in vacuo. The residue is purified by flash silica gel chromatography ( 100g Silica flash column, 0-40% ethyl acetate / petroleum ether gradient (200mL / min) eluent. The product was dissolved in PE / EA (5:1, 50ml) and stirred for 1h. The mixture was filtered. The solid was collected to give tert-butyl N-[(3R,4R)-1-[2-tert-butyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (11g, yield: 68.57%) as a yellow solid.

[0917] LC-MS m / z: 622.3 (M+1) +

[0918] Step 5: N-[4-[(3R,4R)-3-amino-4-methyl-pyrrolidin-1-yl]-2-tert-butyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0919] To a solution of tert-butyl N-[(3R,4R)-1-[2-tert-butyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (11 g, 17.69 mmol, 1 eq) in MeOH (20 mL) was added HCl / MeOH (4 M, 55.00 mL, 12.43 eq). The mixture was stirred at 25 °C for 62 h. LCMS showed that the desired product was formed as a major peak. The reaction mixture was concentrated in vacuo. The residue was dissolved in CH 3 CN / H 2 O (20 mL / 50 mL) and lyophilized. The residue was used in the next step without further purification. Example 234 (9.23 g, yield: 100.00%) was obtained as a white solid.

[0920] LC-MS m / z:492.1(M+1) +

[0921] 1H NMR (400MHz, CD 3 OD)δ8.65(s,1H),8.22(d,J=9.8Hz,1H),7.75-7.63(m,2H),7.37-7.24(m,4H),4.04(dd,J=6.0,10.7Hz,1H),3.88-3.88(m,1H ),3.88-3.81(m,1H),3.71-3.63(m,1H),3.60-3.48(m,2H),2.62(td,J=7.4,14.6Hz,1H),1.81(s,9H),1.18(d,J=7.0Hz,3H).

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929] Example 249: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-[(3S)-tetrahydro-3-furanyl]indazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide

[0930]

[0931] plan

[0932]

[0933] Step 1: 2-methylpropan-2-yl {[(7R)-5-(5-nitro-1H-indazol-4-yl)-5-azaspiro[2.4]hept-7-yl]amino}formate

[0934] To a solution of 4-bromo-5-nitro-1H-indazole (1 g, 4.132 mmol) and 2-methylpropan-2-yl {[(7R)-5-azaspiro[2.4]hept-7-yl]amino}carboxylate (0.92 g, 4.338 mmol) in DMSO (10 mL) was added TEA (1.723 mL, 12.395 mmol). The reaction was stirred at 90 °C for 2 hours to give a brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was poured into water and a large amount of solid precipitated, filtered, and the filter cake was dried using an oil pump to give 2-methylpropan-2-yl {[(7R)-5-(5-nitro-1H-indazole-4-yl)-5-azaspiro[2.4]hept-7-yl]amino}carboxylate (1.47 g, yield: 95.28%) as a yellow solid.

[0935] LC-MS m / z: 374.2 (M+1) +

[0936] Step 2: 2-methylpropan-2-yl {[(7R)-5-{5-nitro-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl}-5-azaspiro[2.4]hept-7-yl]amino}carboxylate

[0937] To a solution of 2-methylpropan-2-yl {[(7R)-5-(5-nitro-1H-indazol-4-yl)-5-azaspiro[2.4]hept-7-yl]amino}formate (150 mg, 0.402 mmol) and (3R)-tetrahydrofuran-3-ol (0.065 mL, 0.803 mmol) in THF (5 mL) was added tributylphosphine (162.55 mg, 0.803 mmol) and DIAD (162.46 mg, 0.803 mmol). The reaction was stirred at 50 ° C for 30 minutes by microwave to give a brown solution. LCMS showed that most of the starting material was consumed and two new peaks with the desired mass were detected. The reaction was washed with H 2 O and extracted with EA (10 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness. The residue was purified by flash column (SiO2, eluted with 30% EA / PE) to give 2-methylpropan-2-yl {[(7R)-5-{5-nitro-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl}-5-azaspiro[2.4]hept-7-yl]amino}carboxylate as a yellow solid (98 mg, yield: 55.01%).

[0938] LC-MS m / z: 444.3 (M+1) +

[0939] Step 3: 2-methylpropan-2-yl {[(7R)-5-{5-amino-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl}-5-azaspiro[2.4]hept-7-yl]amino}carboxylate

[0940] In N 2 To a solution of 2-methylpropan-2-yl{[(7R)-5-{5-nitro-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl}-5-azaspiro[2.4]hept-7-yl]carbamate (98 mg, 0.221 mmol) in MeOH (3 mL) was added Pd / C 10% (20 mg, 0.221 mmol). The resulting mixture was treated with H 2 Degas several times, and stir at room temperature under 45psi for 5 hours, obtain black suspension.LCMS shows that most of starting material is consumed and detects a main peak with required mass.Reaction is filtered through diatomaceous earth pad, and filtrate is concentrated to obtain 2-methylpropane-2-yl {[(7R)-5-{5-amino-1-[(3S)-tetrahydro-3-furanyl] indazole-4-yl}-5-azaspiro [2.4] hept-7-yl] amino} formate (95mg, yield: 103.97%) of brown solid.

[0941] LC-MS m / z: 414.3 (M+1) +

[0942] Step 4: 2-methylpropan-2-yl {[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}carboxylate

[0943] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-carboxylic acid (50 mg, 0.198 mmol) and 2-methylpropan-2-yl {[(7R)-5-{5-amino-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl}-5-azaspiro[2.4]hept-7-yl]amino}carboxylate (90.19 mg, 0.218 mmol) in DMF (1 mL) was added DIEA (0.098 mL, 0.595 mmol) and HATU (113.09 mg, 0.297 mmol). The residue was stirred at room temperature for 1 hour to give a brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The residue was poured into water and a large amount of solid precipitated, which was filtered and dried to give 2-methylpropan-2-yl {[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-yl]carbonyl}amino)-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}carboxylate (115 mg, yield: 89.55%) as a brown solid.

[0944] LC-MS m / z:648.3(M+1) +

[0945] Step 5: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-[(3S)-tetrahydro-3-furanyl]indazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide

[0946] To a solution of {[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-[(3S)-tetrahydro-3-furanyl]indazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}carboxylic acid 2-methylpropan-2-yl ester (115 mg, 0.178 mmol) in DCM (6 mL) was added 50% TFA in DCM (2 mL) dropwise. The reaction mixture was stirred at room temperature for 3 hours to give a brown solution. LCMS showed that the starting material was exhausted and one major peak with the desired mass was detected. The reaction was concentrated to dryness. The residue was washed with NH 4 OH was basified to pH = 7-8, then purified by flash column 5 times (C18, eluted with a gradient of ACN / H2O containing 0.5% HCOOH at a rate of 45 mL / min) and lyophilized to give Example 249 (36.4 mg, yield: 37.44%) as a yellow solid.

