Heteroaryl compounds as HPK1 inhibitors and methods of use thereof

Abstract

The present invention provides, inter alia, heteroaryl compounds of formula (I) or pharma- ceutically acceptable salts, esters, or prodrugs thereof as HPK1 inhibitors and methods of use thereof. JPEG2025502358000229.jpg5156

Description

[Technical field]

[0001] (Related Applications) This application claims priority to U.S. Application No. 63 / 299,000, filed January 12, 2022, International Application No. PCT / CN2022 / 112996, filed August 17, 2022, and U.S. Application No. 63 / 418,888, filed October 24, 2022, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Progenitor kinase 1 (HPK1) is mainly expressed in hematopoietic cells and functions as a negative regulator in T cells and dendritic cells (DCs). Inhibition of the kinase activity of HPK1 by genetic knock-in of kinase death (KD) enzyme was demonstrated to be involved in anti-tumor immune responses (Hernandes et al., US2016 / 0158360). Mechanistically, HPK1 KD reduces phosphorylation of the downstream protein SLP76 in T cells, resulting in increased release of the immune-promoting cytokines IL-2 and IFNγ upon anti-CD3 and anti-CD28 stimulation. In a mouse sarcoma model expressing the KD enzyme, an increase in tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) and reduced tumor growth were observed (Liu et al., PLoS ONE 14(3):e0212670). Furthermore, small molecule HPK1 inhibitors have demonstrated antitumor activity in various cancer models as single agents or in combination with anti-PD1 (Chen et al., AACR Annual Meeting, June 2020, Poster 4513) or anti-CTLA-4 (Ciccone et al., AACR Annual Meeting, June 2020, Poster 942) antibodies.

[0003] HPK1 KD T cells have been shown to be resistant to immunosuppression by PGE2 and adenosine, supporting the investigation of synergistic anti-cancer effects of compounds that block the PGE2 and adenosine pathways. For example, combining HPK1 inhibitors with EP4 or A2a / b inhibitors may provide superior therapeutic benefit for cancer treatment (Liu et al., PLoS ONE 14(3):e0212670).

[0004] Because HPK1 plays a role in regulating immune cell activity, small molecule inhibitors may be effective in cancer treatment as single agents or in combination with existing immunotherapies, targeted therapies, or compounds that block the PGE2 or adenosine pathways. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the present invention provides heteroaryl compounds of formula (I) or a stereoisomer thereof, or a pharma- ceutically acceptable salt, ester, or prodrug thereof: JPEG2025502358000002.jpg5156, where R 1 is H, alkyl, cycloalkyl or substituted alkyl; Ring A is a 5- or 6-membered aryl or heteroaryl, the 5- or 6-membered aryl or heteroaryl being optionally substituted with one or more substituents selected from alkyl, halo, or haloalkyl, the 5- or 6-membered heteroaryl each having at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S, and N is optionally substituted with oxo to form N + -O - wherein a 5- or 6-membered aryl or heteroaryl ring carbon atom is optionally substituted with oxo to form a carbonyl group; Ring B is a 5- or 6-membered monocyclic aryl or heteroaryl, or an 8- to 12-membered fused bicyclic aryl or heteroaryl, wherein the monocyclic or fused bicyclic aryl or heteroaryl is optionally substituted with 1 to 5 substituents, each of which is independently selected from alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkthioalkyl, alk-S(=O)2-alkyl, cyano, hydroxyalkamino, amino, amido, alkamino, -NR 10 R 11, cycloalkyl, alk-cycloalkyl, heterocycloalkyl, alk-heterocycloalkyl, aryl, heteroaryl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or multicycloalkyl, each of which is optionally further substituted; a ring-forming carbon atom of a cycloalkyl or heterocycloalkyl is optionally substituted with oxo to form a carbonyl group; R 10 and R 11 are each independently selected from H, alkyl, halo, haloalkyl, cycloalkyl, alkcycloalkyl, alkheterocycloalkyl, or heterocycloalkyl, each of which is optionally further substituted; Ring C is a 5- or 6-membered aryl or heteroaryl, optionally substituted with one or more substituents, each of which is independently selected from alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkamino, cyano, heterocycloalkyl, cycloalkyl, alkcycloalkyl, or alkheterocycloalkyl; Each heteroaryl has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; Any hydrogen (H) may be optionally replaced with deuterium (D).

[0006] In some embodiments, R 1 is H.

[0007] In some embodiments, Ring A is one of the compounds shown below: JPEG2025502358000003.jpg2774 JPEG2025502358000004.jpg28150, where R 2 is H, alkyl, halo, or haloalkyl, and in some preferred embodiments, R 2is a halo (e.g., F).

[0008] In some embodiments, ring B in formula (I) is one of the compounds shown below: JPEG2025502358000005.jpg2968 JPEG2025502358000006.jpg30150Here, here, R 3 is H, halo, haloalkyl or alkyl, preferably R 3 is H or halo (e.g., F); R 4 is a cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, multicycloalkyl, or -NR 10 R 11 each of the substituents is optionally further substituted; R 10 and R 11 are each independently selected from H, halo, haloalkyl, alkyl, cycloalkyl, alkcycloalkyl, alkheterocycloalkyl, or heterocycloalkyl; Each R 5 are independently H, alkyl, CD3, alkylthioalkyl, alkyl-S(=O)2-alkyl, cyano, amino, hydroxyl, hydroxyalkyl, hydroxyalkamino, amido, alkamino, halo, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spirocycloalkyl, multicycloalkyl, aryl, or heteroaryl, each of which is optionally further substituted, and wherein a hydrogen of an alkyl is optionally replaced by D; R 6 is H, halo, haloalkyl or alkyl.

[0009] In some embodiments, R 3 is H or F.

[0010] In some embodiments, R 6 is H or F.

[0011] In some embodiments, R 4 is cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or multicycloalkyl, each of which is selected from the group consisting of hydroxyl, hydroxyalkyl, hydroxyalkamino, halo, haloalkyl, alkyl, amino, alkylamino, dialkylamino, alkamino, alkoxy, alkoxyalkyl, -NH-C(=O)-(CH2) n It may be further substituted with one or more substituents selected from -NH2 (n is 0, 1, 2 or 3), amido, cycloalkyl, alk-cycloalkyl, alk-heterocycloalkyl, or heterocycloalkyl.

[0012] In some embodiments, ring C in formula (I) is phenyl substituted with one or more substituents, each of which is independently selected from -F, -Cl, or alkoxy, and in some preferred embodiments, alkoxy is -O-CH3.

[0013] A specific example of ring C of formula (I) is one of the compounds shown below. JPEG2025502358000007.jpg2362 JPEG2025502358000008.jpg23150

[0014] In some embodiments, the compound of the present invention is a compound of formula (Ia) or formula (Ib), or a stereoisomer or a pharma- ceutically acceptable salt thereof: JPEG2025502358000009.jpg56137 Ring A is one of the compounds shown below: JPEG2025502358000010.jpg29114 Ring A can be any one or more R 2 is further substituted with X 1 , X 2 , X 3 and X 4 are each independently a carbon atom (C) or N, and optionally R 2 is replaced by R 2 is H, alkyl, halo or haloalkyl; Each R c is independently alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkamino, cyano, cycloalkyl, alkcycloalkyl, or heterocycloalkyl; m is 0, 1, 2, 3 or 4; X, Y or Z are each independently a carbon atom or a heteroatom selected from N or S; The dashed bonds represent single or double bonds necessary to complete the valence of the atoms connected by the bond; R 3 , R 4 , R 5 and R 6 are the same as above, respectively.

[0015] Examples of compounds of formula (I) include the following compounds: JPEG2025502358000011.jpg201150 JPEG2025502358000012.jpg197150 JPEG2025502358000013.jpg178150 JPEG2025502358000014.jpg205150 JPEG2025502358000015.jpg178150 JPEG2025502358000016.jpg206150 JPEG2025502358000017.jpg174150 JPEG2025502358000018.jpg209150 JPEG2025502358000019.jpg206150 JPEG2025502358000020.jpg207150 JPEG2025502358000021.jpg198150 JPEG2025502358000022.jpg204150 JPEG2025502358000023.jpg199150 JPEG2025502358000024.jpg200150 JPEG2025502358000025.jpg189150 JPEG2025502358000026.jpg187150 JPEG2025502358000027.jpg201150 JPEG2025502358000028.jpg175150

[0016] In other embodiments, exemplary compounds of formula (I) include the following compounds: JPEG2025502358000029.jpg203150 JPEG2025502358000030.jpg202150 JPEG2025502358000031.jpg135150

[0017] Another aspect of the present invention includes pharmaceutical compositions, each of which comprises the compound of the present invention described above and a pharma- ceutical acceptable carrier or excipient.Such pharmaceutical compositions can include a second therapeutic agent, which is, for example, an immune checkpoint inhibitor or an inhibitor of PGE2 or adenosine pathway.Examples of suitable immune checkpoint inhibitors include ipilimumab, nivolumab, and pembrolizimab.

[0018] Yet another aspect of the present invention provides a method for treating HPK1-mediated disorders in a subject in need of treatment.The method includes administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of the present invention as described above.In some embodiments, the disorder is cancer.Cancers that can be treated (including reducing the likelihood of recurrence) by the method of the present teachings include breast cancer, colon 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] (definition) Unless the context requires otherwise, reference to formula (I) in all sections herein (including the uses, methods, and other aspects of the invention) includes reference to all other sub-formulas, sub-groups, options, embodiments, and examples defined herein.

[0020] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0021] As used herein, the terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0022] The term "saturated" as used herein refers to a moiety that does not contain any double or triple bonds, i.e., the moiety contains only single bonds.

[0023] As used herein, the term "alkyl" refers to an alkyl group consisting of carbon and hydrogen atoms, containing no unsaturation, and having the stated number of carbon atoms (e.g., C-C 10 or C 1-10"alkyl" refers to a saturated straight chain (i.e., unbranched) or branched hydrocarbon chain radical having a cyclic alkyl group (alkyl). Numeric ranges such as "1-10" as used herein refer to each integer in the specified range. For example, "1-10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to 10 carbon atoms, although this definition also covers the use of the term "alkyl" when no numerical range is specified. Specific examples include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like, while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.

[0024] The term "substituted alkyl" as used herein refers to an alkyl substituted with one or more substituents.Examples of the substituents include, but are not limited to, halogen, hydroxyl, cyano, amino, alkoxyl, alkoxyalkyl, haloalkyl, alkoxy, amino, methylamino, dimethylamino, sulfone, sulfonamide, aryl, heteroaryl, heterocyclyl, trifluoroethyl, hydroxyethyl, cyanoethyl, methoxyethyl and trifluoropropyl.

[0025] The term "alkylene" by itself or as part of another molecule means a divalent radical derived from an alkane, which is straight or branched. As used herein, the prefixes (e.g., C 1-4 , C 1-7 , C 1-20 , C 2-7 , C 3-7 etc.) indicates the number of carbon atoms or range of numbers of carbon atoms. For example, as used herein, "C 1-4 The term "alkylene" refers to an alkylene group having from 1 to 4 carbon atoms.

[0026] The term "alkoxy" or "alkoxyl" as used herein refers to a saturated straight or branched chain hydrocarbon bonded to an oxygen atom. For example, methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc. are included, with methoxy, ethoxy, propoxy, or 2-propoxy being preferred. Representative saturated straight chain alkoxy includes methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, etc., and saturated branched alkoxy includes isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, isopentoxy, etc. Cyclic alkoxy is described herein as "cycloalkoxy." "C 1-4 "Alkoxy" refers to an alkyl having 1, 2, 3 or 4 carbon atoms. The alkoxy can be attached to the molecule by one or two points of attachment.

[0027] The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with one, two or three alkoxy groups.

[0028] The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon. Examples include ethenyl and propenyl. Alkenyl can also be substituted with one or more alkyl groups.

[0029] As used herein, the term "alk" (e.g., as a prefix in alkoxyalkyl and alkthioalkyl) refers to an acyclic hydrocarbon radical of an alkyl, alkenyl, or alkynyl. Unless otherwise specified, the term "alk" encompasses "alkyl," "alkenyl," and "alkynyl."

[0030] The term "carbonyl group" as used herein refers to -C(=O)-.

[0031] The term "cycloalkyl" as used herein, by itself or as part of another substituent, refers to a non-aromatic carbon-based ring of at least three carbon atoms. The term cycloalkyl includes monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, fused cycloalkyl, and spirocycloalkyl groups. In bridged cycloalkyl, the rings share at least two common non-adjacent atoms. In fused bicyclic cycloalkyl, the two rings share a covalent bond. In spirocyclic cycloalkyl, one atom is common to two different rings.

[0032] The term "heterocycloalkyl" is a type of cycloalkyl group, as defined above, included within the meaning of the term "cycloalkyl," in which at least one of the ring carbon atoms is replaced by a heteroatom, such as nitrogen, oxygen, sulfur, phosphorus, etc. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted.

[0033] The term "multicycloalkyl" refers to a cycloalkyl having multiple rings fused together.

[0034] The term "halo" or "halogen" as used herein refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). "Haloalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms are replaced with a halogen independently selected from fluoro, chloro, bromo, and iodo. "Fluoroalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms are replaced with a fluoro atom. Unless otherwise specified by number, a haloalkyl can contain as many halo atoms as chemically possible as substituents on the alkyl group. For example, fluoroethyl is -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0035] As used herein, the term "hydrogen" (or H) includes its isotope deuterium (D or 2H) and tritium ( 3 H), and the hydrogen atoms in the compounds of the present invention are deuterium (D or 2 H) and tritium ( 3 H) can be substituted.

[0036] The term "hydroxyl" or "hydroxy" as used herein refers to an --OH group.

[0037] The term "hydroxyalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more hydrogen atoms have been replaced with a hydroxyl substituent. Thus, the term "hydroxyalkyl" includes monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and the like.

[0038] The term "cyano" as used herein refers to a -C≡N group. The term "cyanoalkyl" as used herein refers to an alkyl group having at least one -CN substituent.

[0039] The term "carbonyl" as used herein refers to a -C(=O)- group.

[0040] As used herein, the term "amino" or "amine" refers to -NH2. The term "alkylamino" refers to a group of formula -NHR and the term "dialkylamino" refers to a group of formula -NRR, where each R is independently alkyl.

[0041] The term "amide" or "amido" refers to either a C-amide group, such as -C(=O)NR'R'', or an N-amide group, such as -NR'C(=O)R'', where R' or R'' is a substituent. Examples of R' and R'' include, but are not limited to, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, hydroxyalkamino, amino, alkamino, cycloalkyl, alkcycloalkyl, aryl, alkaryl, heterocycloalkyl, alkheterocycloalkyl, heteroaryl, and alkheteroaryl.

[0042] The term "nitro" as used herein refers to --NO.

[0043] The term "alkylthioalkyl" or "alkthioalkyl" as used herein refers to an -alkyl-S-alkyl group, where "alk" is an alkylene group. Generally, when a compound is bonded to an "alkthioalkyl" group, the alkylene portion of the "alkthioalkyl" group is bonded to the compound.

[0044] The term "alk-S(=O)2-alkyl" or "alkyl-S(=O)2-alkyl" as used herein refers to an -alkyl-S(=O)2-alkyl group, where "alk" is an alkylene group.

[0045] The term "alkamino" as used herein refers to an amino group linked to an alkylene, as described herein. Generally, when a compound is linked to an alkamino group, the alkylene portion of the alkamino is linked to the compound.

[0046] The term "alkcycloalkyl" refers to a cycloalkyl group bonded to an alkylene. Generally, when a compound is bonded to an alkcycloalkyl group, the alkylene portion of the alkcycloalkyl group is bonded to the compound.

[0047] As used herein, the term "aromatic" or "aromatic ring" or similar terms refer to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is a positive integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, 10 or more than 10 atoms. Aromatics are optionally substituted. The term "aromatic" includes carbocyclic aryl ("aryl", e.g., phenyl) and "heteroaryl" (or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0048] The dashed bonds represent single or double bonds necessary to complete the valence of the atoms connected by the bond, and in some cases it will be understood that the bond has aromatic character.

[0049] The term "aryl" as used herein 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 having a completely conjugated pi-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, etc.

[0050] The term "heteroaryl" as used herein refers to a monocyclic or fused ring (i.e., rings sharing adjacent pairs of atoms) of 5-12 ring atoms containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and further having a fully conjugated pi-electron system. Examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzthiazole, indazole, and quinazoline. Heteroaryl groups can be substituted or unsubstituted.

[0051] The above defined groups may include prefixes and / or suffixes to create additional well-recognized substituents commonly used in the art. As an example, the term "haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group attached to the parent molecular moiety through 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 "hydroxyalkamino" refers to an amino group substituted with one or two hydroxyalkyl groups.

[0052] Stereoisomers are compounds that differ only in spatial arrangement. When a disclosed compound is named or depicted by a structure without indicating stereochemistry, it is understood that the name or structure includes all stereoisomers, geometric isomers, and combinations thereof, including essentially pure stereoisomers or geometric isomers.

[0053] Combinations of substituents are permissible only if such combinations result in stable or chemically feasible compounds (i.e., compounds that are substantially unchanged upon storage at or below 40° C. for at least 1 week).

[0054] The term "optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that alkyl may, but need not, be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with an alkyl group.

[0055] "Pharmaceutically acceptable salts" prepared by acid addition are salts which are produced from an acid with subsequent formation of a non-toxic acidic anion, such as hydrochloride, hydrobromide, sulfate, phosphate, or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and gluconate. References herein to compounds of formula (I) are intended to include pharma- ceutically acceptable salts.

[0056] When the compound of the present invention has a carboxyl group, the compound can be reacted with a corresponding alcohol (e.g., a C1-6 alcohol) to convert it into a pharma- ceutically acceptable ester by a conventional method (e.g., condensation reaction of a carboxylic acid with an alcohol).

[0057] "Pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharma- ceutically acceptable salts or prodrugs thereof, with other chemical components, such as pharma- ceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0058] The term "pharmaceutical 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 starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, etc.

[0059] The term "therapeutically effective amount" refers to the amount of compound administered which will relieve to some extent one or more of the symptoms of the disease being treated. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing tumor size, (2) inhibiting tumor metastasis, (3) inhibiting tumor growth, and / or (4) alleviating one or more symptoms associated with cancer.

[0060] As used herein, the terms "subject" or "patient" are used interchangeably and as used herein refer to any mammal, including but not limited to a human patient or subject, to which the compositions of the invention can be administered. The term "mammal" includes human patients and non-human primates, as well as laboratory animals such as rabbits, rats, mice, and other animals.

[0061] As those skilled in the art can understand, the compounds taught herein can be administered to patients in various forms depending on the selected administration route.The compounds of the present invention can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump or transdermal administration, and the pharmaceutical composition is formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, spinal, rectal and local administration modes.Parenteral administration can be carried out by continuous infusion over a selected period of time.

