Novel indazole derivatives

Abstract

The present invention relates to a compound of formula (I) TIFF2023553830000186.tif46170[where, R 1 -R 4 and A is as defined in the description and claims, or a pharmaceutically acceptable salt thereof. The compounds of formula (I) can be used as medicines.

Description

[Technical Field]

[0001] The present invention relates to compounds that are selective allosteric inhibitors of EGFR mutations including T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, their preparation, pharmaceutical compositions containing them, and their use as therapeutically active substances.

[0002] The present invention relates in particular to novel compounds of formula (I): TIFF0007798887000001.tif48170[In the formula, A is -N- or -CH-; R 1 and R 2 are independently selected from halogen and hydrogen; R 3 is alkyl; R 4 is selected from heterocycloalkyl, heterocycloalkylalkoxy, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkylheterocycloalkylalkoxy, hydroxyalkylheterocycloalkylalkyl, hydroxyheterocycloalkylalkyl, hydroxyheterocycloalkylalkoxy, (alkyl)(halo)heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkylheterocycloalkylalkylcycloalkyl, alkylsulfonylheterocycloalkyl, hydroxyheterocycloalkylalkylcycloalkyl, hydroxyalkylheterocycloalkylalkylheterocycloalkyl, hydroxyalkylheterocycloalkyl, haloalkylheterocycloalkyl, (hydroxy)(alkyl)heterocycloalkyl, hydroxycycloalkyl(alkylamino)alkyl, dialkylaminoalkylheterocycloalkyl, and heterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] The HER family of receptor tyrosine kinases are mediators of cell proliferation, differentiation, and survival. This receptor family includes four distinct members: epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homodimers and heterodimers, and the subsequent activation of intrinsic tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signaling molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signaling network. Nature Review Mol Cell Biol Biol. 2001, Feb;2(2):127-37). Deregulation of EGFR by overexpression or mutation has been implicated in many human cancer types, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC), and several EGFR-targeting agents have been developed over the years (Ciardiello, F., and Tortora, G. (2008), EGFR antagonists in cancer treatment, The New England journal of medicine 358, 1160-1174). Erlotinib (Tarceva®), a reversible inhibitor of EGFR tyrosine kinase, has been approved in many countries for the treatment of recurrent NSCLC.

[0004] Although significant single-agent activity of EGFR tyrosine kinase inhibitors is observed in some NSCLC patients whose tumors harbor somatic kinase domain mutations, clinical benefit is significantly reduced in patients with wild-type EGFR (Paez, J. et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497-1500)). The most common somatic mutations in EGFR are exon 19 deletions, with delta 746-750 being the most common mutation, and exon 21 amino acid substitutions, with L858R being the most frequent mutation (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-81).

[0005] Treatment resistance occurs frequently and is often due to a secondary T790M mutation within the ATP site of the receptor. Although several mutant-selective irreversible inhibitors have been developed that are highly active against T790M mutants, their efficacy can be compromised by an acquired C797S mutation, a cysteine ​​residue that forms a key covalent bond (Thress, KSet et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560-562 (2015)). Wang further reported that the C797S mutation is a major mechanism of resistance to T790M-targeted EGFR inhibitors (Wang et al. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol. 2016;9:59). Additional mutations causing resistance to osimertinib have been described by Yang (e.g., L718Q) (Yang et al., Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients, Clinical Cancer Research, DOI:10.1158 / 1078-0432.CCR-17-2310). Lu et al. (Targeting EGFR L858R / T790M and EGFR L858R / T790M / C797S Resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32) discusses the role of EGFR in NSCLC treatment. L858R / T790M and EGFR L858R / T790M / C797STargeting resistance mutations has been reported in review articles.

[0006] Because most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents that work differently, for example, by targeting drug-resistant EGFR mutations, are needed.

[0007] Recent studies suggest that intentional targeting of allosteric sites may lead to mutant-selective inhibitors (Jia et al., Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129-132).

[0008] Therefore, there is an unmet need for the generation of selective molecules that specifically inhibit T790M / L858R, T790M / L858R / C797S, L858R, and / or / L858R / C797S containing EGFR mutations, particularly T790M and C797S containing EGFR mutations, that are useful in the therapeutic and / or prophylactic treatment of cancer. Summary of the Invention

[0009] The compounds of formula (I) described herein have improved EGFR potency and selectivity against EGFR mutants comprising T790M / L858R, T790M / L858R / C797S, L858R and / or L858R / C797S, in particular against EGFR mutants comprising T790M and C797S, as well as improved physicochemical properties.

[0010] As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, particularly a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and more particularly a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, isomeric pentyls, isomeric hexyls, isomeric heptyls, and isomeric octyls, particularly methyl, ethyl, propyl, butyl, and pentyl. Specific examples of alkyl are methyl, ethyl, propyl, isopropyl, and tert-butyl. Methyl and ethyl are specific examples of "alkyl" in compounds of formula (I).

[0011] The term "cycloalkyl," alone or in combination, means a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cycloheptyl, and cyclooctanyl. Specific examples of "cycloalkyl" are cyclobutyl and cyclohexyl.

[0012] The terms "alkoxy" or "alkyloxy", alone or in combination, mean a group of formula alkyl-O-, wherein the term "alkyl" has the meaning previously given, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular examples of "alkoxy" are methoxy and ethoxy. Ethoxy is a particular example of "alkoxy" in compounds of formula (I).

[0013] The term "oxy", alone or in combination, signifies the group --O--.

[0014] The term "halogen" or "halo", alone or in combination with another group, denotes substitution of the group in question with, in particular, 1 to 5 halogens, in particular 1 to 4 halogens, i.e., at least one halogen substituted with 1, 2, 3 or 4 halogens. Examples of "halogen" or "halo" mean fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine. A particular "halogen" is fluoro.

[0015] The term "haloalkyl," alone or in combination, refers to an alkyl group substituted with at least one halogen, particularly substituted with 1 to 5 halogens, and especially substituted with 1 to 3 halogens. Particular examples of "haloalkyl" are fluoromethyl, fluoroethyl, and fluoropropyl, more particularly fluoropropyl.

[0016] The terms "hydroxyl" and "hydroxy," alone or in combination, refer to an --OH group.

[0017] The term "carbonyl", alone or in combination, signifies the -C(O)- group.

[0018] The term "amino," alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0019] The term "alkylamino", alone or in combination, means an alkyl group attached to an -NH- group. The term "dialkylamino", alone or in combination, means two alkyl groups attached to an -N- atom.

[0020] The term "sulfonyl", alone or in combination, means a -SO2- group.

[0021] The term "alkylsulfonyl", alone or in combination, means an alkyl group attached to a -SO2- group.

[0022] The term "cyano", alone or in combination, signifies the radical --CN.

[0023] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings that share one or two ring atoms in common. Examples of "heterocycloalkyl" are morpholinyl, piperidinyl, piperidyl, azetidinyl, piperazinyl, tetrahydro-1H-pyrrolo, and hexahydropyrrolo[3,4-c]pyrrolyl. Specific examples of "heterocycloalkyl" are morpholinyl, piperidinyl, piperidyl, and piperazinyl.

[0024] The terms "piperidinyl" and "piperidyl" are interchangeable and refer, alone or in combination, to a saturated monocyclic ring containing five carbon ring atoms and one nitrogen ring atom.

[0025] The term "pharmaceutically acceptable salt" refers to a salt of a compound of Formula (I) that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, particularly hydrochloric acid, as well as organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. These salts may also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. A particular pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0026] If one of the starting materials or compounds of formula (I) of the present invention contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (e.g., as described in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 3 rdProtecting groups (such as those described in "Protein-Based Synthesis" ...

[0027] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0028] The term "asymmetric carbon atom" means a carbon atom that has four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0029] Thus, the present invention relates to: A compound according to the present invention wherein A is -CH-; A compound according to the present invention wherein A is -N-; R 1 and R 2 is independently selected from fluoro and hydrogen; R 1 and R 2 a compound according to the present invention, wherein one of R 1 and R 2 are simultaneously both hydrogen; R 3 is methyl; R 4is selected from morpholinyl, (alkyl)(halo)piperidinyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkylpiperidinylalkoxy, hydroxyalkylpiperidinylalkyl, hydroxypiperidinylalkyl, hydroxypiperidinylalkoxy, hydroxypiperidinyl, 1,4-diazabicyclo[3.2.1]octan-4-yl, hydroxyalkylpiperidinylalkylcycloalkyl, alkylsulfonylpiperidinyl, hydroxypiperidinylalkylcycloalkyl, morpholinylalkoxy, hydroxyalkylpiperidinylalkylazetidinyl, hydroxyalkylpiperazinyl, haloalkylpiperidinyl, (hydroxy)(alkyl)piperidinyl, alkyl(halohexahydropyrrolo[3,4-c]pyrrolyl), dialkylaminoalkylmorpholinyl, hydroxycycloalkyl(alkylamino)alkyl, and haloalkyl(hexahydropyrrolo[3,4-c]pyrrolyl); R 4 However, morpholinyl, (ethyl)(fluoro)piperidinyl, methylaminoethyl, dimethylaminoethyl, hydroxymethylpiperidinylethoxy, hydroxyethylpiperidinylethoxy, hydroxymethylpiperidinylmethyl, hydroxymethylpiperidinylethyl, hydroxyethylpiperidinylmethyl, hydroxyethylpiperidinylethyl, hydroxypiperidinylmethyl, hydroxypiperidinylethyl, hydroxypiperidinylethoxy, hydroxypiperidinyl, 1,4-diazabicyclo[3.2.1]octan-4-yl, hydroxymethylpiperidine, a compound according to the present invention selected from lysinylmethylcyclobutyl, methylsulfonylpiperidinyl, hydroxypiperidinylmethylcyclobutyl, morpholinylethoxy, hydroxymethylpiperidinylmethylazetidinyl, hydroxyethylpiperazinyl, fluoropropylpiperidinyl, (hydroxy)(methyl)piperidinyl, ethyl(fluorohexahydropyrrolo[3,4-c]pyrrolyl), dimethylaminomethylmorpholinyl, hydroxycyclohexyl(methylamino)methyl, and fluoropropyl(hexahydropyrrolo[3,4-c]pyrrolyl); R 4is selected from heterocycloalkyl, dialkylaminoalkyl, hydroxyheterocycloalkylalkyl, hydroxyheterocycloalkyl, and hydroxyalkylheterocycloalkyl; R 4 is selected from morpholinyl, dialkylaminoalkyl, hydroxypiperidinylalkyl, hydroxypiperidinyl, and hydroxyalkylpiperazinyl; and R 4 is selected from morpholinyl, dimethylaminoethyl, hydroxypiperidinylmethyl, hydroxypiperidinyl, and hydroxyethylpiperazinyl.

[0030] The present invention further relates to a compound selected from the following: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-[4-[2-(methylamino)ethyl]phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide hydrochloride; 2-[4-(difluoromethyl)-6-[4-[2-(dimethylamino)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[[4-(1-hydroxyethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-methylsulfonyl-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-[4-(2-morpholinoethoxy)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-(4-(difluoromethyl)-6-(4-(3-((4-(hydroxymethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[4-(difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[1-(2-fluoropropyl)-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-[(3aR,6aS)-2-ethyl-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[(dimethylamino)methyl]morpholin-4-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(Difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; and 2-[6-[4-[(3aS,6aR)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; or a pharmaceutically acceptable salt thereof.

[0031] The present invention further relates to a compound selected from the following: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-(dimethylamino)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; and 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide or a pharmaceutically acceptable salt thereof.

[0032] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

[0033] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is 2-[4-(difluoromethyl)-6-[4-[2-(dimethylamino)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

[0034] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is 2-[4-(difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

[0035] A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide.

[0036] Processes for preparing the compounds of formula (I) described herein are also an object of the present invention.

[0037] The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in Scheme 1 below and in the description of specific examples. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings previously indicated herein unless otherwise indicated. The order of the reactions is not limited to that shown in Scheme 1, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0038] TIFF0007798887000002.tif139170 (In Scheme 1, A, R 1 , R 2 , R 3 and R4 is as defined herein).

[0039] Compounds of formula (I) can be prepared according to Scheme 1 or as described in the Examples. Starting materials are commercially available or can be prepared according to known methods.

[0040] Aldehydes of formula A can be converted to haloalkyl compounds B by treatment with a deoxyfluorinating agent such as morpholinosulfur trifluoride in a solvent such as DCM at temperatures between 0°C and room temperature. Lithiation with a base such as LDA in a solvent such as THF at temperatures between -78°C and -55°C, followed by quenching with an electrophilic formylating agent such as ethyl formate or DMF at temperatures between -78°C and room temperature, affords aldehydes of formula C. These can be reacted directly with hydrazine hydrate in a solvent such as dioxane at elevated temperatures to form indazoles D. Alternatively, following the procedure described by Lukin et al. (J. Org. Chem., 2006, 71, 8166), C can be first reacted with O-methylhydroxylamine hydrochloride in a solvent such as DME in the presence of a base such as potassium carbonate at elevated temperatures to give an intermediate oxime, which can then be reacted with hydrazine hydrate at elevated temperatures to give indazoles of formula D. Indazoles of formula D can be alkylated with alkylating agents such as ethyl bromoacetate or methyl bromoacetate in solvents such as dimethylacetamide or acetonitrile, in the presence or absence of a base such as triethylamine or cesium carbonate, at ambient or elevated temperatures to give indazoles of formula E. This compound can be deprotonated with a base such as LDA or LHMDS and treated with a proline derivative preactivated, for example, by treatment with CDI, to give compounds of formula F. This reaction can be carried out in a solvent such as THF at temperatures between −78° C. and room temperature. The protecting group of compound F can be cleaved by treatment with an acid such as HCl or TFA in dioxane. Subsequent treatment with potassium thiocyanate in a solvent such as EtOH at room temperature or slightly elevated temperatures gives compounds of formula G. Conversion to imidazole H can be achieved by treatment with hydrogen peroxide in a solvent such as acetic acid, or with hydrogen peroxide and paratoluenesulfonic acid in acetonitrile, or by treatment with Raney nickel, or by other methods known in the art. Compounds of formula J can be obtained using known synthetic methods for functional group transformations such as Suzuki reaction, Sonogashira reaction, Negishi reaction, Buchwald reaction, and the like.Alternatively, bromide H can be converted to boronic acid or boronic ester I by reaction with bis(pinacolato)diboron in the presence of a base such as KOAc and a catalyst such as Pd(dppf)Cl in a solvent such as dioxane. Compound H can then be converted to compound J by well-known methods such as the Suzuki reaction. Conversion to compounds of formula (I) can be achieved by saponification with a base such as LiOH or NaOH in a solvent such as EtOH, THF, MeOH, and water, followed by amide coupling with aminothiazole or its derivatives using a coupling agent such as HATU. Alternatively, direct ester-amide conversion can be performed using aminothiazole and reagents such as trimethylaluminum or isopropylmagnesium chloride.