[0947] LC-MS m / z:548.2(M+1) +

[0948] 1 H NMR (400MHz, CD 3 OD): δ8.30–8.19(m,2H),7.75(d,J=9.0Hz,1H),7.66(tt,J=8.6,6.3Hz,1H),7.29(ddd,J=10.7,8.7,3.5Hz,4H),5.40(tt,J=8.0,3.9H z,1H),4.24–4.10(m,3H),4.05(dd,J=9.3,3.8Hz,1H),3.96(td,J=8.5,6.0Hz,2H),3.57(dd,J=10.2,3.0Hz,1H),3.25(dd,J=5.5,2.9 Hz,1H),3.12(d,J=9.2 Hz,1H),2.51(dq,J=12.8,7.8Hz,1H),2.46–2.34(m,1H),0.92(dt,J=8.7,4.5 Hz,1H),0.67(tdd,J=15.5,7.0,2.6 Hz,3H).

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972] Example 283: N-(4-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0973]

[0974] plan

[0975]

[0976] Step 1: 4-bromo-1-(2-methoxyethyl)-5-nitro-1H-indazole

[0977] 4-Bromo-5-nitro-1H-indazole (200 mg, 826.35 μmol, 1 eq.) and K 2 CO 3 1-Bromo-2-methoxy-ethane (229 mg, 1.65 mmol, 154.73 μL, 1.99 equiv) was added to a solution of (571.03 mg, 4.13 mmol, 5 equiv) in DMF (4 mL). The mixture was stirred at 70 ° C for 2 hours. LC-MS showed that the starting material was completely consumed and the required mass was detected. The residual mixture was poured into water (30 ml) and extracted with EtOAc (15 ml×3). The combined organic phase was washed with brine over Na 2 SO 4 Wash, filter and concentrate in vacuo. The residue is purified by flash silica gel chromatography ( 4g Silica flash column, 0-45% ethyl acetate / petroleum ether gradient eluent). 4-Bromo-1-(2-methoxyethyl)-5-nitro-indazole (70 mg, yield: 28.23%) was obtained as a yellow solid.

[0978] LC-MS m / z: 300.1 (M+1) +

[0979] Step 2: tert-Butyl ((3R, 4R)-1-(1-(2-methoxyethyl)-5-nitro-1H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[0980] To a solution of tert-butyl N-[(3R, 4R)-4-methylpyrrolidin-3-yl]carbamate (93.99 mg, 469.28 μmol, 1.01 eq) in DMSO (1 mL) was added 4-bromo-1-(2-methoxyethyl)-5-nitro-indazole (140 mg, 466.50 μmol, 1 eq) and TEA (141.61 mg, 0.01 mg, 1.40 mmol, 194.79 uL, 3 eq). The mixture was stirred at 100 ° C for 2 hours. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residual mixture was poured into water (30 ml) and extracted with EtOAc (15 ml×3). The combined organic phase was washed with brine over Na 2 SO 4 Wash, filter and concentrate in vacuo. The residue is purified by flash silica gel chromatography ( 4g Silica flash column, 0-45% ethyl acetate / petroleum ether gradient eluent). N-[(3R,4R)-1-[1-(2-methoxyethyl)-5-nitro-indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (120 mg, yield: 61.32%) was obtained as a yellow oil.

[0981] LC-MS m / z: 420.3 (M+1) +

[0982] Step 3: tert-butyl ((3R,4R)-1-(5-amino-1-(2-methoxyethyl)-1H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[0983] To a solution of tert-butyl N-[(3R,4R)-1-[1-(2-methoxyethyl)-5-nitro-indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (120 mg, 286.07 μmol, 1 eq) in DMF (3 mL) was added 4-(4-pyridyl)pyridine (48 mg, 307.34 μmol, 1.07 eq) and subboric acid (256.46 mg, 2.86 mmol, 10 eq). The mixture was stirred at 20 °C for 30 minutes. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residual mixture was poured into water (20 ml) and extracted with EtOAc (15 ml×3). The combined organic phases were washed with brine over Na 2 SO 4 Wash, filter, and concentrate in vacuo. The residue is used directly in the next step without further purification. N-[(3R,4R)-1-[5-amino-1-(2-methoxyethyl)indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (105 mg, yield: 94.24%) is obtained as a brown oil.

[0984] LC-MS m / z: 390.3 (M+1) +

[0985] Step 4: tert-butyl ((3R,4R)-1-(5-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1-(2-methoxyethyl)-1H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[0986] To a solution of tert-butyl N-[(3R,4R)-1-[5-amino-1-(2-methoxyethyl)indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (105 mg, 269.58 μmol, 1 eq), 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (68 mg, 269.66 μmol, 1 eq) and TEA (137 mg, 1.35 mmol, 188.45 uL, 5.02 eq) in DMF (3 mL) was added T 3 P (257 mg, 807.72 μmol, 240.19 uL, 3 eq.). The mixture was stirred at 20 °C for 15 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residual mixture was poured into water (20 ml) and extracted with EtOAc (15 ml x 3). The combined organic phases were washed with brine over Na 2 SO 4 Wash, filter and concentrate in vacuo. The residue is used directly in the next step without further purification. Obtain dark brown oily N-[(3R,4R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-(2-methoxyethyl)indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (168 mg, yield: 99.93%).

[0987] LC-MS m / z:624.4(M+1) +

[0988] Step 5: N-(4-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0989] To a solution of tert-butyl N-[(3R,4R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]-1-(2-methoxyethyl)indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (168 mg, 269.38 μmol, 1 eq) in dioxane (0.5 mL) was added HCl / dioxane (2 mL). The mixture was stirred at 20° C. for 1 hour. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water (FA)-ACN]; B%: 14%-44%, 12 min). Example 283 (110 mg, yield: 78.00%) was obtained as a yellow solid.

[0990] LC-MS m / z: 524.3 (M+1) + .

[0991] 1 H NMR (400MHz, CD 3 OD)δ8.51(br s,1H),8.29-8.13(m,2H),7.71-7.63(m,1H),7.63-7.57(m,1H),7.34-7.2 3(m,3H),7.19-7.12(m,1H),4.52(t,J=5.2Hz,2H),4.10-3.92(m,1H),3.8 1-3.76(m,2H),3.76-3.71(m,1H),3.67-3.59(m,1H),3.56-3.50(m,1H),3 .48-3.40(m,1H),3.28-3.19(m,3H),2.60-2.44(m,1H),1.21-1.05(m,3H).