[0062] Isomers The present invention provides compounds of formula (I) below, or pharma- ceutically acceptable salts, esters, or prodrugs thereof, which are useful as HPK1 inhibitors, and methods of using them. JPEG2025502358000032.jpg5156

[0063] Certain compounds of formula (I) (or salts, prodrugs, or complexes) may exist in and be isolated in isomeric forms, including tautomers, geometric isomers (i.e., cis or trans isomers), optical isomers (i.e., enantiomers and diastereomers), racemates, or any mixture of the above isomers. It should be understood that the present invention encompasses the compounds of formula (I) in the form of any isomer or mixtures thereof, for example, an active single enantiomer, a racemate, or any mixture thereof. The present invention is intended to encompass all such isomers of the compounds of formula (I).

[0064] Furthermore, the compounds of formula (I) (or salts, prodrugs or conjugates thereof) may exhibit polymorphism or form solvates with water or organic solvents. The present invention encompasses such polymorphisms, solvates or mixtures thereof. Example 1: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide JPEG2025502358000033.jpg73150 Step 1: tert-Butyl (1S,4S)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0065] A mixture of 1,4-difluoro-2-nitrobenzene (0.85 g, 5.4 mmol, 1.00 eq), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.00 g, 5.4 mmol, 1.00 eq), and Et3N (1 mL) was stirred in ACN (15 mL) at 60 °C for 10 h. TLC showed the reaction was complete. The mixture was poured into 100 mL water and extracted with 100 mL EA (2 times). The organic layer was dried over Na2SO4 and concentrated to dryness under vacuum to give tert-butyl (1S,4S)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g). LC-MS m / z: 338.3 (M+1) + . Step 2: tert-Butyl (1S,4S)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0066] 2.5 g of tert-butyl (1S,4S)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was dissolved in 30 mL of methanol and 0.25 g of Pd / C was added under hydrogen atmosphere for 15 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to dryness under vacuum 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. LC-MS m / z: 308.2 (M+1) + Step 3: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0067] To a solution of tert-butyl (1S,4S)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (95 mg, 0.36 mmol, 1.00 eq) in 5 mL of DCM, 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (111 mg, 0.36 mmol, 1.00 eq) and HATU (274 mg, 0.72 mmol, 2.00 eq) were added and stirred at room temperature (RT) for 4 h. LCMS showed MS of the target compound and the reaction was completed. The mixture was poured into 30 mL of water and extracted with EA 30 mL x 2, the organic layer was dried over Na2SO4 and concentrated to dryness under vacuum. The obtained residue was purified by column chromatography (EA:PE=1:1) to give 58 mg as a white solid. To this was added 1 mL of CF3COOH and 1 mL of DCM, stirred at room temperature for 2 h, and concentrated to dryness in vacuo to give Example 1 (30 mg) as a white solid. LC-MS m / z: 455.6 (M+1) + . 1H NMR (400MHz, CDCl3): 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=10.3H) z, 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). JPEG2025502358000034.jpg63150 Example 3: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxamide JPEG2025502358000035.jpg71150 Step 1: 2,2'-Difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxylic acid

[0068] A mixture of 3-bromo-2-fluorobenzoic acid (500 mg, 2.27 mmol, 1.00 eq), (2-fluoro-6-methoxyphenyl)boronic acid (772 mg, 4.54 mmol, 2.00 eq), Pd(PPh3)4 (127 mg, 0.11 mmol, 0.05 eq), K2CO3 (941 mg, 6.81 mmol, 3.00 eq), 1,4-dioxane (5 mL), EtOH (5 mL), and water (1 mL) was stirred in a microwave at 100 °C for 2 h. 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 x 2). The organic layer was dried over MgSO4 and concentrated to dryness under vacuum. The obtained residue was purified by column chromatography (EA:MeOH=3:1) to obtain 2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-3-carboxylic acid (135 mg, yield 23%) as a white solid. LC-MS m / z: 263.2 (M-1) - . Step 2: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxamide

[0069] A solution of 2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (50 mg, 0.19 mmol, 1.00 eq) in 10 mL of toluene was added with 2 mL of SOCl2, stirred at 80 °C for 2 h, and then concentrated to dryness under vacuum. The residue was added with 5 mL of DCM, 2 mL of Et3N, and tert-butyl (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (58 mg, 0.19 mol, 1.1 eq) and stirred at room temperature for 3 h, after which LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was poured into 30 mL of water and extracted with 30 mL x 2 of EA. The organic layer was dried over Na2SO4 and concentrated to dryness under vacuum. The resulting residue was purified by column chromatography (EA:PE=1:1) to give 30 mg of a white solid. Then 1 mL of CF3COOH and 1 mL of DCM were added, stirred at room temperature for 2 hours, concentrated to dryness under vacuum, then 3 mL of ammonium hydroxide and 10 mL of water were added, extracted with 10 mL of EA, concentrated to dryness under vacuum to give Example 3 (7 mg, yield: 8%) as a white solid. LC-MS m / z: 454.5 (M+1) + . 1H NMR (400MHz, CDCl3): 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, 1 H), 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). Example 4: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamide JPEG2025502358000036.jpg75150 Step 1: tert-Butyl (1R,4R)-5-(2-(2-bromo-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0070] To a solution of 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) and stirred at 26 °C for 30 min, followed by the addition of tert-butyl (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (600 mg, 1.95 mmol, 1.0 eq). The reaction was stirred overnight at 26 °C to give a brown solution. LCMS showed one major peak at the desired mass and the material was nearly consumed. The reaction was washed with water and extracted with DCM. The organic phase was concentrated to dryness under reduced pressure to obtain the compound tert-butyl (1R,4R)-5-(2-(2-bromo-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.71 g, yield: 71.4%) as a dark brown oily liquid. LC-MS m / z: 509.1 (M+1) + . Step 2: tert-Butyl (1R,4R)-5-(2-(2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0071] To a suspension of tert-butyl (1R,4R)-5-(2-(2-bromo-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 196.33 μmol, 1.0 eq) in toluene (2 mL) was added (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (120.38 mg, 588.98 μmol, 3.0 eq), K3PO4 (83.35 mg, 392.66 μmol, 2.0 eq), and xphos Pd G2 (15.43 mg, 19.633 μmol, 0.1 eq). The reaction was stirred at 100 °C for 2 h to give a brown suspension. LCMS showed a major peak of the desired mass with some reactant still remaining. The reaction was washed with water and extracted with DCM. The organic phase was concentrated under reduced pressure to dryness and purified by flash column (SiO2, eluted with 0-30% EA in PE, COMBI FLASH NEXTAGEN 300) to give tert-butyl (1R,4R)-5-(2-(2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamido)-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (102 mg, yield: 88%) as a pale yellow oil. LC-MS m / z: 589.2 (M+1) + . Step 3: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(3-chloro-2-fluoro-6-methoxyphenyl)-3-fluoroisonicotinamide

[0072] A mixture of tert-butyl (1R,4R)-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 eq) in 4M HCl dioxane (2 mL) was stirred at 25° C. overnight to give a yellow solution. LCMS showed one peak of the desired mass and the material was nearly consumed. The reaction was concentrated to dryness under reduced pressure and purified by flash column (C18, peak time=50% ACN in H2O, COMBI FLASH NEXTAGEN 300) to give the compound of Example 4 (30.1 mg, yield: 35.5%) as a yellow solid. LC-MS m / z: 489.1(M+1)+. 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000037.jpg136150 Example 7: N-(4-((1S,4S)-2-azabicyclo[2.2.1]heptan-5-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide JPEG2025502358000038.jpg93150 Step 1: N-(2-chloro-6-fluorophenyl)acetamide

[0073] Acetic anhydride was added to a solution of 2-chloro-6-fluoroaniline (10 g, 68.7 mmol, 1 eq) in AcOH (40 mL). The reaction was stirred at 90° C. for 2 h. 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. LC-MS m / z: 188.1 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide

[0074] A mixture of N-(2-chloro-6-fluorophenyl)acetamide (9.28 g, 49.47 mmol, 1 eq) in H2SO4 (43 mL) was cooled to -78 °C in a reaction vessel and HNO3 (2.67 mL, 64.31 mmol, 1.3 eq) was added dropwise. The mixture was stirred for 2 h. LCMS analysis showed the reaction was complete with the desired mass detected. 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. LC-MS m / z: 233.1 (M+1) + . Step 3: 4-Chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole

[0075] A solution of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (5.0 g, 21.5 mmol, 1 eq), 33% EtOH solution of CH3NH2 (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 purged with N2 for 30 min, additional TEA (6 mL, 43 mmol, 1 eq) was added, and the reaction mixture was heated at 120 °C for 4 h. LCMS analysis showed the desired mass was detected, indicating the reaction was complete. After cooling to room temperature, water was added and the solid precipitate was collected by filtration, washed with water, and air-dried to give 4-chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole (1.25 g, yield: 25.8%) as a pale yellow solid. LC-MS m / z: 226.1 (M+1) + . Step 4: 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

[0076] A solution of tert-butyl (1R,4R)-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 at 80 °C for 3 h. LCMS analysis showed the desired mass was detected, indicating the reaction was complete. After cooling to room temperature, the solid precipitate was collected by filtration, washed with water, and air-dried to give 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, yield: 61.66%) as an orange solid. LC-MS m / z: 388.3 (M+1) + . Step 5: tert-Butyl (1R,4R)-5-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0077] 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 under H2 atmosphere (60 psi) for 16 h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was filtered and concentrated to give tert-butyl (1R,4R)-5-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (239.5 mg, yield: 101.6%) as a dark purple solid. LC-MS m / z: 358.2 (M+1) + . Step 6: tert-Butyl (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-carboxylate

[0078] To a solution of tert-butyl (1R,4R)-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 h. 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 on an oil pump to give tert-butyl (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-carboxylate (235.1 mg, yield: 93.28%) as a green solid. LC-MS m / z: 605.3 (M+1) + . Step 7: N-(4-((1S,4S)-2-azabicyclo[2.2.1]heptan-5-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0079] A solution of tert-butyl (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-carboxylate (235.1 mg, 0.389 mmol, 1 eq) in TFA (2 mL) was stirred at room temperature for 1 h 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 on top of the phase was then separated. The water was basified to pH=11 with NaOH, and the solid precipitate was collected by filtration, washed with water, and lyophilized to give Example 7 (62.5 mg, yield: 50.27%) as a yellow solid. LC-M Sm / z: 504.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000039.jpg174150 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 JPEG2025502358000040.jpg107150 Step 1: N-(2-chloro-6-((2-methoxyethyl)amino)-3-nitrophenyl)acetamide

[0080] 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, 2 M), and triethylamine (0.45 mL, 3.22 mmol, 1.5 eq) in DMSO (5 mL) was stirred at 25 °C for 2 h. After completion of the reaction, it was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-(2-chloro-6-((2-methoxyethyl)amino)-3-nitrophenyl)acetamide (400 mg, yield: 38.8%) as a brown solid without further purification. LC-MS m / z: 288.0 (M+1) + . Step 2: 4-Chloro-1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazole

[0081] 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) was dissolved in DMSO (5 mL) and stirred at 120 °C for 4 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate = 1 / 1) to give 4-chloro-1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazole (300 mg, yield: 76.0%) as a grey solid. LC-MS m / z: 270.1 (M+1) + . Step 3: tert-Butyl (S)-(1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0082] A mixture of tert-butyl (S)-(1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.37 mmol, 1 eq), tert-butyl (S)-pyrrolidin-3-ylcarbamate (104 mg, 0.56 mmol, 1.5 eq) and diisopropylethylamine (0.13 mL, 0.74 mmol, 2 eq) in DMSO was stirred at 100° C. for 3 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate (=1 / 1)) to give tert-butyl (S)-(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. LC-MS m / z: 420.2 (M+1) + . Step 4: tert-Butyl (S)-(1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0083] A mixture of Pd / C (72 mg, 10%) and tert-butyl (S)-(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 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(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 pale yellow solid. LC-MS m / z: 390.1 (M+1) + . 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

[0084] To a solution of tert-butyl (S)-(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 eq) and 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (74 mg, 0.28 mmol, 1.0 eq) in DMF (3 mL) was added HATU (128 mg, 0.34 mmol, 1.2 eq) and DIPEA (0.24 mL, 1.40 mmol, 5.0 eq). The reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. This was purified by flash column chromatography (eluted with DCM / MeOH=97 / 3) to give tert-butyl ((3S)-1-(5-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide)-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (112 mg, yield: 59.7%) as a pale yellow solid. LC-MS m / z: 637.2 (M+1) + . 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

[0085] 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 h. The reaction mixture was concentrated to give the trifluoroacetic acid of Example 11 (33.7 mg, yield: 39.1%) as a yellow solid. LC-MS m / z: 537.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). Example 12: N-(2-((S)-3-aminopyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide JPEG2025502358000041.jpg115150 Step 1: tert-Butyl (S)-(1-(5-bromo-2-nitrophenyl)pyrrolidin-3-yl)carbamate

[0086] To a solution of 4-bromo-2-fluoro-1-nitrobenzene [500 mg, 2.27 mmol, 1.0 eq] in DMSO was added tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate [508 mg, 2.72 mmol, 1.2 eq] and diisopropylethylamine [587 mg, 4.54 mmol, 2.0 eq]. The reaction mixture was stirred under nitrogen at 60 °C for 2 h. The mixture was then diluted with water and extracted with ethyl acetate (3 × 30 mL). The organic layer was dried over Na2SO4 and evaporated in vacuum to give the crude product. The residue was purified by flash chromatography eluting with petroleum ether / ethyl acetate (= 10:1) to give tert-butyl (S)-(1-(5-bromo-2-nitrophenyl)pyrrolidin-3-yl)carbamate (660 mg, yield: 72.3%) as a yellow solid. LC-MS m / z: 387.2 (M+1) + . Step 2: tert-Butyl (S)-(1-(2-amino-5-bromophenyl)pyrrolidin-3-yl)carbamate

[0087] To a mixture of tert-butyl N-[(3S)-1-(5-bromo-2-nitrophenyl)pyrrolidin-3-yl]carbamate [300 mg, 0.77 mmol, 1.0 eq] and iron [217 mg, 3.88 mmol, 5.0 eq] in EtOH [8.0 mL] was added dropwise a solution of ammonium chloride [210 mg, 3.88 mmol, 5.0 eq] in HO [8.0 mL]. The reaction mixture was refluxed for 2 h. The mixture was filtered and the filtrate was collected and concentrated. The residue was purified by flash chromatography eluting with petroleum ether / ethyl acetate to give tert-butyl (S)-(1-(2-amino-5-bromophenyl)pyrrolidin-3-yl)carbamate (200 mg, yield: 70.3%) as a red solid. LC-MS m / z: 357.2 (M+1) + . Step 3: tert-Butyl ((3S)-1-(5-bromo-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamido)phenyl)pyrrolidin-3-yl)carbamate

[0088] 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, 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] were added. The reaction mixture was stirred at 50°C for 3 h. The mixture was diluted with brine solution [5.0 mL] and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over Na2SO4 and evaporated under vacuum to give the crude product. The residue was purified by flash chromatography eluting with petroleum ether / ethyl acetate=5:1 to give tert-butyl ((3S)-1-(5-bromo-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide)phenyl)pyrrolidin-3-yl)carbamate (60 mg, yield: 54.4%). LC-MS m / z: 604.1 (M+1) + . 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

[0089] 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 eq] in dioxane was added 4-cyanopyridine-3-borate [46 mg, 0.19 mmol, 2.1 eq], potassium phosphate anhydrous [42.2 mg, 0.19 mmol, 2.1 eq] and XPhos Pd G2 [7.81 mg, 0.01 mmol, 0.11 eq]. The reaction mixture was stirred at 80° C. under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure at 40° C. The residue was purified by flash chromatography (DCM / MeOH=20:1) to give tert-butyl ((3S)-1-(5-(4-cyanopyridin-3-yl)-2-(3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide)phenyl)pyrrolidin-3-yl)carbamate (50 mg, yield: 74.5%) as a yellow solid. LC-MS m / z: 627.2 (M+1) + . Step 5: N-(2-((S)-3-aminopyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinamide

[0090] To a solution of tert-butyl N-[(3S)-1-[5-(4-cyanopyridin-3-yl)-2-[3-fluoro-2-(2-fluoro-6-methoxyphenyl)pyridin-4-amido]phenyl]pyrrolidin-3-yl]carbamate [40 mg, 0.06 mmol] in DCM [1.5 mL] was added a solution of hydrogen chloride-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 lyophilized to give Example 12 (25 mg, yield: 66.4%) as a yellow solid. LC-MS m / z: 527.2 (M+1) + . 1H NMR (400MHz, CD3OD): 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). JPEG2025502358000042.jpg65150 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 JPEG2025502358000043.jpg113150 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

[0091] 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 eq) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (73 mg, 0.39 mmol, 1 eq) in DMSO (1.5 mL) was added DIPEA (0.16 mL, 0.78 mmol, 2 eq) at room temperature. The reaction mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction was quenched with ethyl acetate (10 mL×3) and extracted. The combined organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. This was purified by SGC (UV254, petroleum ether:ethyl acetate = 1:1) to obtain 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. LC-MS m / z: 457.2 (M+1) + . 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

[0092] 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 h. 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. LC-MS m / z: 427.1 (M+1) + . 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

[0093] To a solution of tert-butyl (S)-(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 eq) and 3-fluoro-2-(2-fluoro-6-methoxyphenyl)isonicotinic acid (49.75 mg, 0.18 mmol, 1. eq) in DMF (15 mL) was added HATU (85.6 mg, 0.22 mmol, 1.2 eq) and DIPEA (0.12 mL, 0.75 mmol, 4.0 eq) at room temperature. The reaction temperature was raised to 50 °C and the reaction was stirred at 50 °C for 4 h. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 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. LC-MS m / z: 674.3 (M+1) + . 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

[0094] 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 eq) in DCM (0.5 mL) was added a solution of trifluoroacetic acid in DCM (0.3 mL, 4 M, 30.0 eq) at 25° C. The reaction mixture was kept stirring at 25° C. for 2 hours. The reaction mixture was concentrated and washed with MTBE to give Example 14 (8.7 mg, yield: 23.3%) as a yellow solid. LC-MS m / z: 574.2 (M+1) + . 1 H NMR (400MHz, CD3OD): δ8.70(d, J=1.6Hz, 1H), 8.58(d, J=4.8Hz, 2H), 8.22(d, J=8.3Hz, 1H), 7.89(s, 1 H), 7.77-7.65(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), 3.9 0(d, J=16.2Hz, 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). 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 JPEG2025502358000044.jpg124150Step 1: N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide

[0095] To a solution of 2-chloro-6-fluoroaniline (2.0 g, 13.7 mmol, 1.0 eq) and DIPEA (2.66 g, 20.6 mmol, 1.5 eq) in DCM (20 mL) stirred at 0° C., a solution of 2-methoxyacetyl chloride (1.75 g, 16.4 mmol, 1.2 eq) 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 eluting with petroleum ether / ethyl acetate=5:1 to give N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, yield: 57.7%) as a white solid. Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide

[0096] To a solution of N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, 8.3 mmol, 1.0 eq) in H2SO4 (10 mL) stirred at -55°C, a solution of concentrated nitric acid (0.6 mL, 11.6 mmol, 1.4 eq) in H2SO4 (2 mL) was added dropwise. The reaction mixture was stirred at -55°C for 2 h. The resulting mixture was warmed to room temperature, poured into ice water (30 mL) and the resulting precipitate was filtered. The filter cake was dissolved in DCM (80 mL), dried over Na2SO4 and concentrated to give N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide (1.2 g, yield: 49.4%). LC-MS m / z: 263.1 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2,2-trifluoroacetamide