[0041] The corresponding pharmaceutically acceptable salts of compounds of formula (I) with acids can be obtained by standard methods known to those skilled in the art, for example, by dissolving the compound of formula I in a suitable solvent, such as dioxane or tetrahydrofuran, and adding an appropriate amount of the corresponding acid. The product can usually be isolated by filtration or chromatography. The conversion of compounds of formula (I) into pharmaceutically acceptable salts with a base can be carried out by treating such compounds with such bases. One possible method for forming such salts is, for example, by adding 1 / n equivalent of a basic salt, such as M(OH)n (M = metal or ammonium cation, and n = hydroxide anion number), to a solution of the compound in a suitable solvent (e.g., ethanol, ethanol-water mixture, tetrahydrofuran-water mixture), and removing the solvent by evaporation or lyophilization. Particular pharmaceutically acceptable salts are hydrochlorides, formates, and trifluoroacetates.

[0042] Unless their preparation is described in the examples, the compounds of formula (I) and all intermediate products may be prepared according to analogous methods or methods described herein.

[0043] It will be appreciated, that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

[0044] Therefore, the present invention also relates to a process for preparing a compound according to the invention, said process comprising the steps of: (a) A compound of formula (B1) TIFF0007798887000003.tif38170 in a suitable solvent in the presence of a base to obtain a compound of formula (B2) TIFF0007798887000004.tif37170[In formula, M + But Na + , Li + , or a protonated base] get; (b) reacting a compound of formula (B2) in the presence of an acid to obtain a compound of formula (B3) TIFF0007798887000005.tif37170[where A, R 1 , R 2 , R 3 , and R 4 is as defined above, and R is hydrogen or alkyl. obtain; and (c) reacting a compound of formula (B3) with a compound of formula (B4) in the presence of a coupling agent and a base; React with TIFF0007798887000006.tif23170.

[0045] Conveniently, R is hydrogen or methyl.

[0046] In step (a), the base may be, for example, LiOH or NaOH. Conveniently, the base is LiOH.

[0047] In step (a), the concentration of the base may be between about 0.1 M and about 5 M, particularly between about 0.2 M and about 4 M, more particularly between about 0.5 M and about 2 M. Conveniently, the concentration of the base is about 1 M.

[0048] Step (a) may be carried out in a solvent such as EtOH, THF, MeOH, water, or a mixture thereof. Conveniently, the solvent is MeOH, THF, or a mixture thereof.

[0049] Convenient conditions for step (a) may be between about 0°C and about 90°C, particularly between about 5°C and about 80°C, and more particularly between about 10°C and about 50°C.

[0050] The reaction of step (b) can conveniently be carried out in a solvent, which can be, for example, EtOH, MeOH, THF, water, or a mixture thereof.

[0051] In step (b), the acid may be, for example, hydrochloric acid.

[0052] Convenient conditions for step (b) may be between about 0°C and about 90°C, particularly between about 5°C and about 80°C, more particularly between about 10°C and about 50°C.

[0053] The reaction of step (c) can conveniently be carried out in a solvent, which can be, for example, DMSO.

[0054] The reaction of step (c) may conveniently be carried out in the presence of a base, which may be, for example, DIPEA.

[0055] The reaction of step (c) is conveniently carried out in the presence of a coupling agent, which may be, for example, HATU.

[0056] Convenient conditions for the reaction of step (c) may be between about 0°C and about 90°C, particularly between about 5°C and about 80°C, more particularly between about 10°C and about 50°C.

[0057] The present invention also relates to compounds according to the invention when prepared according to the processes of the invention.

[0058] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of formula (I) may be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to recipients at the dosages and concentrations used in herbal dosage forms, at an appropriate pH and desired purity, at ambient temperature. The pH of the formulation will depend primarily on the particular application and compound concentration, but is preferably in the range of about 3 to about 8. In one example, a compound of formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0059] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0060] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural and intranasal, as well as intralesional administration, if desired for local treatment. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0061] The compounds of the present invention may be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions contain elements common in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0062] Typical formulations are prepared by mixing the compound of the present invention with carriers or excipients.Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical composition (i.e., a medicament).

[0063] The invention therefore also relates in particular to: a compound according to the invention for use as a therapeutically active substance; a pharmaceutical composition comprising a compound according to the invention and a therapeutically inert carrier; A compound according to the invention for use in the treatment or prevention of cancer. a compound according to the invention for use in the treatment or prevention of non-small cell lung cancer; the use of the compounds according to the invention for the treatment or prevention of cancer, in particular non-small cell lung cancer; Use of a compound according to the invention for the preparation of a medicament for the treatment or prevention of cancer, in particular non-small cell lung cancer; and A method for the treatment or prevention of cancer, particularly non-small cell lung cancer, which method comprises administering to a patient in need thereof an effective amount of a compound according to the present invention.

[0064] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

[0065] A particular embodiment of the present invention relates to a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer characterized by at least one EGFR mutation selected from T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S, in particular non-small cell lung cancer.

[0066] Certain embodiments of the present invention relate to a method for treating or preventing cancer, particularly non-small cell lung cancer, wherein the cancer has at least one EGFR mutation selected from T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S, The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0067] Furthermore, the present invention includes all substituents, where appropriate, of the corresponding deuterated forms of compounds of formula (I).

[0068] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0069] The compounds of formula (I) may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers and diastereomers, both as mixtures and as pure or partially purified compounds, are intended to be encompassed by the present invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. Resolution can be carried out by methods known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0070] In embodiments in which optically pure enantiomers are provided, optically pure enantiomer means that the compound contains greater than 90% by weight of the desired isomer, specifically greater than 95% by weight of the desired isomer, or more specifically greater than 99% by weight of the desired isomer, said weight percentages being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0071] Also, one embodiment of the present invention is a compound of formula (I) as described herein when prepared by any one of the processes described.

[0072] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used as a medicine (e.g., in the form of a pharmaceutical preparation). The pharmaceutical preparation of the present invention can be administered orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of a nasal spray), rectally (e.g., in the form of a suppository), or topically to the eye (e.g., in the form of a solution, ointment, gel, or water-soluble polymer insert). However, administration can also be carried out parenterally (e.g., in the form of a sterile injection solution), such as intramuscularly, intravenously, or intraocularly.

[0073] The compound of formula (I) or its pharmaceutically acceptable salt can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections or external preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dolazates and hard gelatin capsules, for example.

[0074] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, and the like.

[0075] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0076] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0077] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0078] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0079] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may further contain other therapeutically valuable substances.

[0080] Dosages can vary widely and are tailored to the individual needs of each particular case. Generally, oral administration is from about 0.1 mg to about 20 mg per kg of body weight, preferably from about 0.5 mg to about 4 mg per kg of body weight (e.g., about 300 mg per person), as a daily dose, preferably in 1 to 3 separate doses, which, if appropriate, can be composed of equal amounts. For topical administration, the formulation can contain 0.001% to 15% by weight of the pharmaceutical agent, and the required amount, which can be between 0.1 and 25 mg, can be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0081] Pharmaceutical Preparations The compound of formula (I) or its pharmaceutically acceptable salt can be used as a therapeutically active substance, for example, in the form of pharmaceutical preparations.The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions.However, administration can also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

[0082] The compound of formula (I) or its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic carriers to produce pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, and stearic acid or its salts can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, soft gelatin capsules usually do not require a carrier. Suitable carrier materials for the production of solutions and syrups include water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0083] Furthermore, pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0084] A medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier is also provided by the present invention, the process for producing which comprises bringing a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically useful substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0085] The dosage can vary within a wide range and must be adjusted to the individual requirements in each specific case. For oral administration, the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compound of general formula (I) or the corresponding amount of its pharmaceutically acceptable salt. The daily dosage can be administered in a single dose or in divided doses, and can also exceed the upper limit if it proves to be indicated.

[0086] The following examples illustrate the invention without limiting it, but are merely representative of the invention. Conveniently, pharmaceutical preparations contain about 1 to 500 mg, in particular 1 to 100 mg, of a compound of formula (I). Examples of compositions according to the invention are as follows:

[0087] Example A Tablets of the following composition are prepared in the usual way: TIFF0007798887000007.tif98170Manufacturing procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0088] Example B-1 Capsules of the following composition are prepared: TIFF0007798887000008.tif98170Manufacturing procedure 1. Mix ingredients 1, 2, and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0089] The compound of formula (I), lactose and cornstarch are mixed first in a mixer, then in a pulverizer. The mixture is returned to the mixer; talc is added and mixed thoroughly. The mixture is filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0090] Example B-2 Soft gelatin capsules of the following composition are prepared: TIFF0007798887000009.tif86170TIFF0007798887000010.tif86170

[0091] Manufacturing Procedure The compound of formula (I) is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to conventional procedures.

[0092] Example C Prepare suppositories with the following composition: TIFF0007798887000011.tif53170

[0093] Manufacturing Procedure The suppository mass is melted in a glass or steel container, mixed thoroughly, and cooled to 45°C. To this is added a finely powdered compound of formula (I) and stirred until completely dispersed. The mixture is poured into a suitable sized suppository mold and allowed to cool, after which the suppositories are removed from the molds and individually wrapped in wax paper or metal foil.

[0094] Example D An injection solution of the following composition is prepared: TIFF0007798887000012.tif63170

[0095] Manufacturing Procedure A compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (partially). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

[0096] Example E A sachet of the following composition is prepared: TIFF0007798887000013.tif114170

[0097] Manufacturing Procedure A compound of formula (I) is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring agents and filled into sachets. [Example]

[0098] Example Abbreviation 2-MeTHF = 2-methyltetrahydrofuran; AcOH = acetic acid; ATP = adenosine triphosphate; BOC = tert-butyloxycarbonyl; DCM = dichloromethane; CAS = Chemical Abstracts Service; CDI = 1,1'-carbonyldiimidazole; dba = dibenzylideneacetone; DCM = dichloromethane; DIPEA = diisopropylethylamine; DME = dimethoxyethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; HATU = azabenzotriazole tetramethyluronium hexafluorophosphate; HPLC = high-performance liquid chromatography; LDA = lithium diisopropylamide; LHMDS = lithium bis(trimethylsilyl)amide; MeOH = methanol; MS = mass spectrometry; NMR = nuclear magnetic resonance; RP-HPLC; reverse-phase HPLC; rt = room temperature; SFC = supercritical fluid chromatography; TBAF = tetra-n-butylammonium fluoride; TBDMS-Cl = tert-butyldimethylsilyl chloride; TBME = tert-butylmethyl ether; THF = tetrahydrofuran

[0099] The following examples are provided to illustrate the invention and should not be construed as limiting the scope of the invention, but rather as merely representative.

[0100] Intermediate 1 Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate TIFF0007798887000014.tif31170

[0101] Step 1: 1-Bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene A solution of 3-bromo-5-fluoro-4-methylbenzaldehyde (CAS 1370411-47-4, 20.5 g, 89.7 mmol, equiv.: 1.0) in DCM (98 mL) was cooled in an ice bath. Morpholinosulfur trifluoride (CAS 51010-74-3, 24.8 g, 17.3 mL, 135 mmol, equiv.: 1.5) was added portionwise. The reaction mixture was stirred at 0-5 °C for 20 min and then at room temperature overnight. With ice cooling, saturated aqueous NaHCO3 (300 mL) was carefully added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 100% pentane) to give the title compound as a colorless oil (18.6 g, 87% yield). 1 H NMR(300MHz,chloroform-d)δ=7.50(s,1H),7.16(d,J=9.1Hz,1H),6.57(t,J=56.0Hz,1H),2.50-2.22(m,3H)

[0102] Step 2: 6-Bromo-4-(difluoromethyl)-7-methyl-1H-indazole A solution of 1-bromo-5-(difluoromethyl)-3-fluoro-2-methylbenzene (26.4 g, 110 mmol, equivalents: 1.0) in THF (240 mL) was cooled to −75° C. LDA (2 M in THF / heptane / ethylbenzene, 66.3 mL, 133 mmol, equivalents: 1.2) was added dropwise below −70° C. The reaction mixture was stirred at −75° C. for 30 minutes. Ethyl formate (16.4 g, 17.7 mL, 220 mmol, equivalents: 2.0) was added below −70° C. The reaction mixture was stirred at −75° C. for 30 minutes. AcOH (16.6 g, 15.8 mL, 277 mmol, equivalents: 2.5) was added below −55° C. The reaction mixture was warmed to room temperature, poured into EtOAc, and washed with dilute aqueous HCl, water, and brine. The organic layer was dried over NaSO and concentrated in vacuo to give presumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde as a yellow oil (29.5 g), which was used without further purification. Crude presumed 4-bromo-6-(difluoromethyl)-2-fluoro-3-methylbenzaldehyde (29.5 g) was dissolved in DME (150 mL). O-Methylhydroxylamine hydrochloride (10.2 g, 122 mmol, equiv.: 1.84) and K2CO3 (30.6 g, 221 mmol, equiv.: 3.34) were added. The reaction mixture was stirred for 2.5 h at 45 °C, filtered through a sintered glass filter, and washed with DME (2x). The filtrate was concentrated in vacuo. The oxime ether intermediate was dissolved in DMSO (150 mL). Hydrazine hydrate (83 g, 80.5 mL, 1.66 mol, equiv.: 25) was added. The reaction mixture was stirred for 3 h at 110 °C. The reaction mixture was poured into 5:1 EtOAc / THF and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2×120 g, 0% to 30% EtOAc in heptane) to give the title compound as a white solid (13.5 g, 74% yield). m / z 258.9, 260.8 [M+H] + ,ESI pos,Br isotopes.

[0103] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate TIFF0007798887000017.tif32170 To a solution of 6-bromo-4-chloro(difluoromethyl)-7-methyl-1H-indazole (19 g, 72.8 mmol, equiv.: 1.0) in DMF (75 mL) was added 2-bromoethyl acetate (18.2 g, 12.2 mL, 109 mmol, equiv.: 1.5). The reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 2 x 120 g, 0% to 20% EtOAc in heptane) to afford the title compound as a yellow solid (21.2 g, 80% yield). m / z 346.9, 348.8, [M+H] + ,ESI pos,Br isotopes.