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001] Example 298: N-[4-[(3R,4R)-3-amino-4-methyl-pyrrolidin-1-yl]-1-cyclopropyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[1002]

[1003] plan

[1004]

[1005]

[1006] Step 1: N-[(3R, 4R)-1-(1-cyclopropyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[1007] Cu(OAc)2(110.57mg, 608.75μmol, 1.1eq) was added to a solution of tert-butyl N-[(3R,4R)-4-methyl-1-(5-nitro-1H-indazol-4-yl)pyrrolidin-3-yl]carbamate (200mg, 553.41μmol, 1eq), cyclopropylboronic acid (142.61mg, 1.66mmol, 3eq), 2-(2-pyridyl)pyridine (86.43mg, 553.41μmol, 1eq) and disodium carbonate (175.97mg, 1.66mmol, 3eq) in DCE (6mL). The mixture was stirred at 70°C for 2 hours. LC-MS showed that a major peak with the desired mass was detected. The reaction mixture was poured into water (50mL) and extracted with EtOAc (30mL×3). The organic layer was washed with brine (30 mL) and 2 SO 4 The filtrate was concentrated and flash chromatographed on silica gel ( 4g Silica flash column, 30% ethyl acetate / petroleum ether gradient eluent). The compound N-[(3R,4R)-1-(1-cyclopropyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (160 mg, yield: 72.02%) was obtained as a yellow solid.

[1008] LC-MS m / z:402.2(M+1) +

[1009] Step 2: N-[(3R,4R)-1-(5-amino-1-cyclopropyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[1010] To a solution of tert-butyl N-[(3R,4R)-1-(1-cyclopropyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (160 mg, 398.55 umol, 1 eq.) in THF (10 mL) and H 2 Add NH 4Cl (170.55 mg, 3.19 mmol, 8 equiv) and Zn (208.49 mg, 3.19 mmol, 8 equiv). The mixture was stirred at 25 °C for 1 hour. LC-MS showed that a major peak with the desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (30 mL) and purified by Na 2 SO 4 Drying and filtration gave the product. Without further purification, tert-butyl N-[(3R,4R)-1-(5-amino-1-cyclopropyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (105 mg, yield: 70.92%) was obtained as an unnoticeable green solid.

[1011] LC-MS m / z: 372.2 (M+1) + .

[1012] Step 3: N-[(3R,4R)-1-[1-cyclopropyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester

[1013] To a solution of 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (71.28 mg, 282.66 μmol, 1 eq.) and N-[(3R,4R)-1-(5-amino-1-cyclopropyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (105 mg, 282.66 μmol 1 eq.) in Py (2 mL) was added POCl 3 (43.34 mg, 282.66 μmol, 26.27 uL, 1 eq.), the mixture was stirred at 25 °C for 0.5 h. LC-MS showed that a main peak with the desired mass was detected. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL) and purified by Na 2 SO 4 The filtrate was concentrated and flash chromatographed on silica gel ( 4g Silica flash column, 35% ethyl acetate / petroleum ether gradient eluent). The compound N-[(3R,4R)-1-[1-cyclopropyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamic acid tert-butyl ester (140 mg, yield: 81.78%) was obtained as a yellow solid.

[1014] LC-MS m / z:606.3(M+1) +

[1015] Step 4: N-[4-[(3R,4R)-3-amino-4-methyl-pyrrolidin-1-yl]-1-cyclopropyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[1016] To a solution of tert-butyl N-[(3R, 4R)-1-[1-cyclopropyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (140 mg, 231.16 umol, 1 equivalent) in dioxane (5 mL) and HCl / dioxane (10 mL). The mixture was stirred at 25 ° C for 1.5 hours. LC-MS showed that a major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (Boston Prime C18 150x30mm x5μm, water (HCl)-ACN, start B19, end B 39, gradient time (min) 2, 100% B hold time (min) 10, flow rate (ml / min) 25). Example 298 (28.39 mg, yield: 24.29%) was obtained as a yellow solid.

[1017] LC-MS m / z: 506.3 (M+1) +

[1018] 1 H NMR (400MHz, CD 3 OD)δ8.25-8.18(m,2H),7.73-7.63(m,1H),7.63-7.59(m,1H),7.36-7.26(m,4H),4.10(dd,J=5.9,10.7Hz,1H),3.88- 3.81(m,1H),3.74-3.67(m,1H),3.65-3.56(m,2H),3.53-3.45(m,1H),2.67-2.56(m,1H),1.24-1.16(m,4H),1.14(br s,3H).

[1019]

[1020]

[1021] Example 302: N-[4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-tert-butyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[1022]

[1023] plan

[1024]

[1025] Step 1: 2-Bromo-6-fluoro-3-nitro-benzoic acid

[1026] To a solution of 2-bromo-6-fluoro-benzoic acid (5 g, 22.83 mmol, 1 eq.) in sulfuric acid (15 mL) was added HNO at 0 °C. 3 (3.76 g, 59.67 mmol, 2.69 mL, 2.61 equiv.). The mixture was stirred at 20 °C for 2 hours. TLC showed that the starting material was consumed and new spots were formed. The reaction mixture was poured into 80 ml of water, filtered, and the solid was washed with water and dried in vacuo. The residue was used in the next step without further purification. 2-Bromo-6-fluoro-3-nitro-benzoic acid (4.2 g, yield: 69.68%) was obtained as a white solid.

[1027] 1 H NMR (500MHz, CD 3 OD)δ=8.03(dd,J=5.1,9.1Hz,1H),7.47(dd,J=8.2,8.9Hz,1H).

[1028] Step 2: (2-bromo-6-fluoro-3-nitro-phenyl)methanol

[1029] To a solution of 2-bromo-6-fluoro-3-nitro-benzoic acid (3.8 g, 14.39 mmol, 1 eq.) in THF (40 mL) was added BH 3 THF (1M, 28.79 mL, 2 eq). The mixture was stirred at 60 °C for 2 h. TLC showed that the starting material was consumed and a new spot was formed. The reaction mixture was added to H 2 O 30mL and extracted with EtOAc (30mL×3). The combined organic layer was washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue. The residue was used in the next step without further purification. (2-Bromo-6-fluoro-3-nitro-phenyl)methanol (3.59 g, yield: 99.76%) was obtained as a white solid.

[1030] 1 H NMR (400 MHz, CDCl 3 )δ7.73(dd,J=5.1,8.9Hz,1H),7.15(t,J=8.5Hz,1H),4.88(d,J=2.5Hz,1H),4.86(br s,1H),4.90-4.85(m,1H).

