Fused Bicyclic Compounds and Their Use as Mer and Axl Inhibitors

Abstract

Formula (I) (in the formula, rings A, W, X, Y, L 1 , R 1 , R 3 and R 4 Compounds of Formula (I), and pharmaceutically acceptable salts thereof, are useful for treating or preventing cancer or immune-related diseases or conditions. Also described are pharmaceutical compositions of the compounds of Formula (I), and methods of using such compounds and compositions.

Description

[Technical Field]

[0001] Disclosed are compounds of formula (I) and methods for inhibiting Mer kinase and Axl kinase. Additionally, the disclosure relates to compositions comprising the disclosed compounds and methods of using the same. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are enzymes that can phosphorylate specific tyrosine residues in target proteins using ATP and share a highly conserved catalytic domain. This high conservation of the catalytic domain of receptor tyrosine kinases makes the development of selective tyrosine kinase inhibitors (TKIs) challenging. The TAM receptor family, consisting of Tyro3, ​​Axl, and Mer, plays important roles in cancer, hemostasis, and inflammation. In particular, Mer is a key regulator of macrophage and dendritic cell activation. Mer activation promotes the clearance of apoptotic cells by macrophages and other cell types, such as retinal pigment epithelial cells. Furthermore, Mer is aberrantly overexpressed in human cancers, including AML, ALL, lung cancer, glioma, melanoma, prostate cancer, schwannoma, mantle cell lymphoma, and rhabdomyosarcoma. Axl is more widely expressed in various cell types and tissues and is involved in diverse cellular processes, such as angiogenesis and tumorigenesis. Overexpression of Axl is crucial for tumor initiation, growth, and progression, involving tumor proliferation, invasiveness, and immune regulation. Axl has also been implicated in resistance to chemotherapy and to treatments targeting oncogenic drivers such as BRAF and EGFR. Overexpression of Axl in resistant tumors correlates with poor survival in many aggressive tumors, including triple-negative breast cancer, acute myeloid leukemia, non-small cell lung cancer, pancreatic cancer, and ovarian cancer. While much remains unknown about Tyro3, ​​its primary functions are implicated in innate immune responses, platelet aggregation, and neuronal signaling.

[0003] The search for specific inhibitors of Mer and Axl kinases has been challenging due to the similarity of the ATP-binding sites in all protein kinases. Compound 52, a 2,6,9-trisubstituted purine that competitively binds to the ATP-binding pocket, was the first molecule to successfully inhibit Mer (J Struct Biol. 2009 Feb;165(2):88-96). However, this inhibitor had limited efficacy and lacked selectivity. Several compounds have been discovered, most of which were discovered by modifying compound 52, including UNC-569, UNC-1062, and UNC-2025 (ACS Med Chem Lett. 2012 Feb 9;3(2):129-134, Eur J Med Chem. 2013 Jul;65:83-93, J Med Chem. 2014 Aug 28;57(16):7031-41). More recently, highly potent Mer kinase selective inhibitors have been disclosed in US Patent Publication No. 10,125,118 and WO2018071343.

[0004] The present invention aims to provide reagents and methods for modulating the receptor tyrosine kinases Mer and Axl. This and other objects of the present invention are achieved by one or more of the embodiments described below. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides novel compounds capable of selectively inhibiting Mer kinase and Axl kinase, which are useful for the prevention and / or treatment of cancer and other immune-related diseases (e.g., infections, sepsis, etc.). Herein, highly potent receptor tyrosine kinase Mer-selective inhibitors and Axl-selective inhibitors based on an aminopyridine scaffold are described. These compounds have the following formula (I):

[0006] The present disclosure provides a compound of formula (I): [ka] (In the formula, Ring A is selected from the group consisting of benzofuran, benzimidazole, chroman, dihydroindene, dihydropyrrolopyridine, indazole, indole, indoline, isoindoline, pyrrolopyridine, tetrahydroisoquinoline, tetrahydronaphthalene, tetrahydronaphthyridine, and tetrahydroquinoline; W is N and CR 2 selected from the group consisting of: X is -CR 6 R 7 -, -O-, and -NR 8 - selected from the group consisting of; Y is selected from the group consisting of a bond, piperidinediyl, piperazinediyl, and octahydropyrrolopyrazinediyl; L 1 is the bond, -(CH2) m -, -C(O)-(CH2) n -, -N(R a )-, and -NHCO2-(CH2) p - selected from the group consisting of; R a is C1-C4 alkyl; R 1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 is hydrogen or C1-C4 alkoxy; R 3 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3aR 3b , -C(O)OH, C(O)OR 3c and —C(O)NH; R 3 Each of the azetidinyl and dioxolanyl may be substituted with one or more C1-C4 alkyl substituents; R 3a and R 3b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R 3c is C1-C4 alkyl; R 4 is selected from the group consisting of F, Cl, Br, I, ═O, C1-C4 alkyl, C1-C4 alkoxyalkyl, and C1-C4 hydroxyalkyl; R 4 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; R 6 is selected from the group consisting of hydrogen, C1-C4 alkyl, and —OH; R 7 is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8 is C1-C4 alkyl; k is 1, 2, 3, or 4; m is 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3) or a pharmaceutically acceptable salt thereof.

[0007] In one embodiment of the compounds of formula (I), W is CR 2 and the remaining variable atoms are as defined above in formula (I). In another embodiment, W is CR 2 and X is -CR 6 R 7 - and;R 1is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in 2 , R 6 and R 7 are each independently hydrogen; and the remaining variable atoms are as defined above in formula (I). In another embodiment, ring A is selected from the group consisting of dihydroindene and tetrahydronaphthalene; W is CR 2 and X is -CR 6 R 7 - and;R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in 2 , R 6 and R 7 are each independently hydrogen; and the remaining variable atoms are as defined above in formula (I). In yet another embodiment of the compounds of formula (I), ring A is indoline; W is CR 2 and the remaining variable atoms are as defined above in formula (I).

[0008] In one embodiment, the present disclosure provides a compound of formula (II): [ka] (In the formula, Y is selected from the group consisting of a bond, piperidinediyl, piperazinediyl, and octahydropyrrolopyrazinediyl; L 1 is the bond, -(CH2) m -, -C(O)-(CH2) n -, -N(R a )-, and -NHCO2-(CH2) p - selected from the group consisting of; R a is C1-C4 alkyl; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 3 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c and —C(O)NH; R 3 Each of the azetidinyl and dioxolanyl may be substituted with one or more C1-C4 alkyl substituents; R 3a and R 3b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R 3c is C1-C4 alkyl; R 5 is selected from the group consisting of hydrogen, F, Cl, Br, I, ═O, C1-C4 alkyl, C1-C4 alkoxyalkyl, and C1-C4 hydroxyalkyl; More than three R's 5 But at the same time, not hydrogen; R 5two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; m is 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 1 or 2) The present invention relates to a compound having the structure:

[0009] In one embodiment of the compound of formula (II), L 1 is a bond; R 3 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -OH, and -NR 3a R 3b R 5 is selected from the group consisting of F and C1-C4 alkyl; the remaining variable atoms are as defined above in formula (II).

[0010] In one embodiment, the present disclosure provides a compound of formula (III): [ka] (In the formula, Y is selected from the group consisting of a bond, piperidinediyl, piperazinediyl, and octahydropyrrolopyrazinediyl; L 1 is the bond, -(CH2) m -, -C(O)-(CH2) n -, -N(R a )-, and -NHCO2-(CH2) p - selected from the group consisting of; R a is C1-C4 alkyl; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 3 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c and —C(O)NH; R 3 Each of the azetidinyl and dioxolanyl may be substituted with one or more C1-C4 alkyl substituents; R 3a and R 3b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R 3c is C1-C4 alkyl; R 5 is selected from the group consisting of hydrogen, F, Cl, Br, I, ═O, C1-C4 alkyl, C1-C4 alkoxyalkyl, and C1-C4 hydroxyalkyl; More than three R's 5 But at the same time, not hydrogen; R 5 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; m is 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; r is 1 or 2) The present invention relates to a compound having the structure:

[0011] In one embodiment of the compounds of formula (III), Y is piperazinediyl; L 1is a bond; and the remaining variable atoms are as defined above in formula (III). In another embodiment of the compound of formula (III), Y is octahydropyrrolopyrazinediyl; L 1 is a bond; the remaining variable atoms are as defined above in formula (III).

[0012] In another embodiment, the present disclosure provides a compound of formula (IV): [ka] (In the formula, R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 3 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 hydroxyalkyl; R 5 is selected from the group consisting of hydrogen, F, Cl, Br, I, ═O, C1-C4 alkyl, C1-C4 alkoxyalkyl, and C1-C4 hydroxyalkyl; R 5 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; r is 1 or 2) The present invention relates to a compound having the structure:

[0013] In one embodiment of the compound of formula (IV), R 3 is C1-C4 hydroxyalkyl; and the remaining variable atoms are as defined above in formula (IV). In another embodiment of the compound of formula (IV), R 1 is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl; R1 Each of the pyrazolyl, pyridinyl, and thiazolyl in

[0014] In another embodiment of the compound of formula (IV), R 1 teeth, [ka] the remaining variable atoms are as defined above in formula (IV).

[0015] In another embodiment, the present disclosure provides a compound of formula (V): [ka] (In the formula, R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 3 is C1-C4 hydroxyalkyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c and —C(O)NH; R 5 is selected from the group consisting of hydrogen, F, Cl, Br, I, ═O, C1-C4 alkyl, C1-C4 alkoxyalkyl, and C1-C4 hydroxyalkyl; r is 1 or 2) The present invention relates to a compound having the structure:

[0016] In one embodiment of a compound of formula (V), ring A is indole; the remaining variable atoms are as defined above for formula (V). In another embodiment of a compound of formula (V), ring A is indole; Y is piperidinediyl; L 1 is a bond; the remaining variable atoms are as defined above in formula (V).

[0017] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] Additionally, the disclosed compounds, or pharmaceutically acceptable salts thereof, useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable in their preparation and use.