[0104] Step 4: tert-Butyl (2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-fluoro-pyrrolidine-1-carboxylate TIFF0007798887000018.tif38170 Preparation of tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate: To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (CAS 203866-14-2, 30 g, 129 mmol, equivalents: 1.0) in DCM (300 mL) was added 1,1'-carbonyldiimidazole (25 g, 154 mmol, equivalents: 1.2) in portions at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was washed with water (3x) and 1 M aqueous NaHCO3 (1x). The organic layer was dried over Na2SO4 and concentrated in vacuo at 30 °C to give tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (36.6 g, 129 mmol, 100% yield) as a white solid, which was stored at -20 °C before use. 1H NMR(chloroform-d,300MHz)δ 8.27(s,1H),7.56(br d,1H,J=1.4Hz),7.15(br d,1H,J=12.1Hz),4.9-5.2(m,1H),3.6-4.1(m,2H),2.0-2.9(m,2H),1.2-1.5(m,9H). KO t Bu (4.53 g, 40.3 mmol, equiv.: 2.0) was dissolved in THF (18 mL). The reaction mixture was cooled to -55°C. A solution of ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate (7 g, 20.2 mmol, equiv.: 1) in THF (24 mL) was added dropwise below -50°C. The reaction mixture was stirred at -50°C to -55°C for 1 hour. The previously prepared solution of tert-butyl (2S,4R)-4-fluoro-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (6.85 g, 24.2 mmol, equiv.: 1.2) in THF (50 mL) was added dropwise below -50°C. The reaction mixture was stirred at -50°C for 15 minutes and then warmed to -30°C. 10% aqueous citric acid (60 mL) was added below -20 °C, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo at 30 °C to give the title compound as a yellow amorphous semi-solid (12.9 g, 20.2 mmol, 88% purity, 100% yield) m / z 562.1, 563.9 [M+H] + ,ESI pos,Br isotopes.

[0105] Step 5: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate To a solution of tert-butyl (2S,4R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-3-ethoxy-3-oxo-propanoyl]-4-fluoro-pyrrolidine-1-carboxylate (12.9 g, 20.2 mmol, equivalents: 1) in ethanol (24 mL) was added HCl (1.25 M in ethanol, 80.6 mL, 101 mmol, equivalents: 5). The reaction mixture was stirred at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and water (6 mL) and potassium thiocyanate (2.55 g, 26.2 mmol, equivalents: 1.3) were added. The reaction mixture was stirred at room temperature for 30 minutes. The ethanol was removed in vacuo at 30° C., and pyridine (23.9 g, 24.5 mL, 302 mmol, equiv: 15) was added. The reaction mixture was stirred at room temperature for 75 minutes. The reaction mixture was poured into EtOAc and washed with 2N aqueous HCl, water, and brine (until the aqueous phase was pH 1). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow semi-solid (9.65 g, 60% purity, 57% yield). m / z 502.9, 505.9 [M+H] + ,ESI pos,Br isotopes.

[0106] Step 6: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate To a suspension of p-toluenesulfonic acid monohydrate (10.9 g, 57.5 mmol, equivalents: 5) in acetonitrile (70 mL) was added hydrogen peroxide (35% aq., 8.38 g, 7.42 mL, 86.3 mmol, equivalents: 7.5) at 0-3 °C, resulting in a colorless solution. After 10 minutes, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate (9.65 g, 11.5 mmol, equivalents: 1) in acetonitrile (28 mL) was added dropwise below 8° C. The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was poured into EtOAc and washed with Na2CO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 60% in heptane (EtOAc / EtOH / aq. NH3 75:25:2) to give the title compound as a yellow foam (3.96 g, 73% yield). m / z 469.1, 471.1, [M+H] + ,ESI pos.

[0107] Intermediate 2 Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007798887000022.tif29170

[0108] Step 1: tert-butyl (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]acetate (0.65 g, 1.87 mmol, equivalents: 1), prepared as described in TIFF0007798887000023.tif42170 Intermediate 1, Step 3, was dissolved in THF (7.58 mL) and cooled to −75° C. LDA (2 M in THF, 1.12 mL, 2.25 mmol, equivalents: 1.20) was added dropwise within 5 minutes. The reaction mixture was stirred at −75° C. for 40 minutes. A solution of tert-butyl (2S)-2-(imidazole-1-carbonyl)pyrrolidine-1-carboxylate (prepared from (2S)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid as in Intermediate 1, Step 4) (0.77 g, 2.9 mmol, equivalents: 1.55) in THF (7.58 mL) was added slowly at −75° C., stirred for 30 min at −75° C., warmed to room temperature, and stirred for 18 h at room temperature. After addition of saturated aqueous NH4Cl, the reaction mixture was extracted twice with EtOAc. The organic layer was washed with water. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (1.41 g, 72% purity, 99% yield), which was used in the next step without further purification. m / z 544.1, 546.0 [M+H] + ,ESI pos. Br isotopes.

[0109] Step 2: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007798887000024.tif38170 Intermediate 1, Step 5: Similar to step 5, tert-butyl (2R)-2-[2-[6-bromo-4-(difluoromethyl)-7-methylindazol-2-yl]-3-ethoxy-3-oxopropanoyl]pyrrolidine-1-carboxylate (1.4 g, 72% purity, 1.85 mmol) was treated with 4 M HCl in dioxane and potassium thiocyanate to give the title compound (1.07 g, 85% purity, 100% yield) as a brown oil, which was used in the next step without further purification. m / z 485.0, 486.9 [M+H] + ,ESI pos,Br isotopes.

[0110] Step 3: Ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Similarly to TIFF0007798887000025.tif31170 Intermediate 1, Step 6, ethyl 2-[6-bromo-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-(3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl)acetate (1.06 g, 85% purity, 1.86 mmol) was treated with hydrogen peroxide and p-toluenesulfonic acid monohydrate to afford the title compound (360 mg, 43% yield) as a yellow foam. m / z 453.0, 454.9 [M+H] + ,ESI pos,Br isotopes.

[0111] Intermediate 3 Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate To a solution of Intermediate 1 (200 mg, 424 μmol, equiv.: 1.0) in dioxane (2.02 mL), bis(pinacolato)diboron (162 mg, 637 μmol, equiv.: 1.5), KOAc (208 mg, 2.12 mmol, equiv.: 5.0), and Pd(dppf)Cl·CHCl (62.1 mg, 84.9 μmol, equiv.: 0.20) were added at room temperature under nitrogen. The mixture was stirred at 90 °C for 6 h. Water and EtOAc were added to the reaction mixture, and the organic layer was separated, dried over NaSO, and evaporated. The crude material was purified by flash chromatography (silica gel, 25 g, 0% to 10% MeOH in EtOAc) to give the title compound as a light brown solid (80 mg, 29% yield). m / z 219.2 [M+H] + ,ESI pos.

[0112] Example 1 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000027.tif42170

[0113] Step 1: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate A suspension of Intermediate 1 (0.5 g, 1.06 mmol, equiv.: 1.0), (4-morpholinophenyl)boronic acid (CAS 186498-02-2, 329 mg, 1.59 mmol, equiv.: 1.5), and K2CO3 (183 mg, 1.33 mmol, equiv.: 1.25) in 2-MeTHF (6 mL) and water (1 mL) was degassed with argon for 10 min. Dichloro[bis(diphenylphosphinophenyl)ether]palladium(II) (CAS 205319-06-8, 91 mg, 127 μmol, equiv.: 0.12) was added. The reaction mixture was stirred at 85 °C for 5 h. AcOH (191 mg, 182 μL, 3.18 mmol, equiv: 3.0) was added. The reaction mixture was poured into 2:1 EtOAc / THF and washed with water and brine. The organic layer was dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% in heptane (EtOAc / EtOH / aq. NH3 75:25:2) to afford the title compound as an off-white solid (433 mg, 743 μmol, 70% yield). m / z, 471.1, [M+H] + ,ESI pos.

[0114] Step 2: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide To a solution of ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (720 mg, 1.3 mmol, equiv.: 1.0) and MeOH (9 mL) in THF (9 mL) was added LiOH (1 M aqueous solution, 2.6 mL, 2.6 mmol, equiv.: 2.0). The reaction mixture was stirred at room temperature for 2 hours. HCl (5 N aqueous solution, 520 μL, 2.6 mmol, equiv.: 2.0) was added (pH 6). Toluene was added, and the reaction mixture was concentrated in vacuo. The carboxylic acid was dissolved in DMSO (6 mL) and thiazol-2-amine (195 mg, 1.95 mmol, equiv.: 1.5), DIPEA (840 mg, 1.14 mL, 6.5 mmol, equiv.: 5.0), and HATU (742 mg, 1.95 mmol, equiv.: 1.5) were added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 2:1 EtOAc / THF and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 5% MeOH in DCM). The product was lyophilized to give the title compound as an off-white solid (501 mg, 63% yield). m / z 608.3 [M+H] + ,ESI pos.

[0115] Example 2 2-[4-(Difluoromethyl)-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide or 2-[4-(Difluoromethyl)-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000030.tif42170

[0116] Step 1: tert-butyl (3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate A solution of tert-butyl 4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 273727-44-9, 30 g, 79.8 mmol, equivalents: 1.0, 90% purity) in THF (275 mL) was cooled to 0° C. Borane tetrahydrofuran complex (1.0 M solution in THF, CAS 14044-65-6, 87.8 mL, 87.8 mmol, equivalents: 1.1) was added dropwise at 0° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C., and NaOH (5 M in water, 40 mL, 200 mmol, equivalents: 2.51) was added dropwise, and the reaction mixture was stirred at 0° C. for 30 minutes. Hydrogen peroxide (35% wt. aq., 19.4 g, 17.5 mL, 200 mmol, equiv.: 2.5) was added and the reaction mixture was stirred at 50° C. for 2.5 h. The reaction mixture was cooled to room temperature and excess peroxide was quenched by the addition of 2 M aqueous NaSO. The mixture was diluted with ethyl acetate and water. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was suspended in diisopropyl ether and filtered. The solid was washed with diisopropyl ether and dried in vacuo to give the title compound as a white solid (26.74 g, 92% yield). m / z 258.1 [M-BOC+H] + ,ESI pos.

[0117] Step 2: tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate A solution of tert-butyl (3S,4S)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate (37.2 g, 99.2 mmol, equivalents: 1.0) in dichloromethane (500 mL) was cooled to -78 °C. Deoxofluor® (50% solution in THF, CAS 202289-38-1, 79 g, 65.8 mL, 179 mmol, equivalents: 1.8) was added dropwise at -78 °C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. The mixture was quenched with saturated NaHCO3. The mixture was stirred for 30 min (pH 7). The organic layer was separated. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was adsorbed onto Isolute HM-N and purified by flash chromatography (silica gel, 330 g, 0% to 40% EtOAc in heptane) to afford the title compound as a light yellow oil (31.7 g, 85% yield). m / z 304.1 [M-tBu+H] + ,ESI pos.

[0118] Step 3: tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate, or tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate Chiral separation of tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate and tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate (31.8 g, 88.8 mmol, equivalent weight: 1.0) using SFC (column: IG, 12 nm, 5 μm, 250 × 30 mm, eluent: isocratic 5% isopropanol-BPR 120 bar, 80 g / min) gave the title compound as a colorless oil (13.27 g, 40% yield). m / z 304.0 [M-tBu+H] + ,ESI pos. Absolute stereochemistry was not determined.

[0119] Step 4: (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride, or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride To a solution of tert-butyl (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate or tert-butyl (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine-1-carboxylate (10.5 g, 29.3 mmol, equivalents: 101.0) in DCM (100 mL) was added HCl (4 M in 1,4-dioxane, 73.3 mL, 293 mmol, equivalents: 10). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 40 mL of EtO, and the mixture was stirred for 10 minutes. The reaction mixture was filtered through a sintered glass tube and washed with EtO. The white solid was dried in vacuo to give the title compound (9.5 g, 90% purity, 99% yield). m / z 260.0 [M+H] +,E SI pos.

[0120] Step 5: (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine To a suspension of (3S,4S)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride or (3R,4R)-4-(4-bromophenyl)-3-fluoro-piperidine hydrochloride (9.50 g, 32.2 mmol, equivalents: 1.0) in THF (148 mL) was added NEt (6.53 g, 8.99 mL, 64.5 mmol, equivalents: 2.0). Diethyl sulfate (CAS 64-67-5, 5.97 g, 5.07 mL, 38.7 mmol, equivalents: 1.2) was added dropwise at room temperature. The reaction mixture was stirred at 35° C. for 30 minutes and at 55° C. for 3 hours. The reaction mixture was poured into EtOAc and washed with NaCO / water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 1% MeOH in DCM) to give the title compound as a yellow oil (7.20 g, 74% yield). m / z 287.9 ​​[M+H] + ,ESI pos.

[0121] Step 6: [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid A solution of (3S,4S)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine or (3R,4R)-4-(4-bromophenyl)-1-ethyl-3-fluoro-piperidine (1.000 g, 3.49 mmol, equivalents: 1.0) in THF (8.0 mL) was cooled to -76 °C. n-Butyllithium (1.6 M in hexanes, 2.4 mL, 3.84 mmol, equivalents: 1.1) was added dropwise, and the reaction mixture was stirred at -76 °C for 2 hours. Triethyl borate (618 mg, 0.72 mL, 4.23 mmol, equivalents: 1.21) was added at -76 °C, and the reaction mixture was stirred at -76 °C for 15 minutes. The dry ice bath was then removed, and the reaction mixture was stirred at room temperature (1.5 h). The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and stirred at room temperature for 15 min. The mixture was extracted with EtOAc. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 10% MeOH in DCM) to give the title compound as an off-white solid (744 mg, 90% purity, 76% yield). m / z 252.2 [M+H] + ,ESI pos.

[0122] Step 7: Ethyl 2-[4-(difluoromethyl)-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate or ethyl 2-[4-(difluoromethyl)-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate A mixture of Intermediate 1 (450 mg, 0.955 mmol, equivalent weight: 1.0), [4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid or [4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]boronic acid (334 mg, 1.2 mmol, equivalent weight: 1.25, 90% purity), CsCO (933 mg, 2.86 mmol, equivalent weight: 3.0), and Pd(dppf)Cl·CHCl (117 mg, 0.143 mmol, equivalent weight: 0.15) in 1,4-dioxane (7.0 mL) was flushed with argon. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc and water. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was adsorbed onto Isolute HM-N and purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in heptane, then switched to 0% to 10% MeOH in DCM) to afford the title compound as a brown foam (587 mg, 98% yield). m / z 598.3 [M+H] + ,ESI pos.

[0123] Step 8: 2-[4-(difluoromethyl)-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide or 2-[4-(difluoromethyl)-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000038.tif44170 Ethyl 2-[4-(difluoromethyl)-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate, or ethyl 2 in MeOH (3.4 mL) and THF (3.4 mL). To a solution of -[4-(difluoromethyl)-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (580 mg, 0.922 mmol, equiv.: 1), LiOH (1 M aqueous solution, 1.1 mL, 1.1 mmol, equiv.: 1.19) was added dropwise. The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was evaporated, coevaporated twice with toluene, and dried under high vacuum. The residue and thiazol-2-amine (111 mg, 1.11 mmol, equiv.: 1.2) were suspended in DMF (8.0 mL). DIPEA (370 mg, 0.50 mL, 2.86 mmol, equiv.: 3.11) was added, followed by HATU (421 mg, 1.11 mmol, equiv.: 1.2). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was back-extracted twice with EtOAc. The organic layer was washed three times with water and once with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was adsorbed onto Isolute HM-N and purified by flash chromatography (Si-amine, 25 g, 0% to 10% MeOH in EtOAc) to afford the title compound as a brown foam (314 mg, 50% yield). m / z 652.3 [M+H]+, ESI pos.