[0097] A solution of compound N-(2-chloro-6-fluorophenyl)-2,2,2-trifluoroacetamide (2.82 g, 11.7 mmol, 1.0 eq) in sulfuric acid (25 mL) was cooled to 0° C. and potassium nitrate (1.3 g, 12.8 mmol, 1.1 eq) 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), dried over Na2SO4, and concentrated to obtain compound N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2,2-trifluoroacetamide (2.94 g, yield: 78.6%). 1 H NMR (400MHz, d6-DMSO): δ11.91(s, 1H), 8.30(dd, J=8.8, 5.2Hz, 1H), 7.76(t, J=8.8Hz, 1H). Step 3: 4-Chloro-1-methyl-5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0098] A mixture of compound N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2,2-trifluoroacetamide (2.94 g, 10.3 mmol, 1.0 eq), a solution of CH3NH2 (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 at 25 °C for 2 h. Then, the mixture was sparged with N2 for 30 min, 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 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=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. 1H NMR (400MHz, d6-DMSO): δ8.22 (d, J=9.2Hz, 1H), 8.05 (d, J=9.2Hz, 1H), 4.06 (d, J=0.2Hz, 3H). Step 4: tert-Butyl (S)-(1-(1,5-dimethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0099] To a 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 tert-butyl (S)-pyrrolidin-3-ylcarbamate (300 mg, 1.61 mmol, 1.5 eq) in DMSO (5 mL), DIPEA (555 mg, 4.30 mmol, 4 eq) was added. The mixture was stirred at 100° C. for 1 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (10 mL×2). The organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=10:1) to give tert-butyl (S)-(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. 1 H NMR (400MHz, d6-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). Step 5: tert-Butyl (S)-(1-(5-amino-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0100] 10% Pd / C (50 mg, 0.47 mmol) was added to a solution of compound tert-butyl (S)-(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 obtain compound tert-butyl (S)-(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. 1 H NMR (400MHz, d6-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, 3H), 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). Step 6: tert-Butyl (S)-(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

[0101] To a solution of tert-butyl (S)-(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) was 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 ethyl acetate (5 mL×3). The organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=10:1) to give tert-butyl (S)-(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. 1 H NMR (400MHz, d6-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=6.8 Hz, 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). 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

[0102] To a solution of tert-butyl (S)-(1-(5-amino-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.13 mmol, 1.0 eq) in DCM (1.5 mL) was added a solution of HCl in 1,4-dioxane (1 mL, 4 M, 30.0 eq). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to give Example 39 (57 mg, yield: 85.6%) as a yellow solid. LC-MS m / z: 534.1 (M+1) + . 1 H NMR (400MHz, d6-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). JPEG2025502358000045.jpg119150 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 JPEG2025502358000046.jpg106150 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

[0103] 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 eq) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (73 mg, 0.39 mmol, 1 eq) in DMSO (1.5 mL) was added DIPEA (0.16 mL, 0.78 mmol, 2 eq) at room temperature. The reaction mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction was quenched with ethyl acetate (10 mL×3) and extracted. The combined organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. This was purified by SGC (UV254, petroleum ether:ethyl acetate = 1:1) to obtain 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. LC-MS m / z: 457.2 (M+1) + . 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

[0104] 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. LC-MS m / z: 427.1 (M+1) + . Step 3: tert-Butyl N-[(3S)-1-{5-[2-(2,6-difluorophenyl)-3-oxopyridazin-4-amido]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0105] To a mixture 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 eq) and 2-(2,6-difluorophenyl)-3-oxopyridazine-4-carboxylic acid (30 mg, 0.12 mmol, 1.0 eq) in DMF (2 mL) was added HATU (54 mg, 0.14 mmol, 1.2 eq) and DIPEA (0.4 mL, 0.48 mmol, 4.0 eq). The reaction mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by SGC (UV254, petroleum ether:ethyl acetate=3:1) to give tert-butyl N-[(3S)-1-{5-[2-(2,6-difluorophenyl)-3-oxo-pyridazin-4-amido]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (40 mg, yield: 49.1%) as a yellow solid. 1 H NMR (400MHz, CD3OD): 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). 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

[0106] To a solution of tert-butyl N-[(3S)-1-{5-[2-(2,6-difluorophenyl)-3-oxopyridazin-4-amido]-2-(3-fluoropyridin-4-yl)-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (30 mg, 0.045 mmol, 1.0 eq) in DCM (3 mL) was added HCl in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 25° C. for 2 h. 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. LC-MS m / z: 561.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000047.jpg67150 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 JPEG2025502358000048.jpg127150 Step 1: N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide

[0107] To a solution of 2-chloro-6-fluoroaniline (2.0 g, 13.7 mmol, 1.0 eq) and DIPEA (2.66 g, 20.6 mmol, 1.5 eq) in DCM (20 mL) was added dropwise a solution of 2-methoxyacetyl chloride (1.75 g, 16.4 mmol, 1.2 eq) in DCM (10 ml) with stirring at 0° C. 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 eluting with petroleum ether / ethyl acetate=5:1 to give N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, yield: 57.7%) as a white solid. LC-MS m / z: 218.1 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide

[0108] To a solution of N-(2-chloro-6-fluorophenyl)-2-methoxyacetamide (1.8 g, 8.3 mmol, 1.0 eq) in H2SO4 (10 mL) stirred at -55 °C, a solution of concentrated nitric acid (0.6 mL, 11.6 mmol, 1.4 eq) in H2SO4 (2 mL) was added dropwise. The reaction mixture was stirred at -55 °C for 2 h. The resulting mixture was warmed to room temperature, poured into ice water (30 mL) and the resulting precipitate was filtered. The filter cake was dissolved in DCM (80 mL), dried over Na2SO4 and concentrated to give N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide (1.2 g, yield: 49.4%). LC-MS m / z: 263.1 (M+1) + . Step 3: 4-Chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole

[0109] A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)-2-methoxyacetamide (500 mg, 1.92 mmol, 1 eq), a solution of CH3NH2 in THF [2 M] (1.5 mL, 2.85 mmol, 1.5 eq), and TEA (289 mg, 2.85 mmol, 1.5 eq) in DMSO (2 mL) was stirred at room temperature for 2 h. The mixture was then extracted with water and ethyl acetate. The organic phase was concentrated and the residue was dissolved in DMSO. More TEA was added and the mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate = 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. LC-MS m / z: 255.2 (M+1) + . Step 4: tert-Butyl (S)-(1-(2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0110] To a solution of 4-chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole (120 mg, 0.47 mmol, 1.0 eq) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (105 mg, 0.56 mmol, 1.2 eq) in DMSO (1.5 mL) was added diisopropylethylamine (121 mg, 0.94 mmol, 2 eq). The mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (10 mL×2). The organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=3:1) to give tert-butyl (S)-(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. LC-MS m / z: 405.2 (M+1) + . Step 5: tert-Butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0111] To a solution of tert-butyl (S)-(1-(2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (548 mg, 1.0 eq) in MeOH (10 mL) was added 10% Pd / C (60 mg). The reaction was stirred for 16 h. It was filtered through a pad of Celite. The organic phase was washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=1:1) to give the compound tert-butyl (S)-(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. LC-MS m / z: 376.2 (M+1) + . Step 6: 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

[0112] To a mixture of tert-butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.45 mmol, 1.0 eq) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.18 mmol, 1 eq) in DMF (2 ml) was added HATU (85.6 mg, 0.22 mmol, 1.5 eq) and DIPEA (0.29 mL, 1.35 mmol, 3.0 eq). The resulting mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by SGC (UV254, petroleum ether:ethyl acetate=3:1) to give 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 (100 mg, yield: 69.3%) as a yellow solid. LC-MS m / z: 610.3 (M+1) + . 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

[0113] 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 eq) in DCM (3 mL) was added TFA (0.3 mL, 4 M, 30.0 eq) at room temperature. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 44 as a yellow solid. LC-MS m / z: 510.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). 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 JPEG2025502358000049.jpg128150 Step 1: tert-Butyl (S)-((1-(1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate

[0114] A mixture of 4-chloro-1-(2-methoxyethyl)-2-methyl-5-nitro-1H-benzo[d]imidazole (270 mg, 1.00 mmol, 1.0 eq), tert-butyl (S)-(pyrrolidin-2-ylmethyl)carbamate (305 mg, 1.50 mmol, 1.5 eq) and diisopropylethylamine (518 mg, 4.00 mmol, 4 eq) in DMSO (8 mL) was stirred for 16 h at 100° C. After cooling to room temperature, the reaction mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=10 / 1) to give tert-butyl (S)-((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. LC-MS m / z: 434.3 (M+1) + . Step 2: tert-Butyl (S)-((1-(5-amino-1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-2-yl)methyl)carbamate

[0115] A mixture of Pd / C (40 mg, 10%) and tert-butyl (S)-((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 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-((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. LC-MS m / z: 404.2 (M+1) + . 1H NMR (400MHz, d6-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). Step 3: tert-Butyl (S)-((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

[0116] To a solution of tert-butyl (S)-((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 eq) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (87 mg, 0.35 mmol, 1.0 eq) in DMF (2 mL) was added HATU (197 mg, 0.52 mmol, 1.5 eq) and DIPEA (0.23 mL, 1.38 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 ethyl acetate (5 mL x 3). The organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=1:1) to give tert-butyl (S)-((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. 1H NMR (400MHz, d6-DMSO): δ11.99(s, 1H), 8.45(d, J=4.4Hz, 1H), 8.39(s, 1H), 8.37(d, J=4.8Hz, 1 H), 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). 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

[0117] 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 eq) in DCM (1 mL) was added TFA (0.5 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated to give Example 45 as a yellow solid. LC-MS m / z: 538.2 (M+1) + . 1H NMR (400MHz, d6-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). 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 JPEG2025502358000050.jpg121150 Step 1: tert-Butyl N-[(3S)-1-(2-isopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0118] A mixture of 4-chloro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (100 mg, 0.39 mmol, 1.0 eq), diisopropylethylamine (130 mL, 0.79 mmol, 2 eq) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (88 mg, 0.43 mmol, 1.2 eq) in DMSO was stirred at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=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. LC-MS m / z: 404.1 (M+1) + . Step 2: tert-Butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0119] 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 h. 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. LC-MS m / z: 374.2 (M+1) + . Step 3: 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

[0120] To a solution of tert-butyl (S)-(1-(5-amino-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.27 mmol, 1.0 eq) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (67 mg, 0.27 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (122 mg, 0.32 mmol, 1.2 eq) and DIPEA (0.2 mL, 1.33 mmol, 5.0 eq). The reaction mixture was stirred at 50 °C for 10 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated 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-(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, yield: 58.4%) as a yellow solid. LC-MS m / z: 608.7 (M+1) + . 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

[0121] 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). The reaction mixture was stirred at 25° C. for 1 h. 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. LC-MS m / z: 508.7 (M+1) + . 1 H NMR: (400MHz, CD3OD): 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). 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 JPEG2025502358000051.jpg121150 Step 1: N-(2-chloro-3-nitro-6-((tetrahydro-2H-pyran-4-yl)amino)phenyl)acetamide

[0122] 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 at 25 °C for 2 h. After the reaction was completed, it was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(2-chloro-3-nitro-6-((tetrahydro-2H-pyran-4-yl)amino)phenyl)acetamide (370 mg, yield: 54.9%) as a yellow solid without further purification. LC-MS m / z: 313.9 (M+1) + . Step 2: 4-Chloro-2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole

[0123] 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 at 120 °C for 4 h. 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), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 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. LC-MS m / z: 295.9 (M+1) + . Step 3: tert-Butyl (S)-(1-(2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0124] 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), tert-butyl (S)-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 at 100° C. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=13 / 7) to give tert-butyl (S)-(1-(2-methyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (345 mg, yield: 68.0%) as a yellow solid. LC-MS m / z: 446.1 (M+1) + . Step 4: tert-Butyl (S)-(1-(5-amino-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0125] A mixture of Pd / C (170 mg, 10%) and tert-butyl (S)-(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 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(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 grey solid. LC-MS m / z: 416.2 (M+1) + . Step 5: tert-Butyl (S)-(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

[0126] To a solution of tert-butyl (S)-(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 eq) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (61 mg, 0.24 mmol, 1.0 eq) in DMF (2 mL) was added HATU (110 mg, 0.29 mmol, 1.2 eq) and DIPEA (0.21 mL, 1.20 mmol, 5.0 eq). The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH = 19 / 1) to give tert-butyl (S)-(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. LC-MS m / z: 650.3 (M+1) + . 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

[0127] To a solution of tert-butyl (S)-(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 h. Water (5 mL) was added and extracted with DCM (5 mL). The combined organic phase was concentrated under reduced pressure to give Example 47 (80.9 mg, yield: 90%) as a yellow solid. LC-MS m / z: 550.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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=9.2Hz, 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). 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 JPEG2025502358000052.jpg68150 Step 1: N-(2-chloro-6-(cyclopropylamino)-3-nitrophenyl)acetamide

[0128] A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (500 mg, 2.15 mmol, 1.0 eq), cyclopropanamine (184 mg, 3.22 mmol, 1.5 eq), triethylamine (0.45 mL, 3.22 mmol, 1.5 eq) in DMSO (3 mL) was stirred at 25 °C for 2 h. After the reaction was completed, it was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(2-chloro-6-(cyclopropylamino)-3-nitrophenyl)acetamide (451 mg, yield: 78%) as a yellow solid without further purification. LC-MS m / z: 270.0 (M+1) + . Step 2: 4-Chloro-1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazole

[0129] 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 at 120 °C for 4 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate (= 97 / 3)) to give 4-chloro-1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazole (294 mg, yield: 48.9%) as a pale yellow solid. LC-MS m / z: 251.9 (M+1) + . Step 3: tert-Butyl (S)-(1-(1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0130] A mixture of 4-chloro-1-cyclopropyl-2-methyl-5-nitro-1H-benzo[d]imidazole (150 mg, 0.60 mmol, 1.0 eq), tert-butyl (S)-pyrrolidin-3-ylcarbamate (167 mg, 0.89 mmol, 1.48 eq) and diisopropylethylamine (0.16 mL, 0.89 mmol, 1.48 eq) in DMSO (3 mL) was stirred for 3 h at 100° C. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=4 / 1) to give tert-butyl (S)-(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. LC-MS m / z: 402.0 (M+1) + . Step 4: tert-Butyl (S)-(1-(5-amino-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0131] A mixture of Pd / C (55 mg, 10%) and tert-butyl (S)-(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 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(1-(5-amino-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (82 mg, yield: 72.5%) as a grey solid. LC-MS m / z: 372.2 (M+1) + . Step 4: tert-Butyl (S)-(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

[0132] To a solution of tert-butyl (S)-(1-(5-amino-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (82 mg, 0.22 mmol, 1.0 eq) and 2-(2,6-difluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (56 mg, 0.22 mmol, 1.0 eq) in DMF (2 mL) was added HATU (101 mg, 0.26 mmol, 1.18 eq) and DIPEA (0.19 mL, 1.10 mmol, 5.0 eq) at room temperature. The reaction temperature was raised to 50 °C and the reaction was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate = 7 / 3) to give tert-butyl (S)-(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. LC-MS m / z: 606.2 (M+1) + . 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

[0133] To a solution of tert-butyl (S)-(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) was added trifluoroacetic acid (1 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h. Water (5 mL) was added and the mixture was extracted with DCM (5 mL). The aqueous phase was lyophilized to give Example 48 as a yellow solid. LC-MS m / z: 506.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, ), 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). 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 JPEG2025502358000053.jpg98150 Step 1: (Z)-2-(2-(2,6-dichlorophenyl)hydrazinylidene)acetaldehyde

[0134] 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) in H2O / HOAc (volume ratio = 5 / 1, 48 mL) at 25 °C. The reaction mixture was kept stirring at the same temperature for 1 h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was quenched by adding saturated NaHCO3 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-9%) to give (Z)-2-(2-(2,6-dichlorophenyl)hydrazinylidene)acetaldehyde (4 g, yield: 44.3%) as a yellow solid. LC-MS m / z: 218.9 (M+1) + . Step 2: (Z)-5-(2-(2-(2,6-dichlorophenyl)hydrazinylidene)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0135] To a solution of (Z)-2-(2-(2,6-dichlorophenyl)hydrazinylidene)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. The reaction mixture was kept stirring at the same temperature for 1 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, then diluted with HO and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated to give (Z)-5-(2-(2-(2,6-dichlorophenyl)hydrazinylidene)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. Step 3: 2-(2,6-dichlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0136] To a solution of (Z)-5-(2-(2-(2,6-dichlorophenyl)hydrazinylidene)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) under N2. 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, diluted with H2O (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), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 0-1%) to give 2-(2,6-dichlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid as a yellow solid (0.6 g, yield: 26.0%). LC-MS m / z: 283 (M-1) - . 1 H NMR (400MHz, d6-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). Step 4: tert-Butyl N-[(3S)-1-{5-[2-(2,6-dichlorophenyl)-3-oxopyridazin-4-amido]-1,2-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0137] 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 eq) and 2-(2,6-dichlorophenyl)-3-oxopyridazine-4-carboxylic acid (41 mg, 0.14 mmol, 1.0 eq) in DMF (0.5 mL) was added HATU (66 mg, 0.17 mmol, 1.2 eq) and DIPEA (0.12 mL, 0.72 mmol, 5.0 eq). The reaction mixture was stirred at 50 °C for 16 h. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. This was purified by flash column chromatography (eluted with DCM / MeOH=97 / 3) to give tert-butyl N-[(3S)-1-{5-[2-(2,6-dichlorophenyl)-3-oxopyridazin-4-amido]-1,2-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (76 mg, yield: 85.7%) as an orange solid. LC-MS m / z: 612.18 (M+1) + . 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

[0138] To a solution of tert-butyl N-[(3S)-1-{5-[2-(2,6-dichlorophenyl)-3-oxopyridazin-4-amido]-1,2-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 h. 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. LC-MS m / z: 512.1 (M+1) + . 1 H NMR (400MHz, CD3OD): 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), 4.10-4.07(m, 1H), 4.01(s, 3H), 3.87-3.83(m, 1H), 3.56-3, 52(m, 1 H), 3.44-3.36(m, 1H), 2.93(s, 3H), 2.74-2.70(m, 1H), 2.17-1.97(m, 1H). Example 50: tert-Butyl-N-[(3S)-1-{5-[2-(5-fluoro-2-methoxyphenyl)-3-oxopyridazin-4-amido]-1,2-dimethyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate hydrochloride JPEG2025502358000054.jpg94150 Step 1: (5-Fluoro-2-methoxyphenyl)hydrazine