[0019] In one embodiment, the present disclosure provides: 1. A method of treating a disease, disorder, or condition, comprising: The present invention relates to a method comprising administering to a subject in need of treatment for a disease, disorder, or condition an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease, disorder, or condition is cancer or an immune-related disease.

[0020] These and other objects of the present disclosure are set forth in the following paragraphs, and are not intended to limit the scope of the present disclosure. [Means for solving the problem]

[0021] As used herein, the term "compound of formula (I)" refers to a compound of formula (I): [ka] (In the formula, R 1 , R 3 , R 4 , L 1 , k, X, Y, W and ring A are as described in the Summary of the Invention above. or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula (II): [ka] (In the formula, R 1 , R 3 , R 5 , L 1 , Y and q are as described in the Summary of the Invention above. It is shown as follows.

[0023] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has formula (III): [ka] (In the formula, R 1 , R 3 , R 5 , L 1 , Y and q are as described in the Summary of the Invention above. It is shown as follows.

[0024] In yet another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula (IV): [ka] (In the formula, R 1 , R 3 , R 5 and r are as described in the Summary of the Invention above. It is shown as follows.

[0025] In yet another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula (V): [ka] (In the formula, R 1 , R 5 and r are as described in the Summary of the Invention above. It is shown as follows.

[0026] Also described are compositions comprising any of such compounds of Formula (I), (II), (III), (IV) or (V), and methods of using such compounds or compositions to treat conditions and disorders.

[0027] The compounds contained herein may contain one or more variable atoms that are described multiple times in the substituents or formulas described herein. The definition of a variable atom in each description is independent of the definition of that variable atom in another description. Furthermore, combinations of substituents are permissible only if such combinations result in stable compounds. A stable compound is one that can be isolated from a reaction mixture.

[0028] Definition of Terms As used in this specification and the appended claims, the following terms have the meanings set forth below unless otherwise specified.

[0029] As used in the specification and claims, it should be noted that the singular forms "a," "an," and "the" include the plural unless expressly stated otherwise. Thus, for example, when referring to a "compound," this includes a single compound and one or more of the same or different compounds. When referring to a "pharmaceutically acceptable carrier," this pharmaceutically acceptable carrier means a single pharmaceutically acceptable carrier and one or more pharmaceutically acceptable carriers.

[0030] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain group containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, buta-1,3-dienyl, etc.

[0031] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0032] As used herein, the term "alkoxyalkyl" refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.

[0033] As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon chain group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, 1,2,2-trimethylpropyl, and the like.

[0034] It should be noted that where the terms "comprise" or "comprising" are used in this patent application (including the claims), it is the applicants' intention, and it is clearly intended, that these terms be construed as inclusive rather than exclusive terms unless the context otherwise requires. It should also be noted that the applicants intend these terms to be so construed in interpreting this patent application, including the claims set forth below.

[0035] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group containing ring carbon atoms. Cycloalkyls can be monocyclic cycloalkyls, bicyclic cycloalkyls, tricyclic cycloalkyls, or spirocyclic cycloalkyls. Monocyclic cycloalkyls are carbocyclic ring systems containing 3 to 8 carbon atoms but no heteroatoms or double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyls are monocyclic cycloalkyls fused to a monocyclic cycloalkyl ring or bridged monocyclic ring systems in which two non-adjacent carbon atoms of the monocyclic cycloalkyl ring are connected by an alkylene bridge containing 1, 2, 3, or 4 carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]nonanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, and the like. Examples of tricyclic cycloalkyls include bicyclic cycloalkyls fused to monocyclic cycloalkyls and bicyclic cycloalkyls in which two non-adjacent ring carbon atoms are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Representative examples of tricyclic ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonanyl (octahydro-2,5-methanopentalenyl or noradamantanyl) and tricyclo[3.3.1.13,7]decanyl (adamantane), and the like. Examples of spirocyclic cycloalkyls include monocyclic or bicyclic cycloalkyls in which two substituents on one carbon atom of the cycloalkyl ring, taken together with that carbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl. Examples of spirocyclic cycloalkyls include spiro[2.5]octanyl.

[0036] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced with halogen.Representative examples of haloalkyl include but are not limited to chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, trifluoropropyl etc.

[0037] As used herein, the term "halo" or "halogen" refers to Cl, Br, I and F.

[0038] As used herein, the term "heteroatom" means a nitrogen atom, an oxygen atom, or a sulfur atom.

[0039] The term "heterocycloalkyl" refers to a non-aromatic saturated monocyclic heterocycloalkane group or a non-aromatic saturated polycyclic heterocycloalkane group having one or more heteroatoms and carbon atoms independently selected from S, N, and O. Heterocycloalkyls may be a single ring (monocyclic). Examples of monocyclic heterocycloalkyls include oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, and pyrazolidinyl. Heterocycloalkyls include, but are not limited to, pyrazolinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, trithianyl, azepanyl, 2,3,4,5-tetrahydro-1H-azepinyl, oxepanyl, 2,3,4,5-tetrahydro-1H-oxepinyl, thiepanyl, 3,4,5-tetrahydro-1H-thiepinyl, azocanyl, thiocanyl, oxocanyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, 3,4,5,6-tetrahydro-2H-oxocinyl, and the like. Alternatively, heterocycloalkyls may be polycyclic (comprising two or more rings). Examples of polycyclic heterocycloalkyls include bridged heterocycloalkyls, fused heterocycloalkyls, and spirocyclic heterocycloalkyls in which at least one ring is a heterocycloalkyl ring and the remaining rings are heterocycloalkyl or cycloalkyl rings.

[0040] The term "hydroxy" or "hydroxyl" means --OH.

[0041] As used herein, the term "hydroxyalkyl" refers to a group in which a hydroxy group, as defined herein, is attached to the parent molecular moiety through an alkyl group, as defined herein. A "hydroxyalkyl" group may contain one or more hydroxyl groups. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, 2,3-dihydroxypropyl, and the like.

[0042] In some cases, the number of carbon atoms in a moiety is referred to as "C x ~C y ". In this prefix, x indicates the minimum number of carbon atoms contained in the substituent, and y indicates the maximum number of carbon atoms contained in the substituent. Thus, for example, "C1-C6 alkyl" means an alkyl substituent containing 1 to 6 carbon atoms, and "C1-C3 alkyl" means an alkyl substituent containing 1 to 3 carbon atoms. Also, for example, in this specification, "C6-C 10 "Aryl" means phenyl or a bicyclic aryl having 6 to 10 carbon atoms. In some cases, the number of ring atoms in a moiety is indicated with the prefix "x- to y-membered." In this prefix, x indicates the minimum number of ring atoms in the substituent, and y indicates the maximum number of ring atoms in the substituent. Thus, for example, "5- to 6-membered heteroaryl" means a heteroaryl containing 5 to 6 ring atoms.

[0043] When a moiety is described as being "optionally substituted," the moiety can be either (1) unsubstituted or (2) substituted. When a moiety is described as being optionally substituted with up to a certain number of non-hydrogen groups, the moiety can be either (1) unsubstituted or (2) substituted with up to the certain number of non-hydrogen groups or the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, when a moiety is described as being heteroaryl that is optionally substituted with up to three non-hydrogen groups, a heteroaryl having fewer than three substitutable positions can be substituted with up to the same number of non-hydrogen groups as there are substitutable positions on the heteroaryl. To illustrate this, a tetrazolyl (which has only one substitutable position) can be substituted with up to one non-hydrogen group. To further illustrate, when a moiety is described as being optionally substituted with up to two non-hydrogen groups, the nitrogen of a primary amino group can be substituted with up to two non-hydrogen groups, and the nitrogen of a secondary amino group can be substituted with up to only one non-hydrogen group.

[0044] As used herein, the term "oxo" refers to the group =O.

[0045] The term "pharmaceutical composition" refers to a composition suitable for administration in medical and veterinary applications.

[0046] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or lower animals without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are described in S.M. Berge et al., Journal of Pharmaceutical Science, vol. 66, 1977, pp. 1-16.

[0047] The terms "prevent" and "prevention" refer to a method of preventing the onset of a disease and / or its associated symptoms or barring a subject from contracting a disease. As used herein, the terms "prevent" and "prevention" also include delaying the onset of a disease and / or its associated symptoms, as well as reducing a subject's risk of contracting or developing a disease or disorder.

[0048] As used herein, the term "subject" refers to an animal, such as, but not limited to, a mammal, such as a primate (e.g., a human), cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, mouse, etc. In one embodiment, the subject is a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0049] When a moiety is described as "substituted," a hydrogen radical on a substitutable atom within the moiety has been replaced with a radical other than hydrogen. Thus, for example, a substituted heterocyclic moiety is one in which a hydrogen radical on the heterocycle has been replaced with at least one radical other than hydrogen. When there are two or more substituents on a moiety, each radical other than hydrogen can be the same or different (unless otherwise specified).

[0050] As used herein, the term "tautomer" refers to a mixture of compounds in equilibrium in which a proton moves from one atom to another. Examples of tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine, etc. Even if only one tautomer is shown, the other tautomers are within the scope of the invention.

[0051] The term "therapeutically effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt thereof that, when administered to a particular subject or population of subjects, alone or in combination with one or more other therapeutic agents, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of, the condition or disorder being treated. A "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject being treated. For example, a therapeutically effective amount in a human or other mammal may be determined by experiments conducted in a laboratory or clinical setting, or may be the amount required for the particular disease and subject being treated, according to guidelines from the U.S. Food and Drug Administration or equivalent foreign authority.

[0052] As used herein, the terms "treat" and "treatment" refer to a method of alleviating or alleviating a disease and / or its associated symptoms.

[0053] compound Compounds of the present disclosure may have formula (I), as set forth in the Summary and Detailed Description above.

[0054] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and the remaining variable atoms are as defined in formula (I).

[0055] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 Ring A is indoline; the remaining variable atoms are as defined in formula (I).

[0056] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -CR 6 R 7 - and; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 , R 6 , and R 7 are each independently hydrogen; The remaining variable atoms are as defined in formula (I).

[0057] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -CR 6 R 7 - and; Ring A is indole; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 , R 6 , and R 7 are each independently hydrogen; The remaining variable atoms are as defined in formula (I).