[1031] Step 3: 2-Bromo-6-fluoro-3-nitro-benzaldehyde

[1032] To a solution of (2-bromo-6-fluoro-3-nitro-phenyl)methanol (1.0 g, 4.00 mmol, 1 eq.) in DCM (10 mL) was added DMP (1.87 g, 4.40 mmol, 1.36 mL, 1.1 eq.). The mixture was stirred at 20 °C for 2 hours. TLC showed that most of the starting material was consumed and the desired mass was detected. The mixture was added to saturated 10 mL NaHCO 3 The mixture was filtered and the filtrate was extracted with DCM (15 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 20g Silica flash column, 0-10% ethyl acetate / petroleum ether gradient eluent). Compound 2-bromo-6-fluoro-3-nitro-benzaldehyde (764 mg, yield: 77.02%) was obtained as a white solid.

[1033] 1 H NMR (500 MHz, CDCl 3 )δ=10.36-10.29(m,1H),10.36-10.29(m,1H),7.97(br dd,J=4.7,9.0Hz,1H),7.38-7.28(m,1H).

[1034] Step 4: 4-Bromo-1-tert-butyl-5-nitro-indazole

[1035] To a solution of 2-bromo-6-fluoro-3-nitro-benzaldehyde (700 mg, 2.82 mmol, 1 eq.) and Py (1.12 g, 14.11 mmol, 1.14 mL, 5 eq.) in ethanol (7 mL) was added tert-butylhydrazine (422.06 mg, 3.39 mmol, 1.2 eq., HCl). The mixture was stirred at 140 °C by microwave for 1 hour. LCMS showed that the starting material was consumed and the desired mass was detected. The reaction mixture was added to 15 ml of H2 O and extracted with EtOAc (15 ml×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 4g Silica flash column, 0-10% ethyl acetate / petroleum ether gradient eluent). Compound 4-bromo-1-tert-butyl-5-nitro-indazole (350 mg, yield: 41.59%) was obtained as a yellow solid.

[1036] 1 H NMR (500 MHz, CDCl 3 )δ=8.19(s,1H),7.96(d,J=9.2Hz,1H),7.69(d,J=9.2Hz,1H),1.79(s,9H).

[1037] Step 5: N-[(7R)-5-(1-tert-butyl-5-nitro-indazol-4-yl)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester

[1038] To a solution of 4-bromo-1-tert-butyl-5-nitro-indazole (300 mg, 1.01 mmol, 1 eq) and tert-butyl N-[(7R)-5-azaspiro[2.4]hept-7-yl]carbamate (214.29 mg, 1.01 mmol, 1 eq) in DMSO (5 mL) was added TEA (305.47 mg, 3.02 mmol, 420.17 uL, 3 eq). The mixture was stirred at 90 °C for 1 hour. LCMS showed that the starting material was consumed and the desired mass was detected. The reaction mixture was added to 20 mL of H 2 O and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give a residue. The residue was used in the next step without further purification. The compound N-[(7R)-5-(1-tert-butyl-5-nitro-indazole-4-yl)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester (432 mg, yield: 99.95%) was obtained as a yellow solid.

[1039] LC-MS m / z: 430.3 (M+1) +

[1040] 1 H NMR (400 MHz, CDCl 3)δ=8.17(s,1H),7.87(d,J=9.4Hz,1H),7.00(d,J=9.4Hz,1H),4.80(br s,1H),4.14(s,1H),4.12(br d,J=3.1Hz,1H),4.02(d,J=10.6Hz,1H),3.93(br s,1H),3.63(br d,J=8.9Hz,1H),3.05(br d,J=10.8Hz,1H),1.78(s,9H),1.01-0.94(m,1H),0.90-0.82(m,1H),0.71(br s,2H).

[1041] Step 6: N-[(7R)-5-(5-amino-1-tert-butyl-indazol-4-yl)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester

[1042] To tert-butyl N-[(7R)-5-(1-tert-butyl-5-nitro-indazol-4-yl)-5-azaspiro[2.4]hept-7-yl]carbamate (432 mg, 1.01 mmol, 1 eq.) was dissolved in THF (6 mL) and H 2 O (6 mL) solution was added with Zn (550 mg, 8.41 mmol, 8.36 equiv) and NH 4 Cl (430.41 mg, 8.05 mmol, 8 eq.). The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the starting material was consumed and the desired mass was detected. The mixture was filtered and the filtrate was added to H 2 O 15mL and extracted with EtOAc (15mL×3). The combined organic layer was washed with brine and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give a residue. The residue was used directly in the next step without further purification. The compound N-[(7R)-5-(5-amino-1-tert-butyl-indazole-4-yl)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester (400 mg, yield: 99.54%) was obtained as a brown solid.

[1043] LC-MS m / z: 400.3 (M+1) +

[1044] Step 7: N-[(7R)-5-[1-tert-butyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester

[1045] To a solution of 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (277.72 mg, 1.10 mmol, 1.1 eq) and tert-butyl N-[(7R)-5-(5-amino-1-tert-butyl-indazol-4-yl)-5-azaspiro[2.4]hept-7-yl]carbamate (400 mg, 1.00 mmol, 1 eq) in MeCN (10 mL) was added NMI (246.60 mg, 3.00 mmol, 239.42 uL, 3 eq) and TCFH (309.00 mg, 1.10 mmol, 1.1 eq). The mixture was stirred at 20 °C for 1 hour. LCMS showed that the starting material was consumed and the desired mass was detected. The reaction mixture was added to H 2 O 20mL and extracted with EtOAc (20mL×3). The combined organic layer was washed with brine and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 12g Silica flash column, 0-30% ethyl acetate / petroleum ether gradient eluent). The crude product was purified by recrystallization from EtOAc (5 mL). Tert-butyl N-[(7R)-5-[1-tert-butyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamate (266 mg, yield: 41.93%) was obtained as a yellow solid.

[1046] LC-MS m / z: 634.4 (M+1) +

[1047] Step 8: N-[4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-tert-butyl-indazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[1048] To a solution of tert-butyl N-[(7R)-5-[1-tert-butyl-5-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]indazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamate (266 mg, 419.77 μmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4M, 3 mL, 28.59 eq). The mixture was stirred at 20 °C for 1 hour. LCMS showed that the starting material was consumed and the desired mass was detected. The mixture was concentrated under reduced pressure. Example 302 (222.88 mg, yield: 93.15%) was obtained as a yellow solid.

[1049] LC-MS m / z:534.3(M+1) +

[1050] 1 H NMR (400MHz, CD 3 OD)δ8.25(d,J=9.78Hz,1H),8.19(s,1H),7.76(d,J=9.18Hz,1H),7.64-7.73(m,1H),7. 56(d,J=9.30Hz,1H),7.28-7.36(m,3H),4.19(dd,J=5.72,10.61Hz,1H),3.99(d,J=9.1 8Hz,1H),3.66(dd,J=2.92,10.55Hz,1H),3.38-3.40(m,1H),3.10(d,J=9.18Hz,1H),1. 78(s,9H),0.94-1.07(m,1H),0.79-0.86(m,1H),0.71-0.77(m,1H),0.61-0.70(m,1H).