[0139] To a solution of 5-fluoro-2-methoxyaniline (1 g, 7.7 mmol, 1 eq) in 5 M HCl (10 mL) was slowly added NaNO2 (0.64 g, 9.2 mmol, 1.3 eq) at 0-5 °C. After stirring at 0-5 °C for 2 h, SnCl2 (3.37 g, 17.7 mmol, 2.5 eq) was added to the reaction at 0-5 °C. The reaction mixture was warmed to 25 °C and stirred for 2 h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The reaction mixture was quenched by addition of 1 M NaOH and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with 50 mL of brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give (5-fluoro-2-methoxyphenyl)hydrazine (0.8 g, yield: 57.8%) as a black solid. LC-MS m / z: 157.1 (M+1) + . Step 2: (Z)-2-(2-(5-fluoro-2-methoxyphenyl)hydrazinylidene)acetaldehyde

[0140] 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) in HO / HOAc (volume ratio = 1 / 1, 10 mL) at 25 °C. The reaction mixture was kept stirring at the same temperature for 1 h. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The mixture was quenched by adding saturated NaHCO3 and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-10%) to give (Z)-2-(2-(5-fluoro-2-methoxyphenyl)hydrazinylidene)acetaldehyde (0.8 g, yield: 72.6%) as a yellow solid. LC-MS m / z: 197.1 (M+1) + . Step 3: (Z)-5-(2-(2-(5-fluoro-2-methoxyphenyl)hydrazinylidene)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0141] To a solution of (Z)-2-(2-(5-fluoro-2-methoxyphenyl)hydrazinylidene)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 kept stirring at the same temperature for 1 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, then diluted with HO 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)hydrazinylidene)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. MS(ES-API Negative): 321.0(M-1) - . Step 4: 2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0142] To a solution of (Z)-5-(2-(2-(5-fluoro-2-methoxyphenyl)hydrazinylidene)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) under N2. 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, diluted with H2O, 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), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 0-1%) 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. LC-MS m / z: 264.9 (M+1) + . 1 H NMR (400MHz, d6-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). Step 5: tert-Butyl (S)-(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

[0143] To a solution of tert-butyl (S)-(1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (157 mg, 0.45 mmol, 1.2 eq) and 2-(5-fluoro-2-methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.38 mmol, 1.0 eq) in DMF (2 mL) was added HATU (216 mg, 0.57 mmol, 1.5 eq) and N,N-diisopropylethylamine (0.19 mL, 1.14 mmol, 3.0 eq). The reaction was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by SGC (UV254, DCM:MeOH=20:1) to give tert-butyl (S)-(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. LC-MS m / z: 592.3 (M+1) + . 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

[0144] To a solution of tert-butyl (S)-(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 eq) in DCM (5 mL) was added a solution of HCl in 1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated and washed with DCM to give the hydrogen chloride of Example 50 (26.6 mg, yield: 42.3%) as a yellow solid. LC-MS m / z: 492.1 (M+1) + . 1 H NMR (400MHz, d6-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). Example 51: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide JPEG2025502358000055.jpg117150 Step 1: Methyl 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0145] To a solution of 3-(methoxycarbonyl)-2-oxo-1,2-dihydropyrylium (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) at 0 °C. After stirring for 7 h, 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 h to give a brown solution. LCMS showed the reaction was messy and the starting material was consumed. The reaction was diluted with H2O and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with i-PrOH, 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 that was used directly in the next step. LC-MS m / z: 278.1 (M+1) + . Step 2: 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0146] 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 a solution of NaOH (2.08 g, 51.92 mmol, 8 eq) in HO (30 mL). The reaction was stirred at 65 °C for 1 h to give a dark brown solution. LCMS showed the reaction where the starting material was consumed and one peak with the desired mass was detected. The reaction was treated with HO and washed with EA (30 mL x 3). The aqueous layer was acidified to pH = 1-2 with 1 N HCl and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (523 mg, yield: 30.58%) as a brown solid. LC-MS m / z: 262.1 (M-1) - . Step 3: tert-Butyl (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-carboxylate

[0147] 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 tert-butyl (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (65 mg, 200.98 umol, 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 reaction had consumed the starting material and one peak with the desired mass was detected. The reaction was treated with HO and acidified to pH = 4-5 with 1N HCl. The mixture was extracted with EA (10 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, concentrated to dryness and used directly in the next step. LC-MS m / z: 553.2 (M+1) + . Step 4: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-1-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0148] A solution of tert-butyl (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-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 to pH = 10-11 with concentrated aqueous Na2CO3 and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (C18, eluted with 70% ACN in H2O, 0.01% TFA). The collected streams were concentrated and lyophilized to give Example 51 (38.5 mg, yield: 42.34%) as an off-white solid. LC-MS m / z: 453.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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. , 1H), 6.87(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= 2.5Hz, 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). JPEG2025502358000056.jpg208150 Example 55: 2-((2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide JPEG2025502358000057.jpg108150 Step 1: 6-(2-fluoro-6-methoxyphenyl)picolinic acid

[0149] To a solution of 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 HO (3 mL) was added K3PO4 (2.1 g, 9.9 mmol, 2 eq) and XPhos Pd G2 (0.19 g, 0.25 mmol, 0.05 eq) under N2. The reaction was warmed to 80 °C and stirred for 2 h to give a yellow suspension. LCMS showed that most of the starting material was consumed and one 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 × 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The resulting product was triturated with ACN and filtered. The filtrate was concentrated and lyophilized to give 6-(2-fluoro-6-methoxyphenyl)picolinic acid (1.09 g, yield: 89.34%) as an off-white solid. LC-MS m / z: 246.2 (M-1) - . Step 2: 2-Carboxy-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0150] To a solution of 6-(2-fluoro-6-methoxyphenyl)picolinic acid (1 g, 4.04 mmol, 1 eq) in DCE (80 mL) was added K2HPO4 (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 h to give a pale yellow suspension. LCMS showed that about half of the starting material remained and one major peak with the desired mass was detected. The reaction was stirred at 70 °C for another 5 h to give a pale yellow suspension. LCMS showed that most of the starting material had been consumed and one major peak with the desired mass was detected. The reaction was diluted with HO and extracted with IPA / DCM=1 / 3 (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-carboxy-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (1.2 g) as a brown oil. LC-MS m / z: 264.2 (M+1) + . Step 3: 2-((2-((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0151] To a solution of 2-carboxy-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (256.91 mg, 976.02 μmol, 3 eq) and tert-butyl (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (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 h 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 treated with HO and acidified to pH = 4-5 with 1 N HCl. The mixture was extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-((2-((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide (450 mg, crude) as a brown oil. LC-MS m / z: 553.3 (M+1) + . Step 4: 2-((2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)carbamoyl)-6-(2-fluoro-6-methoxyphenyl)pyridine 1-oxide

[0152] A solution of 2-((2-((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-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 diluted with H2O and basified to pH = 10-11 with concentrated aqueous Na2CO3. The mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (C18, eluted with 70% ACN in H2O with TFA). The collected streams were concentrated and lyophilized to give Example 55 (104.4 mg, yield: 70.92%) as an off-white foam. LC-MS m / z: 453.2 (M+1) + . 1 H NMR (400MHz, d6-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(d d, 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=1.3Hz, 3H), 3.48(t, J=10.1Hz, 1H), 3.04(d, J=8.9Hz, 1H), 2.14-2.03(m, 1H), 1.74(t, J=10.5Hz, 1H). JPEG2025502358000058.jpg189150 JPEG2025502358000059.jpg202150 JPEG2025502358000060.jpg133150 Example 64: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxamide JPEG2025502358000061.jpg73150 Step 1: 2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxylic acid

[0153] To a solution of 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 H2O (3 mL) was added K3PO4 (2.04 g, 9.61 mmol, 2 eq) and Xphos Pd G2 (113.47 mg, 0.14 mmol, 0.03 eq) under N2. The reaction was heated to 80 °C in a microwave and stirred for 1.5 h to give an off-white suspension. LCMS showed one peak at the desired mass, indicating starting material was consumed. The reaction was diluted with DCM / MeOH=10 / 1 and filtered through a pad of Celite. The solution was concentrated to dryness. The residue was triturated with EA, filtered and dried in air to give 2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxylic acid (0.85 g, 69.67%) as a grey solid. LC-MS m / z: 252.1 (M-1) - . Step 2: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxamide

[0154] 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) was added HATU (911.10 mg, 2.40 mmol, 1.5 eq) and DIEA (412.93 mg, 3.19 mmol, 2 eq) under N2. After stirring for 5 min, (2-fluoro-6-methoxyphenyl)boronic acid (491 mg, 1.60 mmol, 1 eq) was added to the reaction. The resulting mixture was stirred for 0.5 h to give a dark brown solution. Two peaks of the desired mass were detected by LCMS. The reaction was diluted with H2O and extracted with DCM (10 mL x 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 h to give a black solution. LCMS showed two peaks of the desired mass. The reaction was concentrated to remove most of the solvent and purified by flash column (C18, eluting with 90% ACN in H2O with TFA). The collected flow was concentrated and lyophilized to give Example 64 (9.9 mg) as a grey solid. LC-MS m / z: 443.2 (M+1) + . 1 H NMR (400MHz, d6-DMSO): δ10.05(s, 1H), 8.87(s, 1H), 8.78(s, 1H), 8.71(s, 1H), 8 .11(dd, J=10.6, 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), 3.5 2(d, J=11.1Hz, 1H), 3.10(s, 1H), 2.21(d, J=11.2Hz, 1H), 1.88(d, J=10.8Hz, 1H). Example 65: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)thiazole-4-carboxamide JPEG2025502358000062.jpg74150 Step 1: 4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxylic acid

[0155] To a solution of 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 H2O (3 mL) was added K3PO4 (2.04 g, 9.61 mmol, 2 eq) and Xphos Pd G2 (113.47 mg, 0.14 mmol, 0.03 eq) under N2. The reaction was heated to 80 °C in a microwave and stirred for 1.5 h to give an off-white suspension. LCMS showed one peak at the desired mass, indicating starting material was consumed. The reaction was diluted with DCM / MeOH=10 / 1 and filtered through a pad of Celite. The solution was concentrated to dryness. The residue was triturated 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. LC-MS m / z: 252.1 (M-1) - . Step 2: N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-4-(2-fluoro-6-methoxyphenyl)thiazole-2-carboxamide

[0156] 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) was added HATU (556.68 mg, 1.46 mmol, 1.5 eq) and DIEA (252.30 mg, 1.95 mmol, 2 eq) under N2. After stirring for 5 min, tert-butyl (1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 0.98 mmol, 1 eq) was added to the reaction. The resulting mixture was stirred for 0.5 h to give a dark brown solution. LCMS showed one major peak with the desired mass. The reaction was diluted with HO and extracted with DCM (10 mL x 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 for 16 h to give a dark brown solution. LCMS showed one major peak with the desired mass. The reaction was concentrated to remove most of the solvent and purified by flash column (C18, eluted with 90% ACN in H2O with TFA). The collected flow was concentrated and lyophilized to give Example 65 (141.5 mg, yield: 32.76%) as an off-white solid. LC-MS m / z: 443.2 (M+1) + . 1 H NMR (400MHz, d6-DMSO): δ10.13(s, 1H), 8.99(s, 1H), 8.78(s, 1H), 8.22(s, 1H), 7.82(dd, J =10.3, 3.0Hz, 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). Example 66: N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-meth(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 JPEG2025502358000063.jpg100150 Step 1: 2H-pyran-2,6(3H)-dione

[0157] 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 h to give a dark brown solution. No measurements were taken. The reaction was concentrated to give 2H-pyran-2,6(3H)-dione (2.6 g, 100.78% yield) as a black solid. Step 2: (Z)-3-(2-(2-fluoro-6-methoxyphenyl)hydrazinylidene)-2H-pyran-2,6(3H)-dione

[0158] To a solution of 2-fluoro-6-methoxyaniline (1.5 g, 10.63 mmol, 1 eq) in HO (40 mL) and 12 N HCl (12 mL) was added NaNO (0.95 g, 13.82 mmol, 1.3 eq) portionwise at 0 °C. After stirring for 1 h at 0 °C, a solution of 2H-pyran-2,6(3H)-dione (1.19 g, 10.63 mmol, 1 eq) and NaCO (0.56 g, 5.31 mmol, 0.5 eq) in HO (40 mL) was added dropwise to the reaction at 0 °C. The reaction was stirred for 16 h to give a brown suspension. LCMS showed the reaction to be messy with one peak of the desired mass detected. The reaction was filtered, and the filter cake was washed with HO and dried on an oil pump to give (Z)-3-(2-(2-fluoro-6-methoxyphenyl)hydrazinylidene)-2H-pyran-2,6(3H)-dione (1 g, yield: 35.59%) as a brown solid. LC-MS m / z: 265.1 (M+1) + . Step 3: 1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0159] To a solution of (Z)-3-(2-(2-fluoro-6-methoxyphenyl)hydrazinylidene)-2H-pyran-2,6(3H)-dione (1 g, 3.78 mmol, 1 eq) in HO (30 mL) was added KOH (1.06 g, 18.92 mmol, 5 eq). The reaction was stirred at 100 °C for 3 h to give a dark brown solution. LCMS showed that the starting material was consumed and one new peak with the desired mass was detected. The reaction 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, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (C18, eluted with 62% ACN in HO with 0.1% HCOOH). The collected flow was acidified with 1N HCl to pH=2-3 and extracted with EA (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting 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. LC-MS m / z: 263.1 (M-1) - . Step 4: tert-Butyl (S)-(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

[0160] 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 tert-butyl (S)-(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 HO and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over NaSO, filtered and concentrated to give tert-butyl (S)-(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, yield: 130.78%) as a light brown solid. LC-MS m / z: 592.3 (M+1) + . 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

[0161] To a solution of tert-butyl (S)-(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 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 to pH=9-10 with concentrated aqueous NaHCO3 and extracted with DCM / i-PrOH=3 / 1 (10 mL×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash column (C18, eluted with 48% ACN in H2O containing 0.1% HCOOH) and the flow-through was lyophilized to give Example 66 (32.18 mg, yield: 24.72%) as a pale yellow solid. LC-MS m / z: 492.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, 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), 3.65-3 .37(m, 3H), 3.35(s, 1H), 3.28-3.11(m, 1H), 2.62(s, 3H), 2.13-1.93(m, 2H). Example 67: (R)-N-(4-(3-aminopiperidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide JPEG2025502358000064.jpg136150 Step 1: 2H-pyran-2,6(3H)-dione

[0162] 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 h 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. Step 2: (Z)-3-(2-(2,6-difluorophenyl)hydrazono)-2H-pyran-2,6(3H)-dione

[0163] To a solution of 2,6-difluoroaniline (22.33 g, 172.95 mmol, 1.5 eq) in HO (300 mL) and 12 N HCl (80 mL) was added NaNO (11.93 g, 172.95 mmol, 1.5 eq) in portions at 0 °C to give a light brown solution. After stirring for 1 h at 0 °C, a solution of 2H-pyran-2,6(3H)-dione (115.3 mmol, 1 eq) and NaCO (7.33 g, 69.18 mmol, 0.6 eq) in HO (100 mL) and THF (50 mL) was added dropwise to the reaction at 0 °C. The reaction was stirred at room temperature for 16 h to give a brown suspension. LCMS showed that the starting material was consumed and one peak with the desired mass was detected. The reaction was filtered, and the filter cake was washed with HO and dried on an 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. LC-MS m / z: 253.1 (M+1) + . Step 3: 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0164] To a solution of (Z)-3-(2-(2,6-difluorophenyl)hydrazinylidene)-2H-pyran-2,6(3H)-dione (23 g, 91.21 mmol, 1 eq) in HO (300 mL) was added KOH (10.23 g, 182.41 mmol, 2 eq). The reaction was stirred at 100 °C for 3 h to give a dark brown solution. LCMS showed that the starting material was consumed and one new peak with the desired mass was detected. The reaction was acidified to pH = 2-3 with 1N HCl and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column (silica column, eluted with 30% to 50% EA in PE) to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (5 g) as a pale red solid. LC-MS m / z: 253.1 (M+1) + . Step 4: tert-Butyl (R)-(1-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate

[0165] To a solution of 4-chloro-1,2-dimethyl-5-nitro-1H-benzo[d]imidazole (300 mg, 1.33 mmol, 1.0 eq) in DMSO (5 mL) was added TEA (269.09 mg, 2.66 mmol, 2.0 eq) and tert-butyl (R)-piperidin-3-ylcarbamate (532.59 mg, 2.66 mmol, 2.0 eq). The reaction was stirred at 100° C. for 2 h to give a yellow solution. LCMS showed a major peak of the desired mass and the material was nearly consumed. The reaction was poured into water and filtered. The filter cake was dried to give the compound tert-butyl (R)-(1-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate (517.8 mg, yield: 100%) as a yellow solid. LC-MS m / z: 390.2 (M+1) + . Step 5: tert-Butyl (R)-(1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate

[0166] To a solution of tert-butyl (R)-(1-(1,2-dimethyl-5-nitro-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate (517.82 mg, 1.33 mmol, 1.0 eq) in MeOH (5 mL) was added Pd / C (26 mg). The reaction was stirred at 20° C. overnight to give a brown-green suspension. LCMS showed a major peak of the desired mass and the material was nearly consumed. The reaction was diluted with DCM:MeOH=10:1 and filtered through a pad of Celite. The filtrate was concentrated to dryness to give the compound tert-butyl (R)-(1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate (532 mg, yield: 111%) as a brown solid. LC-MS m / z: 360.23 (M+1) + . Step 6: (R)-N-(4-(3-aminopiperidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0167] 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), HATU (113.09 mg, 297.41 μmol, 1.5 eq), DIEA (0.065 mL) were added and stirred at 20° C. for 40 min, followed by the addition of tert-butyl (R)-(1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)piperidin-3-yl)carbamate (71.27 mg, 198.27 umol, 1.0 eq). The reaction was stirred overnight at 20° C. to give a brown suspension. LCMS showed one major peak with the desired mass and the material was nearly consumed. The reaction was washed with water, extracted with DCM (x3), the organic phase was concentrated to dryness under reduced pressure, and TFA (1 mL) was added and stirred for 10 min. The mixture was adjusted to pH 7-8 with NaHCO3, extracted with DCM (x3), and the organic phase was concentrated to dryness under reduced pressure. The crude product was purified by flash column (C18, peak time = 30% ACN in H2O, COMBI FLASH NEXTAGEN300) to give Example 67 (57.83 mg, yield: 49%) as a yellow solid. LC-MS m / z: 494.20 (M+1) + . 1 H NMR (400MHz, CD3OD): δ8.40(d, J=8.8Hz, 1H), 8.24(d, J=9.8Hz, 1H), 7.74(m, J =8.6, 6.3Hz, 1H), 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), 1.9 0-1.69(m, 2H), 1.52(m, J=23.9, 12.2, 3.7Hz, 1H), 1.32(m, J=16.3, 8.6Hz, 1H). JPEG2025502358000065.jpg179150 JPEG2025502358000066.jpg206150 JPEG2025502358000067.jpg200150 JPEG2025502358000068.jpg186150 JPEG2025502358000069.jpg205150 JPEG2025502358000070.jpg201150 JPEG2025502358000071.jpg208150 JPEG2025502358000072.jpg205150 JPEG2025502358000073.jpg177150 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 JPEG2025502358000074.jpg138150Step 1: N-(2-chloro-6-fluorophenyl)cyclopropanecarboxamide