[0058] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2and; X is -CR 6 R 7 - and; Y is piperidinediyl; L 1 is a bond; Ring A is indole; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 , R 6 , and R 7 are each independently hydrogen; The remaining variable atoms are as defined in formula (I).

[0059] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -CR 6 R 7 - and; Ring A is selected from the group consisting of dihydroindene and tetrahydronaphthalene; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 , R 6 , and R7 are each independently hydrogen; The remaining variable atoms are as defined in formula (I).

[0060] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I), wherein X is —O—; and the remaining variable atoms are as defined in formula (I).

[0061] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is N; X is -O-; and the remaining variable atoms are as defined in formula (I).

[0062] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 X is -O-; and the remaining variable atoms are as defined in formula (I).

[0063] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -O-; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 is hydrogen; The remaining variable atoms are as defined in formula (I).

[0064] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -O-; R 1 is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, and thiazolyl in R 2 is hydrogen; The remaining variable atoms are as defined in formula (I).

[0065] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I), wherein X is —NR 8 -; and the remaining variable atoms are as defined in formula (I).

[0066] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by Formula (I), wherein W is N; and X is —NR 8 -; and the remaining variable atoms are as defined in formula (I).

[0067] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -NR 8 -; and the remaining variable atoms are as defined in formula (I).

[0068] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -NR 8 - and; R 1 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R1 Each of the pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl in R 2 is hydrogen; The remaining variable atoms are as defined in formula (I).

[0069] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (I): W is CR 2 and; X is -NR 8 - and; R 1 is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, and thiazolyl in R 2 is hydrogen; The remaining variable atoms are as defined in formula (I).

[0070] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is benzofuran; and the remaining variable atoms are as defined in Formula (I).

[0071] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is benzofuran; and the remaining variable atoms are as defined in formula (I).

[0072] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is benzimidazole; and the remaining variable atoms are as defined in Formula (I).

[0073] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is benzimidazole; and the remaining variable atoms are as defined in formula (I).

[0074] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is chroman; and the remaining variable atoms are as defined in Formula (I).

[0075] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is chroman; and the remaining variable atoms are as defined in formula (I).

[0076] In one embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is dihydroindene; and the remaining variable atoms are as defined in Formula (I).

[0077] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is dihydroindene; and the remaining variable atoms are as defined in formula (I).

[0078] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is dihydropyrrolopyridine; and the remaining variable atoms are as defined in Formula (I).

[0079] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is a dihydropyrrolopyridine; and the remaining variable atoms are as defined in formula (I).

[0080] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is indazole; and the remaining variable atoms are as defined in Formula (I).

[0081] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is indazole; and the remaining variable atoms are as defined in formula (I).

[0082] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is indole; and the remaining variable atoms are as defined in Formula (I).

[0083] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is indole; and the remaining variable atoms are as defined in formula (I).

[0084] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is indoline; and the remaining variable atoms are as defined in Formula (I).

[0085] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is indoline; and the remaining variable atoms are as defined in formula (I).

[0086] In one embodiment, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by Formula (I), wherein Ring A is isoindoline; and the remaining variable atoms are as defined in Formula (I).

[0087] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is isoindoline; and the remaining variable atoms are as defined in formula (I).

[0088] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is pyrrolopyridine; and the remaining variable atoms are as defined in Formula (I).

[0089] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is pyrrolopyridine; and the remaining variable atoms are as defined in formula (I).

[0090] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is tetrahydroisoquinoline; and the remaining variable atoms are as defined in Formula (I).

[0091] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is tetrahydroisoquinoline; and the remaining variable atoms are as defined in formula (I).

[0092] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by Formula (I), wherein Ring A is tetrahydronaphthalene; and the remaining variable atoms are as defined in Formula (I).

[0093] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is tetrahydronaphthalene; and the remaining variable atoms are as defined in formula (I).

[0094] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by Formula (I), wherein Ring A is tetrahydronaphthyridine; and the remaining variable atoms are as defined in Formula (I).

[0095] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is tetrahydronaphthyridine; and the remaining variable atoms are as defined in formula (I).

[0096] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by Formula (I), wherein Ring A is tetrahydroquinoline; and the remaining variable atoms are as defined in Formula (I).

[0097] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), wherein W is CR 2 and X is -CR 6 R 7 -; Ring A is tetrahydroquinoline; and the remaining variable atoms are as defined in formula (I).

[0098] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (II), wherein R 1 is selected from the group consisting of pyrazolyl and pyridinyl; R 1 Each of the pyrazolyl and pyridinyl, wherein is optionally substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, CN, F, Cl, Br, and I; the remaining variable atoms are as defined in formula (II).

[0099] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (II): 1 is a bond; R 3 is hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -OH, and -NR 3a R 3b R 5 is selected from the group consisting of F and C1-C4 alkyl; the remaining variable atoms are as defined in formula (II).

[0100] In one embodiment, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III), wherein Y is piperazinediyl; L 1 is a bond; the remaining variable atoms are as defined in formula (III).

[0101] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (III), wherein Y is octahydropyrrolopyrazinediyl; L 1 is a bond; the remaining variable atoms are as defined in formula (III).

[0102] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (III), wherein Y is a bond; L 1 is -N(R a )- and -NHCO2-(CH2) p -; the remaining variable atoms are as defined in formula (III).

[0103] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (III), wherein Y is a bond; L 1 is -N(R a )- and -NHCO2-(CH2) p - selected from the group consisting of; R 3 is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c and —C(O)NH; R 3 Each of the azetidinyl and dioxolanyl groups may be optionally substituted with one or more C1-C4 alkyl substituents; the remaining variable atoms are as defined in formula (III).

[0104] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (III), wherein Y is a bond; L 1 is -N(R a )- and -NHCO2-(CH2) p - selected from the group consisting of; R 3 is C1-C4 alkyl, C1-C4 hydroxyalkyl, azetidinyl, and -NR 3a R 3b R3 Each of the azetidinyl and dioxolanyl groups may be optionally substituted with one or more C1-C4 alkyl substituents; the remaining variable atoms are as defined in formula (III).

[0105] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III), wherein Y is a bond; L 1 is -N(R a )- and -NHCO2-(CH2) p - selected from the group consisting of; R 1 is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, and thiazolyl, wherein is optionally substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, CN, F, Cl, Br, and I; the remaining variable atoms are as defined in formula (III).

[0106] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III), wherein Y is a bond; L 1 is -N(R a )- and -NHCO2-(CH2) p - selected from the group consisting of; R 1 is selected from the group consisting of pyrazolyl and pyridinyl; R 1 Each of the pyrazolyl and pyridinyl, wherein is optionally substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl and F; the remaining variable atoms are as defined in formula (III).

[0107] In one embodiment, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (IV), wherein r is 1; and the remaining variable atoms are as defined in formula (IV).

[0108] In one embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein r is 2; and the remaining variable atoms are as defined in formula (IV).

[0109] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 1 is selected from the group consisting of pyrazolyl and pyridinyl; R 1 Each of the pyrazolyl and pyridinyl, wherein is optionally substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, CN, F, Cl, Br, and I; the remaining variable atoms are as defined in formula (IV).

[0110] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 5 is selected from the group consisting of hydrogen, F, and C1-C4 alkyl; the remaining variable atoms are as defined in formula (IV).

[0111] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 1 is selected from the group consisting of pyrazolyl and pyridinyl; R 1 Each of the pyrazolyl and pyridinyl groups may be substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, CN, F, Cl, Br, and I; R 3 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; R 5 is selected from the group consisting of hydrogen, F, and C1-C4 alkyl; the remaining variable atoms are as defined in formula (IV).

[0112] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 3is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; R 5 is selected from the group consisting of hydrogen, F, and C1-C4 alkyl; the remaining variable atoms are as defined in formula (IV).

[0113] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 3 is selected from the group consisting of C1-C4 alkyl and C1-C4 hydroxyalkyl; the remaining variable atoms are as defined in formula (IV).

[0114] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 3 is C1-C4 hydroxyalkyl; the remaining variable atoms are as defined in formula (IV).

[0115] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV), wherein R 1 is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl; R 1 Each of the pyrazolyl, pyridinyl, and thiazolyl in 3 is C1-C4 hydroxyalkyl; the remaining variable atoms are as defined in formula (IV).

[0116] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (IV): R 3 is C1-C4 hydroxyalkyl; R 1 teeth, [ka] selected from the group consisting of: The remaining variable atoms are as defined in formula (IV).

[0117] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (V), wherein r is 1; and the remaining variable atoms are as defined in formula (V).

[0118] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by formula (V), wherein r is 2; and the remaining variable atoms are as defined in formula (V).

[0119] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has formula (V), wherein R 5 is hydrogen; the remaining variable atoms are as defined in formula (V).

[0120] In one embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has formula (V), wherein R 1 is selected from the group consisting of pyrazolyl and pyridinyl; R 1 Each of the pyrazolyl and pyridinyl groups may be substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, CN, F, Cl, Br, and I; R 5 is hydrogen; the remaining variable atoms are as defined in formula (V).