[0124] Example 3 2-[4-(Difluoromethyl)-7-methyl-6-[4-[2-(methylamino)ethyl]phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide hydrochloride TIFF0007798887000039.tif37170

[0125] Step 1: Ethyl 2-(6-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)phenyl)-4-(difluoromethyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007798887000040.tif37170 Similarly to Example 2, Step 7 (100 mg, 212 μmol, equivalents: 1.0) and (4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)phenyl)boronic acid (CAS 945756-49-0, 71 mg, 255 μmol, equivalents: 1.2) were reacted in the presence of Cs2CO3 and Pd(dppf)Cl2.CH2Cl2 in dioxane at 105 °C for 1 hour to give the title compound as a light brown solid (101 mg, 72% yield). m / z 626.8 [M+H]+, ESI pos.

[0126] Step 2: tert-butyl N-[2-[4-[4-(difluoromethyl)-2-[1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-methyl-indazol-6-yl]phenyl]ethyl]-N-methyl-carbamate As in Example 2, Step 8, ethyl 2-(6-(4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)phenyl)-4-(difluoromethyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (101 mg, 161 μmol, equiv.: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a light brown solid (81 mg, 70% yield). m / z 680.5 [M+H] + ,ESI pos.

[0127] Step 3: 2-[4-(difluoromethyl)-7-methyl-6-[4-[2-(methylamino)ethyl]phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide hydrochloride TIFF0007798887000042.tif37170 tert-Butyl (4-(4-(difluoromethyl)-2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-methyl-2H-indazol-6-yl)phenethyl)(methyl)carbamate (81 mg, 119 μmol, equiv.: 1.0) was dissolved in dry dioxane (1 mL) and HCl (4 M in dioxane, 298 μL, 1.19 mmol, equiv.: 10). The flask was spun on a rotary evaporator at room temperature and pressure, using sonication to aid dissolution. After 2 hours, the reaction was concentrated in vacuo to give the title compound as an off-white solid (90 mg, 94% purity, 98% yield). m / z [M+H] + 580.4.

[0128] Example 4 2-[4-(Difluoromethyl)-6-[4-[2-(dimethylamino)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide To a solution of Example 3 (85 mg, 0.139 mmol, equiv.: 1.0), sodium triacetoxyborohydride (294 mg, 1.39 mmol, equiv.: 10) and formaldehyde solution (101 mg, 0.093 mL, 1.25 mmol, equiv.: 9.0, 37% purity) were added. The reaction mixture in dioxane (1.0 mL) was stirred at room temperature for 72 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and anhydrous MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (Si-amine, 25 g, 0% to 5% MeOH in DCM). The residue was re-purified by preparative RP-HPLC to give the title compound as a white solid (16 mg, 18% yield). m / z 594.3 [M+H] + ,ESI pos.

[0129] Example 5 2-[4-(Difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000044.tif35170

[0130] Step 1: [1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-piperidyl]methanol To a mixture of [1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]methanol (CAS 1226008-23-6, 1.3 g, 4.14 mmol, equivalents: 1.0), bis(pinacolato)diboron (1.16 g, 4.55 mmol, equivalents: 1.1), and KOAc (1.22 g, 12.4 mmol, equivalents: 3.0) in 1,4-dioxane (15 mL) was added Pd(dppf)Cl₂·CHCl₂ (303 mg, 414 μmol, equivalents: 0.1). The reaction mixture was flushed with argon and stirred at 90 °C for 3 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 50 g, 0% to 20% MeOH in DCM) to give the title compound as a dark brown oil (1.45 g, 80% purity, 77% yield). m / z 362.2 [M+H] + ,ESI pos.

[0131] Step 2: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Example 2, Step 7, Intermediate 1 (150 mg, 318 μmol, equiv.: 1.0) and [1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-piperidyl]methanol (149 mg, 414 μmol, equiv.: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70°C for 2.5 hours. Purification by flash chromatography (Si-Amine, 25 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a brown gum (67.4 mg, 68.9 μmol, 64% purity, 21.7% yield). m / z 626.4 [M+H] + ,ESI pos.

[0132] Step 3: 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (67.4 mg, 68.9 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (Si-Amine, 12 g, 0% to 20% MeOH in EtOAc) afforded the title compound as a light brown solid (54 mg, 75% yield). m / z 340.8 [M+H] + ,ESI pos.

[0133] Example 6 2-[4-(Difluoromethyl)-6-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000048.tif51170

[0134] Step 1: [1-[(4-bromophenyl)methyl]-4-piperidyl]methanol TIFF0007798887000049.tif181702 In a 50 mL round-bottom flask, piperidin-4-ylmethanol (1.49 g, 13 mmol, equiv.: 1.2) was combined with DCM (60 mL) to give a colorless solution. 4-Bromobenzaldehyde (2 g, 10.8 mmol, equiv.: 1.0) and sodium triacetoxyborohydride (2.75 g, 13 mmol, equiv.: 1.2) were added at 0 °C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with DCM (2x). The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% in DCM (4:1 DCM / MeOH + 0.5% NHOH)) to give the title compound as a colorless liquid (2.90 g, 95% purity, 89% yield). m / z 284.1 [M+H] + ,ESI pos.

[0135] Step 2: [1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-piperidyl]methanol Similar to Step 1 of Example 5, [1-[(4-bromophenyl)methyl]-4-piperidyl]methanol (2.9 g, 10.2 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and Pd(dppf)Cl₂·CHCl₂ at 90 °C for 2 h. Purification by flash chromatography (Si-amine, 40 g, then 25 g, second run with 0% to 80% EtOAc (4:1 EtOAc / MeOH)) afforded the title compound as a colorless oil (3.60 g, 85% purity, 90% yield). m / z 332.3 [M+H]₂, ESI pos.

[0136] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and [1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-piperidyl]methanol (91.4 mg, 276 μmol, equivalent weight: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70°C for 2.5 hours. Purification by flash chromatography (silica gel, 25 g, 0% to 10% MeOH in DCM) afforded the title compound as a brown oil (105 mg, 89% purity, 83% yield). m / z 596.3 [M+H] + ,ESI pos.

[0137] Step 4: 2-[4-(Difluoromethyl)-6-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000052.tif49170 In a manner similar to Step 8 of Example 2, ethyl 2-[4-(difluoromethyl)-6-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (100 mg, 168 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a light brown foam (55 mg, 90% purity, 45% yield). m / z 650.3 [M+H] + ,ESI pos.

[0138] Example 7 2-[4-(Difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000053.tif48170

[0139] Step 1: 1-[(4-bromophenyl)methyl]piperidin-4-ol TIFF0007798887000054.tif181704-Bromobenzaldehyde (1.5 g, 8.11 mmol, equiv.: 1) and piperidin-4-ol (1.07 g, 10.5 mmol, equiv.: 1.3) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (5.15 g, 24.3 mmol, equiv.: 3.0) was then added, followed by stirring at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous Na2CO3 and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% MeOH in DCM) to afford the title compound as a colorless oil (2.11 g, 96% yield). m / z 271.9 [M+H] + ,ESI pos.

[0140] Step 2: 1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperidin-4-ol As in Example 5, Step 1, 1-[(4-bromophenyl)methyl]piperidin-4-ol (2.11 g, 7.81 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 2 h. Purification by flash chromatography (Si-amine, 40 g, then 40 g again, 0% to 80% in EtOAc (4:1 EtOAc-MeOH)) afforded the title compound as a colorless oil (2.28 g, 75% purity, 96% yield). m / z 317.9 [M+H] + ,ESI pos.

[0141] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and 1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperidin-4-ol (117 mg, 75% purity, 276 μmol, equivalent weight: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70°C for 2.5 hours. Purification by flash chromatography (silica gel, 25 g, 0% to 10% MeOH in DCM) afforded the title compound as a colorless oil (60 mg, 73% purity, 48% yield). m / z 582.3 [M+H] + ,ESI pos.

[0142] Step 4: 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (0.06 g, 103 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a colorless oil (60 mg, 73% purity, 48% yield). m / z 636.3[M+H] + ,ESI pos.

[0143] Example 8 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007798887000058.tif36170

[0144] Step 1: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate Intermediate 2 (120 mg, 265 μmol, equiv.: 1.0), (4-morpholinophenyl)boronic acid (66.3 mg, 320 μmol, equiv.: 1.21), Pd(dppf)Cl2·CHCl2 (22.2 mg, 29.1 μmol, equiv.: 0.11), and CsCO3 (259 mg, 794 μmol, equiv.: 3.0) were combined in a sealed tube and dissolved in 1.6 mL of dry dioxane. Ar gas was bubbled through the mixture while sonicating. The reaction was heated at 100 °C for 2 h, cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3, and back-extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in EtOAc) to give the title compound as a yellow oil (105 mg, 74% yield). m / z 536.2 [M+H] + ,ESI pos.

[0145] Step 2: 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007798887000060.tif35170 Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (0.1 g, 187 μmol, equiv.: 1.0) was dissolved in 1 mL THF, and 1 mL MeOH.LiOH (1 M aqueous solution, 224 μL, 224 μmol, equiv.: 1.2) was added dropwise. The reaction mixture was stirred at room temperature for 45 min (a precipitate formed). The reaction mixture was carefully neutralized with HCl (1 M aqueous solution, 224 μL, 224 μmol, equiv.: 1.2) (pH ∼6), concentrated, coevaporated twice from toluene, and dried under high vacuum. The residue and 2-aminothiazole (28 mg, 280 μmol, equiv.: 1.5) were suspended in 1 mL DMF. DIPEA (72.4 mg, 97.8 μL, 560 μmol, equiv.: 3.0) was added, followed by HATU (92.3 mg, 243 μmol, equiv.: 1.3). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was back-extracted with EtOAc. The organic layer was washed three times with water and once with brine, dried over Na2SO4, filtered, and concentrated. The residue was adsorbed onto Isolute HM-N and purified by flash chromatography (silica gel, 12 g, EtOAc followed by 0% to 5% MeOH in DCM) to give the title compound as a light yellow solid (60 mg, 90% purity, 54% yield). m / z 590.2 [M+H] + ,ESI pos.

[0146] Example 9 2-[4-(Difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000061.tif42170

[0147] Step 1: [1-[2-(4-bromophenyl)ethyl]-4-piperidyl]methanol TIFF0007798887000062.tif29170 2-(4-Bromophenyl)acetaldehyde (2 g, 10 mmol, equiv.: 1.0) and piperidin-4-ylmethanol (1.5 g, 13.1 mmol, equiv.: 1.3) were dissolved in DCM (20 mL). Sodium triacetoxyborohydride (6.39 g, 30.1 mmol, equiv.: 3.0) was then added, followed by stirring at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous NaHCO3 and extracted twice with DCM. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.5)). The pure fractions were combined and concentrated in vacuo to give the title compound as a colorless liquid (2.16 g, 72% yield). m / z 300.1 [M+H] + ,ESI pos.

[0148] Step 2: [1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-4-piperidyl]methanol As in Example 5, Step 1, [1-[2-(4-bromophenyl)ethyl]-4-piperidyl]methanol (2.16 g, 7.24 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 4 hours. Purification by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM) afforded the title compound as a dark brown oil (3.60 g, 60% purity, 86% yield). m / z 345.9 [M+H] + ,ESI pos.

[0149] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, TIFF0007798887000064.tif41170, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and [1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-4-piperidyl]methanol were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70 °C for 2.5 h. Purification by flash chromatography (silica gel, 25 g, 0% to 100% in DCM (DCM:MeOH:NHOH 9:1:0.05)) afforded the title compound as a brown solid (85 mg, 65% yield). m / z 610.3 [M+H] + ,ESI pos.

[0150] Step 4: 2-[4-(Difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000065.tif38170 In a manner similar to Step 8 of Example 2, ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (85 mg, 139 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a light brown foam (35 mg, 90% purity, 34% yield). m / z 664.3 [M+H] + ,ESI pos.

[0151] Example 10 2-[4-(Difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000066.tif32170

[0152] Step 1: 1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]piperidin-4-ol As in Example 5, Step 1, 1-[2-(4-bromophenoxy)ethyl]piperidin-4-ol (CAS 1226008-23-6, 708 mg, 2.12 mmol, equivalents: 1) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl₂·CHCl₂ at 90 °C for 3 h. Purification by flash chromatography (silica gel, 25 g, 0% to 20% MeOH in DCM) afforded the title compound as a brown oil (537 mg, 79% yield). m / z 348.3 [M+H]₂, ESI pos.

[0153] Step 2: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxycyclohexyl)ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and 1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]piperidin-4-ol (96 mg, 276 μmol, equivalent weight: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70°C for 2.5 hours. Purification by flash chromatography (Si-Amine, 25 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a brown oil (123 mg, 76% purity, 72% yield). m / z 306.8 [M+H] + ,ESI pos.

[0154] Step 3: 2-[4-(Difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxycyclohexyl)ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (123 mg, 200 μmol, equiv.: 1.0) was first treated with LiOH, and the resulting salt was reacted with thiazol-2-amine in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 24 g, 0% to 20% MeOH in DCM) afforded the title compound as a brown solid (36 mg, 27% yield). m / z 334.0 [M+H]+, ESI pos.

[0155] Example 11 2-[4-(Difluoromethyl)-6-[4-(4-hydroxy-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000070.tif58170 Step 1: [1-(4-bromophenyl)-4-piperidyl]oxy-tert-butyl-dimethyl-silane TIFF0007798887000071.tif33170To a solution of 1-(4-bromophenyl)piperidin-4-ol (CAS 1226154-84-2, 300 mg, 1.17 mmol, equiv.: 1.0) in DCM (5 mL), imidazole (319 mg, 4.68 mmol, equiv.: 4.0) and tert-butyldimethylsilyl chloride (441 mg, 2.93 mmol, equiv.: 2.5) were added and stirred at room temperature. After 1 h, the reaction mixture was diluted with DCM and washed with water, saturated aqueous NaHCO3, and brine. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained as an off-white solid (431 mg, 99% yield). m / z 372.1 [M+H] + ,ESI pos.

[0156] Step 2: tert-butyl-dimethyl-[[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-piperidyl]oxy]silane Similar to Step 1 of Example 5, [1-(4-bromophenyl)-4-piperidyl]oxy-tert-butyl-dimethyl-silane (280 mg, 756 μmol, equivalent weight: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 3 hours. Purification by flash chromatography (20 g silica gel, 0% to 20% EtOAc in heptane) afforded the title compound as a white solid (264 mg, 85% purity, 71% yield). m / z 418.1 [M+H] + ,ESI pos.