[0168] To a solution of 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) was added dropwise a solution of cyclopropanecarbonyl chloride (1.48 mL, 16.44 mmol, 1.2 eq) in DCM (10 mL) at 0° C. The reaction mixture was stirred at the same temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=1 / 1) to give N-(2-chloro-6-fluorophenyl)cyclopropanecarboxamide (2.2 g, yield: 71.5%) as a white solid. LC-MS m / z: 214.1 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)cyclopropanecarboxamide

[0169] To a solution of N-(2-chloro-6-fluorophenyl)cyclopropanecarboxamide (2.2 g, 10.3 mmol, 1.0 eq) in H2SO4 (10 mL) was added dropwise concentrated nitric acid (0.6 mL, 11.6 mmol, 1.13 eq) solution at -55 °C. The reaction mixture was kept stirring at the same temperature for 2 h. The resulting mixture was warmed to room temperature and 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. LC-MS m / z: 259.1 (M+1) + . Step 3: 4-Chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole

[0170] To a mixture 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 a solution of CH3NH2 in THF (2 M, 72 mg, 3.83 mmol, 1.5 eq) at room temperature. The reaction was kept stirring at room temperature for 4 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate = 2 / 1) to give 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole (210 mg, yield: 42.8%) as a yellow solid. LC-MS m / z: 252.0 (M+1) + . Step 4: tert-Butyl N-[(3S)-1-(2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0171] To a solution of 4-chloro-2-(methoxymethyl)-1-methyl-5-nitro-1H-benzo[d]imidazole (100 mg, 0.40 mmol, 1.0 eq) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (89 mg, 0.48 mmol, 1.2 eq) in DMSO (1.5 mL) was added diisopropylethylamine (103 mg, 0.79 mmol, 2 eq). The reaction mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=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. LC-MS m / z: 402.1 (M+1) + . Step 5: tert-Butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0172] 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 h. 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. LC-MS m / z: 372.3 (M+1) + . Step 6: tert-Butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazin-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0173] To a mixture of tert-butyl (S)-(1-(5-amino-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, 0.21 mmol, 1.2 eq) and 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.18 mmol, 1.0 eq) in DMF (2 mL) was added HATU (86 mg, 0.22 mmol, 1.5 eq) and DIPEA (0.14 mL, 0.63 mmol, 3.0 eq). The reaction mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by SGC (UV254, petroleum ether:ethyl acetate=3:1) to give tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazin-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (55 mg, yield: 40.1%) as a yellow solid. LC-MS m / z: 606.3 (M+1) + . 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

[0174] To a solution of tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazin-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (35 mg, 0.052 mmol, 1.0 eq) in DCM (3 mL) was added HCl in EtOAC (0.5 mL). The reaction mixture was stirred at 25° C. for 2 h. 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. LC-MS m / z: 506.3 (M+1) + . 1 H NMR (400MHz, CD3OD): 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), 3.8 4-3.70(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). 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 JPEG2025502358000075.jpg142150 Step 1: N-(2-chloro-6-fluorophenyl)-2,2-dimethylpropanamide

[0175] To a solution of 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) was added a solution of 2,2-dimethylpropanoyl chloride (1.98 g, 16.44 mmol, 1.2 eq) in DCM (10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=3 / 1) to give N-(2-chloro-6-fluorophenyl)pivalamide (2.4 g, yield: 55.3%) as a white solid. LC-MS m / z: 230.2 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-2,2-dimethylpropanamide

[0176] To a solution of N-(2-chloro-6-fluorophenyl)-2,2-dimethylpropanamide (2.4 g, 10.4 mmol, 1.0 eq) in H2SO4 (10 mL) was added dropwise a solution of concentrated nitric acid (0.6 mL, 11.6 mmol, 1.12 eq) in H2SO4 (2 mL) at -55oC. The reaction mixture was kept stirring at the same temperature for 2 h. The resulting mixture was warmed to room temperature and quenched with ice water (30 mL) to give N-(2-chloro-6-fluoro-3-nitrophenyl)pivalamide (2.8 g, yield: 88.5%) as a yellow solid. LC-MS m / z: 275.1 (M+1) + . Step 3: 4-Chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole

[0177] To 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 a solution of CH3NH2 in THF (2 M, 113 mg, 3.64 mmol, 2 eq). The reaction was allowed to stir for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole (150 mg, yield: 43.6%) as a yellow solid. LC-MS m / z: 268.0 (M+1) + . Step 4: tert-Butyl N-[(3S)-1-(2-tert-butyl-1-methyl-5-nitro-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0178] A mixture of 4-chloro-2-cyclopropyl-1-methyl-5-nitro-1,3-benzodiazole (150 mg, 0.56 mmol, 1.0 eq), diisopropylethylamine (290 mg, 2.24 mmol, 4 eq) and tert-butyl (S)-pyrrolidin-3-ylcarbamate (88 mg, 0.43 mmol, 1.2 eq) in DMSO was stirred for 4 h at 100° C. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by SGC (UV254, petroleum ether:ethyl acetate=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, yield: 77.2%) as a yellow solid. LC-MS m / z: 418.2 (M+1) + . Step 5: tert-Butyl N-[(3S)-1-(5-amino-2-tert-butyl-1-methyl-1,3-benzodiazol-4-yl)pyrrolidin-3-yl]carbamate

[0179] 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 h. 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. LC-MS m / z: 388.2 (M+1) + . Step 6: tert-Butyl N-[(3S)-1-{2-tert-butyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazin-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate

[0180] To 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 eq) and 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.20 mmol, 1 eq) in DMF (2 mL) was added HATU (86 mg, 0.22 mmol, 1.5 eq) and DIPEA (0.12 mL, 0.60 mmol, 3.0 eq). The mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by SGC (UV254, petroleum ether:ethyl acetate=3:1) to give tert-butyl N-[(3S)-1-{2-tert-butyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazin-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (60 mg, yield: 44.4%) as a yellow solid. LC-MS m / z: 622.4 (M+1) + . 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

[0181] To a solution of tert-butyl N-[(3S)-1-{2-cyclopropyl-5-[1-(2,6-difluorophenyl)-6-oxopyridazin-3-amido]-1-methyl-1,3-benzodiazol-4-yl}pyrrolidin-3-yl]carbamate (35 mg, 0.052 mmol, 1.0 eq) in DCM (3 mL) was added HCl in EtOAc (0.5 mL). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated and washed with tert-butyl methyl ether to give Example 98 as a yellow solid. LC-MS m / z: 522.4 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, 3 H), 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). JPEG2025502358000076.jpg174150 JPEG2025502358000077.jpg168150 JPEG2025502358000078.jpg58150 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 JPEG2025502358000079.jpg180150 Step 1: N-(2-chloro-6-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)acetamide

[0182] 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 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the 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. LC-MS m / z: 327.8 (M+1) + . Step 2: 4-Chloro-2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazole

[0183] A solution of N-(2-chloro-6-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)acetamide (300 mg, 0.92 mmol, 1.0 eq), TEA (186 mg, 1.84 mmol, 2.0 eq) in DMSO (5 mL) was stirred at 100 °C for 12 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-2%) 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. LC-MS m / z: 308.8 (M+1) + . Step 3: tert-Butyl (S)-(1-(2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0184] A solution of 4-chloro-2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazole (120 mg, 0.88 mmol, 1.9 eq), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (87 mg, 0.47 mmol, 1.0 eq) and DIPEA (0.15 mL, 0.78 mmol, 1.7 eq) in DMSO was stirred under nitrogen at 100° C. for 4 h. After cooling to room temperature, the reaction was quenched with water (5.0 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (eluted with DCM / MeOH=50 / 1) to give tert-butyl (S)-(1-(2-methyl-1-(1-methylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (150 mg, yield: 80.1%) as a red solid. LC-MS m / z: 459.9 (M+1) + . Step 4: tert-Butyl (S)-(1-(5-amino-2-methyl-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0185] A mixture of Pd / C (78 mg, 10%) and tert-butyl (S)-(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 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (S)-(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. LC-MS m / z: 429.3 (M+1) + . Step 5: 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

[0186] To a solution of tert-butyl (S)-(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 eq) and 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (80 mg, 0.21 mmol, 1.3 eq) and DIPEA (0.1 mL, 0.65 mmol, 4.1 eq). The reaction mixture was stirred at 50° C. for 10 h. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated 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-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (80 mg, yield: 77.7%) as a yellow solid. LC-MS m / z: 663.7 (M+1) + . 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

[0187] 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 h. 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. LC-MS m / z: 563.6 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). Example 107: (S)-N-(4-(3-aminopyrrolidin-1-yl)-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide JPEG2025502358000080.jpg101150 Step 1: 6-Hydroxy-2H-pyran-2-one

[0188] A solution of (2E)-pent-2-enedioic acid (3 g, 23.1 mmol, 1 eq) in AcO (9.4 g, 92.4 mmol, 4 eq) was stirred at 150° C. for 1 h to give a dark brown solution. The reaction mixture was concentrated to give 6-hydroxy-2H-pyran-2-one (3.0 g, yield: 94.0%) as a black solid. 1H NMR (400MHz, CDCl3): δ6.99 (dd, J=6.0, 4.0Hz, 1H), 6.31 (d, J=9.8Hz, 1H). Step 2: (Z)-5-(2-(2,6-dichlorophenyl)hydrazinylidene)-6-hydroxy-5,6-dihydro-2H-pyran-2-one

[0189] To a solution of 2,6-dichloroaniline (5.78 g, 35.7 mol) in 3 M HCl (120 mL) was added NaNO2 (3.2 g, 46.4 mmol) portionwise at 0 °C. After stirring at 0 °C for 1 h, a solution of 6-hydroxypyran-2-one (4 g, 26.8 mmol) and Na2CO3 (1.89 g, 17.8 mmol) in HO (50 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred for 16 h to give a brown suspension. The reaction was filtered, the filter cake was washed with HO and dried under vacuum to give (Z)-5-(2-(2,6-dichlorophenyl)hydrazinylidene)-6-hydroxy-5,6-dihydro-2H-pyran-2-one (3 g, yield: 23.5%) as a brown solid. Step 3: 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0190] To a solution of compound (Z)-5-(2-(2,6-dichlorophenyl)hydrazinylidene)-6-hydroxy-5,6-dihydro-2H-pyran-2-one (3.0 g, 10.4 mmol, 1 eq) in HO (50 mL) was added KOH (2.2 g, 39.5 mmol, 5 eq.). The reaction mixture was stirred at 100 °C for 3 h to obtain a dark brown solution. The reaction was acidified to pH = 2-3 with 1N HCl and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated in vacuum to obtain 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.6 g, yield: 19.7%) as a black solid. LC-MS m / z: 285.0 (M+1) + . Step 4: 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

[0191] To a solution of tert-butyl (S)-(1-(5-amino-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (69 mg, 0.20 mmol, 1.0 eq) and 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.20 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (113 mg, 0.30 mmol, 1.5 eq) and DIPEA (0.15 ml, 0.79 mmol, 4.0 eq). The reaction mixture was stirred at 50° C. for 10 h. After cooling to room temperature, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated 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-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamido)-1,2-dimethyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (20 mg, yield: 15.8%) as a yellow solid. LC-MS m / z: 613.5 (M+1) + . 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

[0192] 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 h. 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. LC-MS m / z: 513.5 (M+1) + . 1 H NMR (400MHz, CD3OD): 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=9.9) Hz, 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). JPEG2025502358000081.jpg67150 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 JPEG2025502358000082.jpg114150 Step 1: N-(2-chloro-6-fluorophenyl)isobutyramide

[0193] 2-Chloro-6-fluoroaniline (6.5 g, 44.65 mmol, 1 eq) was dissolved in isobutyric anhydride (8.48 g, 53.59 mmol, 1.2 eq) and pyridine (Py., 4.24 g, 53.59 mmol, 1.2 eq). The reaction was stirred in a microwave at 155 °C for 2 h to give a light brown solution. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. Two reactions were run in parallel and combined for workup. The reaction was poured into water and a large amount of solid precipitated. Filtration and drying of the filter cake on an oil pump gave N-(2-chloro-6-fluorophenyl)isobutyric acid amide (19.8 g, yield: 103%) as a light brown solid. LC-MS m / z: 216.1 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)isobutyramide

[0194] To a solution of N-(2-chloro-6-fluorophenyl)isobutyramide (89.31 mmol, 1 eq) in 98% H2SO4 (40 ml) was added 66% HNO3 (7.34 mL, 107.17 mmol, 1.2 eq) dropwise at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 30 min. The reaction was then warmed to 50 °C and stirred for an additional 1 h 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, basified to pH = 2-3 with Na2CO3, and extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column (silica column, eluted with 5% to 15% EA in PE) to give N-(2-chloro-6-fluoro-3-nitrophenyl)isobutyramide (9.5 g, yield: 41%) as a brown solid. LC-MS m / z: 261.1 (M+1) + . Step 3: 4-Chloro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole

[0195] 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% methanamine in EtOH (7.77 mL, 54.67 mmol, 1.5 eq). The reaction was stirred at room temperature for 1 h, then warmed to 130 °C and stirred for an additional 10 h to give a dark brown solution. LCMS showed that the starting material was consumed and two new peaks were detected. The mixture was diluted with H2O and extracted with EA (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (silica column, eluted with 10% to 20% EA in 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. LC-MS m / z: 254.1 (M+1) + . Step 4: tert-Butyl (R)-(1-(2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0196] 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 tert-butyl (R)-pyrrolidin-3-ylcarbamate (2.2 g, 11.83 mmol, 1 eq). The reaction was stirred at 100 °C for 6 h 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 HO and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 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. LC-MS m / z: 404.3 (M+1) + . Step 5: tert-Butyl (R)-(1-(5-amino-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0197] To a solution of tert-butyl (R)-(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) was added Pd / C (0.4 g) under N2. The reaction was degassed several times with H2 and stirred at room temperature under 45 psi for 3 h to give a dark brown suspension. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to give tert-butyl (R)-(1-(5-amino-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (4.2 g, yield: 97.7%) as a brown gum. LC-MS m / z: 374.3 (M+1) + . Step 6: 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

[0198] 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 tert-butyl (R)-(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 h to give a dark brown solution. LCMS showed that the starting material had been consumed 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 filtrate cake was washed with water and dried on an oil pump. The product was triturated with MTBE / hexane 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. LC-MS m / z: 608.3 (M+1) + . 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

[0199] To a solution of 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, 4.44 mmol, 1 eq) in DCM (10 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 1 h 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 basified to pH=9 with aqueous NaHCO3 and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The resulting product was triturated with EA / MTBE, filtered, and the filter cake was lyophilized with 3M aqueous HCl to give Example 109 (1489.32 mg) as a yellow solid. LC-MS m / z: 508.3 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000083.jpg207150 JPEG2025502358000084.jpg201150 JPEG2025502358000085.jpg137150 JPEG2025502358000086.jpg145150 JPEG2025502358000087.jpg202150 JPEG2025502358000088.jpg141150 JPEG2025502358000089.jpg141150 JPEG2025502358000090.jpg142150 JPEG2025502358000091.jpg143150 JPEG2025502358000092.jpg203150 JPEG2025502358000093.jpg207150 JPEG2025502358000094.jpg146150 JPEG2025502358000095.jpg206150 JPEG2025502358000096.jpg70150 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 JPEG2025502358000097.jpg120150 Step 1: 4-Bromo-6-chloro-2,3-difluoroaniline

[0200] To a solution of 4-bromo-2,3-difluoroaniline (10 g, 48.08 mmol, 1 eq) in ACN (80 mL) was added NCS (7.06 g, 52.88 mmol, 1.1 eq) portionwise at 70 °C. The reaction was stirred at 70 °C for 1 h to give a dark brown solution. LCMS showed that the starting material was consumed and one new major peak was detected. The reaction was diluted with water and extracted with EA (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 4-bromo-6-chloro-2,3-difluoroaniline (12.21 g, yield: 104.7%) as a dark oil. LC-MS m / z: 242.1 (M+1) + . Step 2: 6-Chloro-2,3-difluoroaniline

[0201] 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 give a dark brown solution. The reaction was quenched with H2O and LCMS showed that the starting material was consumed and one new major peak was detected. The reaction was diluted with H2O and extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 6-chloro-2,3-difluoroaniline (7 g, yield: 89%) as a black oil. LC-MS m / z: 164.1 (M+1) + . Step 3: N-(6-chloro-2,3-difluorophenyl)isobutyramide

[0202] 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 obtained. The reaction was stirred in a microwave at 150 °C for 2 h 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 (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (silica column, eluted with 5%-10% EA in PE) to give N-(6-chloro-2,3-difluorophenyl)isobutyramide (2.7 g, yield: 27%) as an off-white solid. LC-MS m / z: 234.1 (M+1) + . Step 4: N-(2-chloro-5,6-difluoro-3-nitrophenyl)isobutyramide

[0203] To a solution of N-(6-chloro-2,3-difluorophenyl)isobutyramide (2.1 g, 8.99 mmol, 1 eq) in 98% H2SO4 (8 ml) was added 66% HNO3 (0.68 mL, 9.89 mmol, 1.1 eq) dropwise at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for 1 h 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, basified to pH = 1-2 with Na2CO3, and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give N-(2-chloro-5,6-difluoro-3-nitrophenyl)isobutyramide (1.8 g, yield: 72%) as a dark brown solid. LC-MS m / z: 279.1 (M+1) + . Step 5: 4-Chloro-7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole

[0204] 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 methanamine hydrochloride (0.43 g, 6.46 mmol, 1 eq). The reaction was stirred at room temperature for 1 h, then warmed to 100 °C and stirred for an additional 10 h to give a dark brown solution. LCMS showed the starting material was consumed and a small peak with the desired mass was detected. The mixture was diluted with H2O and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 4-chloro-7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazole (1.3 g, yield: 74%) as a brown solid. LC-MS m / z: 272.1 (M+1) + . Step 6: tert-Butyl (R)-(1-(7-fluoro-2-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0205] 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 tert-butyl (R)-pyrrolidin-3-ylcarbamate (342.79 mg, 1.84 mmol, 1 eq). The reaction was stirred at 90 °C for 3 h 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 HO and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 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. LC-MS m / z: 422.3 (M+1) + . Step 7: tert-Butyl (R)-(1-(5-amino-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0206] To a solution of tert-butyl (R)-(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) under N2. The reaction was degassed several times with H2 and stirred at room temperature under 45 psi for 3 h to give a dark brown suspension. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to give tert-butyl (R)-(1-(5-amino-7-fluoro-2-isopropyl-1-methyl-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (0.7 g, yield: 97.2%) as a dark brown solid. LC-MS m / z: 392.3 (M+1) + . Step 8: 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

[0207] 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 tert-butyl (R)-(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 h 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 mLx3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 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. LC-MS m / z: 626.3 (M+1) + . 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