[0121] In one embodiment, the compounds of the disclosure are 2-amino-N-{(1S,2S)-2-[(4-{2-[3-(dimethylamino)propanoyl]-2,3-dihydro-1H-isoindol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazole 2-Amino-N-[(1S,2S)-2-{[4-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;4-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}piperidine- tert-Butyl 1-carboxylate;2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[1-(piperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide;2-amino-N-[(1S,2S)-2-({4-[1-(1-methylpiperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-amino-N -{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{2-[2-(dimethylamino)acetamido]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{2-[(1-methylpiperidine-4-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl -1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{2-[(1-methylazetidine-3-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H- 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(3S,4R) -4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[3-(1-methylpiperidin-4-yl)-1H-indol-6-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(3S,4R)-4-{[4-(1-methyl-1H-indol-5-yl)phenyl]methoxy}oxolan-3-yl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-{[4-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]pyridine-3-carboxamide;2-Amino-N-{(3S,4R)-4-[(4-{1 -[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-amino-6'-fluoro 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide; 6-Amino-6'-fluoro-N- {(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2,3-dihydroxypropyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(trifluoromethyl)pyridine-3-carboxamide; 6-Amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5 -carboxamide;2-amino-N-{(1S,2S)-2-[(4-{3-[1-(2-hydroxyethyl)piperidin-4-yl]-1-methyl-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-amino-2-oxoethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl 2-Amino-N-{(1S,2S)-2-[(4-{1'-[1-(2-hydroxyethyl)piperidin-4-yl]-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-5'-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2 -{[4-(1H-indol-7-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide;6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-Amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1- Methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-indene-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide -yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide;6-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidine-4 -yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-6'-oxo-1',6'-dihydro[3,3'-bipyridine]-5-carboxamide;6-amino-6'-fluoro-N-{(3S,4S)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]-1-methylpyrrolidin-3-yl}[3,3'-bipyridine]-5-carboxamide;rac-2-amino-N-{(1S,2S,4S)-4-hydroxy-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-3-propan-2-yl] 2-Amino-N-{(1S,2S)-2-[(4-{3-ethyl-1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{3-ethyl-1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3 -carboxamide;3-amino-6-(6-fluoropyridin-3-yl)-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}pyrazine-2-carboxamide;2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidine -4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide;2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1,2-dihydrospiro[indol-3,3'-oxolan]-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-5'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(3S,4R)-4-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-6'-fluoro-N-{(1S,2S)- 2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl); Piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide; 2-Amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2 -Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(prop-1-en-2-yl)pyridine-3-carboxamide; 3-Amino-6-(6-fluoropyridin-3-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(prop-1-en-2-yl)pyridine-3-carboxamide 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[2-(trifluoromethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-{[4-(1,3-dimethyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-indol-5-yl)phenyl -pyrazol-4-yl)pyridine-3-carboxamide;2-amino-N-[(1S,2S)-2-{[4-(2,3-dimethyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-amino-N-[(1S,2S)-2-{[4-(2-methyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[1-(2-hydroxyethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;3-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}propanoic acid;2-Amino-N-[(1S,2S)-2-{[4-(1-{4 -[(2S)-2,3-Dihydroxypropyl]piperazin-1-yl}-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[1-(propan-2-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide;{5-[4-({[(1S,2S)-2 -{[2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}acetic acid;6-Amino-N-[(1S,2S)-2-{[4-(1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-6'-fluoro[3,3'-bipyridine]-5-carboxamide;6-Amino-N-[(1S,2S)-2 -{[4-(1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(difluoromethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1R)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro- 2-Amino-N-[(1S,2S)-2-({4-[1-(2-aminoethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-{[4-(1H-indol-5-yl)phenyl]meth 2-Amino-N-{(1S,2S)-2-[(4-{3-[4-(2-hydroxyethyl)piperazin-1-yl]-2-oxo-2,3-dihydro-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[2-(dimethylamino)methyl]pyrazole-4-yl)phenyl]- 3-Amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{2'-[1-(2-hydroxyethyl)piperidin-4-yl]-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-6'-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2-oxo-2,3-di Hydro-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{2'-[1-(2-hydroxyethyl)piperidin-4-yl]-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-6'-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-N-[(1S,2S)-2-{[4-(1-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-6'-fluoro[3,3'-bipyridine]-5-carboxamide;2-Amino-N-[(1S,2S)-2-{[4-(1-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl] 6-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl] 6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydro 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1R,2S)-2-fluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl 6-Amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydro- 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1R,2S)-2-fluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-Amino-N-{(1S,2S)-2-[(4-{(1R,2S)-2-fluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide N-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-6'-oxo-1',6'-dihydro[3,3'-bipyridine]-5-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl) Pyridine-3-carboxamide;6-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-6'-fluoro[3,3'-bipyridine]-5-carboxamide;2-amino-N-{(1S,2S)-2-[(4-{3-[4-(2-hydroxyethyl)piperazin-1-yl]-1-benzofuran-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-Amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl) 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3- 6-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1R) -1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl) 2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;rac-6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{5-[4-(2-hydro 6-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide;6-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(dimethylamino)-2,2-dimethyl-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indazol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H -pyrazol-4-yl)pyridine-3-carboxamide;2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1,2,3,4-tetrahydroquinolin-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-pyrrolidone 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-Amino-1'-methyl-N-[(1S ,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide;6-amino-2'-fluoro-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide;6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1R)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]phenyl) ]-2,3-Dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[5-(4-methylpiperazine- 2-Amino-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide 6-amino-5'-fluoro-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[(3,4-dihydroxybutyl)(methyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H -pyrazol-4-yl)pyridine-3-carboxamide;6-amino-N-{(1S,2S)-2-[(4-{1-[(3,4-dihydroxybutyl)(methyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide;6-amino-N-{(1S,2S)-2-[(4-{1-[(3,4-dihydroxybutyl)(methyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl) 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(1,3- Dihydroxypropan-2-yl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide;6-Amino-5'-fluoro-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide 2-Amino-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide;6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4 -dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;2-amino-N-{(1S,2S)-2-[( 4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-4-methoxypyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-4-methoxypyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-4-methoxypyridine-3-carboxamide;2-Amino-4-methoxy-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide 6-amino-N-{(1S,2S)-2-[(4-{1-[4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[(5S)-5-(piperazin-1-yl)-5,; 2-Amino-N-{(1S,2S)-2-[(4-{(5S)-5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3- 2-Amino-N-[(1S,2S)-2-({4-[(1S)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[(1R)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide 2-Amino-N-[(1S,2S)-2-({4-[8,8-dimethyl-5-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[8,8-diphenyl-5-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Methyl-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-Amino-N-[(1S,2S)-2-({4-[(1S)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl ]-2'-Fluoro[3,3'-bipyridine]-5-carboxamide;6-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-methoxy[3,3'-bipyridine]-5-carboxamide;6-Amino-6'-methoxy-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro- 6-Amino-6'-cyano-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide;6-Amino-6'-cyano-N-[(1S,2S)-2-({4-[(1S)-1-( 4-Methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-benzimidazol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-4-methoxy-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine 2-Amino-N-{(1S,2S)-2-[(4-{8-[1-(2-hydroxyethyl)piperidin-4-yl]-5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H- 6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide 2-Amino-N-{(1S,2S)-2-[(4-{8-[1-(2-hydroxyethyl)piperidin-4-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-Amino-N-{(1S,2S)-2-[(4-{8-[1-(2-hydroxyethyl)piperidin-4-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;6-Amino-2'-fluoro-N-[(1S,2S)-2-({4-[(5S)-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[(5S)-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine 6-Amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(5S)-5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-Amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl]phenyl}meth 6-Amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2R)-2,3-dihydroxypropyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide;6-Amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2S)-2,3-dihydroxypropyl]piperazine- 1-yl}-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide;2-amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;2-Amino-N-[(1S,2S)-2-({4-[(5R)-5-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-Amino-N-[(1S,2S)-2-({4-[(5S)-5-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(2-methyl-1,3-thiazol-5-yl)pyridine-3-carboxamide; 6-Amino-N-[(1S,2S)-2-({4-[(5S)-5-{4-[(2S)-2,3-dihydroxypropyl 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1,2-thiazol-5-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{( 1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(3-methyl-1,2-thiazol-5-yl)pyridine-3-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1,3-thiazol-5-yl)pyridine-3-carboxamide;6'-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[2,3'-bipyridine]-5'-carboxamide;6'-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[2,3'-bipyridine]-5'-carboxamide 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6-methoxy[2,3'-bipyridine]-5'-carboxamide;2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6-methoxy[2,3'-bipyridine]-5'-carboxamide 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(2-methyl-1,3-thiazole-4-yl)pyridine-3-carboxamide and 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(4-methyl-1,3-thiazol-2-yl)pyridine-3-carboxamide;

[0122] Compound names were generated using the Advanced Chemical Development (ACD) / ChemSketch 2018.1.1 naming algorithm, Name 2018.

[0123] The compounds of the present disclosure may exist as stereoisomers where asymmetric or chiral centers exist. Such stereoisomers are referred to as "R" or "S" configurations, depending on the configuration of substituents around the chiral carbon atom. As used herein, the terms "R" and "S" refer to the configurations defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. Various stereoisomers and mixtures thereof are contemplated and expressly included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present disclosure may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution methods known to those skilled in the art. Examples of methods for resolving racemic mixtures include (1) coupling the enantiomeric mixture to a chiral auxiliary, recrystallization or chromatographic separation of the resulting diastereomeric mixture, and optional liberation of the optically pure product from the chiral auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England; (2) direct separation of the optically enantiomeric mixture using a chiral chromatographic column; or (3) fractional recrystallization.

[0124] The compounds of the present disclosure may exist as cis or trans isomers, where in cis isomers, the substituents on the ring may be attached on the same side of the ring (cis) relative to each other, and in trans isomers, the substituents on the ring may be attached on opposite sides of the ring (trans) relative to each other. For example, cyclobutane may exist in the cis or trans configuration, and may exist as a single isomer or a mixture of cis and trans isomers. Each cis or trans isomer of the compounds of the present disclosure may be synthetically prepared from commercially available starting materials using selective organic transformations, or may be prepared as a single isomer by purifying a mixture of cis and trans isomers. Such methods are well known to those skilled in the art and may include separation of isomers by recrystallization or chromatography.

[0125] The compounds of the present disclosure may have tautomers and geometric isomers, and these tautomers and geometric isomers also form an aspect of the present disclosure.