[0157] Step 3: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-tert-butyl-dimethylsilyloxy-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and 4-((tert-butyldimethylsilyl)oxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (156 mg, 318 μmol, equivalent weight: 1.5) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 1.5 hours. Purification by flash chromatography (silica gel, 24 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a white solid (138 mg, 70% purity, 95% yield). m / z 682.5 [M+H] + ,ESI pos.

[0158] Step 4: 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-tert-butyl-dimethylsilyloxy-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-tert-butyl-dimethylsilyloxy-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a yellow oil (55 mg, 80% purity, 45% yield). m / z 736.4 [M+H] + ,ESI pos.

[0159] Step 5: 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000075.tif38170 2-[4-(Difluoromethyl)-7-methyl-6-[4-(4-tert-butyl-dimethylsilyloxy-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide was dissolved in THF (2.3 mL) and TBAF (1 M in THF, 149 μL, 149 μmol, equivalents: 2.0) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was washed with a mixture of water and brine and brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) to give the title compound as a light yellow foam (25 mg, 51% yield). m / z 622.2 [M+H] + ,ESI pos.

[0160] Example 12 2-[4-(Difluoromethyl)-6-[4-[[4-(1-hydroxyethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000076.tif47170

[0161] Step 1: 1-[1-[(4-bromophenyl)methyl]-4-piperidyl]ethanol TIFF0007798887000077.tif18170 4-Bromobenzaldehyde (1 g, 5.4 mmol, equiv.: 1.0) and 1-(piperidin-4-yl)ethan-1-ol (CAS 6457-48-3, 908 mg, 7.03 mmol, equiv.: 1.3) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (1.72 g, 8.11 mmol, equiv.: 1.5) was then added, followed by stirring at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous Na2CO3 and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% MeOH in DCM). The product-containing fractions were combined and concentrated to give the title compound as a light yellow foam (1.15 g, 71% yield). m / z 299.8 [M+H] + ,ESI pos.

[0162] Step 2: 1-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-piperidyl]ethanol As in Example 5, Step 1, 1-[1-[(4-bromophenyl)methyl]-4-piperidyl]ethanol (1.5 g, 5.03 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 2 hours. Purification by flash chromatography (silica gel, 24 g, 0% to 10% MeOH in DCM) afforded the title compound as a dark brown solid (850 mg, 48% yield). m / z 346.1 [M+H] +,ESI pos.

[0163] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[[4-(1-hydroxyethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and 1-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-piperidyl]ethanol (112 mg, 85% purity, 276 μmol, equivalent weight: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70 °C for 2.5 h. Purification by flash chromatography (silica gel, 25 g, 0% to 100% in DCM (DCM:MeOH:NHOH 9:1:0.05)) afforded the title compound as a light brown oil (56 mg, 72% purity, 43% yield). m / z 610.3[M+H] + ,ESI pos.

[0164] Step 4: 2-[4-(difluoromethyl)-6-[4-[[4-(1-hydroxyethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[[4-(1-hydroxyethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a light brown foam (45 mg, 65% yield). m / z 664.3 [M+H] +,E SI pos.

[0165] Example 13 2-[6-[4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000081.tif34170

[0166] Step 1: 4-(4-bromophenyl)-1,4-diazabicyclo[3.2.1]octane TIFF0007798887000082.tif211701-Bromo-4-iodobenzene (1.88 g, 6.64 mmol, equivalent weight: 1.3), 1,4-diazabicyclo[3.2.1]octane dihydrochloride (CAS 5492-61-5, 945 mg, 5.11 mmol, equivalent weight: 1.0), NaO t Bu (2.45 g, 25.5 mmol, equiv.: 5.0), Xantphos (369 mg, 638 μmol, equiv.: 0.125), and Pd(dba) (234 mg, 255 μmol, equiv.: 0.05) were dissolved in toluene (10 mL) and then stirred at 85 °C for 1 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% in DCM (DCM:MeOH:NHOH 9:1:0.05)) to afford the title compound as a light yellow solid (596 mg, 90% purity, 39% yield). m / z 268.7 [M+H] + ,ESI pos.

[0167] Step 2: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-diazabicyclo[3.2.1]octane As in Example 5, Step 1, 4-(4-bromophenyl)-1,4-diazabicyclo[3.2.1]octane (596 mg, 2.23 mmol, equivalent weight: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 3 h. Purification by flash chromatography (silica gel, 24 g, 0% to 10% MeOH in (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a dark brown solid (453 mg, 80% purity, 51% yield). m / z 315.0 [M+H] + ,ESI pos.

[0168] Step 3: Ethyl 2-[6-[4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Example 2, Step 7, Intermediate 1 (100 mg, 212 μmol, equiv.: 1.0) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-diazabicyclo[3.2.1]octane (100 mg, 318 μmol, equiv.: 1.5) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 1.5 h. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in (DCM:MeOH:NHOH 9:1:0.05)) afforded the title compound as a yellow solid (90 mg, 82% purity, 73% yield). m / z 579.3 [M+H] + ,ESI pos.

[0169] Step 4: 2-[6-[4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000085.tif34170 In a manner similar to Step 8 of Example 2, ethyl 2-[6-[4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (0.09 g, 124 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a yellow solid (43 mg, 92% purity, 50% yield). m / z 633.3 [M+H] + ,ESI pos.

[0170] Example 14 2-[4-(Difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000086.tif39170

[0171] Step 1: 1-[1-[2-(4-bromophenyl)ethyl]-4-piperidyl]ethanol To a solution of 2-(4-bromophenyl)acetaldehyde (CAS 27200-79-9, 1.00 g, 5.02 mmol, equiv.: 1) and 1-(4-piperidyl)ethanol (CAS 6457-48-3, 844 mg, 6.53 mmol, equiv.: 1.3) in DCM (10 mL) was added sodium triacetoxyborohydride (3.19 g, 15.1 mmol, equiv.: 3.0). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous Na2CO3 and extracted twice with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% MeOH in DCM) to give the title compound as a colorless oil (1.15 g, 23% yield). m / z 314.0 [M+H]+, ESI pos.

[0172] Step 2: 1-[1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-4-piperidyl]ethanol As in Example 5, Step 1, 1-[1-[2-(4-bromophenyl)ethyl]-4-piperidyl]ethanol (1.15 g, 3.68 mmol, equiv.: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl₂·CHCl₂ at 90°C for 3 hours. Purification by flash chromatography (silica gel, 24 g, 0% to 100% in DCM (DCM:MeOH:NH₄OH 9:1:0.05)) afforded the title compound as a dark brown oil (1.35 g, 60% purity, 61% yield). m / z 360.3 [M+H] + ,ESI pos.

[0173] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Example 2, Step 7, Intermediate 1 (100 mg, 0.212 μmol, equiv.: 1.0) and 1-[1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-4-piperidyl]ethanol (191 mg, 0.318 mmol, equiv.: 1.5, 60% purity) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65 °C for 2 h. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NHOH 9:1:0.05)) afforded the title compound as a light yellow solid (43 mg, 33% yield). m / z 624.3 [M+H] + ,ESI pos.

[0174] Step 4: 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000090.tif37170 In a manner similar to Step 2 of Example 8, ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxyethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (43 mg, 0.069 mmol, equivalents: 1.0) was first treated with LiOH and then with aqueous HCl, and the resulting carboxylic acid was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a yellow solid (14 mg, 30% yield). m / z 678.4 [M+H] + ,ESI pos.

[0175] Example 15 2-[4-(Difluoromethyl)-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000091.tif34170

[0176] Step 1: [1-[[3-(4-bromophenyl)cyclobutyl]methyl]-4-piperidyl]methanol To a solution of [3-(4-bromophenyl)cyclobutyl]methanol (CAS 1782303-81-4, 0.74 g, 3.07 mmol, equiv.: 1) and NEt3 (621 mg, 0.856 mL, 6.14 mmol, equiv.: 2) in DCM (14 mL) was added methanesulfonyl chloride (422 mg, 0.287 mL, 3.68 mmol, equiv.: 1.2) at 0 °C. The reaction mixture was stirred at 0 °C–20 °C for 2 h. The reaction mixture was extracted with saturated aqueous NaHCO3 and twice with DCM. The organic layer was washed with water, dried over NaSO, and concentrated in vacuo to give the presumed [3-(4-bromophenyl)cyclobutyl]methyl methanesulfonate as a light brown oil (1.1 g, 85% purity, 95% yield), which was used in the next step without further purification. To a solution of the presumed [3-(4-bromophenyl)cyclobutyl]methyl methanesulfonate (550 mg, 1.72 mmol, equiv.: 1.0) in acetonitrile (2 mL) was added 4-piperidylMeOH (CAS 6457-49-4, 298 mg, 2.58 mmol, equiv.: 1.5) and NEt (523 mg, 0.72 mL, 5.17 mmol, equiv.: 3). The reaction mixture was stirred at 20 °C for 1 h and at 60 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO and extracted twice with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 20% MeOH in DCM) to afford the title compound as a light yellow oil (270 mg, 46% yield). m / z338.1, 339.9[M+H]+, ESI pos, Br isotopes.

[0177] Step 2: [1-[[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl]methyl]-4-piperidyl]methanol As in Example 5, Step 1, [1-[[3-(4-bromophenyl)cyclobutyl]methyl]-4-piperidyl]methanol (270 mg, 0.798 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl₂·CHCl₂ at 90°C for 3 hours. Purification by flash chromatography (silica gel, 24 g, 0% to 20% MeOH in DCM) afforded the title compound as a brown solid (138 mg, 70% purity, 31% yield). m / z 386.2 [M+H] + ,ESI pos.

[0178] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 0.212 mmol, equiv.: 1.0) and [1-[[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl]methyl]-4-piperidyl]methanol (138 mg, 0.358 mmol, equiv.: 1.69) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65 °C for 1.5 h. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NHOH 9:1:0.05)) afforded the title compound as a light yellow solid (79 mg, 88% purity, 50% yield). m / z 650.5[M+H] + ,ESI pos.

[0179] Step 4: 2-[4-(Difluoromethyl)-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 8, Step 2, ethyl 2-[4-(difluoromethyl)-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (79 mg, 0.121 mmol, equivalents: 1.0) was treated first with LiOH and then with aqueous HCl, and the resulting carboxylic acid was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a light brown solid (39 mg, 93% purity, 42% yield). m / z704.5[M+H] + ,ESI pos.

[0180] Example 16 2-[4-(Difluoromethyl)-7-methyl-6-[4-(4-methylsulfonyl-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000096.tif40170

[0181] Step 1: 1-(4-bromophenyl)-4-methylsulfonyl-piperidine TIFF0007798887000097.tif26170 In the same manner as in Step 1 of Example 13, 1-bromo-4-iodo-benzene (953 mg, 3.37 mmol, equivalent weight: 1.1) and 4-methylsulfonylpiperidine (CAS 290328-55-1, 500 mg, 3.06 mmol, equivalent weight: 1.0) were dissolved in NaO t The reaction was carried out in the presence of Bu, Xantphos, and Pd(dba)·CHCl at 80° C. for 16 hours. Purification by flash chromatography (silica gel, 40 g, 0% to 70% EtOAc in heptane) afforded the title compound as a brown solid (522 mg, 51% yield). m / z 318.0, 320.0 [M+H] + ,ESI pos,Br isotopes.

[0182] Step 2: 4-Methylsulfonyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine As in Example 5, Step 1, 1-(4-bromophenyl)-4-methylsulfonyl-piperidine (350 mg, 1.04 mmol, equiv.: 1) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 5 h and room temperature for 16 h. Purification by flash chromatography (silica gel, 24 g, 0% to 70% EtOAc in heptane) afforded the title compound as a light brown oil (160 mg, 90% purity, 38% yield). m / z 366.2 [M+H] + ,ESI pos.

[0183] Step 3: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-methylsulfonyl-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Example 2, Step 7, Intermediate 1 (120 mg, 0.255 mmol, equiv.: 1.0) and 4-methylsulfonyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (155 mg, 0.382 mmol, equiv.: 1.5, 90% purity) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 2.25 h. After this, additional Pd(dppf)Cl·CHCl was added and the reaction mixture was heated at 65°C for 45 min. Purification by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) afforded the title compound as a brown oil (66 mg, 90% purity, 37% yield). m / z 630.3 [M+H] + ,ESI pos.

[0184] Step 4: 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-methylsulfonyl-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000100.tif42170 In a manner similar to Step 2 of Example 8, ethyl 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-methylsulfonyl-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (63 mg, 0.090 mmol, equivalents: 1.0, 90% purity) was treated first with LiOH and then with aqueous HCl, and the resulting carboxylic acid was reacted with 2-aminothiazole in the presence of HATU and DIPEA. After purification by flash chromatography (silica gel, 12 g, 0% to 60% in DCM (DCM:MeOH:NH4OH 9:1:0.05)), the product-containing fractions were repurified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give the title compound as a light brown foam (25 mg, 39% yield). m / z 684.3 [M+H] + ,ESI pos.

[0185] Example 17 2-[4-(Difluoromethyl)-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000101.tif51170

[0186] Step 1: [3-(4-bromophenyl)cyclobutyl]methanol TIFF0007798887000102.tif141703-(4-Bromophenyl)cyclobutane-1-carboxylic acid (CAS 149506-16-1, 1 g, 3.92 mmol, equiv.: 1.0) was suspended in THF (10 mL), and borane-tetrahydrofuran complex (1 M, 7.84 mL, 7.84 mmol, equiv.: 2.0) was added at 0 °C. The mixture was stirred at 5 °C for 30 min. The mixture was then warmed to 20 °C and stirred for 1 h. Additional borane-tetrahydrofuran complex (1 M, 7.84 mL, 7.84 mmol, equiv.: 2.0) was then added, and the mixture was stirred overnight. NaOH (2 N aqueous solution) was added to the reaction mixture until pH = 10. The reaction mixture was diluted with HO and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane) to give the title compound as a colorless oil (740 mg, 85% purity, 66% yield). m / z 224.9 [M-H2O+H] + ,ESI pos.