[1051]

[1052] Example 304: N-(4-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)-2-(bicyclo[2.2.2]octan-1-yl)-2H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[1053]

[1054] plan

[1055]

[1056]

[1057] Step 1: 2-(Bicyclo[2.2.2]octan-1-yl)-4-bromo-2H-indazole

[1058] A mixture of 6-bromo-2-nitrobenzene-1-carboxaldehyde (345 mg, 1.5 mmol) and bicyclo[2.2.2]octane-1-amine chloride (266.76 mg, 1.65 mmol) was stirred in dioxane (10 mL) at 90 ° C for 0.5 h to form a black solution, and then tributylphosphine (910.44 mg, 4.500 mmol) was added and stirred at 90 ° C for 24 h to form a black solution. The mixture was poured into 30 mL of water and extracted with EA (30 mL x 2). The reaction mixture was concentrated to dryness in vacuo. The column (SiO2 , eluted with 20% EA / PE, COMBI FLASH NEXTAGEN 300) to give 2-(bicyclo[2.2.2]octan-1-yl)-4-bromoindazole (260 mg, yield: 56.79%) as a white solid.

[1059] LC-MS m / z: 306.2 (M+1) +

[1060] Step 2: 2-(Bicyclo[2.2.2]octan-1-yl)-4-bromo-5-nitro-2H-indazole

[1061] At 0°C, 2-(bicyclo[2.2.2]octan-1-yl)-4-bromoindazole (150 mg, 0.491 mmol) was added to a mixture of H 2 SO 4 Fuming nitric acid (0.25 mL, 0.491 mmol) was added to the solution of 1,4-dihydro-1,4-dihydro-2-nitric acid (5 mL, 93.811 mmol) and stirred at 0°C for 30 minutes to obtain a brown solution. The target compound MS was detected by LC-MS. The reactants were heated at 0°C with H 2 O 30mL dilution, and extracted with EA 30mLX2. The combined organic layer was washed with NaHCO 3 Wash and use Na 2 SO 4 Drying, filtration and concentration gave 2-(bicyclo[2.2.2]octan-1-yl)-4-bromo-5-nitroindazole (162 mg, yield: 94.12%) as a yellow solid, which was used directly in the next reaction.

[1062] LC-MS m / z: 351.2 (M+1) +

[1063] Step 3: tert-Butyl ((3R,4R)-1-(2-(bicyclo[2.2.2]octan-1-yl)-5-nitro-2H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[1064] To a solution of 2-(bicyclo[2.2.2]octan-1-yl)-4-bromo-5-nitroindazole (162 mg, 0.463 mmol) in dioxane (5 mL) was added 2-methylpropan-2-yl {[(3R,4R)-4-methyltetrahydro-1H-pyrrol-3-yl]amino}carboxylate (102.00 mg, 0.509 mmol) and TEA (0.5 mL, 0.509 mmol). The reaction mixture was stirred at 110 ° C for 5 hours as a brown suspension. LC-MS showed that the reaction was complete. The reactants were washed with H 2O 100mL diluted and extracted with EA (50mL×2). The combined organic layers were washed with Na 2 SO 4 Drying, filtration and concentration gave 2-methylpropan-2-yl {[(3R,4R)-1-[2-(bicyclo[2.2.2]octan-1-yl)-5-nitroindazol-4-yl]-4-methyltetrahydro-1H-pyrrol-3-yl]amino}carboxylate (210 mg, yield: 96.68%) as a yellow solid.

[1065] LC-MS m / z:470.6(M+1) +

[1066] Step 4: tert-butyl ((3R,4R)-1-(5-amino-2-(bicyclo[2.2.2]octan-1-yl)-2H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[1067] To a solution of 2-methylpropan-2-yl {[(3R,4R)-1-[2-(bicyclo[2.2.2]octan-1-yl)-5-nitroindazol-4-yl]-4-methyltetrahydro-1H-pyrrol-3-yl]amino}carboxylate (210 mg, 0.447 mmol) in MeOH (10 mL) was added Pd / C 10% (20 mg, 0.447 mmol) and maintained under hydrogen at room temperature (60 Psi) for 18 h to give a black suspension, and the target compound MS was detected by LC-MS. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give 2-methylpropan-2-yl{[(3R,4R)-1-[5-amino-2-(bicyclo[2.2.2]octan-1-yl)indazol-4-yl]-4-methyltetrahydro-1H-pyrrol-3-yl]carbamate (182 mg, yield: 92.58%) as a black solid, which was used directly in the next reaction.

[1068] LC-MS m / z:440.6(M+1) +

[1069] Step 5: N-(4-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)-2-(bicyclo[2.2.2]octan-1-yl)-2H-indazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[1070] HATU (226.43 mg, 0.596 mmol) and ethyl diisopropylamine (0.5 mL, 3.025 mmol) were added to a solution of 1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-carboxylic acid (100 mg, 0.397 mmol) {[(3R, 4R)-1-[5-amino-2-(bicyclo[2.2.2]octan-1-yl)indazol-4-yl]-4-methyltetrahydro-1H-pyrrol-3-yl]amino}carboxylic acid-2-methylpropan-2-yl ester (174.32 mg, 0.397 mmol) in ACN (10 mL) and stirred at room temperature for 2 h to give a black suspension. LC-MS showed that most of the starting material was consumed and one peak was detected. The reactant was purified by H 2 O 30mL diluted and extracted with EA 30mL × 2. The combined organic layer was purified by Na 2 SO 4 The mixture was dried, filtered and concentrated. The residue was purified by column (SiO2, eluted with 60% EA / PE, COMBIFLASH NEXTAGEN 300) to give 68 mg of a yellow solid. 15 mL of HCl / EtOH (4 mol / L) was added to the residue and stirred at 50°C for 3 h to give a yellow suspension, which was filtered and dried to give Example 304 (44.76 mg, yield: 18.48%) as a yellow solid.

[1071] LC-MS m / z:574.6(M+1) +

[1072] 1 H NMR (400 MHz, MeOD) δ8.38(s,1H),8.22(d,J=9.9 Hz,1H),7.73–7.62(m,1H),7.57(d,J=9.1 Hz,1H),7.36–7.22(m,4H),3.99(dd,J=10.6,6.1 Hz,1H),3.82(dd,J=9.8,6.3 Hz,1H),3.60(dd,J=9.2,7.6 Hz,1H),3.54–3.44(m,1H),3.42–3.35(m,1H),2.83(s,1H),2.59(dt,J=14.8,7.3 Hz,1H),2.23(dd,J=9.8,6.2 Hz, 6H), 1.91 (dd, J=9.4, 6.2 Hz, 6H), 1.81 (dd, J=6.1, 3.0 Hz, 1H), 1.15 (d, J=7.1 Hz, 3H).