[0126] The present disclosure includes any isotopically-labeled pharmaceutically acceptable compound of formula (I), in which one or more atoms are replaced with an atom having the same atomic number but a different atomic mass or mass number than the atom that occurs predominantly in nature. Examples of isotopes suitable for incorporation into compounds of the present disclosure include: 2 H and 3 hydrogen isotopes such as H; 11 C. 13 C. 14 carbon isotopes such as C; 36 chlorine isotopes such as Cl; 18 fluorine isotopes such as F; 123 I and 125 iodine isotopes such as I; 13 N and 15 nitrogen isotopes such as N; 15 O. 17 O. 18 oxygen isotopes such as O; 32 phosphorus isotopes such as P; and 35Certain isotopically labeled compounds of formula (I), for example compounds of formula (I) incorporating a radioactive isotope, are useful in drug tissue distribution studies and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) is particularly useful for this purpose due to its ease of incorporation and easy detection methods. 2 Substitution with heavier isotopes, such as H, may be preferable in some situations because they may provide therapeutic advantages due to increased metabolic stability, e.g., increased in vivo half-life and reduced dosage requirements. 11 C. 18 F, 15 O. 13 Substitution with positron-emitting isotopes, such as N, may be useful in positron emission tomography (PET) studies to examine receptor occupancy by substrates. In general, isotopically labeled compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the Examples herein, employing suitable isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0127] Thus, the chemical formulas set forth herein may represent only one of the possible tautomers, geometric isomers, or stereoisomers that the chemical formula may possess, and the present disclosure encompasses all tautomers, geometric isomers, or stereoisomers, and mixtures thereof, and is not limited to any one of the tautomers, geometric isomers, or stereoisomers depicted in the chemical formulas set forth herein.

[0128] General synthesis method The compounds of the present disclosure can be further understood by reference to the following synthetic schemes and methods, which illustrate the means by which these compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. Representative procedures are shown below in Schemes 1-5, but are not limited thereto. In Schemes 1-5, the variable atoms R 1, X and W are as explained in the summary of the invention.

[0129] [ka] As shown in Scheme 1, compounds of formula (1-2) can be prepared from compounds of formula (1-1). 10 is I, Br or Cl) can be converted to R under Suzuki coupling conditions that are widely used in the literature and are well known to those skilled in the art. 12 Boronic acids of formula (1-5) (or R 12 The reaction can be coupled with a boronic acid ester equivalent (wherein R is alkyl) to give compounds of formula (1-2). This reaction typically requires the use of a base and a catalyst. Examples of bases include, but are not limited to, potassium carbonate, potassium tert-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride. Examples of catalysts include, but are not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, and tris(dibenzylideneacetone)dipalladium(0). The reaction can be carried out in a solvent, such as, but not limited to, water, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol, tetrahydrofuran, or the like, or a mixture thereof. Alternatively, the above reaction may be carried out at ambient or elevated temperature, or in a microwave oven. Alternatively, the ester of formula (1-3) (wherein R 10 is I, Br or Cl; R 11 is alkyl), R 12 Boronic acids of formula (1-5) (or R 12wherein R is alkyl) to give a compound of formula (1-4). Compounds of formula (1-4) may then be hydrolyzed to give carboxylic acids of formula (1-2) using conditions known to those skilled in the art, including basic conditions such as, for example, lithium hydroxide.

[0130] [ka] As shown in Scheme 2, compounds of formula (2-3) can be prepared from compounds of formula (2-1). Compounds of formula (2-1) can be converted to compounds of formula (2-2) (wherein R 13 is I, Br or Cl; LG 1 is a leaving group such as a halogen or a sulfonic acid group) to provide compounds of formula (2-3). This nucleophilic substitution reaction is carried out in the presence of a suitable base such as potassium tert-butoxide in a suitable solvent such as dimethyl sulfoxide.

[0131] [ka] As shown in Scheme 3, compounds of formula (3-5) can be prepared from compounds of formula (1-2). 14 is H, to an amine of formula (2-2) 13is I, Br, or Cl) to give a compound of formula (3-1). Examples of conditions known to allow the formation of amides from a mixture of a carboxylic acid and an amine include, but are not limited to, the addition of coupling reagents. Coupling reagents include N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC, or EDCI) or their corresponding hydrochlorides; 1,3-dicyclohexylcarbodiimide (DCC); bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl); N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; or 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate N-oxide. Coupling reagents include, but are not limited to, hexafluorophosphate, or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HBTU); and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®). Coupling reagents may be added as a solid, a solution, or a reagent bound to a solid support resin.

[0132] Next, in the presence of a palladium(II) catalyst, such as, for example, chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), and a suitable base, such as, for example, potassium acetate, a compound of formula (3-1) (wherein R 13 is I, Br or Cl) with R 12 Diboronic acid (or R 12Compounds of formula (3-3) may be prepared by treatment with a diboronic ester equivalent where R is alkyl. Compounds of formula (3-5) may then be prepared from compounds of formula (3-3). Under Suzuki coupling conditions as described in Scheme 1 above, R 12 is H (or R 12 is alkyl) to prepare a compound of formula (3-4) 15 is I, Br or Cl).

[0133] [ka] As shown in Scheme 4, compounds of formula (3-5) can be prepared from compounds of formula (4-1). Compounds of formula (4-1) (wherein R 10 is I) to prepare a compound of formula (2-3) 13 is Br or Cl, or in another embodiment, R 10 is Br and R 13 is Cl) to give a compound of formula (4-2). Compound of formula (4-2) can then be coupled with R 12 Boronic acids of formula (1-5) (or R 12 Compounds of formula (3-1) can be prepared by coupling with a boronic ester equivalent where R is alkyl. Compounds of formula (3-5) can be prepared by converting compounds of formula (3-1) via compounds of formula (3-3) to compounds of formula (3-5) as described in Scheme 3. Alternatively, compounds of formula (3-1) can be converted to compounds of formula (3-5) by coupling with a boronic ester equivalent where R is alkyl under Suzuki coupling conditions as described in Scheme 1 above. 12 is H (or R 12 The compound of formula (3-5) can also be coupled with a diboronic ester equivalent where M is alkyl to give compounds of formula (3-5).

[0134] [ka] As shown in Scheme 5, compounds of formula (3-5) can be prepared from compounds of formula (2-2). 13 is I, Br, or Cl) with a suitable protecting group (PG) to give compounds of formula (5-1). For example, but not limited to, treatment of amines of formula (2-2) with di-tert-butyl dicarbonate in a solvent such as tetrahydrofuran at ambient temperature gives compounds of formula (5-1) (where PG is tert-butoxycarbonyl). Compounds of formula (5-1) can then be reacted with a palladium(II) catalyst, such as chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), in the presence of a suitable base, such as potassium acetate, to give compounds of formula (5-2), such as R 12 Diboronic acid (or R 12 Compounds of formula (5-2) may be prepared by treatment with a diboronic ester equivalent where R is alkyl. Compounds of formula (5-2) may then be coupled to compounds of formula (3-4) (where R is alkyl) under Suzuki coupling conditions as described in Scheme 1 above. 15 is I, Br, or Cl) to give compounds of formula (5-3).

[0135] Compounds of formula (5-4) may be prepared from compounds of formula (5-3) by removing the protecting group (PG) to expose the corresponding amine under conditions known to those skilled in the art. For example, when PG is tert-butoxycarbonyl, the protecting group can be removed by treatment with acidic conditions, such as trifluoroacetic acid in dichloromethane, to give the corresponding amine. The resulting amine may then be coupled with a carboxylic acid of formula (1-1) under amide bond forming conditions as described in Scheme 3 to give compounds of formula (5-4). Compounds of formula (5-4) may then be coupled with a carboxylic acid of formula (1-1) under Suzuki coupling conditions as described in Scheme 1 to give compounds of formula (5-4) with R 12 Boronic acids of formula (1-5) (or R 12is alkyl) to give compounds of formula (3-5).

[0136] The compounds and intermediates of the present disclosure may be isolated and purified by methods known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica functionalized with alkylsilane groups, recrystallization at high or low temperatures, which may be pretreated with activated carbon, thin layer chromatography, distillation at various pressures, sublimation under reduced pressure, and trituration, as described, for example, in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0137] Since many of the compounds of the present disclosure have at least one basic nitrogen, a desired salt can be obtained by treating the compound of the present disclosure with an acid. For example, the desired salt can be obtained by reacting the compound of the present disclosure with an acid at room temperature or higher, and the salt is deposited and filtered off after cooling.

[0138] Optimum reaction conditions and reaction times for the individual steps may vary depending on the particular reactants used and substituents present in the reactants. Unless otherwise specified, solvents, temperatures, and other reaction conditions can be readily selected by one skilled in the art. Specific procedures are described in the Examples section. Workup after the reaction can be carried out according to conventional methods, for example, by removing the solvent from the residue followed by further purification by methods commonly known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, chromatography, and the like. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared from commercially available materials by one skilled in the art using methods described in the chemical literature.

[0139] Routine experimentation, including appropriate manipulation of reaction conditions, reagents, and synthetic route sequences, protection of chemical functional groups incompatible with the reaction conditions, and deprotection at appropriate points in the reaction sequences of the disclosed methods, are within the scope of the present disclosure. Suitable protecting groups and methods for protecting and deprotecting various substituents using suitable protecting groups are well known to those skilled in the art, and such protecting groups and methods for protecting and deprotecting are described in Greene's book entitled "Protective Groups in Organic Synthesis" (4th ed.) by P. G. M. Wuts and T. W. Greene (John Wiley & Sons, NY (2006)), which is incorporated herein by reference in its entirety. The compounds of the present disclosure can be synthesized by methods similar to those described in the above synthetic schemes and specific examples.

[0140] If the starting materials are not commercially available, such starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known compounds of similar structure, or procedures analogous to those described in the Schemes or Synthetic Examples sections above.

[0141] If an optically active form of a compound of the present disclosure is required, the optically active form of the compound of the present disclosure can be obtained by carrying out any of the procedures described herein using optically active starting materials (e.g., by preparation by asymmetric induction of an appropriate reaction step), or can be obtained by resolving a stereoisomeric mixture of a compound or intermediate of the present disclosure using standard procedures (chromatographic separation, recrystallization, enzymatic resolution, etc.).

[0142] Similarly, if a pure geometric isomer of a compound of the present disclosure is required, the pure geometric isomer of the compound of the present disclosure can be obtained by carrying out any of the procedures described above using the pure geometric isomer as a starting material, or can be obtained by resolving a mixture of geometric isomers of a compound or intermediate of the present disclosure using standard procedures such as chromatographic separation.

[0143] The synthetic schemes and specific examples described in the Examples section are for illustrative purposes only and should not be construed as limiting the scope of the disclosure, which is defined by the appended claims, which include all alternatives, modifications, and equivalents of the synthetic methods and specific examples.