[0208] To a solution of 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 (475.86 μmol, 1 eq) in DCM (6 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 1 h 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 basified to pH = 10-11 with concentrated aqueous Na2CO3 and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (C18 column, gradient solution of ACN / H2O with 0.1% HCOOH, flow rate 30 mL / min). The collected flow was basified with concentrated aqueous Na2CO3 to pH=10-11 and extracted with EA (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (silica column, eluted with 10% MeOH in DCM0). The collected flow was concentrated and lyophilized with 2M aqueous HCl (3 drops) to give Example 143 (43 mg, 17.2%) as a brown solid. LC-MS m / z: 526.3 (M+1) + . 1 H NMR (400MHz, CD3OD): δ8.27-8.17(m, 2H), 7.69(tt, J=8.6, 6.2Hz, 1H), 7.38-7.29(m, 3H), 4.01(d, J=0.9Hz, 3H), 4.01-3. 96(m, 1H), 3.64(dd, J=12.6, 4.9Hz, 3.49-3.33(m, 3H), 2.35-2.24(m, 1H), 2.20-2.07(m, 1H), 1.42(dd, J=6.8, 3.2Hz, 6H). JPEG2025502358000098.jpg159150 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 JPEG2025502358000099.jpg140150 Step 1: N-(2-chloro-6-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide

[0209] To a solution of 2-chloro-6-fluoroaniline (1.46 g, 10.03 mmol, 1.0 eq), 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (1.54 g, 10.03 mmol, 1.00 eq) in 10 mL of pyridine was added POCl3 (2.50 g, 16.33 mmol, 1.60 eq). The mixture was stirred at 25° C. for 1 h to give a black solution. LCMS analysis of the reaction mixture indicated the reaction was complete. The mixture was poured into 100 mL of water, filtered, and the filtrate was dried under vacuum to give N-(2-chloro-6-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.20 g) as a white solid. LC-MS m / z: 282.6 (M+1) + . Step 2: N-(2-chloro-6-fluoro-3-nitrophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide

[0210] To a solution of N-(2-chloro-6-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.20 g, 7.82 mol, 1.00 eq) in 7 mL of concentrated sulfuric acid at 0° C., 0.6 mL of fuming nitric acid was added 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, filtered, and the filtrate cake was dried under vacuum to give N-(2-chloro-6-fluoro-3-nitrophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.30 g) as a pale yellow solid. LC-MS m / z: 327.6 (M+1) + . Step 3: 4-Chloro-1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazole

[0211] A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (2.30 g, 7.18 mmol, 1.0 eq), CH3NH2HCl (0.53 g, 7.90 mmol, 1.10 eq), 2 mL of Et3N and 20 mL of DMSO was stirred at 120 °C for 3 h to give a brown suspension. The MS of the target compound was detected by LC-MS. The mixture was poured into 100 mL of water and extracted with DCM (30 mL x 2). The reaction mixture was concentrated to dryness under vacuum. The obtained residue was purified by column (SiO2, eluted with 80%-90% EA in PE, COMBI FLASH NEXTAGEN300) to give 4-chloro-1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazole (1.2 g) as a yellow solid. LC-MS m / z: 320.7 (M+1) + . Step 4: tert-Butyl (R)-(1-(1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0212] A mixture of 4-chloro-1-methyl-5-nitro-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazole (2.20 g, 6.88 mmol, 1.0 eq), tert-butyl (R)-pyrrolidin-3-ylcarbamate (1.67 g, 8.95 mmol, 1.30 eq), 20 mL of dioxane and 2 mL of Et3N was obtained. The reaction mixture was stirred at 100° C. for 4 h to give a brown suspension. MS of the target compound was detected by LC-MS. The reaction mixture was concentrated to dryness under vacuum. The resulting residue was purified by column (SiO2, eluted with 50%-60% EA in PE, COMBI FLASH NEXTAGEN300) 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. LC-MS m / z: 470.5 (M+1) + . Step 5: tert-Butyl (R)-(1-(5-amino-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate

[0213] To a solution of tert-butyl (R)-(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 eq) in 10 mL of EtOH, Fe (0.24 g, 4.25 mmol, 5.00 eq) and AcOH (1 mL) were added, and the resulting black suspension was stirred at 25° C. for 5 hours. The MS of the target compound was detected by LC-MS, and no SM remained. The reaction mixture was filtered, and the filtrate was concentrated, NaHCO3 solution was added until pH = 8, concentrated with 30 mL of EA, and then dried in vacuum to give tert-butyl (R)-(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 used directly in the next reaction. LC-MS m / z: 440.5 (M+1) + . 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

[0214] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (150 mg, 0.43 mmol, 1.00 eq), tert-butyl (R)-(1-(5-amino-1-methyl-2-(1-(trifluoromethyl)cyclopropyl)-1H-benzo[d]imidazol-4-yl)pyrrolidin-3-yl)carbamate (251 mg, 0.57 mmol, 1.34 eq) in ACN (10 mL) was added 0.3 mL of DIEA followed by HATU (245 mg, 0.65 mmol, 1.5 eq.) and stirred for 3 h to give a black suspension. LC-MS showed that most of the starting material was consumed and one peak was detected. The reaction was diluted with H2O and extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by FLASH column (EA 50%-60% in PE, COMBI FLASH NEXTAGEN300) to give 170 mg of intermediate as a yellow solid. The intermediate was added with 10 ML dioxane and 10 mL HCl / dioxane (4 mol / L) and stirred for 4 hours as a yellow suspension. The reaction mixture was concentrated to give Example 146 (78 mg) as a yellow solid. LC-MS m / z: 574.5 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, 6.1Hz, 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, 2)H). JPEG2025502358000100.jpg196150The following compounds were obtained in a similar manner to the synthesis method described above. JPEG2025502358000101.jpg167150 JPEG2025502358000102.jpg206150 JPEG2025502358000103.jpg205150 JPEG2025502358000104.jpg183150 JPEG2025502358000105.jpg181150 JPEG2025502358000106.jpg118150 Example 166: N-[4-[(3R,4R)-3-amino-4-methylpyrrolidin-1-yl]-1-methylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide JPEG2025502358000107.jpg144150 Step 1: 4-Bromo-1-methyl-5-nitro-indazole

[0215] To a solution of 4-bromo-5-nitro-1H-indazole (500 mg, 2.07 mmol, 1 eq) in DMF (2 mL) was added K2CO3 (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 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 ethyl acetate (40 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient solution). The compound 4-bromo-1-methyl-5-nitro-indazole (205 mg, yield: 38.75%) was obtained as a yellow solid. LC-MS m / z: 258.1 (M+1) + . Step 2: tert-Butyl N-[(3R,4R)-4-methyl-1-(1-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate

[0216] To a solution of tert-butyl N-[(3R,4R)-4-methylpyrrolidin-3-yl]carbamate (78.22 mg, 390.54 μmol, 1 eq) in DMSO (3 mL) was added TEA (118.55 mg, 1.17 mmol, 163.07 μL, 3 eq) and 4-bromo-1-methyl-5-nitroindazole (100 mg, 390.54 μmol, 1 eq). The mixture was stirred at 110° C. for 2 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 ethyl acetate (40 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound tert-butyl N-[(3R,4R)-4-methyl-1-(1-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate (140 mg, yield: 95.49%) was obtained as a yellow oil. LC-MS m / z: 376.3 (M+1) + . Step 3: tert-Butyl N-[(3R,4R)-1-(5-amino-1-methyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate

[0217] To a solution of tert-butyl N-[(3R,4R)-4-methyl-1-(1-methyl-5-nitroindazol-4-yl)pyrrolidin-3-yl]carbamate (130 mg, 346.28 μmol, 1 eq) in DMF (2 mL) was added hypoboric 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 ethyl acetate (40 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used in the next step without further purification. Compound tert-butyl N-[(3R,4R)-1-(5-amino-1-methyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (100 mg, yield: 83.60%) was obtained as a yellow oil. LC-MS m / z: 346.3 (M+1) + . Step 4: 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

[0218] 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 T3P (552.66 mg, 868.46 μmol, 516.50 μL, 50% purity, 3 eq) and 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (73.00 mg, 289.49 μmol, 1 eq) and TEA (146.46 mg, 1.45 mmol, 201.46 μL, 5 eq). The mixture was stirred at 20 °C for 1 h. 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 ethyl acetate (40 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was used in the next step without further purification. Compound 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, yield: 71.52%) was obtained as a brown oil. LC-MS m / z: 580.4 (M+1) + . Step 5: N-[4-[(3R,4R)-3-amino-4-methylpyrrolidin-1-yl]-1-methylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0219] 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 mL, 19.32 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 concentrated under vacuum. The residue was purified by preparative HPLC (Boston Green ODS 150×30 mm×5 μm, mobile phase: [water (HCl)-ACN], B%: 23%-43%, 10 min). Example 166 (13.22 mg, yield: 13.32%) was obtained as a brown solid. 1 H NMR (400MHz, CD3OD): 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), 7.3 8-7.21(m, 1H), 7.13(d, J=8.9Hz, 1H), 7.34-7.06(m, 1H), 4.90(s, 21H), 4.10(dd, J=5.9, 10.7Hz, 1H), 4.02(s, 3H), 3.84(br d, J=3.3Hz, 1H), 3.70(br t,J=8.5Hz,1H), 3.61(br dd,J=3.0,10.7Hz,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). LC-MS m / z: 480.1 (M+1) + . JPEG2025502358000108.jpg200150 JPEG2025502358000109.jpg206150 JPEG2025502358000110.jpg129150 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 JPEG2025502358000111.jpg105150 Step 1: (R)-tert-Butyl (1-(2-methyl-5-nitro-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

[0220] 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 μL, 2 eq). The mixture was stirred at 110 °C for 2 h. LCMS showed the desired mass was formed. TLC showed the formation of a new spot. The reaction mixture was quenched by the addition of water (10 mL) at 25 °C. The combined organic layers were extracted with 30 mL of ethyl acetate (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-60% ethyl acetate / petroleum ether gradient solution). The compound tert-butyl N-[(3R)-1-(2-methyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate (400 mg, yield: 94.47%) was obtained as a brown oil. LC-MS m / z: 362.2 (M+1) + . Step 2: (R)-tert-butyl (1-(5-amino-2-methyl-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

[0221] 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%, 0.1 eq). The mixture was stirred with a H2 balloon at 25 °C for 2 h. LCMS showed the desired material was formed and the starting material was consumed. The reaction mixture was filtered. The filtrate was concentrated under vacuum to give the crude product. The crude product was used directly in the next step without further purification. Compound tert-butyl N-[(3R)-1-(5-amino-2-methyl-indazol-4-yl)pyrrolidin-3-yl]carbamate (250 mg, yield: 90.87%) was obtained as a blue solid. LC-MS m / z: 332.2 (M+1) + . 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

[0222] 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), TEA (120.38 mg, 1.19 mmol, 165.58 μL, 2 eq) and HATU (339.26 mg, 892.24 μmol, 1.5 eq) and stirred at 25 °C for 2 h. LCMS showed the desired mass was formed. TLC showed the formation of a new spot. The reaction mixture was quenched by the addition of water (15 mL) at 25 °C. The combined organic layers were extracted with ethyl acetate (15 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-67% ethyl acetate / petroleum ether gradient solution). The product 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, yield: 74.31%) was obtained as a brown solid. LC-MS m / z: 566.2 (M+1) + . 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

[0223] 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) and the mixture was stirred at 25° C. for 2 h. LCMS indicates the desired material was formed. The combined organic phase was concentrated under vacuum to give the crude product. The crude product was purified by pre-HPLC (Boston Prime C18 150×30 mm×5 μm, 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. LC-MS m / z: 466.2 (M+1) + . 1 H NMR (500MHz, CD3OD): 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) JPEG2025502358000112.jpg182150 Example 179: N-[4-[(3R)-3-aminopyrrolidin-1-yl]-1-isopropylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide JPEG2025502358000113.jpg117150 Step 1: 4-Bromo-1-isopropyl-5-nitro-1H-indazole

[0224] 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) portionwise at 0-5 °C. The reaction was stirred at room temperature for 2 h to give a dark brown solution. LCMS showed that the starting material was consumed and two peaks of desired mass were detected. The reaction was quenched with H2O and extracted with EA (60 mLx3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (SiO2, eluted with PE to 5% EA in PE) to give 4-bromo-5-nitro-1-(prop-2-yl)indazole (2.6 g, yield: 44.29%) as a yellow solid. LC-MS m / z: 284.1 (M+1) + . Step 2: tert-Butyl N-[(3R)-1-(1-isopropyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate

[0225] To a solution of 4-bromo-1-isopropyl-5-nitroindazole (300 mg, 1.06 mmol, 1 eq) in DMSO (4 mL) was added TEA (213.70 mg, 2.11 mmol, 293.94 μL, 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 h. TLC showed that the starting material was consumed and a new spot was formed. LCMS showed that the desired mass was formed. The reaction mixture was poured into H2O (40 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent [0-30]% petroleum ether / ethyl acetate gradient solution). The compound tert-butyl N-[(3R)-1-(1-isopropyl-5-nitro-indazol-4-yl)pyrrolidin-3-yl]carbamate (395 mg, yield: 96.05%) was obtained as a red solid. LC-MS m / z: 390.2 (M+1) + . Step 3: tert-Butyl N-[(3R)-1-(5-amino-1-isopropyl-indazol-4-yl)pyrrolidin-3-yl]carbamate

[0226] 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 μmol, 10%, w%, 0.1 eq). The reaction mixture was stirred with a H2 balloon at 25 °C for 1 h. LCMS showed that the starting material was consumed and the desired mass was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure. Compound tert-butyl N-[(3R)-1-(5-amino-1-isopropyl-indazol-4-yl)pyrrolidin-3-yl]carbamate (305 mg, yield: 83.66% yield) was obtained as a brown oil. LC-MS m / z: 360.2 (M+1) + . Step 4: tert-Butyl N-[(3R)-1-[5-[[1-(2,6-difluorophenyl)-6-oxopyridazine-3-carbonyl]amino]-1-isopropylindazol-4-yl]pyrrolidin-3-yl]carbamate

[0227] 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 h. LCMS showed that the desired material was formed. TLC showed that the starting material was consumed and a new spot was formed. The reaction mixture was poured into H2O (30 mL) and extracted with ethyl acetate (10 × 3 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent [0-30]% petroleum ether / ethyl acetate gradient solution). 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, yield: 90.83%) was obtained as a brown solid. LC-MS m / z: 594.2 (M+1) + . Step 5: N-[4-[(3R)-3-aminopyrrolidin-1-yl]-1-isopropylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0228] 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 eq) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at 25° C. for 1 h. LCMS showed the desired material was formed and the starting material was consumed. The reaction mixture was concentrated under vacuum to give the crude product. The crude product was purified by pre-HPLC (Boston Prime C18 150×30 mm×5 um, water (FA)-ACN, start B 15, end B 35, gradient time (min) 12, 100% B hold time (min) 2, flow rate (ml / min) 25) to give Example 179 (116.33 mg, yield: 58.30%, FA) as a yellow solid. LC-MS m / z: 494.3 (M+1) + . 1 H NMR (400MHz, CD3OD): δ8.24-8.19(m, 2H), 7.77(d, J=8.9Hz, 1H), 7.71-7.62(m, 1H), 7.35-7.2 5(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). JPEG2025502358000114.jpg202150 JPEG2025502358000115.jpg187150 JPEG2025502358000116.jpg199150 JPEG2025502358000117.jpg204150 JPEG2025502358000118.jpg209150 JPEG2025502358000119.jpg199150 JPEG2025502358000120.jpg202150 JPEG2025502358000121.jpg203150 JPEG2025502358000122.jpg203150 JPEG2025502358000123.jpg193150 JPEG2025502358000124.jpg202150 JPEG2025502358000125.jpg152150 JPEG2025502358000126.jpg199150 JPEG2025502358000127.jpg146150 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 JPEG2025502358000128.jpg109150 Step 1: tert-Butyl (R)-(1-(2-isopropyl-5-nitro-2H-indazol-4-yl)-3-methylpyrrolidin-3-yl)carbamate

[0229] To a solution of 4-chloro-5-nitro-2-(prop-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}methanoate (200.56 mg, 1.001 mmol) and EtN (0.418 mL, 3.004 mmol) and the reaction was stirred at 100° C. for 5 h to give a brown suspension. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give tert-butyl (R)-(1-(2-isopropyl-5-nitro-2H-indazol-4-yl)-3-methylpyrrolidin-3-yl)carbamate (405 mg) as a yellow solid. LC-MS m / z: 404.5 (M+1) + . Step 2: tert-Butyl (R)-(1-(5-amino-2-isopropyl-2H-indazol-4-yl)-3-methylpyrrolidin-3-yl)carbamate

[0230] To a solution of 2-methylpropan-2-yl {[(3R)-3-methyl-1-[5-nitro-2-(prop-2-yl)indazol-4-yl]tetrahydro-1H-pyrrol-3-yl]amino}methanoate (405 mg, 1.004 mmol) in 20 mL of MeOH, Pd / C 10% (100 mg, 0.940 mmol) was added and the mixture was incubated under hydrogen atmosphere at room temperature (60 Psi) for 15 hours as a black suspension, and the MS of the target compound was detected by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated to dryness under vacuum 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. LC-MS m / z: 374.5 (M+1) + . 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

[0231] 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 eq), 2-methylpropan-2-yl {[(3R)-1-[5-amino-2-(prop-2-yl)indazol-4-yl]-3-methyltetrahydro-1H-pyrrol-3-yl]amino}methanoate (244.38 mg, 0.654 mmol) in ACN (10 mL) was added ethyldiisopropylamine (0.3 mL, 1.815 mmol) followed by HATU (339.17 mg, 0.892 mmol) and stirred 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 reaction was diluted with 50 mL of H2O and extracted twice with 30 mL of EA. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by FLASH column (SiO2, EAinPE60%, COMBI FLASH NEXTAGEN300) to give 120 mg of intermediate as a yellow solid. The intermediate was added with 10 mL of HCl / dioxane (4 mol / L) and stirred for 3 hours as a yellow suspension. The reaction mixture was concentrated to give Example 220 (22.32 mg) as a yellow solid. LC-MS m / z: 508.5 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, ), 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), 7(s, 3H). JPEG2025502358000129.jpg207150 JPEG2025502358000130.jpg199150 JPEG2025502358000131.jpg206150 JPEG2025502358000132.jpg124150 Example 234: N-[4-[(3R,4R)-3-amino-4-methylpyrrolidin-1-yl]-2-tert-butylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide JPEG2025502358000133.jpg94150 Step 1: 4-Bromo-2-tert-butyl-5-nitro-indazole

[0232] 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 h. LCMS showed the desired product was formed as the major peak. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EA (40 mL x 3). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum. 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. LC-MS m / z: 298.0 (M+1) + . Step 2: tert-Butyl N-[(3R,4R)-1-(2-tert-butyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate

[0233] To a solution of 4-bromo-2-tert-butyl-5-nitroindazole (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 h. LCMS showed the desired product was formed as the major peak. The reaction mixture was poured into water (400 mL) and the formed solid was collected by filtration. The solid was dissolved in EA (500 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was used directly in the next step without further purification. tert-Butyl N-[(3R,4R)-1-(2-tert-butyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (11 g, yield: 87.28%) was obtained as a yellow solid. LC-MS m / z: 418.4 (M+1) + . Step 3: tert-Butyl N-[(3R,4R)-1-(5-amino-2-tert-butyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate

[0234] 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 H2O (60 mL) was added NH4Cl (11.27 g, 210.78 mmol, 8 eq) and Zn (13.89 g, 212.42 mmol, 8.06 eq) in portions, keeping the temperature below 25 °C using ice water. The mixture was stirred at 25 °C for 1 h. LCMS showed that the desired product was formed as the major 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 dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum. The remaining Zn was treated with 1N HCl, neutralized with 1N NaOH and discarded. The residue was used directly in the next step without purification. tert-Butyl N-[(3R,4R)-1-(5-amino-2-tert-butyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (10 g, yield: 97.94%) was obtained as a green solid. LC-MS m / z: 388.3 (M+1) + . Step 4: 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

[0235] To a solution of tert-butyl N-[(3R,4R)-1-(5-amino-2-tert-butylindazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (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) in CH3CN (200 mL) was added NMI (6.36 g, 77.42 mmol, 6.17 mL, 3 eq) and TCFH (8.69 g, 30.97 mmol, 1.2 eq). The mixture was stirred at 25 °C for 3 h. LCMS showed the desired product formed as the major peak. The reaction mixture was poured into water (400 mL) and extracted with EA (100 mL × 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 100 g SepaFlash® silica flash column, eluent 0-40% ethyl acetate / petroleum ether gradient solution, 200 mL / min). The product was dissolved in PE / EA (5:1, 50 ml) and stirred for 1 h. The mixture was filtered and the solid was collected. 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, yield: 68.57%) was obtained as a yellow solid. LC-MS m / z: 622.3 (M+1) + . 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

[0236] 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 the main peak. The reaction mixture was concentrated under vacuum. The residue was dissolved in CH3CN / H2O (20 mL / 50 mL) and lyophilized. The residue was used directly in the next step without further purification. Example 234 (9.23 g, yield: 100.00%) was obtained as a white solid. LC-MS m / z: 492.1 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000134.jpg204150 JPEG2025502358000135.jpg190150 JPEG2025502358000136.jpg203150 JPEG2025502358000137.jpg186150 Example 249: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1-[(3S)-tetrahydro-3-furyl]indazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide JPEG2025502358000138.jpg110150Step 1: 2-Methylpropan-2-yl{[(7R)-5-(5-nitro-1H-indazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0237] 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]heptan-7-yl]amino}methanoate (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 h to give a brown solution. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The reaction mixture was poured into water to precipitate a large amount of solid, filtered, and the filter cake was dried with an oil pump to give 2-methylpropan-2-yl{[(7R)-5-(5-nitro-1H-indazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (1.47 g, yield: 95.28%) as a yellow solid. LC-MS m / z: 374.2 (M+1) + . Step 2: 2-Methylpropan-2-yl {[(7R)-5-{5-nitro-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl}-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0238] To a solution of 2-methylpropan-2-yl{[(7R)-5-(5-nitro-1H-indazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (150 mg, 0.402 mmol) and (3R)-tetrahydrofuran-3-ol (0.065 mL, 0.803 mmol) in THF (5 mL) was added tributylphosphane (162.55 mg, 0.803 mmol) and DIAD (162.46 mg, 0.803 mmol). The reaction was stirred in a microwave at 50 °C for 30 min 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 diluted with H2O and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column (SiO2, eluted with 30% EA in PE) to give 2-methylpropan-2-yl {[(7R)-5-{5-nitro-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl}-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (98 mg, yield: 55.01%) as a yellow solid. LC-MS m / z: 444.3 (M+1) + . Step 3: 2-Methylpropan-2-yl {[(7R)-5-{5-amino-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl}-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0239] To a solution of 2-methylpropan-2-yl {[(7R)-5-{5-nitro-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl}-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (98 mg, 0.221 mmol) in MeOH (3 mL) was added Pd / C 10% (20 mg, 0.221 mmol) under N2. The resulting mixture was degassed several times with H2 and stirred at room temperature under 45 psi for 5 h to give a black suspension. LCMS showed that most of the starting material was consumed and one major peak with the desired mass was detected. The reaction was filtered through a pad of Celite and the filtrate was concentrated to give 2-methylpropan-2-yl {[(7R)-5-{5-amino-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl}-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (95 mg, yield: 103.97%) as a brown solid. LC-MS m / z: 414.3 (M+1) + . 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-furyl]indazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0240] 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-furyl]indazol-4-yl}-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (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 h to give a brown solution. LCMS showed that the starting material had been consumed and one major peak with the desired mass was detected. The residue was poured into water to precipitate a large amount of solid, which was filtered and dried to give 2-methylpropan-2-yl{[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (115 mg, yield: 89.55%) as a brown solid. LC-MS m / z: 648.3 (M+1) + . Step 5: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1-[(3S)-tetrahydro-3-furyl]indazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide

[0241] To a solution of 2-methylpropan-2-yl {[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-[(3S)-tetrahydro-3-furyl]indazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (115 mg, 0.178 mmol) in DCM (6 mL) was added dropwise a solution of 50% TFA in DCM (2 mL). The reaction mixture was stirred at room temperature for 3 h 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 to dryness. The residue was basified with NH4OH to pH=7-8, purified five times by flash column (C18, eluted with a gradient solution 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. LC-MS m / z: 548.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, 3.9Hz, 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), 7(dd,J=10.2, 3.0Hz, 1H), 3.25(dd, J=5.5, 2.9Hz, 1H), 3.12(d, J=9.2Hz, 1H), 2.51( dq, J=12.8, 7.8Hz, 1H), 2.46-2.34(m, 1H), 0.92(dt, J=8.7, 4.5Hz, 1H), 0.67(tdd, J=15.5, 7.0, 2.6Hz, 3H). JPEG2025502358000139.jpg207150 JPEG2025502358000140.jpg145150 JPEG2025502358000141.jpg196150 JPEG2025502358000142.jpg197150 JPEG2025502358000143.jpg143150 JPEG2025502358000144.jpg147150 JPEG2025502358000145.jpg200150 JPEG2025502358000146.jpg203150 JPEG2025502358000147.jpg141150 JPEG2025502358000148.jpg193150 JPEG2025502358000149.jpg196150 JPEG2025502358000150.jpg191150 JPEG2025502358000151.jpg63150 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 JPEG2025502358000152.jpg108150Step 1: 4-Bromo-1-(2-methoxyethyl)-5-nitro-1H-indazole

[0242] To a solution of 4-bromo-5-nitro-1H-indazole (200 mg, 826.35 μmol, 1 eq) and K2CO3 (571.03 mg, 4.13 mmol, 5 eq) in DMF (4 mL) was added 1-bromo-2-methoxyethane (229 mg, 1.65 mmol, 154.73 μL, 1.99 eq). The mixture was stirred at 70 °C for 2 h. 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 ethyl acetate (15 ml × 3). The combined organic phase was washed with brine over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-45% ethyl acetate / petroleum ether gradient). 4-Bromo-1-(2-methoxyethyl)-5-nitro-indazole (70 mg, yield: 28.23%) was obtained as a yellow solid. LC-MS m / z: 300.1 (M+1) + . Step 2: tert-Butyl ((3R,4R)-1-(1-(2-methoxyethyl)-5-nitro-1H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[0243] 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-nitroindazole (140 mg, 466.50 μmol, 1 eq) and TEA (141.61 mg, 1.40 mmol, 194.79 μL, 3 eq). The mixture was stirred at 100 °C for 2 h. 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 ethyl acetate (15 ml × 3). The combined organic phase was washed with brine over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-45% ethyl acetate / petroleum ether gradient). tert-Butyl N-[(3R,4R)-1-[1-(2-methoxyethyl)-5-nitro-indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (120 mg, yield: 61.32%) was obtained as a yellow oil. LC-MS m / z: 420.3 (M+1) + . Step 3: tert-Butyl ((3R,4R)-1-(5-amino-1-(2-methoxyethyl)-1H-indazol-4-yl)-4-methylpyrrolidin-3-yl)carbamate

[0244] 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 hypoboric acid (256.46 mg, 2.86 mmol, 10 eq). The mixture was stirred at 20° C. for 30 min. 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 ethyl acetate (15 ml×3). The combined organic phase was washed with brine over Na2SO4, filtered and concentrated under vacuum. The residue was used directly in the next step without further purification. tert-Butyl N-[(3R,4R)-1-[5-amino-1-(2-methoxyethyl)indazol-4-yl]-4-methyl-pyrrolidin-3-yl]carbamate (105 mg, yield: 94.24%) was obtained as a brown oil. LC-MS m / z: 390.3 (M+1) + . 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

[0245] 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 μL, 5.02 eq) in DMF (3 mL), T3P (257 mg, 807.72 μmol, 240.19 μL, 3 eq) was added. 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 remaining mixture was poured into water (20 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic phase was washed with brine over Na2SO4, filtered and concentrated in vacuo. The residue was used directly in the next step without further purification. 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, yield: 99.93%) was obtained as a dark brown oil. LC-MS m / z: 624.4 (M+1) + . 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

[0246] 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 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 14%-44%, 12 min). Example 283 (110 mg, yield: 78.00%) was obtained as a yellow solid. LC-MS m / z: 524.3 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000153.jpg192150 JPEG2025502358000154.jpg198150 JPEG2025502358000155.jpg188150 JPEG2025502358000156.jpg192150 JPEG2025502358000157.jpg143150 Example 298: N-[4-[(3R,4R)-3-amino-4-methylpyrrolidin-1-yl]-1-cyclopropylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide JPEG2025502358000158.jpg126150 Step 1: tert-Butyl N-[(3R,4R)-1-(1-cyclopropyl-5-nitroindazol-4-yl)-4-methylpyrrolidin-3-yl]carbamate

[0247] To a solution of tert-butyl N-[(3R,4R)-4-methyl-1-(5-nitro-1H-indazol-4-yl)pyrrolidin-3-yl]carbamate (200 mg, 553.41 μmol, 1 eq), cyclopropylboronic acid (142.61 mg, 1.66 mmol, 3 eq), 2-(2-pyridyl)pyridine (86.43 mg, 553.41 μmol, 1 eq) and disodium carbonate (175.97 mg, 1.66 mmol, 3 eq) in DCE (6 mL) was added Cu(OAc)2 (110.57 mg, 608.75 μmol, 1.1 eq). The mixture was stirred at 70 °C for 2 h. LC-MS showed one main peak with the desired mass. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 30% ethyl acetate / petroleum ether gradient). Compound tert-butyl N-[(3R,4R)-1-(1-cyclopropyl-5-nitro-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (160 mg, yield: 72.02%) was obtained as a yellow solid. LC-MS m / z: 402.2 (M+1) + . Step 2: tert-Butyl N-[(3R,4R)-1-(5-amino-1-cyclopropylindazol-4-yl)-4-methylpyrrolidin-3-yl]carbamate

[0248] 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 μmol, 1 eq) in THF (10 mL) and HO (5 mL) was added NH4Cl (170.55 mg, 3.19 mmol, 8 eq) and Zn (208.49 mg, 3.19 mmol, 8 eq). The mixture was stirred at 25 °C for 1 h. LC-MS showed that one main peak with the desired mass was detected. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). 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 invisible green solid. LC-MS m / z: 372.2 (M+1) + . Step 3: 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

[0249] To a solution of 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (71.28 mg, 282.66 μmol, 1 eq) and tert-butyl N-[(3R,4R)-1-(5-amino-1-cyclopropyl-indazol-4-yl)-4-methyl-pyrrolidin-3-yl]carbamate (105 mg, 282.66 μmol, 1 eq) in Py (2 mL) was added POCl3 (43.34 mg, 282.66 μmol, 26.27 μL, 1 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed one main peak with the desired mass. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 35% ethyl acetate / petroleum ether gradient solution). Compound 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, yield: 81.78%) was obtained as a yellow solid. LC-MS m / z: 606.3 (M+1) + . Step 4: N-[4-[(3R,4R)-3-amino-4-methylpyrrolidin-1-yl]-1-cyclopropylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0250] A solution of tert-butyl N-[(3R,4R)-1-[1-cyclopropyl-5-[[1-(2,6-difluorophenyl)-6-oxopyridazine-3-carbonyl]amino]indazol-4-yl]-4-methylpyrrolidin-3-yl]carbamate (140 mg, 231.16 μmol, 1 eq) in dioxane (5 mL) and HCl / dioxane (10 mL). The mixture was stirred at 25 °C for 1.5 h. LC-MS showed that one main peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by pre-HPLC (Boston Prime C18 150 × 30 mm × 5 μm, water (HCl)-ACN, start B19, end B39, 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. LC-MS m / z: 506.3 (M+1) + . 1 H NMR (400MHz, CD3OD): 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, 1 H), 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). JPEG2025502358000159.jpg144150 JPEG2025502358000160.jpg71150 Example 302: N-[4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1-tert-butylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide JPEG2025502358000161.jpg139150 Step 1: 2-Bromo-6-fluoro-3-nitrobenzoic acid

[0251] To a solution of 2-bromo-6-fluorobenzoic acid (5 g, 22.83 mmol, 1 eq) in sulfuric acid (15 mL) was added HNO3 (3.76 g, 59.67 mmol, 2.69 mL, 2.61 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. TLC showed that the starting material was consumed and a new spot was formed. The reaction mixture was poured into 80 ml of water, filtered, the solid was washed with water and dried under vacuum. The residue was used in the next step without further purification. 2-Bromo-6-fluoro-3-nitrobenzoic acid (4.2 g, yield: 69.68%) was obtained as a white solid. 1 H NMR (500MHz, CD3OD): δ=8.03(dd, J=5.1, 9.1Hz, 1H), 7.47(dd, J=8.2, 8.9Hz, 1H). Step 2: (2-Bromo-6-fluoro-3-nitro-phenyl)methanol)

[0252] To a solution of 2-bromo-6-fluoro-3-nitrobenzoic acid (3.8 g, 14.39 mmol, 1 eq) in THF (40 mL) was added BH3THF (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 30 mL of H2O and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was used in the next step without further purification. (2-Bromo-6-fluoro-3-nitrophenyl)methanol (3.59 g, yield: 99.76%) was obtained as a white solid. 1 H NMR (400MHz, CDCl3): 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). Step 3: 2-Bromo-6-fluoro-3-nitrobenzaldehyde

[0253] To a solution of (2-bromo-6-fluoro-3-nitrophenyl)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 h. TLC showed that most of the starting material was consumed and the desired mass was detected. The mixture was added to 10 mL of saturated aqueous NaHCO3. The mixture was filtered and the filtrate was extracted with DCM (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, elution with 0-10% ethyl acetate / petroleum ether gradient). Compound 2-bromo-6-fluoro-3-nitro-benzaldehyde (764 mg, yield: 77.02%) was obtained as a white solid. 1 H NMR (500MHz, CDCl3): 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). Step 4: 4-Bromo-1-tert-butyl-5-nitro-indazole

[0254] To a solution of 2-bromo-6-fluoro-3-nitrobenzaldehyde (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 for 1 h by microwave. LCMS showed that the starting material was consumed and the desired mass was detected. The reaction mixture was added to 15 mL of H2O and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient). Compound 4-bromo-1-tert-butyl-5-nitro-indazole (350 mg, yield: 41.59%) was obtained as a yellow solid. 1 H NMR (500MHz, CDCl3): δ=8.19(s, 1H), 7.96(d, J=9.2Hz, 1H), 7.69(d, J=9.2Hz, 1H), 1.79(s, 9H). Step 5: tert-Butyl N-[(7R)-5-(1-tert-butyl-5-nitroindazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]carbamate

[0255] 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]heptan-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 μL, 3 eq). The mixture was stirred at 90 °C for 1 h. LCMS showed that the starting material was consumed and the desired mass was detected. The reaction mixture was added to 20 mL of H2O and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was used in the next step without further purification. Compound tert-butyl N-[(7R)-5-(1-tert-butyl-5-nitro-indazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]carbamate (432 mg, yield: 99.95%) was obtained as a yellow solid. LC-MS m / z: 430.3 (M+1) + . 1 H NMR (400MHz, CDCl3): 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(brs, 2H). Step 6: tert-Butyl N-[(7R)-5-(5-amino-1-tert-butylindazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]carbamate

[0256] To a solution of tert-butyl N-[(7R)-5-(1-tert-butyl-5-nitroindazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]carbamate (432 mg, 1.01 mmol, 1 eq) in THF (6 mL) and H2O (6 mL) was added Zn (550 mg, 8.41 mmol, 8.36 eq) and NH4Cl (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 15 mL of H2O and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was used directly in the next step without further purification. Compound tert-butyl N-[(7R)-5-(5-amino-1-tert-butylindazol-4-yl)-5-azaspiro[2.4]heptan-7-yl]carbamate (400 mg, yield: 99.54%) was obtained as a brown solid. LC-MS m / z: 400.3 (M+1) + . Step 7: 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]heptan-7-yl]carbamate.