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088] Example 340: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-(propan-2-yl)benzo[d][1,2,3]triazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide

[1089]

[1090] plan

[1091]

[1092] Step 1: 5-nitro-2-(propan-2-ylamino)aniline

[1093] To a solution of 2-fluoro-5-nitroaniline (1 g, 6.405 mmol) in DMSO (10 mL) was added propan-2-amine (0.40 g, 6.726 mmol) and TEA (0.890 mL, 6.405 mmol). The resulting mixture was stirred at 80 ° C for 16 hours to give a dark brown solution. LCMS showed that most of the starting material remained and a new peak with the desired mass was detected. More additional propan-2-amine (0.40 g, 6.726 mmol) was added to the reaction. The mixture was warmed to 110 ° C and stirred for another 10 hours to give a dark brown solution. LCMS showed that most of the starting material was consumed and a main peak with the desired mass was detected. There was no manipulation and the reaction was used directly in the next step.

[1094] LC-MS m / z:196.1(M+1) +

[1095] Step 2: 5-Nitro-1-(propan-2-yl)benzo[d][1,2,3]triazole

[1096] To a solution of 5-nitro-2-(propan-2-ylamino)aniline (1.25 g, 6.403 mmol) in DMF was added HOAc (4 mL) and sodium nitrite (0.66 g, 9.605 mmol) at 0-5°C. 2 O (3mL) solution. The reaction was stirred at room temperature for 1 hour to give a brown suspension. LCMS showed that the starting material was exhausted and a main peak with the desired mass was detected. The reaction was filtered and washed with water, and the filter cake was dried by an oil pump to give 5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazole (1.17 g, yield: 88.61%) as a brown solid.

[1097] LC-MS m / z: 207.1 (M+1) +

[1098] Step 3: 1-(Propan-2-yl)benzo[d][1,2,3]triazol-5-amine

[1099] To a solution of 5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazole (1.17 g, 5.674 mmol) in MeOH (15 mL) was added Pd / C 10% (0.1 g, 0.325 mmol) under N2. The resulting mixture was treated with H 2Degas several times and stir at room temperature at 45psi for 30 hours to obtain a black suspension. LCMS shows that the starting material is consumed and a main peak with the desired mass is detected. The reaction is filtered through a diatomaceous earth pad and the filtrate is concentrated to obtain 1-(propan-2-yl)benzo[d][1,2,3]triazole-5-amine (0.98 g, yield: 98.02%) as a brown oil.

[1100] LC-MS m / z:177.1(M+1) +

[1101] Step 4: 4-Bromo-1-ethylbenzo[d][1,2,3]triazol-5-amine

[1102] 1-(Propan-2-yl)benzo[d][1,2,3]triazol-5-amine (0.98 g, 5.561 mmol) in CHCl 3 Pyridinium tribromide (1.77 g, 5.561 mmol) was added to the (20 mL) solution. The reaction was stirred at room temperature for 3 hours to give a dark brown solution. LCMS showed that most of the starting material was consumed and a main peak with the desired mass was detected. The reaction was filtered and the filter cake was washed with hexane. The solid was dissolved in EA and concentrated NaHCO 3 Neutralize. Separate the organic layer and use Na 2 SO 4 The residue was dried, filtered and concentrated to obtain 4-bromo-1-ethylbenzo[d][1,2,3]triazol-5-amine (1.2 g, yield: 89.55%) as a dark brown oil.

[1103] LC-MS m / z: 255.1 (M+1) +

[1104] Step 5: 4-Bromo-5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazole

[1105] To a solution of 4-bromo-1-(propan-2-yl)benzo[d][1,2,3]triazol-5-amine (1.2 g, 4.704 mmol) in DCE (15 mL) was added m-CPBA (3.82 g, 18.816 mmol). The reaction was stirred at 80 °C for 6 hours to give a brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was heated to 40 °C with NaHCO 3 The aqueous solution was quenched and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4Drying, filtration and concentration gave 4-bromo-5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazole (1.3 g, yield: 97.01%) as a brown solid.

[1106] LC-MS m / z: 285.1 (M+1) +

[1107] Step 6: 2-methylpropan-2-yl{[(7R)-5-[5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamate

[1108] To a solution of 4-bromo-5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazole (200 mg, 0.702 mmol) and 2-methylpropan-2-yl{[(7R)-5-azaspiro[2.4]hept-7-yl]amino}formate chloride (183.23 mg, 0.737 mmol) in DMSO (3 mL) was added TEA (0.244 mL, 1.754 mmol). The reaction was stirred at 90 °C for 2 hours to give a brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was concentrated by H 2 O and extracted with EA (10 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Drying, filtration and concentration gave 2-methylpropan-2-yl{[(7R)-5-[5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamate (290 mg, yield: 99.26%) as a brown oil.

[1109] LC-MS m / z:417.2(M+1) +

[1110] Step 7: 2-methylpropan-2-yl{[(7R)-5-[5-amino-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}formate

[1111] In N 2To a solution of 2-methylpropan-2-yl{[(7R)-5-[5-nitro-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamate (290 mg, 0.696 mmol) in MeOH (5 mL) was added Pd / C 10% (50 mg, 0.442 mmol). The resulting mixture was treated with H 2 Degassing several times, and stirring at room temperature at 45psi for 16 hours, obtain black suspension.LCMS shows that starting material is consumed and detects a main peak with required mass.Reaction is filtered through diatomaceous earth pad, and filtrate is concentrated to obtain 2-methylpropan-2-yl {[(7R)-5-[5-amino-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}formate (265mg, yield: 98.47%) of brown solid.

[1112] LC-MS m / z: 386.3 (M+1) +

[1113] Step 8: 2-methylpropan-2-yl{[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}carboxylate

[1114] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-carboxylic acid (130 mg, 0.516 mmol) and 2-methylpropan-2-yl {[(7R)-5-[5-amino-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}carboxylate (259.02 mg, 0.670 mmol) in DMF (3 mL) was added DIEA (0.256 mL, 1.547 mmol) and HATU (294.02 mg, 0.773 mmol). The residue was stirred at room temperature for 1 hour to give a green suspension. LCMS showed that the starting material was exhausted and one major peak with the desired mass was detected. The reaction was purified by flash column (C18, eluting with a gradient of ACN / H2O containing 0.5% HCOOH at a rate of 45 mL / min) to give 2-methylpropan-2-yl{[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]carbamate as a brown solid (235 mg, yield: 73.45%).