[0144] Pharmaceutical Composition Additionally, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0145] As used herein, the term "pharmaceutically acceptable carrier" means any non-toxic and inert solid, semi-solid or liquid excipient, diluent, encapsulating material or formulation auxiliary.

[0146] The pharmaceutical compositions of the present disclosure may be in unit dosage form, in which the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient.

[0147] The dosage administered to a subject may be determined according to the effectiveness of the specific compound used, the condition of the subject, and the body weight or body surface area of ​​the subject to be treated.In addition, the dosage is determined according to the presence, nature and extent of adverse side effects associated with the administration of a specific compound to a specific subject.When determining the effective amount of a compound to be administered in the treatment or prevention of disease, a doctor can evaluate factors such as the circulating plasma volume of the compound, the toxicity of the compound and / or the progression of the disease.

[0148] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound represented by any one of Formulas (I), (II), (III), (IV), and (V) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0149] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0150] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0151] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0152] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (IV) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0153] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (V) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0154] How to use The novel compounds of the present invention, their stereoisomers, their enantiomers, or their pharmaceutically acceptable salts, exhibit a modulating effect on Mer kinase.

[0155] The novel compounds of the present invention, their stereoisomers, their enantiomers, or their pharmaceutically acceptable salts exhibit a modulating effect on Axl kinase.

[0156] The novel compounds of the present invention, their stereoisomers, their enantiomers, or their pharmaceutically acceptable salts can be used in the prevention or treatment of cancer or immune-related diseases.

[0157] The compounds described herein, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts thereof, may be administered to a subject suffering from a disorder or condition associated with expression / overexpression or upregulation of Mer kinase and activated genetic and epigenetic alterations. The term "administering" refers to the method of contacting a subject with a compound.

[0158] A "Mer kinase-mediated disease or condition" is characterized by the involvement of Mer kinase in the initiation of the disease or condition, the manifestation of one or more symptoms or disease markers of the disease or condition, the maintenance, severity or progression of the disease or condition, or resistance to therapeutic intervention for the disease or condition. Accordingly, in various embodiments, the present disclosure provides methods for treating cancer, comprising administering to a subject in need of cancer treatment a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable carrier, or a therapeutically effective amount of a compound disclosed herein without a pharmaceutically acceptable carrier.

[0159] An "Axl kinase-mediated disease or condition" is characterized by the involvement of Axl kinase in the initiation of the disease or condition, the manifestation of one or more symptoms or disease markers of the disease or condition, the maintenance, severity, or progression of the disease or condition, or resistance to therapeutic intervention for the disease or condition. Accordingly, in various embodiments, the present disclosure provides methods for treating cancer, comprising administering to a subject in need of cancer treatment a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable carrier, or a therapeutically effective amount of a compound disclosed herein without a pharmaceutically acceptable carrier.

[0160] In various embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition comprising the compound for use in medicine. In various embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition comprising the compound for use in treating a disease or disorder as described herein above.

[0161] In one embodiment, a method of treating a disease, disorder, or condition is provided, comprising the step of administering to a subject in need of treatment for the disease, disorder, or condition a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition is cancer or an immune-related disease.

[0162] In one embodiment, there is provided a method of treating a disease, disorder, or condition, comprising the step of administering to a subject in need of treatment for the disease, disorder, or condition a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), or (V) or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is cancer or an immune-related disease.

[0163] In one embodiment, a method of treating a disease, disorder, or condition is provided, comprising the step of administering to a subject in need of treatment for the disease, disorder, or condition a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition is cancer or an immune-related disease.

[0164] One embodiment relates to the use of the compound disclosed herein or its pharmaceutically acceptable salt in the preparation of a medicament. The medicament may contain at least one additional therapeutic agent. In some embodiments, the medicament is for use in the treatment of the diseases and disorders described hereinabove.

[0165] Additionally, the present disclosure relates to the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of the diseases and disorders described herein above, which medicament may also include at least one additional therapeutic agent.

[0166] The compounds disclosed herein may be administered as the sole active agent or co-administered with another therapeutic agent, including compounds that exhibit the same or similar therapeutic activity as the compounds disclosed herein and that have been found to be safe and effective when co-administered.The term "co-administration" refers to the administration of two or more therapeutic agents or two or more treatments (e.g., radiation therapy) to a subject in a single pharmaceutical composition or multiple separate pharmaceutical compositions.Therefore, co-administration includes administering a single pharmaceutical composition containing two or more therapeutic agents, or administering two or more compositions to a subject at the same time or at different times.

[0167] The compounds of the present disclosure may be co-administered with a therapeutically effective amount of at least one additional therapeutic agent for the treatment of cancer.

[0168] Further benefit of the applicants' disclosure will be appreciated by those skilled in the art from a perusal of this patent application.

[0169] The following examples are for illustrative purposes and are not intended to limit the scope of the present disclosure. [Effects of the Invention]

[0170] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, exhibit modulatory effects on Mer kinase and Axl kinase. [Example]

[0171] General matters The following examples are set forth to facilitate a better understanding of the invention described herein. The synthetic and biological examples described herein are intended to illustrate, but not to limit the scope of, the compounds, pharmaceutical compositions, and methods provided herein.

[0172] Common abbreviations known to those skilled in the art are used throughout this specification: DMSO refers to dimethyl sulfoxide; HATU refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N,N,N',N'-tetramethyl-3-oxo-1H-3λ; 5 -[1,2,3]triazolo[4,5-b]pyridine-1-carboxymidoamidium hexafluoride phosphate(1-), or N,N,N',N'-tetramethyl-1-oxo-3H-1λ 5 -[1,2,3]triazolo[4,5-b]pyridine-3-carboxymidoamidium hexafluoride phosphate (1-). TFA represents trifluoroacetic acid.

[0173] Other common abbreviations known to those skilled in the art are used throughout this specification: ATP refers to adenosine triphosphate; BSA refers to bovine serum albumin; EDTA refers to ethylenediaminetetraacetic acid; DMEM refers to Dulbecco's modified Eagle's medium; DTT refers to dithiothreitol; FBS refers to fetal bovine serum; GI 50 indicates half-maximal growth inhibitory concentration. FRET indicates fluorescence energy transfer. GT indicates glutamic acid-tyrosine. HEPES indicates (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid). HTRF indicates homogeneous time-resolved fluorescence. IC 50 indicates half maximal inhibitory concentration. RPMI indicates Roswell Park Memorial Institute medium. SAR indicates structure-activity relationship. TK indicates tyrosine kinase.

[0174] Additionally, other abbreviations known to those skilled in the art are used throughout this specification: APCI refers to atmospheric pressure chemical ionization; atm refers to atmospheric pressure; ESI refers to electrospray ionization; g refers to grams; h refers to hours; HPLC refers to high performance liquid chromatography; LC / MS or LCMS refers to liquid chromatography mass spectrometry; μL refers to microliters; μm refers to micrometers; mg refers to milligrams; min refers to minutes; mL refers to milliliters; mmol refers to millimole; MS refers to mass spectrometry; NMR refers to nuclear magnetic resonance; psi refers to pounds per square inch; rt refers to room temperature; SFC refers to supercritical fluid chromatography; UPLC® or UHPLC refers to ultra-high performance liquid chromatography.

[0175] Unless otherwise noted, all reagents were of commercial grade and used as is without further purification. Commercially available anhydrous solvents were used for reactions performed under an inert atmosphere. In all other cases, reagent-grade solvents were used unless otherwise noted. Column chromatography was performed using silica gel 60 (35-70 μm). Thin-layer chromatography was performed using precoated silica gel F-254 plates (0.25 mm thick).1 1 H NMR spectral data were recorded using an Agilent 400 MHz NMR spectrometer, or a Varian or Bruker 500 MHz or 501 MHz spectrometer. 1 Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ=0.00) or the appropriate residual solvent peak, i.e., CHCl3 (δ=7.27), as an internal standard. Multiplicities were indicated as singlet (s), doublet (d), doublet-doublet-doublet (ddd), doublet-doublet-doublet-doublet (dddd), quartet-doublet-doublet (ddq), triplet-doublet-doublet (ddt), quartet-doublet-doublet (dq), doublet-triplet-doublet (dtd), heptet (hept), triplet (t), doublet-doublet-triplet (tdd), quartet-triplet (tq), quartet (q), doublet-quartet (qd), triplet-quartet (qt), quintet (quin), multiplet (m), and broad (br). Electrospray ionization MS spectra were obtained using a Thermo Fisher Vanquish UPLC coupled to a Thermo Fisher MSQ Plus mass spectrometer using a Waters Xselect HSS T3 C18 2.5 μm column (2.1 mm x 50 mm). A gradient of 0.1% formic acid and 10 mM ammonium acetate in water (A) and 0.1% formic acid in acetonitrile (B) was used (linear gradient from 100 to 20% A over 0 to 2.3 min). Microwave heating was performed using a Biotage® Initiator.

[0176] Flash chromatography purification was performed using a Biotage® Isolera One Flash, Teledyne ISCO CombiFlash RF+, or Analogix IntelliFlash 280 system. Reverse-phase HPLC purification was performed using a Waters Prep LC 2487, Gilson PLC 2020, or Gilson GX-281. Supercritical fluid chromatography purification was performed using an SFC 80 system. The mobile phase consisted of supercritical CO2 delivered at a methanol flow rate of 80 mL / min from an uncertified dewar containing bone-dry CO2 pressurized to 350 psi. The column was set at ambient temperature, and the backpressure control unit was set to maintain 100 bar. Each sample was dissolved in methanol at a concentration of 50 mg / mL and injected as a 2 mL (100 mg) aliquot into the modifier stream. The mobile phase was maintained at isocratic conditions with 20% cosolvent / CO2.