[0187] Step 2: 1-[[3-(4-bromophenyl)cyclobutyl]methyl]piperidin-4-ol TIFF0007798887000103.tif40170 [3-(4-Bromophenyl)cyclobutyl]methanol (0.74 g, 3.07 mmol, equiv.: 1.0) was dissolved in DCM (14 mL), and EtN (621 mg, 856 μL, 6.14 mmol, equiv.: 2.0) and methanesulfonyl chloride (422 mg, 287 μL, 3.68 mmol, equiv.: 1.2) were added at room temperature. The mixture was stirred at 0-20 °C for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO and extracted twice with DCM. The organic layer was washed with water, dried over NaSO, filtered, and evaporated to dryness to give presumed [1-[[3-(4-bromophenyl)cyclobutyl]methyl]-4-piperidyl]methanesulfonic acid as a light brown oil (1.1 g) which was used without further purification. The crude material (550 mg, 1.72 mmol, equiv.: 1.0) was dissolved in acetonitrile (2 mL), followed by the addition of piperidin-4-ol (261 mg, 2.58 mmol, equiv.: 1.5) and EtN (523 mg, 720 μL, 5.17 mmol, equiv.: 3.0) at room temperature. The mixture was stirred at 0-60°C for 16 h. The reaction mixture was evaporated, diluted with saturated aqueous NaHCO and extracted twice with EtOAc. The organic layer was extracted with water and brine, dried over NaSO, filtered, and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 12 g, 0%-20% MeOH in DCM) to give the title compound as a colorless oil (323 mg, 81% purity, 43% yield). m / z 325.9 [M+H], ESI pos.

[0188] Step 3: 1-[[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl]methyl]piperidin-4-ol As in Example 5, Step 1, 1-[[3-(4-bromophenyl)cyclobutyl]methyl]piperidin-4-ol (0.245 g, 756 μmol, equivalent weight: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl₂·CHCl₂ at 90 °C for 2 h. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH₄OH 9:1:0.05)) afforded the title compound as a light brown solid (260 mg, 86% purity, 92% yield). m / z 372.1 [M+H] + ,ESI pos.

[0189] Step 4: Ethyl 2-[4-(difluoromethyl)-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 2 (130 mg, 276 μmol, equiv.: 1.0) and 1-[[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl]methyl]piperidin-4-ol (260 mg, 420 μmol, equiv.: 1.52) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 70 °C for 2.5 h. Purification by flash chromatography (silica gel, 25 g, 0% to 100% in DCM (DCM:MeOH:NHOH 9:1:0.05)) afforded the title compound as a light brown solid (60 mg, 72% purity, 34% yield). m / z 636.4[M+H] + ,ESI pos.

[0190] Step 5: 2-[4-(difluoromethyl)-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000106.tif53170 In a manner similar to Step 8 of Example 2, ethyl 2-[4-(difluoromethyl)-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (0.06 g, 94.4 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a light yellow foam (25 mg, 90% purity, 34% yield). m / z 690.4 [M+H] + ,ESI pos.

[0191] Example 18 2-[4-(difluoromethyl)-7-methyl-6-[4-(2-morpholinoethoxy)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000107.tif32170

[0192] Step 1: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-[4-(2-morpholinoethoxy)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (130 mg, 276 μmol, equivalent weight: 1.0) and 4-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]morpholine (CAS 690636-28-3, 110 mg, 331 μmol, equivalent weight: 1.2) were reacted in the presence of K2CO3 and Pd(dppf)Cl2·CHCl2 at 70 °C for 3 h. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a light brown foam (53 mg, 90% purity, 29% yield). m / z 598.4 [M+H]+ ,ESI pos.

[0193] Step 2: 2-[4-(difluoromethyl)-7-methyl-6-[4-(2-morpholinoethoxy)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-7-methyl-6-[4-(2-morpholinoethoxy)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (52 mg, 87 μmol, equiv.: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 20% MeOH in DCM) afforded the title compound as an off-white solid (35 mg, 58% yield). m / z 652.3 [M+H] + ,ESI pos.

[0194] Example 19 2-(4-(Difluoromethyl)-6-(4-(3-((4-(hydroxymethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide TIFF0007798887000110.tif55170

[0195] Step 1: (1-(4-bromophenyl)azetidin-3-yl)methanol To a solution of 1-bromo-4-iodobenzene (6 g, 21.2 mmol, equiv.: 1.0) in DMF (11.3 mL), azetidin-3-ylmethanol hydrochloride (CAS 928038-44-2, 2.79 g, 22.5 mmol, equiv.: 1.06), copper(I) iodide (1.62 g, 8.48 mmol, equiv.: 0.40), KPO (18 g, 84.8 mmol, equiv.: 4.0), and (S)-(−)-1,1′-bi-2-naphthol (1.21 g, 4.24 mmol, equiv.: 0.20) were added, and nitrogen was bubbled through the solution. The mixture was stirred under nitrogen at 100°C for 16 h. After cooling, water and EtOAc were added. After separation, the aqueous layer was extracted again with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 330 g, 0% to 50% EtOAc in heptane) to give the title compound as a light brown solid (663 mg, 12% yield). m / z 242.1 [M+H] + ,ESI pos,Br isotopes.

[0196] Step 2: (1-(4-bromophenyl)azetidin-3-yl)methyl methanesulfonate To a stirred solution of (1-(4-bromophenyl)azetidin-3-yl)methanol (400 mg, 1.65 mmol, equiv.: 1.0) and NEt3 (284 mg, 391 μL, 2.81 mmol, equiv.: 1.7) in THF (27.5 mL) was added methanesulfonyl chloride (227 mg, 154 μL, 1.98 mmol, equiv.: 1.2) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to give the title compound as a light brown solid (502 mg, 95% yield), which was used in the next step without further purification. m / z 320.0 [M+H] + ,ESI pos,Br isotopes.

[0197] Step 3: 4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine To a solution of piperidin-4-ylmethanol (1.0 g, 8.68 mmol, equivalents: 1.0) in DMF (5 mL) was added TBDMS-Cl (1.31 g, 8.68 mmol, equivalents: 1.0) and 1H-imidazole (1.18 g, 17.4 mmol, equivalents: 2.0). The reaction mixture was stirred overnight at room temperature, then diluted with water and extracted twice with TBME. To the combined stirred organic layer was added water, followed by AcOH (2.61 g, 2.49 mL, 43.4 mmol, equivalents: 5.0). After stirring for 5 minutes, the two layers were separated. The aqueous phase was neutralized to pH 8 with saturated aqueous NaHCO3 and extracted three times with TBME. The combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a pale yellow liquid (0.69 g, 35% yield) which was used in the next step without further purification. 1 H NMR(300MHz,chloroform-d)δppm0.04(s,6H)0.89(s,9H)1.03-1.21(m,2H)1.51-1.65(m,1H)1.65-1.75(m,2H)2.04(br s,1H)2.52-2.68(m,2H)3.04-3.15(m,2H)3.38-3.48(m,2H)

[0198] Step 4: 1-((1-(4-bromophenyl)azetidin-3-yl)methyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine To a solution of (1-(4-bromophenyl)azetidin-3-yl)methyl methanesulfonate (110 mg, 343 μmol, equiv.: 1.0) in DMF (0.5 mL) was added DIPEA (133 mg, 180 μL, 1.03 mmol, equiv.: 3.0) and 4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine (94.4 mg, 412 μmol, equiv.: 1.2) at room temperature. The reaction mixture was stirred for 20 hours at 80° C. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted a second time, and the combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give the title compound as an off-white solid (80 mg, 51% yield). m / z 455.2 [M+H] + ,ESI pos.

[0199] Step 5: Ethyl 2-(6-(4-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-4-(difluoromethyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007798887000115.tif53170 In a vial, intermediate 3 [ethyl 2-(4-(difluoromethyl)-7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate] (80 mg, 154 μmol, equivalents: 1. To a solution of 1-((1-(4-bromophenyl)azetidin-3-yl)methyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine (70 mg, 154 μmol, equiv.: 1.0), CsCO (151 mg, 463 μmol, equiv.: 3.0), and Pd(dppf)Cl·CHCl (22.6 mg, 30.9 μmol, equiv.: 0.20) were added while argon was bubbled through the solution. The vial was closed, and the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic phases were washed with water and brine and dried over NaSO. The solvent was evaporated in vacuo and the crude material was purified by flash chromatography (silica gel, 10 g, 0% to 100% MeOH in DCM) to give the title compound as an off-white foam (29 mg, 25% yield). m / z 765.5 [M+H] + ,ESI pos.

[0200] Step 6: 2-(6-(4-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-4-(difluoromethyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide To a solution of ethyl 2-(6-(4-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-4-(difluoromethyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (30 mg, 39.2 μmol, equiv.: 1.0) in EtOH (1 mL) was added LiOH (1 M in water, 39.2 μL, 39.2 μmol, equiv.: 1.0). After 1 h, the reaction was concentrated in vacuo and coevaporated twice with toluene. The residue was dissolved in DMF (1 mL) and DIPEA (15.2 mg, 20.5 μL, 118 μmol, equiv.: 3.0), thiazol-2-amine (5.1 mg, 51 μmol, equiv.: 1.3), and HATU (19.4 mg, 51 μmol, equiv.: 1.3) were added. The reaction was stirred at room temperature for 2 h, then diluted with water and extracted with EtOAc (2x). The organic layer was dried over NaSO and concentrated. The residue was purified by flash chromatography (silica gel, 4 g, 0% to 20% MeOH in DCM) to give the title compound as an off-white foam (10 mg, 90% purity, 27% yield). m / z 819.7 [M+H] + ,ESI pos.

[0201] Step 7: 2-(4-(difluoromethyl)-6-(4-(3-((4-(hydroxymethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide To a solution of 2-(6-(4-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-4-(difluoromethyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide (10 mg, 12.2 μmol, equivalents: 1.0) in THF (0.5 mL) was added tetrabutylammonium fluoride (1 M in THF) (24.4 μL, 24.4 μmol, equivalents: 2.0). After stirring the reaction for 4 hours, additional tetrabutylammonium fluoride (1M in THF) (36.6 μL, 36.6 μmol, equiv: 3.0) was added and the reaction was stirred overnight. The reaction mixture was diluted with 20 mL of EtOAc and washed twice with 20 mL of water and once with 20 mL of brine. The organic layer was dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography (Si-amine, 4 g, 0% to 20% MeOH in EtOAc) to give the title compound as a light yellow foam (2.4 mg, 24% yield). m / z 705.4 [M+H] + ,ESI pos.

[0202] Example 20 2-[4-(Difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000118.tif42170

[0203] Step 1: tert-Butyl 4-[4-[4-(difluoromethyl)-2-[2-ethoxy-2-oxo-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethyl]-7-methyl-indazol-6-yl]phenyl]piperazine e-1-carboxylate A suspension of Intermediate 1 (160 mg, 340 μmol, equiv.: 1.0), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (CAS 457613-78-4, 156 mg, 509 μmol, equiv.: 1.5), and K2CO3 (58.7 mg, 424 μmol, equiv.: 1.25) in 2-MeTHF (1.8 mL) and water (0.3 mL) was degassed with argon for 10 minutes. Dichloro[bis(diphenylphosphinophenyl)ether]palladium(II) (12.2 mg, 17 μmol, equiv.: 0.05) was added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) to give the title compound as a colorless amorphous solid (88 mg, 38% yield). m / z 653.6 [M+H] + ,ESI pos.

[0204] Step 2: tert-butyl 4-[4-[4-(difluoromethyl)-7-methyl-2-[2-oxo-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(thiazol-2-ylamino)ethyl]indazol-6-yl]phenyl]piperazine e-1-carboxylate As in Example 1, Step 2, tert-butyl 4-[4-[4-(difluoromethyl)-2-[2-ethoxy-2-oxo-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethyl]-7-methyl-indazol-6-yl]phenyl]piperazine e-1-carboxylate (87 mg, 133 μmol, equivalents: 1.0) was treated first with LiOH and then with aqueous HCl, and the resulting carboxylic acid was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) afforded the title compound as a yellow solid (69 mg, 92.7 μmol, 70% yield). m / z707.8[M+H] + ,ESI pos.

[0205] Step 3: 2-[4-(difluoromethyl)-7-methyl-6-(4-piperazin-1-ylphenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide dihydrochloride To a solution of tert-butyl 4-[4-[4-(difluoromethyl)-7-methyl-2-[2-oxo-1-[r(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(thiazol-2-ylamino)ethyl]indazol-6-yl]phenyl]piperazine e-1-carboxylate (66 mg, 93.4 μmol, equivalents: 1.0) in DCM (2 mL) and 1,4-dioxane (1 mL) was added HCl (4 M in 1,4-dioxane, 350 μL, 1.4 mmol, equivalents: 15). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid (67 mg, 82% purity, 86% yield). m / z 607.2 [M+H] + ,ESI pos.

[0206] Step 4: 2-[4-(difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide To a solution of 2-[4-(difluoromethyl)-7-methyl-6-(4-piperazin-1-ylphenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide dihydrochloride (65 mg, 95.6 μmol, equivalents: 1.0) in DMF (1 mL) was added 2-iodoethan-1-ol (19.7 mg, 8.97 μL, 115 μmol, equivalents: 1.2) and DIPEA (61.8 mg, 83.5 μL, 478 μmol, equivalents: 5.0). The reaction mixture was stirred at 55° C. for 16 hours. The reaction mixture was poured into 2:1 EtOAc / THF and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% MeOH in DCM) and lyophilized to give the title compound as a white solid (22 mg, 34% yield). m / z 651.3 [M+H]+, ESI pos.

[0207] Example 21 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000123.tif35170

[0208] Step 1: Ethyl 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and (6-morpholinopyridin-3-yl)boronic acid (CAS 904326-93-8, 55.2 mg, 265 μmol, equivalent weight: 1.25) were reacted at 90 °C for 2 h in the presence of CsCO and Pd(dppf)Cl·CHCl. ​​Purification by flash chromatography (silica gel, 40 g, EtOAc isocratic) afforded the title compound as a light brown solid (74 mg, 62% yield). m / z 376.2 [M+H], ESI pos.

[0209] Step 2: 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (76.3 mg, 138 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (Si-Amine, 25 g, 0% to 20% MeOH in EtOAc) afforded the title compound as a light brown solid (42 mg, 50% yield). m / z 609.3 [M+H] + ,ESI pos.

[0210] Example 22 2-[4-(Difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000126.tif32170

[0211] Step 1: 1-[1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-piperidyl]ethanol As in Example 5, Step 1, 1-[1-[2-(4-bromophenoxy)ethyl]-4-piperidyl]ethanol (620 mg, 1.89 mmol, equivalent weight: 1.0, CAS 1919662-84-2) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 1.5 h. Purification by flash chromatography (silica gel, 12 g, 0% to 20% MeOH in DCM) afforded the title compound as a brown oil (485 mg, 65% yield). m / z 362.2 [M+H] + ,ESI pos.

[0212] Step 2: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equiv.: 1.0) and 1-[1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-piperidyl]ethanol (104 mg, 276 μmol, equiv.: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 18 hours. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) afforded the title compound as a yellow solid (53 mg, 36% yield). m / z 640.4 [M+H] + ,ESI pos.

[0213] Step 3: 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (52 mg, 81.3 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 20% MeOH in DCM + 0.5% NH4OH) afforded the title compound as a light yellow solid (10 mg, 18% yield). m / z 694.3[M+H] + ,ESI pos.