[1115] LC-MS m / z: 621.3 (M+1) +

[1116] Step 9: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-(propan-2-yl)benzo[d][1,2,3]triazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide

[1117] To a solution of 2-methylpropan-2-yl {[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-yl]carbonyl}amino)-1-(propan-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]hept-7-yl]amino}formate (235 mg, 0.379 mmol) in EA (2 mL) was added a 4M HCl solution of MeOH (5 mL). The resulting mixture was kept at room temperature for 16 hours to give a brown solution. LCMS showed that the starting material was exhausted and one major peak with the desired mass was detected. The reaction was concentrated to dryness. The residue was triturated with MeOH and lyophilized to give Example 340 (175.72 mg, yield: 83.24%) as a yellow solid.

[1118] LC-MS m / z: 521.2 (M+1) +

[1119] 1 H NMR (400MHz, CD 3 OD)δ8.22(d,J=9.9Hz,1H),7.94(d,J=8.9Hz,1H),7.67(tt,J=8.6,6.2Hz,1H),7.43(d,J=8.9Hz,1H) ,7.36–7.25(m,3H),5.16(h,J=6.8Hz,1H),4.30(dd,J=12.0,5.3Hz,1H),4.16–4.05(m,2H),3.41(dd ,J=5.3,1.7Hz,1H),3.20(d,J=9.7Hz,1H),1.70(dd,J=6.8,1.8Hz,6H),1.06(dt,J=9.7,5.8Hz,1H), 0.82(dt,J=9.2,5.7Hz,1H), 0.76(ddd,J=10.5,6.3,4.3Hz,1H), 0.61(ddd,J=10.1,6.2,4.3Hz,1H).

[1120]

[1121]

[1122] Example 342: N-(4-(4-cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[1123]

[1124] plan

[1125]

[1126] Step 1: 3-(3-Fluoro-4-nitrophenyl)isonicotinonitrile

[1127] To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-carbonitrile (1 g, 4.35 mmol, 1 eq) in dioxane (20 mL) and H 2 O (5 mL) solution was added with 4-bromo-2-fluoro-1-nitro-benzene (1.05 g, 4.78 mmol, 1.1 eq) and K 2 CO 3(1.80 g, 13.04 mmol, 3 eq.) and XPhos-Pd-G2 (341.98 mg, 434.65 μmol, 0.1 eq.). The mixture was stirred at 110 °C for 2 hours. LCMS showed the desired mass was formed. TLC showed the formation of a new spot. The reaction mixture was quenched by adding 25 mL of water, extracted with EtOAc (30 mL×3), and washed with Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 4g Silica flash column, 0-50% ethyl acetate / petroleum ether gradient eluent). The purified product 3-(3-fluoro-4-nitro-phenyl)pyridine-4-carbonitrile (800 mg, yield: 75.68%) was obtained as a light brown solid.

[1128] LC-MS m / z: 244.0 (M+1) +

[1129] Step 2: tert-Butyl 4-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)piperazine-1-carboxylate

[1130] To a solution of 3-(3-fluoro-4-nitro-phenyl)pyridine-4-carbonitrile (150 mg, 616.79 umol, 1 eq.) in DMSO (3 mL) was added tert-butyl piperazine-1-carboxylate (172.32 mg, 925.19 umol, 1.5 eq.) and TEA (124.83 mg, 1.23 mmol, 171.70 uL, 2 eq.). The mixture was stirred at 100 °C for 2 hours. LCMS showed the desired mass formed. TLC showed the generation of new spots. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry and filter. Concentrate the filtrate. The residue is purified by flash silica gel chromatography ( 4g Silica flash column, 0-60% ethyl acetate / petroleum ether gradient eluent). The purified product 4-[5-(4-cyano-3-pyridinyl)-2-nitro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (240 mg, yield: 95.04%) was obtained as a brown oil.

[1131] LC-MS m / z:410.2(M+1) +

[1132] Step 3: tert-Butyl 4-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)piperazine-1-carboxylate

[1133] To a solution of tert-butyl 4-[5-(4-cyano-3-pyridinyl)-2-nitro-phenyl]piperazine-1-carboxylate (240 mg, 586.17 umol, 1 eq) in MeOH (10 mL) was added Pd / C (62.13 mg, 58.62 umol, 10% purity, 0.1 eq). LCMS showed the desired mass formed and the starting material was consumed. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give tert-butyl 4-[2-amino-5-(4-cyano-3-pyridinyl)phenyl]piperazine-1-carboxylate (170 mg, yield: 76.43%) as a brown solid.

[1134] LC-MS m / z: 380.2 (M+1) +

[1135] Step 4: tert-Butyl 4-(5-(4-cyanopyridin-3-yl)-2-(1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)phenyl)piperazine-1-carboxylate

[1136] To a solution of tert-butyl 4-[2-amino-5-(4-cyano-3-pyridyl)phenyl]piperazine-1-carboxylate (150 mg, 395.30 μmol, 1 eq) in DMF (3 mL) was added 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (99.69 mg, 395.30 μmol, 1 eq) and TEA (80.00 mg, 790.61 μmol, 110.04 μL, 2 eq) and HATU (225.46 mg, 592.96 μmol, 1.5 eq) and the mixture was stirred at 60 °C for 2 hours. LCMS showed the desired mass formed. TLC showed the generation of new spots. The reaction mixture was quenched by the addition of water (15 mL). The combined organic layers were extracted with EtOAc (5 mL×3) and purified by Na 2 SO 4 The residue was purified by flash silica gel chromatography ( 4g Silica flash column, 0-30% ethyl acetate / petroleum ether gradient eluent). The mixture was purified by centrifugation to give tert-butyl 4-[5-(4-cyano-3-pyridinyl)-2-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]phenyl]piperazine-1-carboxylate (200 mg, yield: 82.45%) as a pale yellow solid.

[1137] LC-MSm / z:614.2(M+1) +

[1138] Step 5: N-(4-(4-cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[1139] To a solution of tert-butyl 4-[5-(4-cyano-3-pyridinyl)-2-[[1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carbonyl]amino]phenyl]piperazine-1-carboxylate (200 mg, 325.94 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 82.87 eq). The mixture was stirred at 25 °C for 2 hours. LCMS showed the desired mass formed. The combined organic phases were concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150X30mm×5μm, water (FA)-ACN, start B17, end B 47, gradient time (min) 12, 100% B hold time (min) 2, flow rate (ml / min) 25). Example 342 (60.27 mg, yield: 36.01%) was obtained as a white solid.