[0177] Intermediate 1 (1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentan-1-amine To a solution of (1S,2S)-2-aminocyclopentanol hydrochloride (25 g, 182 mmol) in dimethyl sulfoxide (250 mL) was added potassium tert-butoxide (51 g, 454 mmol) in several portions, maintaining the temperature at 20–40°C. After stirring for 1 h, a solution of 1-bromo-4-(bromomethyl)benzene (49.9 g, 200 mmol) in dimethyl sulfoxide (150 mL) was added over 1.5 h, and the resulting mixture was stirred at 25°C for 1 h. This reaction was repeated 19 times on the same scale. All reaction mixtures were combined, diluted with ethyl acetate, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4 M HCl in ethyl acetate at 25°C, and the precipitate was filtered and dried under reduced pressure to give the title compound as the HCl salt (520 g). 1H NMR (400 MHz, DMSO-d6) δ 1.49-1.81 (m, 4H), 1.86-2.14 (m, 2H), 3.36-3.46 (m, 1H), 3.93-4.03 (m, 1H), 4.45-4.54 (m, 2H), 7.33 (d, J=8.44 Hz, 2H), 7.54 (d, J=8.44 Hz, 2H), 8.37 (br s, 3H).

[0178] Intermediate 2 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxylic acid To a solution of 2-amino-5-bromopyridine-3-carboxylic acid (80 g, 369 mmol) in dioxane (720 mL) / water (240 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 g, 479 mmol), K2CO3 (153 g, 1106 mmol), and tetrakis(triphenylphosphine)palladium(0) (21.3 g, 18.43 mmol). The resulting mixture was heated at 110 °C under a nitrogen atmosphere for 4 hours. After cooling to 20 °C, the mixture was poured into water and extracted with ethyl acetate. The aqueous layer was acidified with 10% HCl to a pH of approximately 4-5 and stirred for 10 minutes. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (25 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.78 (s, 1H), 8.07 (s, 1H), 8.15 (d, J=2.45 Hz, 1H), 8.43 (d, J=2.45 Hz, 1H).

[0179] Intermediate 3 2-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 2 (30 g, 137 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (HATU, 62.7 g, 165 mmol), and N,N-diisopropylethylamine (36 mL, 206 mmol) in N,N-dimethylformamide (400 mL) was stirred at 15 °C until the solution became clear. A solution of Intermediate 1 (44.6 g, 165 mmol) in N,N-dimethylformamide (100 mL) was added, and the resulting mixture was stirred at 15 °C for 2 h. This reaction was repeated twice on the same scale, and all mixtures were combined, diluted with ethyl acetate, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was triturated with ethyl acetate, filtered, and dried under reduced pressure to give the title compound (78 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.52-1.77 (m, 4H), 1.86-2.08 (m, 2H), 3.83-3.92 (m, 4H), 4.22-4.33 (m, 1H), 4.49-4.60 (m, 1H), 4.49-4.60 (m, 2H), 6.96 (s, 2H), 7.28 (d, J=8.16 Hz, 2H), 7.50 (d, J=8.38 Hz, 2H), 7.78 (s, 1H), 7.95-8.03 (m, 2H), 8.27-8.37 (m, 2H).

[0180] Intermediate 4 6-amino[3,3'-bipyridine]-5-carboxylic acid Under a nitrogen atmosphere, pyridin-3-ylboronic acid (12.74 g, 104 mmol) and K2CO3 (28.7 g, 207 mmol) were added to a solution of 2-amino-5-bromopyridine-3-carboxylic acid (15 g, 69.1 mmol) in dioxane (135 mL) / water (45 mL). Tetrakis(triphenylphosphine)palladium(0) (3.99 g, 3.46 mmol) was then added, and the resulting mixture was stirred at 110 °C for 16 h. This reaction was repeated once on the same scale. All reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The aqueous layer was acidified with 3 M HCl to a pH of approximately 5–6. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (18 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.36-7.84 (m, 3H), 8.35 (br d, J=8.07 Hz, 1H), 8.43 (d, J=2.57 Hz, 1H), 8.59-8.70 (m, 2H), 9.01 (d, J=1.71 Hz, 1H).

[0181] Intermediate 5 6-amino-5'-fluoro[3,3'-bipyridine]-5-carboxylic acid To a solution of 2-amino-5-bromopyridine-3-carboxylic acid (8 g, 36.9 mmol) in ethanol (40 mL) / tetrahydrofuran (40 mL) / water (40 mL) was added (5-fluoropyridin-3-yl)boronic acid (7.79 g, 55.3 mmol), Na2CO3 (7.81 g, 73.7 mmol), and (1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II)) (2.70 g, 3.69 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h and then cooled to 20 °C. This reaction was repeated three times on the same scale, and all reaction mixtures were combined, poured into water, and washed with ethyl acetate. The pH of this aqueous solution was adjusted to approximately 5-6 with 1 N HCl and stirred for 20 min. The precipitate was filtered, washed with water, and dried under reduced pressure to give the title compound (16.7 g). 1H NMR (400 MHz, D2O) δ 7.47 (br d, J=10.03 Hz, 1H) 7.97 (d, J=2.32 Hz, 1H) 8.02 (d, J=2.45 Hz, 1H) 8.14 (d, J=2.45 Hz, 1H) 8.23 ​​(s, 1H).

[0182] Intermediate 6 6-amino-2'-fluoro[3,3'-bipyridine]-5-carboxylic acid To a solution of 2-amino-5-bromopyridine-3-carboxylic acid (10 g, 46.1 mmol) in ethanol (50 mL), tetrahydrofuran (50 mL), and water (50 mL) was added (6-fluoropyridin-3-yl)boronic acid (9.74 g, 69.1 mmol), Na2CO3 (9.77 g, 92 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (3.37 g, 4.61 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h and then cooled to 20 °C. This reaction was repeated three times on the same scale. All reaction mixtures were combined, poured into water, and washed with ethyl acetate. The pH of this aqueous solution was adjusted to approximately 5-6 with 1N HCl and stirred for 20 min. The precipitate was filtered, washed with water, and dried under reduced pressure to give the title compound (15 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (ddd, J=7.18, 4.98, 1.77 Hz, 3H) 8.11 - 8.20 (m, 2H) 8.28 (s, 1H) 8.46 (s, 1H).

[0183] Intermediate 7 6-amino-6'-fluoro[3,3'-bipyridine]-5-carboxylic acid To a solution of 2-amino-5-bromopyridine-3-carboxylic acid (20 g, 92 mmol) in dioxane (180 mL) / water (60 mL) was added (6-fluoropyridin-3-yl)boronic acid (15.58 g, 111 mmol), tetrakis(triphenylphosphine)palladium(0) (2.130 g, 1.843 mmol), and K2CO3 (25.5 g, 184 mmol). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 4 h and then cooled to 20 °C. This reaction was repeated nine times on the same scale. All reaction mixtures were combined, poured into water, and extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl to a pH of approximately 5–6, stirred for 20 min, and filtered. The resulting solid was washed with water and dried under reduced pressure to give the title compound (102 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (dd, J=8.56, 2.81 Hz, 1H) 7.40 (br s, 1H) 8.24 (td, J=8.19, 2.57 Hz, 1H) 8.31 (d, J=2.45 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H) 8.56 (d, J=2.45 Hz, 1H).

[0184] Intermediate 8 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one Intermediate 8A Dimethyl [2-(4-bromophenyl)-2-oxoethyl]phosphonate To trimethyl phosphite (500 mL, 4317 mmol) was added 2-bromo-1-(4-bromophenyl)ethanone (100 g, 360 mmol), and the resulting mixture was stirred at 130 °C for 15 h. This reaction was repeated nine times on the same scale. All reaction mixtures were combined and concentrated to remove excess trimethyl phosphite. The residue was purified by silica gel flash chromatography eluting with 8 / 1 to 2 / 1 petroleum ether / ethyl acetate to give the title compound (900 g). 1H NMR (400 MHz, CDCl3) δ 1.44 (4H, d, J=17.64 Hz) 3.52 - 3.62 (2 H, m) 3.68 (3H, s) 3.71 (3H, s) 3.72 - 3.76 (4H, m) 7.59 (2 H, d, J=8.60 Hz) 7.80 - 7.85 (2 H, m).

[0185] Intermediate 8B 1-(4-Bromophenyl)-3-methylbut-2-en-1-one To a solution of Intermediate 8A (75 g, 147 mmol) in ethanol (750 mL) were added K2CO3 (60.8 g, 440 mmol) and acetone (108 mL, 1465 mmol), and the resulting mixture was stirred at 80 °C for 15 h. This reaction was repeated 11 times on the same scale, and all reaction mixtures were combined and filtered. The filtrate was concentrated, added to water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20 / 1 petroleum ether / ethyl acetate to give the title compound (200 g). 1 H NMR (400 MHz, CDCl3) δ 2.02 (3H, s) 2.21 (3H, s) 6.69 (1H, s) 7.57 (2 H, d, J=8.38 Hz) 7.75 - 7.81 (2 H, m).

[0186] Intermediate 8C 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one Intermediate 8B (40 g, 167 mmol) was added to polyphosphoric acid (230 mL, 167 mmol), and the resulting mixture was stirred at 135 °C for 3 h. This reaction was repeated four times on the same scale. All reaction mixtures were combined, poured into ice water with stirring, and adjusted to pH 8 with saturated NaHCO. The mixture was extracted with ethyl acetate, washed with brine, dried over NaSO, filtered, and concentrated. Purification by silica gel flash chromatography eluting with petroleum ether gave the title compound (73 g). 1H NMR (400 MHz, CDCl3) δ 1.42 (6H, s) 2.58 (2 H, s) 7.26 (1H, s) 7.48 - 7.52 (1H, m) 7.53 - 7.58 (1H, m) 7.65 (1H, d, J=1.32 Hz).