[0214] Example 23 2-[4-(Difluoromethyl)-6-[4-[1-(2-fluoropropyl)-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000130.tif37170

[0215] Step 1: 1-[4-(4-bromophenyl)-1-piperidyl]propan-2-ol To a solution of 4-(4-bromophenyl)piperidine (CAS 80980-89-8, 10 g, 41.6 mmol, equiv.: 1.0) in MeOH (100 mL) was added 2-methyloxirane (CAS 75-56-9, 2.65 g, 3.2 mL, 45.7 mmol, equiv.: 1.1). The reaction mixture was stirred at 70 °C overnight. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 330 g, 0% to 5% MeOH in DCM) to give the title compound as an off-white solid (7.94 g, 61% yield). m / z 298.1 [{ 79 Br}M+H] + , 300.1 [{81 Br}M+H] + ,ESI pos.

[0216] Step 2: 4-(4-bromophenyl)-1-(2-fluoropropyl)piperidine A solution of 1-[4-(4-bromophenyl)-1-piperidyl]propan-2-ol (7.9411 g, 25.3 mmol, equiv.: 1.0) in DCM (150 mL) was cooled to -76 °C. Deoxofluor (CAS 202289-38-1, 12.3 g, 13.7 mL, 27.8 mmol, equiv.: 1.1) was added dropwise at -76 °C. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and washed with 140 mL of saturated aqueous NaHCO3. The aqueous layer was back-extracted twice with 150 mL of EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 330 g, 0% to 50% MeOH in EtOAc) to give the title compound as a yellow liquid (6.18 g, 79% yield). 79 Br}M+H] + ,302.1[{ 81 Br}M+H] + ,ESI pos.

[0217] Step 3: 1-(2-fluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine As in Example 5, Step 1, 4-(4-bromophenyl)-1-(2-fluoropropyl)piperidine (1.5 g, 5 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 3 hours. Purification by flash chromatography (silica gel, 25 g, 0% to 30% EtOAc in heptane) afforded the title compound as a dark brown oil (1.45 g, 77% yield). am / z 348.1 [M+H] + ,ESI pos.

[0218] Step 4: Ethyl 2-[4-(difluoromethyl)-6-[4-[1-(2-fluoropropyl)-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (200 mg, 424 μmol, equivalent weight: 1.0) and 1-(2-fluoropropyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (203 mg, 467 μmol, equivalent weight: 1.1) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 100°C for 1 hour. The reaction mixture was purified by flash chromatography (silica gel, 25 g, 0% to 10% MeOH in EtOAc) to give the title compound as a brown oil (144 mg, 94% purity, 52% yield). m / z 612.4 [M+H] + ,ESI pos.

[0219] Step 5: 2-[4-(difluoromethyl)-6-[4-[1-(2-fluoropropyl)-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[1-(2-fluoropropyl)-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (71 mg, 116 μmol, equiv.: 1.0) in ethanol (3 mL) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA at room temperature for 2 h and then at 50 °C for 1 h. Purification by flash chromatography (Si-Amine, 12 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a brown solid (36 mg, 90% purity, 42% yield). m / z 666.3[M+H] +,E SI pos.

[0220] Example 24 2-[4-(Difluoromethyl)-6-[4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000136.tif37170

[0221] Step 1: 1-(4-bromophenyl)-4-methyl-piperidin-4-ol TIFF0007798887000137.tif14170 In the same manner as in Step 1 of Example 13, 1-bromo-4-iodobenzene (1 g, 3.53 mmol, equivalent weight: 1.0) and 4-methylpiperidin-4-ol (407 mg, 3.53 mmol, equivalent weight: 1.0) were dissolved in NaO t The reaction was carried out in the presence of Bu, Xantphos (205 mg, 353 μmol, equivalent weight: 0.10), and Pd2(dba)3 at 85 °C for 1.5 h. Purification by flash chromatography (silica gel, 40 g, 0% to 40% EtOAc in heptane) afforded the title compound as a yellow solid (900 mg, 90% purity, 85% yield). m / z 271.7 [M+H] + ,ESI pos.

[0222] Step 2: 4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-ol As in Example 5, Step 1, 1-(4-bromophenyl)-4-methylpiperidin-4-ol (605 mg, 2.24 mmol, equivalent weight: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 2 hours. Purification by flash chromatography (silica gel, 24 g, 0% to 40% EtOAc in heptane) afforded the title compound as an off-white powder (560 mg, 79% yield). m / z 318.2 [M+H] + ,ESI pos.

[0223] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (100 mg, 212 μmol, equivalent weight: 1.0) and 4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-ol (101 mg, 318 μmol, equivalent weight: 1.5) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 3 hours. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a light brown solid (105 mg, 85% yield). m / z 582.3 [M+H], ESI pos.

[0224] Step 4: 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 8, Step 2, ethyl 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (105 mg, 181 μmol, equivalents: 1.0) was treated first with LiOH and then with aqueous HCl, and the resulting carboxylic acid was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a light brown solid (49.2 mg, 61% yield). m / z 636.2 [M+H] + ,ESI pos.

[0225] Example 25 2-[6-[4-[(3aR,6aS)-2-ethyl-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000141.tif39170

[0226] Step 1: tert-butyl (3aS,6aR)-2-(4-bromophenyl)-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate TIFF0007798887000142.tif32170 In a manner similar to that of Example 13, step 1, 1-bromo-4-iodobenzene (622 mg, 2.2 mmol, equivalent weight: 1.1) and tert-butyl (3aS,6aR)-3a-fluorohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (CAS 2090176-68-2, 500 mg, 2 mmol, equivalent weight: 1.0) were dissolved in NaO t The reaction was carried out in the presence of Bu, Xantphos, and Pd(dba) CHCl at 80 °C overnight. Purification by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in heptane) afforded the title compound as a light brown solid (308 mg, 38% yield). m / z 387.1 [M+H] + ,ESI pos.

[0227] Step 2: tert-butyl (3aS,6aR)-3a-fluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate As in Example 5, Step 1, tert-butyl (3aS,6aR)-2-(4-bromophenyl)-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (0.300 g, 740 μmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl₂·CHCl₂ at 90°C for 6 hours. Purification by flash chromatography (silica gel, 12 g, 0% to 20% EtOAc in heptane) afforded the title compound as a light yellow solid (117 mg, 90% purity, 32% yield). m / z 433.3 [M+H] + ,ESI pos.

[0228] Step 3: tert-Butyl (3aS,6aR)-2-[4-[4-(difluoromethyl)-2-[2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-ethyl]-7-methyl-indazol-6-yl]phenyl]-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate TIFF0007798887000144.tif44170 Similarly to Step 7 of Example 2, Intermediate 1 (115 mg, 244 μmol, equivalent weight: 1.0) and tert-butyl (3aS,6aR)-3a-fluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (110 mg, 254 μmol, equivalent weight: 1.04) were reacted in the presence of Cs2CO3 and Pd(dppf)Cl2·CHCl2 at 70°C for 2.5 hours. Purification by flash chromatography (silica gel, 25 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) afforded the title compound as a brown oil (110 mg, 60% purity, 38% yield). m / z 697.7 [M+H] + ,ESI pos.

[0229] Step 4: tert-Butyl (3aS,6aR)-2-[4-[4-(difluoromethyl)-2-[1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-methyl-indazol-6-yl]phenyl]-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate TIFF0007798887000145.tif44170 In a manner similar to Step 8 of Example 2, tert-butyl (3aS,6aR)-2-[4-[4-(difluoromethyl)-2-[2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-ethyl]-7-methyl-indazol-6-yl]phenyl]-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (110 mg, 158 μmol, equivalents: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in EtOAc) afforded the title compound as a brown oil (60 mg, 35% purity, 17% yield). m / z 751.3 [M+H] + ,ESI pos.

[0230] Step 5: 2-[6-[4-[(3aR,6aS)-3a-fluoro-1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; TIFF0007798887000146.tif41170 tert-Butyl (3aS,6aR)-2-[4-[4-(difluoromethyl)-2-[1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-methyl-indazol-6-yl]phenyl]-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (0.06 g, 79.9 μmol, equivalents: 1.0) was dissolved in 0.3 mL DCM and 0.15 mL MeOH. An aqueous solution of hydrogen chloride (4M in dioxane, 240 μL, 959 μmol, equiv: 12) was then added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue was dissolved in a mixture of DCM and MeOH, carefully basified with saturated aqueous NaHCO3, and then extracted three times with a mixture of DCM and MeOH (19:1). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give the title compound as a brown oil (60 mg, 40% purity, 46% yield). m / z 651.2 [M+H] + ,ESI pos.

[0231] Step 6: 2-[6-[4-[(3aR,6aS)-2-ethyl-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide. TIFF0007798887000147.tif411702-[6-[4-[(3aR,6aS)-3a-fluoro-1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide (0.06 g, 64.5 μmol, equivalents: 1.0) was dissolved in DMF (2.5 mL). DIPEA (41.7 mg, 56.4 μL, 323 μmol, equivalents: 5.0) and ethyl iodide (13.1 mg, 6.78 μL, 83.9 μmol, equivalents: 1.3) were then added at room temperature. The mixture was stirred at 50° C. for 2 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH4OH 9:1:0.05)) to give the title compound as a brown oil (15 mg, 87% purity, 34% yield). m / z 679.3 [M+H] + ,ESI pos.

[0232] Example 26 2-[4-(Difluoromethyl)-6-[4-[2-[(dimethylamino)methyl]morpholin-4-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000148.tif38170

[0233] Step 1: 1-[4-(4-bromophenyl)morpholin-2-yl]-N,N-dimethyl-methanamine TIFF0007798887000149.tif25170 In a manner similar to that of Example 13, step 1, 1-bromo-4-iodo-benzene (1.19 g, 4.2 mmol, equivalent weight: 1.1) and N,N-dimethyl-1-morpholin-2-yl-methanamine (CAS 122894-56-8, 550 mg, 3.81 mmol, equivalent weight: 1.0) were dissolved in NaO t The reaction was carried out in the presence of Bu, Xantphos, and Pd2(dba)3 at 90 °C for 6 hours and at room temperature for 16 hours. Purification by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane) afforded the title compound as a brown oil (0.77 g, 70% purity, 47% yield). m / z 299.0, 300.8 [M+H] + ,ESI pos,Br isotopes.

[0234] Step 2: N,N-dimethyl-1-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholin-2-yl]methanamine As in Example 5, Step 1, 1-[4-(4-bromophenyl)morpholin-2-yl]-N,N-dimethylmethanamine (770 mg, 2.57 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl₂·CHCl₂ at 90°C for 3 hours. Purification by flash chromatography (silica gel, 12 g, 0% to 100% in DCM (DCM:MeOH:NH₄OH 9:1:0.05)) afforded the title compound as a dark brown viscous oil (96 mg, 80% purity, 9% yield). m / z 347.3 [M+H] + ,ESI pos.

[0235] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-[(dimethylamino)methyl]morpholin-4-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2 (TIFF0007798887000151.tif37170), Intermediate 1 (70 mg, 0.149 mmol, equivalent weight: 1.0) and N,N-dimethyl-1-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholin-2-yl]methanamine (96 mg, 0.223 mmol, equivalent weight: 1.5, 80% purity) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 1.5 hours. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) afforded the title compound as a brown solid (70 mg, 65% purity, 50% yield). m / z 611.4 [M+H] + ,ESI pos.

[0236] Step 4: 2-[4-(difluoromethyl)-6-[4-[2-[(dimethylamino)methyl]morpholin-4-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000152.tif35170 In a manner similar to Step 8 of Example 2, ethyl 2-[4-(difluoromethyl)-6-[4-[2-[(dimethylamino)methyl]morpholin-4-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (70 mg, 0.075 mmol, equivalents: 1.0, 65% purity) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (Si-amine, 12 g, 0% to 10% MeOH in EtOAc, then switched to 0% to 20% MeOH in DCM) afforded the title compound as a light brown powder (20 mg, 83% purity, 33% yield). m / z 665.3 [M+H] + ,ESI pos.

[0237] Example 27 2-[4-(Difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000153.tif37170

[0238] Step 1: 1-[2-(4-bromophenyl)ethyl]piperidin-4-ol TIFF0007798887000154.tif25170 To a mixture of 2-(4-bromophenyl)acetaldehyde (CAS 27200-79-9, 400 mg, 2.01 mmol, equivalents: 1.0) and piperidin-4-ol (CAS 5382-16-1, 264 mg, 2.61 mmol, equivalents: 1.3) in DCM (6.0 mL) was added sodium triacetoxyborohydride (681 mg, 3.22 mmol, equivalents: 1.6). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted twice with a mixture of DCM:MeOH (9:1). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (Si-amine, 24 g, 0% to 20% MeOH in EtOAc) to give the title compound as a light brown solid (492 mg, 82% yield). m / z 286.1 [M+H] + ,ESI pos.

[0239] Step 2: 1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]piperidin-4-ol As in Example 5, Step 1, 1-[2-(4-bromophenyl)ethyl]piperidin-4-ol (492 mg, 1.73 mmol, equivalents: 1.0) was reacted with bis(pinacolato)diboron in the presence of KOAc and PdPd(dppf)Cl2·CHCl2 at 90 °C for 1.5 hours. Purification by flash chromatography (silica gel, 24 g, 0% to 10% MeOH in DCM) afforded the title compound as a dark brown oil (226 mg, 37% yield). m / z 332.2 [M+H] +,ESI pos.

[0240] Step 3: Ethyl 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate As in Step 7 of Example 2, Intermediate 1 (150 mg, 0.318 mmol, equiv.: 1.0) and 1-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]piperidin-4-ol (137 mg, 0.414 mmol, equiv.: 1.3) were reacted in the presence of CsCO and Pd(dppf)Cl·CHCl at 65°C for 2 hours. Purification by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) afforded the title compound as an off-white solid (128 mg, 67% yield). m / z 596.3 [M+H] + ,ESI pos.

[0241] Step 4: 2-[4-(Difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (128 mg, 0.214 mmol, equiv.: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 20% MeOH in DCM) afforded the title compound as a yellow solid (32 mg, 23% yield). m / z 650.3 [M+H] + ,ESI pos.