[1140] LC-MS m / z: 514.2 (M+1) +

[1141] 1 H NMR (500MHz, CD 3 OD)δ8.90(s,1H),8.76(d,J=5.04Hz,1H),8.64(d,J=8.54Hz,1H),8.27(d,J=9.77Hz,1H),7.85(d,J=4.73Hz,1H),7.69-7 .76(m,1H),7.66(d,J=1.98Hz,1H),7.56(dd,J=8.47,2.06Hz,1H),7.33-7.40(m,3H),3.09-3.14(m,4H),3.03(brs,4H).

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152] Example A: HPK1 inhibition assay

[1153] Prepare 10 mM stock solutions of test compounds in DMSO. Prepare compounds by 5-fold and 10-point serial dilutions in HPK1 kinase assay buffer. HPK1 kinase assay buffer contains 40 mM Tris, pH 7.5; 20 mM MgCl 2 , 0.1mg / ml BSA and 50μM DTT. 7.5ng / μl active HPK1 (Promega, V4098) and 0.1μg / ml MBP substrate protein were added to the reaction system. The final concentration of ATP in the HPK1 kinase reaction system was 10μM. The serially diluted compounds were transferred to the reaction system and incubated at room temperature for 1 hour. 5μL ADP-Glo TM Reagent (Promega, V9101) and incubate for 40 minutes to stop the kinase reaction and consume unconsumed ATP. Afterwards, 10 μl of kinase detection reagent was added and incubated at room temperature for 30 to 60 minutes. Luminescence was measured using a plate reader luminometer.

[1154] The compounds of the present disclosure as exemplified in the Examples show HPK1 IC in the range 50 (nM): A≤100nM; B 100nM <IC 50 ≤1000nM.

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

Claims

1. A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof: in R 1 is H, alkyl, cycloalkyl or substituted alkyl; Ring A is a 5-membered or 6-membered aryl or heteroaryl group, and is optionally substituted by one or more substituents, each of which is independently an alkyl, halogen or haloalkyl group; wherein the 5-membered or 6-membered heteroaryl group has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms, each of which is independently N, O or S; the ring-forming N atom is optionally substituted by oxo to form N + _ O - ; The ring-forming carbon atoms of the 5- or 6-membered aryl or heteroaryl are optionally substituted with oxo to form a carbonyl group; Ring B is a 5-membered or 6-membered monocyclic aromatic or heteroaryl group, or an 8-membered to 12-membered fused bicyclic aromatic or heteroaryl group; Ring B is optionally substituted by 1-5 substituents, each of which is independently alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkyl-S(=O)2-alkyl, cyano, hydroxyalkylamino, amido, amino, alkylamino, -NR 10 R 11 , cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or polycyclic alkyl; the ring carbon atoms in Ring B are optionally substituted with oxo to form a carbonyl group; Where R 10 and R 11 are each independently H, alkyl, halogen, haloalkyl, cycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl or heterocycloalkyl; Ring C is a 5- or 6-membered aryl or heteroaryl group and is optionally substituted with one or more substituents, each of which is independently alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkylamino, cyano, cycloalkyl, alkylcycloalkyl, or heterocycloalkyl; and the heteroaryl group has at least one ring carbon atom and 1, 2, or 3 ring heteroatoms, each of which is independently N, O, or S.

2. The compound of claim 1, wherein R 1 For H.

3. The compound as claimed in claim 1, wherein ring A is And R 2 is H, alkyl, halogen or haloalkyl.

4. The compound as claimed in claim 3, wherein R 2 is H or halogen.

5. The compound of claim 4, wherein halogen is -F.

6. The compound as claimed in claim 1, wherein ring B is R 3 is H, halogen, haloalkyl or alkyl; R 4 is cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, polycyclic alkyl, or -NR 10 R 11 ; wherein each substituent is optionally further substituted by one or more substituents; wherein R 10 and R 11 Each is independently selected from H, alkyl, halogen, haloalkyl, cycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl or heterocycloalkyl; Each R 5 D is independently H, alkyl, C D 3 , alkylthioalkyl, alkyl-S(═O) 2 -alkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkyl-S(═O) 2 -alkyl, cyano, amino, hydroxy, hydroxyalkyl, hydroxyalkylamino, amido, alkylamino, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spirocycloalkyl, polycycloalkyl, aryl or heteroaryl, wherein each substituent is optionally further substituted; wherein any hydrogen of the alkyl group can be optionally replaced by D; and R 6 is H, halogen, haloalkyl or alkyl.

7. The compound of claim 6, wherein R 3 It is H or F.

8. The compound of claim 6, wherein R 6 It is H or F.

9. The compound of claim 6, wherein R 4 is cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or polycycloalkyl, each of which is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, alkyl, amino, alkylamino, dialkylamino, alkylamino, alkoxy, alkoxyalkyl, -NH-C(=O)-(CH2) n -NH2, amido, cycloalkyl, alkylcycloalkyl, heterocycloalkyl or alkylheterocycloalkyl; and n is 0, 1, 2 or 3.

10. The compound of claim 1, wherein Ring C is phenyl substituted with one or more substituents, each of which is independently -F, -Cl or alkoxy.

11. The compound as claimed in claim 10, wherein ring C is 12. The compound of claim 1, wherein the compound has formula (Ia) or formula (Ib), or a stereoisomer or a pharmaceutically acceptable salt thereof, Wherein ring A is and optionally further represented by one or more R 2 replace; X 1 , X 2 , X 3 and X 4 are each independently a carbon atom (C) or N, and are optionally replaced by R 2 Replacement; R 2 is H, alkyl, halogen or haloalkyl; Each R c is independently alkyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkylamino, cyano, cycloalkyl, alkylcycloalkyl, or heterocycloalkyl; m is 0, 1, 2, 3, or 4; X, Y and Z are each independently a carbon atom or a heteroatom selected from N or S; Dashed bonds represent single or double bonds required to complete the valence of the atoms connected by the bond; R 3 , R 4 , R 5 and R 6 Same as claim 6.

13. The compound according to any one of claims 1 to 12, wherein the compound is 14. The compound according to any one of claims 1 to 13, wherein the compound is 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier or excipient.

16. The pharmaceutical composition of claim 15, further comprising a second therapeutic agent.

17. The pharmaceutical composition of claim 16, wherein the second therapeutic agent is an immune checkpoint inhibitor or an inhibitor of the PGE2 or adenosine pathway.

18. The pharmaceutical composition of claim 17, wherein the immune checkpoint inhibitor is ipilimumab, nivolumab or pembrolizumab.

19. A method for treating a disorder mediated by HPK1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutical composition of any one of claims 15 to 18.

20. The method of claim 19, wherein the disorder is cancer.

21. The method of claim 20, wherein the cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, or pancreatic cancer.

22. Use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment of a disorder mediated by HPK1.

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