[0257] 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-butylindazol-4-yl)-5-azaspiro[2.4]heptan-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 μL, 3 eq) and TCFH (309.00 mg, 1.10 mmol, 1.1 eq). The mixture was stirred at 20 °C for 1 h. LCMS showed that the starting material was consumed and the desired mass was detected. The reaction mixture was added to 20 mL of HO and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient solution). The crude product was purified by recrystallization from ethyl acetate (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]heptan-7-yl]carbamate (266 mg, yield: 41.93%) was obtained as a yellow solid. LC-MS m / z: 634.4 (M+1) + . Step 8: N-[4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1-tert-butylindazol-5-yl]-1-(2,6-difluorophenyl)-6-oxopyridazine-3-carboxamide

[0258] 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]heptan-7-yl]carbamate (266 mg, 419.77 μmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 3 mL, 28.59 eq). The mixture was stirred at 20° C. for 1 h. 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. LC-MS m / z: 534.3 (M+1) + . 1 H NMR (400MHz, CD3OD): 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), 36(m, 3H), 4.19(dd, J=5.72, 10.61Hz, 1H), 3.99(d, J =9.18Hz, 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). JPEG2025502358000162.jpg71150 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 JPEG2025502358000163.jpg88150 Step 1: 2-(bicyclo[2.2.2]octan-1-yl)-4-bromo-2H-indazole

[0259] A mixture of 6-bromo-2-nitrobenzene-1-carbaldehyde (345 mg, 1.5 mmol) and bicyclo[2.2.2]octan-1-aminechlorane (266.76 mg, 1.65 mmol) in dioxane (10 mL) was stirred at 90 °C for 0.5 h as a black solution, then tributylphosphine (910.44 mg, 4.500 mmol) was added and stirred at 90 °C for 24 h as 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 under vacuum. The obtained residue was purified by column (SiO2, eluted with 20% EA in PE, COMBI FLASH NEXTAGEN300) to give 2-(bicyclo[2.2.2]octan-1-yl)-4-bromoindazole (260 mg, yield: 56.79%) as a white solid. LC-MS m / z: 306.2 (M+1) + . Step 2: 2-(bicyclo[2.2.2]octan-1-yl)-4-bromo-5-nitro-2H-indazole

[0260] Fuming nitric acid (0.25 mL, 0.491 mmol) was added to a solution of 2-(bicyclo[2.2.2]octan-1-yl)-4-bromoindazole (150 mg, 0.491 mmol) in H2SO4 (5 mL, 93.811 mmol) at 0 °C, stirred at 0 °C for 30 min, and the MS of the target compound was detected by LC-MS as a brown solution. The reaction was diluted with 30 mL of H2O at 0 °C and extracted with 30 mL x 2 of EA. The combined organic layer was washed with NaHCO3, dried over Na2SO4, filtered, and concentrated to give 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. LC-MS m / z: 351.2 (M+1) + . 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

[0261] 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}methanoate (102.00 mg, 0.509 mmol) and TEA (0.5 mL, 3.597 mmol). The reaction mixture was stirred at 110° C. for 5 h, resulting in a brown suspension. LC-MS showed the reaction was complete. The reaction was diluted with 100 mL of H2O and extracted with EA (50 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 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}methanoate (210 mg, yield: 96.68%) as a yellow solid. LC-MS m / z: 470.6 (M+1) + . 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

[0262] 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}methanoate (210 mg, 0.447 mmol) in MeOH (10 mL) was added with Pd / C 10% (20 mg, 0.188 mmol) and incubated under hydrogen for 18 h at room temperature (60 Psi) to form a black suspension. The MS of the target compound 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]amino}methanoate (182 mg, yield: 92.58%) as a black solid which was used directly in the next reaction. LC-MS m / z: 440.6 (M+1) + . 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

[0263] To a solution of 1-(2,6-difluorophenyl)-6-oxo-1,2-diazine-3-carboxylic acid (100 mg, 0.397 mmol) and 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]amino}methanoate (174.32 mg, 0.397 mmol) in ACN (10 mL), HATU (226.43 mg, 0.596 mmol) and ethyldiisopropylamine (0.5 mL, 3.025 mmol) were added 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 reaction was diluted with 30 mL of HO and extracted with 2 x 30 mL of EA. The combined organic layer was dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column (SiO2, 60% EA in PE, eluted with COMBI FLASH NEXTAGEN300) to obtain 68 mg as a yellow solid. The residue was added with 15 mL HCl / EtOH (4 mol / L) and stirred at 50° C. for 3 hours as a yellow suspension, filtered and dried to obtain Example 304 (44.76 mg, yield: 18.48%) as a yellow solid. LC-MS m / z: 574.6 (M+1) + . 1 H NMR (400MHz, MeOD): δ8.38(s, 1H), 8.22(d, J=9.9Hz, 1H), 7.73-7.62(m, 1H), 7.57(d, J=9.1Hz, 1H) , 7.36-7.22(m, 4H), 3.99(dd, J=10.6, 6.1Hz, 1H), 3.82(dd, J=9.8, 6.3Hz, 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, 7.3Hz, 1H), 2.23(dd, J=9.8, 6.2Hz, 6H), 1.91(dd, J=9.4, 6.2Hz, 6H), 1.81(dd, J=6.1, 3.0Hz, 1H), 1.15(d, J=7.1Hz, 3H). JPEG2025502358000164.jpg206150 JPEG2025502358000165.jpg209150 JPEG2025502358000166.jpg205150 JPEG2025502358000167.jpg208150 JPEG2025502358000168.jpg208150 JPEG2025502358000169.jpg194150 JPEG2025502358000170.jpg208150 JPEG2025502358000171.jpg199150 JPEG2025502358000172.jpg204150 JPEG2025502358000173.jpg200150 JPEG2025502358000174.jpg55150 Example 340: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1-(prop-2-yl)benzo[d][1,2,3]triazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide JPEG2025502358000175.jpg112150 Step 1: 5-nitro-2-(prop-2-ylamino)aniline

[0264] 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 h to give a dark brown solution. LCMS showed most of the starting material remaining and one new peak with the desired mass. More propan-2-amine (0.40 g, 6.726 mmol) was added to the reaction. The mixture was warmed to 110 °C and stirred for an additional 10 h to give a dark brown solution. LCMS showed most of the starting material was consumed and one major peak with the desired mass. No workup was performed and the reaction was used directly in the next step. LC-MS m / z: 196.1 (M+1) + . Step 2: 5-Nitro-1-(prop-2-yl)benzo[d][1,2,3]triazole

[0265] To a solution of 5-nitro-2-(prop-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) in HO (3 mL) at 0-5 °C. The reaction was stirred at room temperature for 1 h to give a brown suspension. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was filtered, washed with water, and the filter cake was dried on an oil pump to give 5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazole (1.17 g, yield: 88.61%) as a brown solid. LC-MS m / z: 207.1 (M+1) + . Step 3: 1-(prop-2-yl)benzo[d][1,2,3]triazol-5-amine

[0266] To a solution of 5-nitro-1-(prop-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 degassed several times with H2 and stirred at room temperature under 45 psi for 30 h to give a black suspension. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was filtered through a pad of Celite and the filtrate was concentrated to give 1-(prop-2-yl)benzo[d][1,2,3]triazol-5-amine (0.98 g, yield: 98.02%) as a brown oil. LC-MS m / z: 177.1 (M+1) + . Step 4: 4-Bromo-1-ethylbenzo[d][1,2,3]triazol-5-amine

[0267] To a solution of 1-(prop-2-yl)benzo[d][1,2,3]triazol-5-amine (0.98 g, 5.561 mmol) in CHCl3 (20 mL) was added pyridinium tribromide (1.77 g, 5.561 mmol). The reaction was stirred at room temperature for 3 h to give a dark brown solution. LCMS showed most of the starting material was consumed and one major 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 neutralized with concentrated NaHCO3. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give 4-bromo-1-ethylbenzo[d][1,2,3]triazol-5-amine (1.2 g, yield: 89.55%) as a dark brown oil. LC-MS m / z: 255.1 (M+1) + . Step 5: 4-Bromo-5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazole

[0268] To a solution of 4-bromo-1-(prop-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 h to give a brown solution. LCMS showed the starting material was consumed and one major peak with the desired mass was detected. The reaction was quenched with aqueous NaHCO3 and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 4-bromo-5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazole (1.3 g, yield: 97.01%) as a brown solid. LC-MS m / z: 285.1 (M+1) + . Step 6: 2-Methylpropan-2-yl{[(7R)-5-[5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0269] To a solution of 4-bromo-5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazole (200 mg, 0.702 mmol) and 2-methylpropan-2-yl{[(7R)-5-azaspiro[2.4]heptan-7-yl]amino}methanoate chlorane (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 h 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 quenched with HO and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-methylpropan-2-yl{[(7R)-5-[5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (290 mg, yield: 99.26%) as a brown oil. LC-MS m / z: 417.2 (M+1) + . Step 7: 2-Methylpropan-2-yl{[(7R)-5-[5-amino-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0270] To a solution of 2-methylpropan-2-yl{[(7R)-5-[5-nitro-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (290 mg, 0.696 mmol) in MeOH (5 mL) was added Pd / C 10% (50 mg, 0.442 mmol) under N2. The resulting mixture was degassed several times with H2 and stirred at room temperature under 45 psi for 16 h to give a black suspension. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was filtered through a pad of Celite and the filtrate was concentrated to give 2-methylpropan-2-yl{[(7R)-5-[5-amino-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (265 mg, yield: 98.47%) as a brown solid. LC-MS m / z: 386.3 (M+1) + . Step 8: 2-Methylpropan-2-yl{[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate

[0271] 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-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (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 h to give a green suspension. LCMS showed that the starting material was consumed and one major peak with the desired mass was detected. The reaction was purified by flash column (C18, eluted with a gradient of ACN / HO 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-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (235 mg, yield: 73.45%) as a brown solid. LC-MS m / z: 621.3 (M+1) + . Step 9: 1-(2,6-difluorophenyl)-N-{4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1-(prop-2-yl)benzo[d][1,2,3]triazol-5-yl}-6-oxo-1,2-diazine-3-carboxamide

[0272] To a solution of 2-methylpropan-2-yl {[(7R)-5-[5-({[1-(2,6-difluorophenyl)-6-oxo-1,2-diazin-3-yl]carbonyl}amino)-1-(prop-2-yl)benzo[d][1,2,3]triazol-4-yl]-5-azaspiro[2.4]heptan-7-yl]amino}methanoate (235 mg, 0.379 mmol) in EA (2 mL) was added 4M HCl in MeOH (5 mL). The resulting mixture was left at room temperature for 16 h 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 to dryness. The residue was triturated with MeOH and lyophilized to give Example 340 (175.72 mg, yield: 83.24%) as a yellow solid. LC-MS m / z: 521.2 (M+1) + . 1 H NMR (400MHz, CD3OD): 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). JPEG2025502358000176.jpg73150 Example 342: N-(4-(4-cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide JPEG2025502358000177.jpg124150 Step 1: 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile

[0273] To a solution of 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 HO (5 mL) was added 4-bromo-2-fluoro-1-nitrobenzene (1.05 g, 4.78 mmol, 1.1 eq), KCO (1.80 g, 13.04 mmol, 3 eq) and XPhos-Pd-G (341.98 mg, 434.65 μmol, 0.1 eq). The mixture was stirred at 110 °C for 2 h. LCMS showed the desired mass was formed. TLC showed a new spot was formed. The reaction mixture was quenched with 25 mL of water, extracted with ethyl acetate (30 mL × 3), dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient). The purified product 3-(3-fluoro-4-nitrophenyl)pyridine-4-carbonitrile (800 mg, yield: 75.68%) was obtained as a light brown solid. LC-MS m / z: 244.0 (M+1) + . Step 2: tert-Butyl 4-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)piperazine-1-carboxylate

[0274] To a solution of 3-(3-fluoro-4-nitrophenyl)pyridine-4-carbonitrile (150 mg, 616.79 μmol, 1 eq) in DMSO (3 mL) was added tert-butyl piperazine-1-carboxylate (172.32 mg, 925.19 μmol, 1.5 eq) and TEA (124.83 mg, 1.23 mmol, 171.70 μL, 2 eq). The mixture was stirred at 100 °C for 2 h. LCMS showed the desired mass was formed. TLC showed the formation of a new spot. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-60% ethyl acetate / petroleum ether gradient). The purified product tert-butyl 4-[5-(4-cyano-3-pyridyl)-2-nitrophenyl]piperazine-1-carboxylate (240 mg, yield: 95.04%) was obtained as a brown oil. LC-MS m / z: 410.2 (M+1) + . Step 3: tert-Butyl 4-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)piperazine-1-carboxylate

[0275] To a solution of tert-butyl 4-[5-(4-cyano-3-pyridyl)-2-nitrophenyl]piperazine-1-carboxylate (240 mg, 586.17 μmol, 1 eq) in MeOH (10 mL) was added Pd / C (62.13 mg, 58.62 μmol, 10% purity, 0.1 eq). The mixture was stirred with a H2 balloon at 25 °C for 2 h. LCMS showed the desired mass was formed and the starting material was consumed. The reaction mixture was filtered. The filtrate was concentrated under vacuum. tert-Butyl 4-[2-amino-5-(4-cyano-3-pyridyl)phenyl]piperazine-1-carboxylate (170 mg, yield: 76.43%) was obtained as a brown solid. LC-MS m / z: 380.2 (M+1) + . 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

[0276] 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), 1-(2,6-difluorophenyl)-6-oxo-pyridazine-3-carboxylic acid (99.69 mg, 395.30 μmol, 1 eq), TEA (80.00 mg, 790.61 μmol, 110.04 μL, 2 eq), and HATU (225.46 mg, 592.96 umol, 1.5 eq) were added and stirred at 60 °C for 2 h. LCMS showed the desired material was formed. TLC showed a new spot was formed. The reaction mixture was quenched by adding water (15 mL). The combined organic layers were extracted with ethyl acetate (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient solution) to give tert-butyl 4-[5-(4-cyano-3-pyridyl)-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. LC-MS m / z: 614.2 (M+1) + . Step 5: N-(4-(4-cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0277] To a solution of tert-butyl 4-[5-(4-cyano-3-pyridyl)-2-[[1-(2,6-difluorophenyl)-6-oxopyridazine-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 h. LCMS showed the desired mass was formed. The combined organic phase was concentrated under vacuum to give the crude product. The crude product was purified by pre-HPLC (Boston Prime C18 150×30 mm×5 μm, water (FA)-ACN, start B17, end B47, 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. LC-MS m / z: 514.2 (M+1) + . 1 H NMR (500MHz, CD3OD): 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(br s, 4H). JPEG2025502358000178.jpg197150 JPEG2025502358000179.jpg189150 JPEG2025502358000180.jpg192150 JPEG2025502358000181.jpg191150 JPEG2025502358000182.jpg192150 JPEG2025502358000183.jpg200150 JPEG2025502358000184.jpg131150 Example A: HPK1 Inhibition Assay Stock solutions of 10 mM test compounds were prepared in DMSO. Compounds were prepared in 5-fold and 10-point serial dilutions using HPK1 kinase assay buffer. HPK1 kinase assay buffer contained 40 mM Tris, pH 7.5, 20 mM MgCl2, 0.1 mg / ml BSA, and 50 μM DTT. 7.5 ng / μl of activated HPK1 (Promega, V4098) and 0.1 μg / ml of MBP substrate protein were added to the reaction system. The final concentration of ATP in the HPK1 kinase reaction system was 10 μM. The serially diluted compounds were transferred to the reaction system and incubated at room temperature for 1 h. 5 μL of ADP-Glo ​​reagent (Promega, V9101) was added and incubated for 40 min to stop the kinase reaction and deplete unconsumed ATP. Then, 10 μl of kinase detection reagent was added and incubated at room temperature for 30–60 min. Luminescence was measured with a plate-reading luminometer.

[0278] As illustrated in the Examples, compounds of the present disclosure have HPK1 IC values ​​in the following ranges: 50 (nM) was shown: A≦100nM, B100nM <ic50≦1000nm。JPEG2025502358000185.jpg199150 JPEG2025502358000186.jpg200150 JPEG2025502358000187.jpg199150 JPEG2025502358000188.jpg200150 JPEG2025502358000189.jpg44150

Claims

1. A compound of formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof: Here, R １ is H, alkyl, cycloalkyl or substituted alkyl; Ring A is a 5- or 6-membered aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from alkyl, halo, or haloalkyl, said 5- or 6-membered heteroaryl having at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms, each of which is independently N, O, or S, and a ring-forming N atom is optionally substituted with oxo to form N. ＋ -O － wherein said ring-forming carbon atoms of said 5- or 6-membered aryl or heteroaryl are optionally substituted with oxo to form a carbonyl group; Ring B is a 5- or 6-membered monocyclic aryl or heteroaryl, or an 8-12-membered fused bicyclic aryl or heteroaryl, optionally substituted with 1 to 5 substituents, each of which is independently alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkthioalkyl, alk-S(=O) ２ -Alkyl, cyano, hydroxyalkamino, amino, amido, alkamino, -NR １０ R １１ , cycloalkyl, alk-cycloalkyl, heterocycloalkyl, alk-heterocycloalkyl, aryl, heteroaryl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or multicycloalkyl, wherein a ring carbon atom of ring B is optionally substituted with oxo to form a carbonyl group, R １０ and R １１ are each independently H, alkyl, halo, haloalkyl, cycloalkyl, alkcycloalkyl, alkheterocycloalkyl, or heterocycloalkyl; Ring C is a 5- or 6-membered aryl or heteroaryl, optionally substituted with one or more substituents, each of which is independently selected from alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkamino, cyano, heterocycloalkyl, cycloalkyl, alkcycloalkyl, or alkheterocycloalkyl; Heteroaryls have at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O or S.

2. The R １ The compound of claim 1 , wherein

3. The compound of claim 1, wherein Ring A is one of the following compounds: Here, R ２ is H, alkyl, halo, or haloalkyl.

4. The R ２ is H or halo.

5. The R ２ The compound of claim 4 , wherein

6. The compound of claim 1, wherein the ring B is one of the following compounds: Here, R ３ is H, halo, haloalkyl or alkyl; R ４ is a cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, multicycloalkyl, or -NR １０ R １１ each of the substituents is optionally further substituted; R １０ and R １１ are each independently selected from H, halo, haloalkyl, alkyl, cycloalkyl, alkcycloalkyl, alkheterocycloalkyl, or heterocycloalkyl; Each R ５ are independently H, alkyl, or CD ３ , alkylthioalkyl, alkyl-S(=O) ２ -alkyl, cyano, amino, hydroxyl, hydroxyalkyl, hydroxyalkamino, amido, alkamino, halo, haloalkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spirocycloalkyl, multicycloalkyl, aryl or heteroaryl, each of which may be optionally further substituted, and the alkyl hydrogens may be optionally replaced by D; R ６ is H, halo, haloalkyl or alkyl.

7. The R ３ The compound according to claim 6 , wherein is H or F.

8. The R ６ The compound according to claim 6 , wherein is H or F.

9. The R ４ is cycloalkyl, heterocycloalkyl, bridged bicyclic cycloalkyl or heterocycloalkyl, fused bicyclic cycloalkyl or heterocycloalkyl, spirocyclic cycloalkyl or heterocycloalkyl, or multicycloalkyl, each of which is selected from the group consisting of hydroxyl, hydroxyalkyl, hydroxyalkamino, halo, haloalkyl, alkyl, amino, alkylamino, dialkylamino, alkamino, alkoxy, alkoxyalkyl, -NH-C(=O)-(CH ２ ) ｎ -NH ２ 7. The compound of claim 6, optionally further substituted with one or more substituents selected from: (n is 0, 1, 2 or 3), amido, cycloalkyl, alk-cycloalkyl, alk-heterocycloalkyl, or heterocycloalkyl.

10. 2. 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. 11. The compound of claim 10, wherein Ring C is one of the compounds shown below:

12. The compound according to claim 1, wherein the compound is a compound of the following formula (Ia) or the following formula (Ib), or a stereoisomer or a pharma- ceutically acceptable salt thereof: Ring A is one of the compounds shown below: Ring A optionally contains one or more R ２ is further substituted with X １ , X ２ , X ３ and X ４ are each independently a carbon atom (C) or N, and optionally R ２ is replaced by R ２ is H, alkyl, halo or haloalkyl; Each R ｃ is independently alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkamino, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, amido, alkamino, cyano, cycloalkyl, alkcycloalkyl, 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; The dashed bonds represent single or double bonds necessary to complete the valence of the atoms connected by the bond; R ３ , R ４ , R ５ and R ６ are the same as those described in claim 6, respectively.

13. 13. The compound according to any one of claims 1 to 12, wherein the compound is one of the compounds shown below:

14. 14. The compound according to any one of claims 1 to 13, wherein the compound is one of the compounds shown below:

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharma- ceutically acceptable carrier or excipient.

16. 16. The pharmaceutical composition of claim 15, further comprising a second therapeutic agent.

17. 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. 18. The pharmaceutical composition of claim 17, wherein the immune checkpoint inhibitor is ipilimumab, nivolumab, or pembrolizimab.

19. 1. A method for treating a disease mediated by HPK1 in a subject in need thereof, comprising: A method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-14 or a pharmaceutical composition according to any one of claims 15-18.

20. 20. The method of claim 19, wherein the disease is cancer.

21. 21. The method of claim 20, wherein the cancer is breast cancer, colon cancer, lung cancer, ovarian cancer, or pancreatic cancer.

22. 15. Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the treatment of a disease mediated by HPK1.

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