[0242] Example 28 2-[4-(Difluoromethyl)-6-[4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000158.tif41170

[0243] Step 1: [4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]boronic acid To a suspension of (4-formylphenyl)boronic acid (CAS 87199-17-5, 200 mg, 1.33 mmol, equivalent weight: 1.0) and 4-(methylamino)cyclohexan-1-ol (CAS 2987-05-5, 172 mg, 1.33 mmol, equivalent weight: 1.0) in dichloromethane (10 mL), acetic acid (160 mg, 153 μL, 2.67 mmol, equivalent weight: 2.0) was added at room temperature. The reaction mixture was heated at 40 °C for 1 h. Sodium triacetoxyborohydride (565 mg, 2.67 mmol, equivalent weight: 2.0) was added at room temperature. After stirring the reaction mixture overnight at room temperature, additional sodium triacetoxyborohydride (565 mg, 2.67 mmol, equivalents: 2.0) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with 1M aqueous NaHCO3 (10 mL). The layers were separated. The aqueous layer was extracted twice with 10 ml of dichloromethane. The aqueous layer was concentrated in vacuo to give a white solid (1.8 g) containing the title compound along with NaHCO3 and salts. This was used in the next step without further purification. m / z 264.2 [M+H] + ,ESI pos.

[0244] Step 2: Ethyl 2-[4-(difluoromethyl)-6-[4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate In a vial, Intermediate 1 (150 mg, 318 μmol, equiv.: 1.0), impure [4-[[(4-hydroxycyclohexyl)methyl-amino]methyl]phenyl]boronic acid (251 mg), CsCO (311 mg, 955 μmol, equiv.: 3.0), and Pd(dppf)Cl·CHCl (26 mg, 31.8 μmol, equiv.: 0.10) were combined with THF (3.6 mL) and water (600 μL). The red solution was heated to 65 °C under argon and stirred overnight for 18 h. Before the reaction was complete, additional impure [4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]boronic acid (251 mg) was added, and the reaction was stirred under argon at 65 °C for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give the title compound as a dark brown oil (52 mg, 70% purity, 19% yield). m / z 610.3 [M+H] + ,ESI pos.

[0245] Step 3: 2-[4-(difluoromethyl)-6-[4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide As in Example 2, Step 8, ethyl 2-[4-(difluoromethyl)-6-[4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (52 mg, 85.3 μmol, equiv.: 1.0) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (silica gel, 12 g, 0% to 20% MeOH in DCM) afforded the title compound as a dark brown solid (9.7 mg, 16% yield). m / z 664.4 [M+H] + ,ESI pos.

[0246] Example 29 2-[6-[4-[(3aR,6aS)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000162.tif41170

[0247] Step 1: tert-butyl (3aR,6aS)-2-(4-bromophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate TIFF0007798887000163.tif29170 In a manner similar to that of Example 13, step 1, 1-bromo-4-iodo-benzene (1.47 g, 5.18 mmol, equivalent weight: 1.1) and tert-butyl (3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (CAS 250275-15-1, 1.00 g, 4.71 mmol, equivalent weight: 1.0) were dissolved in NaO t The reaction was carried out in the presence of Bu, Xantphos, and Pd(dba) CHCl at 80 °C for 16 h. Purification by flash chromatography (silica gel, 80 g, 0% to 30% EtOAc in heptane) afforded the title compound as a brown solid (1.44 g, 79% yield). m / z 367.1, 369.1 [M+H] + ,ESI pos,Br isotopes.

[0248] Step 2: (3aR,6aS)-5-(4-bromophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole To a solution of tert-butyl (3aR,6aS)-2-(4-bromophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (850 mg, 2.2 mmol, equiv.: 1.0) in DCM (10 mL) and MeOH (5.0 mL), HCl (4 M in 1,4-dioxane, 5.0 mL, 20 mmol, equiv.: 9.1) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM / MeOH, basified with saturated NaHCO3 and saturated NH3, and then extracted four times with a mixture of DCM:MeOH (9:1). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (693 mg, 80% purity, 94% yield), which was used in the next step without further purification. m / z 267.0, 268.7 [M+H] + ,ESI pos,Br isotopes.

[0249] Step 3: 1-[(3aR,6aS)-5-(4-bromophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]propan-2-ol TIFF0007798887000165.tif28170 To a solution of (3aR,6aS)-5-(4-bromophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (685 mg, 2.05 mmol, equiv.: 1.0, 80% purity) in MeOH (5.4 mL) was added 2-methyloxirane (CAS 75-56-9, 141 mg, 0.17 mL, 2.43 mmol, equiv.: 1.18). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature, adsorbed onto Isolute HM-N, and purified by flash chromatography (silica gel, 40 g, 0% to 5% MeOH in DCM) to afford the title compound as an off-white solid (495 mg, 71% yield). m / z 325.1, 327.1 [M+H] + ,ESI pos,Br isotopes.

[0250] Step 4: (3aR,6aS)-5-(4-bromophenyl)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole A solution of 1-[(3aR,6aS)-5-(4-bromophenyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]propan-2-ol (480 mg, 1.4 mmol, equiv.: 1.0) in DCM (8.0 mL) was cooled to -76 °C. Deoxofluor® (2.7 M solution in toluene, CAS 202289-38-1, 0.62 mL, 1.67 mmol, equiv.: 1.19) was added dropwise at -76 °C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was adsorbed onto Isolute HM-N and purified by flash chromatography (silica gel, 24 g, 0% to 70% EtOAc in heptane) to give the title compound as a light yellow solid (275 mg, 57% yield). m / z 327.0, 328.9 [M+H] + ,ESI pos,Br isotopes.

[0251] Step 5: [4-[(3aR,6aS)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]boronic acid A solution of (3aR,6aS)-5-(4-bromophenyl)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole (264 mg, 0.766 mmol, equivalents: 1.0) in THF (3.0 mL) was cooled to −76° C. n-Butyllithium (1.6 M solution in hexanes, 0.53 mL, 0.848 mmol, equivalents: 1.11) was added, and the reaction mixture was stirred at −76° C. for 1.5 hours. Triethyl borate (154 mg, 0.18 mL, 1.06 mmol, equivalents: 1.38) was added at −76° C. The reaction mixture was stirred at −76° C. for 15 minutes. The dry ice bath was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and stirred at room temperature for 30 minutes. The mixture was extracted twice with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a brown solid (223 mg, 85% purity, 85% yield), which was used in the next step without further purification. m / z 292.8 [M+H] + ,ESI pos.

[0252] Step 6: Ethyl 2-[6-[4-[(3aR,6aS)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate A mixture of Intermediate 1 (120 mg, 0.255 mmol, equiv.: 1.0), [4-[(3aR,6aS)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]boronic acid (131 mg, 0.382 mmol, equiv.: 1.5, 85% purity), CsCO (249 mg, 0.764 mmol, equiv.: 3.0), and Pd(dppf)Cl·CHCl (31 mg, 0.038 mmol, equiv.: 0.15) in 1,4-dioxane (1.8 mL) was flushed with argon. The reaction mixture was stirred at 100 °C for 2 h and at room temperature for 16 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude material was adsorbed onto Isolute HM-N and purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) to give the title compound as a light brown foam (141 mg, 90% purity, 78% yield). m / z 639.3 [M+H] + ,ESI pos.

[0253] Step 7: 2-[6-[4-[(3aR,6aS)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide TIFF0007798887000169.tif39170 In a manner similar to that of Example 8, Step 2, ethyl 2-[6-[4-[(3aR,6aS)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (139 mg, 0.196 mmol, equivalents: 1.0, 90% purity) was first treated with LiOH, and the resulting salt was reacted with 2-aminothiazole in the presence of HATU and DIPEA. Purification by flash chromatography (Si-amine, 12 g, 0% to 10% MeOH in EtOAc) followed by repurification of the product-containing fractions by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) afforded the title compound as an off-white solid (52 mg, 36% yield). m / z 693.4 [M+H] + ,ESI pos.

[0254] Example 30 HTRF Phosphorylated EGFR LRCS Assay (Cells) Cell lines and media The BaF3-LRCS cell line was obtained from Crownbio (San Diego, CA, USA). Cells were maintained in RPMI ATCC (Gibco 31870) + 2 mM glutamine + puromycin 0.5 μg / ml supplemented with 10% fetal bovine serum (FBS) (Gibco) at 37°C and 5% CO.

[0255] protocol After pre-filling the plate with 12.5 μl of a DMSO solution of the compound to be tested (dose response) or DMSO alone, cells were transferred to a Greiner Bio-One 784-08 microtiter plate at 20,000 cells / well in 12.5 μl of growth medium / well as described above. After spinning the plate at 300 × g for 30 seconds, the cells were incubated for 4 hours at 37°C, 5% CO2, and 95% humidity. Cells were lysed by adding 4 μl / well of the compound mixture in supplemented lysis buffer (Cis-bio, Phospho-EGFR HTRF Kit, 64EG1PEH), followed by incubation at room temperature for 30 minutes with shaking (400 rpm). The plate was then frozen and stored overnight at -80°C. The next day, after thawing the plate, 4 μl of a mixture of anti-phospho-EGFR cryptate and anti-phospho-EGFR-d2 antibody solutions prepared in supplemented detection buffer was added to each well. The covered plates were then incubated for 4 hours at room temperature, after which the fluorescence was read at 616 and 665 nm using an Envision reader (PerkinElmer). Data were analyzed in the same manner as above, with the normalized ratio of the 665 to 616 signals multiplied by 10,000.

[0256] The results are shown in Table 1.

[0257] TIFF0007798887000170.tif192170TIFF0007798887000171.tif188170TIFF00077988870 00172.tif194170TIFF0007798887000173.tif189170TIFF0007798887000174.tif197170 TIFF0007798887000175.tif195170TIFF0007798887000176.tif200170TIFF00077988870 00177.tif205170TIFF0007798887000178.tif192170TIFF0007798887000179.tif141170

Claims

1. Compounds of formula (I) [In the formula, A is —N— or —CH—; R １ and R ２ are independently selected from halogen and hydrogen; R ３ is a straight or branched chain alkyl group having 1 to 4 carbon atoms; and R ４ is selected from heterocycloalkyl, heterocycloalkylalkoxy, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkylheterocycloalkylalkoxy, hydroxyalkylheterocycloalkylalkyl, hydroxyheterocycloalkylalkyl, hydroxyheterocycloalkylalkoxy, (alkyl)(halo)heterocycloalkyl, hydroxyheterocycloalkyl, hydroxyalkylheterocycloalkylalkylcycloalkyl, alkylsulfonylheterocycloalkyl, hydroxyheterocycloalkylalkylcycloalkyl, hydroxyalkylheterocycloalkylalkylheterocycloalkyl, hydroxyalkylheterocycloalkyl, haloalkylheterocycloalkyl, (hydroxy)(alkyl)heterocycloalkyl, hydroxycycloalkyl(alkylamino)alkyl, and dialkylaminoalkylheterocycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A is —CH—.

3. R １ and R ２ 3. The compound of claim 1 or 2, wherein is independently selected from fluoro and hydrogen.

4. R ３ The compound according to any one of claims 1 to 3, wherein is methyl.

5. R ４ However, morpholinyl, (ethyl)(fluoro)piperidinyl, methylaminoethyl, dimethylaminoethyl, hydroxymethylpiperidinylethoxy, hydroxyethylpiperidinylethoxy, hydroxymethylpiperidinylmethyl, hydroxymethylpiperidinylethyl, hydroxyethylpiperidinylmethyl, hydroxyethylpiperidinylethyl, hydroxypiperidinylmethyl, hydroxypiperidinylethyl, hydroxypiperidinylethoxy, hydroxypiperidinyl, 1,4-diazabicyclo[3.2.1]octan-4-yl, hydroxymethylpiperidinylmethyl 5. The compound of any one of claims 1 to 4, wherein the hydroxymethyl group is selected from hydroxycyclobutyl, methylsulfonylpiperidinyl, hydroxypiperidinylmethylcyclobutyl, morpholinylethoxy, hydroxymethylpiperidinylmethylazetidinyl, hydroxyethylpiperazinyl, fluoropropylpiperidinyl, (hydroxy)(methyl)piperidinyl, ethyl(fluorohexahydropyrrolo[3,4-c]pyrrolyl), dimethylaminomethylmorpholinyl, hydroxycyclohexyl(methylamino)methyl, and fluoropropyl(hexahydropyrrolo[3,4-c]pyrrolyl).

6. R ４ is selected from heterocycloalkyl, (dialkylamino)alkyl, hydroxy(heterocycloalkyl)alkyl, hydroxy(heterocycloalkyl), and hydroxyalkyl(heterocycloalkyl).

7. R ４ The compound of claim 6 , wherein is selected from morpholinyl, (dimethylamino)ethyl, hydroxy(piperidinyl)methyl, hydroxy(piperidinyl), and hydroxyethyl(piperazinyl).

8. 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-[4-[2-(methylamino)ethyl]phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide hydrochloride; 2-[4-(difluoromethyl)-6-[4-[2-(dimethylamino)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(hydroxymethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[[4-(1-hydroxyethyl)-1-piperidyl]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-(1,4-diazabicyclo[3.2.1]octan-4-yl)phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-[4-(4-methylsulfonyl-1-piperidyl)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-[4-(2-morpholinoethoxy)phenyl]indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-(4-(difluoromethyl)-6-(4-(3-((4-(hydroxymethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)-7-methyl-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[4-(difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[4-(1-hydroxyethyl)-1-piperidyl]ethoxy]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[1-(2-fluoropropyl)-4-piperidyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-4-methyl-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[6-[4-[(3aR,6aS)-2-ethyl-3a-fluoro-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-[(dimethylamino)methyl]morpholin-4-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-(4-hydroxy-1-piperidyl)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[[(4-hydroxycyclohexyl)-methyl-amino]methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; and 2-[6-[4-[(3aS,6aR)-2-(2-fluoropropyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]phenyl]-4-(difluoromethyl)-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, selected from:

9. 2-[4-(difluoromethyl)-7-methyl-6-(4-morpholinophenyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[2-(dimethylamino)ethyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-(4-hydroxy-1-piperidyl)phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; 2-[4-(difluoromethyl)-6-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-7-methyl-indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; and 2-[4-(difluoromethyl)-7-methyl-6-(6-morpholino-3-pyridyl)indazol-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-yl-acetamide; The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from:

10. A process for the preparation of a compound according to any one of claims 1 to 9, comprising the following steps: (a) A compound of formula (B1) in a suitable solvent in the presence of a base to give a compound of formula (B2) [In the formula, M ＋ But Na ＋ , Li ＋ or a protonated base] obtaining (b) reacting a compound of formula (B2) in the presence of an acid to produce a compound of formula (B3) obtaining (c) reacting a compound of formula (B3) with a compound of formula (B4) in the presence of a coupling agent and a base. [In the formula, A, R １ , R ２ , R ３ , and R ４ is as defined in any one of claims 1 to 9, and R is hydrogen or alkyl. reacting with A method comprising:

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier.

12. A pharmaceutical for treating or preventing cancer, comprising a compound according to any one of claims 1 to 9.

13. The pharmaceutical described in claim 12, wherein the cancer is non-small cell lung cancer.

14. Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prevention of cancer.

15. The use described in claim 14, wherein the cancer is non-small cell lung cancer.

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