[0187] Intermediate 9 1-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperazine Intermediate 9A tert-Butyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate To a solution of Intermediate 8 (25 g, 105 mmol) and tert-butyl piperazine-1-carboxylate (38.9 g, 209 mmol) in dichloromethane (500 mL), a solution of TiCl (52.3 mL, 52.3 mmol) in dichloromethane (52 mL) was added dropwise, and the resulting mixture was stirred at 25 °C for 17 h. NaCNBH (13.14 g, 209 mmol) was added, and the resulting mixture was stirred for 8 h. This reaction was repeated four times on the same scale. All reaction mixtures were combined and poured into ice water, and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over NaSO, filtered, and concentrated. Purification by silica gel flash chromatography, eluting with 10 / 1 to 3 / 1 petroleum ether / ethyl acetate, gave the title compound (140 g). 1 H NMR (400 MHz, CDCl3) δ 1.21 (3H, s) 1.40 - 1.46 (12 H, m) 1.89 - 2.35 (2 H, m) 2.52 - 2.92 (2 H, m) 3.00 - 3.52 (2 H, m) 4.14 (4H, br s) 5.14 (1H, br t, J=8.16 Hz) 7.32 (1H, d, J=1.76 Hz) 7.43 (1H, dd, J=8.38, 1.76 Hz) 8.20 (1H, d, J=8.38 Hz).

[0188] Intermediate 9B 1-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperazine To a solution of Intermediate 9A (35 g, 85 mmol) in ethyl acetate (350 mL) was added 4 M HCl in ethyl acetate (70 mL, 280 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 3 hours. This reaction was repeated three times on the same scale. All reaction mixtures were combined and concentrated to approximately 500 mL. The solid was collected by filtration, washed with methyl tert-butyl ether, and dried under reduced pressure to give the title compound as the HCl salt (134 g). 1 H NMR (400 MHz, methanol-d4) δ 1.26 (3H, s), 1.49 (3H, s), 2.18–2.50 (2H, m), 3.38–3.49 (2H, m), 3.57–3.80 (6H, m), 5.29 (1H, s), 7.49–7.56 (2H, m), 7.82 (1H, d, J=7.94 Hz).

[0189] Intermediate 10 1-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-4-methylpiperazine To a solution of intermediate 9 (20 g, 64.7 mmol) in methanol (400 mL) was added formaldehyde (7.22 mL, 97 mmol) at 20 °C. After stirring for 15 min, NaCNBH (4.06 g, 64.7 mmol) was added portionwise, and the resulting mixture was stirred for 3 h. This reaction was repeated twice on the same scale. All reaction mixtures were combined, quenched with water, stirred for 30 min, and partially concentrated. The aqueous layer was extracted with ethyl acetate, dried over NaSO, filtered, and concentrated. Purification by silica gel flash chromatography eluting with a gradient from 2 / 1 petroleum ether / ethyl acetate to 100% ethyl acetate followed by trituration with ethanol (200 mL) gave the title compound (50 g). 1H NMR (400 MHz, DMSO-d6) δ 1.11 (3H, s) 1.29 (3H, s) 1.83 (2 H, dd, J=7.94, 4.41 Hz) 2.14 (3H, s) 2.25 - 2.46 (7H, m) 4.32 (1H, t, J=8.05 Hz) 7.11 (1H, d, J=7.94 Hz) 7.33 (1H, dd, J=8.05, 1.87 Hz) 7.37 (1H, d, J=1.76 Hz).

[0190] Intermediate 11 1-[(1S)-5-Bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-4-methylpiperazine Intermediate 10 was separated from Intermediate 11 (20.7 g) as the first eluting peak by supercritical fluid chromatography (column: Chiralpak AD-H; mobile phase: A: CO2 and B: methanol (0.1% diethylamine), 25% B in A).

[0191] Intermediate 12 1-[(1R)-5-Bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-4-methylpiperazine Intermediate 12 (21.5 g) was isolated as the second eluting peak by purification by supercritical fluid chromatography in the same manner as in the preparation of Intermediate 11. 1 H NMR (400 MHz, DMSO-d6) δ 1.12 (3H, s) 1.29 (3H, s) 1.83 (2 H, dd, J=8.05, 3.20 Hz) 2.16 (3H, s) 2.35 (7H, br d, J=5.95 Hz) 3.43 (2 H, br s) 4.32 (1H, s) 7.11 (1H, d, J=7.94 Hz) 7.33 (1H, dd, J=7.94, 1.76 Hz) 7.38 (1H, d, J=1.76 Hz).

[0192] Intermediate 13 2-[4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl]ethan-1-ol To a solution of intermediate 9 (20 g, 64.7 mmol) in methanol (300 mL), K2CO3 (22.35 g, 162 mmol) and 2-bromoethanol (14.55 g, 116 mmol) were added at 25 °C and the reaction was allowed to proceed for 20 hours. This reaction was repeated twice on the same scale. All reaction mixtures were combined, diluted with ethyl acetate, filtered, and concentrated. The residue was suspended in ethanol (200 mL) and stirred for 1 hour. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (53 g).

[0193] Intermediate 14 2-{4-[(1S)-5-Bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}ethan-1-ol Intermediate 14 (15.0 g) was separated from intermediate 13 (53 g, 150 mmol) as the first eluting peak by supercritical fluid chromatography (column: Chiralpak AD-H; mobile phase: A: CO2 and B: methanol (0.1% diethylamine), 25% B in A). 1 H NMR (400 MHz, DMSO-d6) δ 1.12 (3H, s) 1.29 (3H, s) 1.84 (2 H, t, J=7.50 Hz) 1.97 (1H, s) 2.31 - 2.47 (9H, m) 3.46 (2 H, br t, J=5.40 Hz) 4.28 - 4.39 (2 H, m) 7.12 (1H, d, J=7.94 Hz) 7.33 (1H, dd, J=8.16, 1.76 Hz) 7.38 (1H, d, J=1.76 Hz).

[0194] Intermediate 15 2-{4-[(1R)-5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}ethan-1-ol Purification by supercritical fluid chromatography in the same manner as in the preparation of Intermediate 14 gave Intermediate 15 (15.2 g) as the second eluting peak. 1 H NMR (400 MHz, DMSO-d6) δ 1.12 (3H, s) 1.29 (3H, s) 1.84 (2 H, t, J=7.50 Hz) 1.97 (1H, s) 2.31 - 2.47 (9H, m) 3.46 (2 H, br t, J=5.40 Hz) 4.28 - 4.39 (2 H, m) 7.12 (1H, d, J=7.94 Hz) 7.33 (1H, dd, J=8.16, 1.76 Hz) 7.38 (1H, d, J=1.76 Hz).

[0195] Intermediate 16 1-[(1S)-5-Bromo-2,3-dihydro-1H-inden-1-yl]piperazine Intermediate 16A 1-[(1S)-5-Bromo-2,3-dihydro-1H-inden-1-yl]-4-(4-methylbenzene-1-sulfonyl)piperazine A mixture of (1S)-5-bromo-2,3-dihydro-1H-inden-1-amine (20 g, 94 mmol) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (30.7 g, 104 mmol) in N,N-diisopropylethylamine (200 mL, 1145 mmol) was stirred at 145 °C for 12 h. This reaction was repeated once on the same scale. All reaction mixtures were combined and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 10 / 1 petroleum ether / ethyl acetate to give the title compound (40 g). 1H NMR (400 MHz, CDCl3) δ 1.92 - 1.98 (m, 2H) 2.37 (s, 3H) 2.49 (tdd, J=15.74, 15.74, 11.13, 4.71 Hz, 4H) 2.66 - 2.85 (m, 2H) 2.93 (br s, 4H) 4.16 (t, J=7.03 Hz, 1H) 7.00 (d, J=7.95 Hz, 1H) 7.14 - 7.22 (m, 1H) 7.23 - 7.31 (m, 3H) 7.56 (d, J=8.19 Hz, 2H).

[0196] Intermediate 16B 1-[(1S)-5-Bromo-2,3-dihydro-1H-inden-1-yl]piperazine To a solution of Intermediate 16A (20 g, 45.9 mmol) in 33% HBr / acetic acid (200 mL, 698 mmol) was added 4-hydroxybenzoic acid (19.03 g, 138 mmol), and the resulting mixture was stirred at 90 °C for 1 hour and then cooled to 25 °C. This reaction was repeated once on the same scale. All reaction mixtures were combined and concentrated under reduced pressure. The residue was poured into water, and the precipitate was filtered and washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 2 M Na2CO3 and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 4 M HCl in ethyl acetate (500 mL) and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried under reduced pressure to give the title compound as the HCl salt (25.9 g). 1 H NMR (400 MHz, methanol-d4) δ 2.54 - 2.68 (m, 2H), 3.01 - 3.14 (m, 1H), 3.20 - 3.29 (m, 1H), 3.37 - 3.52 (m, 2H), 3.55 - 3.73 (m, 6H), 5.01 - 5.13 (m, 1H), 7.55 (d, J=8.19 Hz, 1H), 7.63 (s, 1H), 7.69 (br d, J=8.19 Hz, 1H).

[0197] Intermediate 17 1-[(1R)-6-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl]piperazine Intermediate 17A tert-Butyl 4-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)piperazine-1-carboxylate To a solution of 6-bromo-3,4-dihydronaphthalen-1(2H)-one (20 g, 89 mmol) in anhydrous dichloromethane (200 mL) was added tert-butyl piperazine-1-carboxylate (49.6 g, 267 mmol) and triethylamine (37.2 mL, 267 mmol). A solution of TiCl4 (6.86 mL, 62.2 mmol) in dichloromethane (44 mL) was added, and the resulting mixture was stirred at 25 °C for 24 h under a nitrogen atmosphere. A solution of NaCNBH4 (22.34 g, 355 mmol) in methanol (60 mL) was added dropwise, and the resulting mixture was stirred at 25 °C for 8 h. This reaction was repeated twice on the same scale. All reaction mixtures were combined, quenched with aqueous Na2CO3, and filtered. The mixture was extracted with dichloromethane, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate from 100 / 1 to 5 / 1 to give the title compound (210 g). 1 H NMR (400 MHz, methanol-d4) δ 1.45 (s, 9H) 1.65 - 1.68 (m, 2H) 1.87 - 2.02 (m, 2H) 2.09 - 2.13 (m, 2H) 2.44 - 2.51 (m, 4H) 2.61 - 2.69 (m, 5H) 2.95 - 2.98 (m, 3H) 3.38 - 3.41 (m, 4H) 3.78 - 3.80 (m, 1H) 7.20 - 7.25 (m, 2H) 7.48 (dd, J=8.55, 1.97 Hz, 1H) 7.53 - 7.59 (m, 1H) 7.58 (d, J=8.33 Hz, 1H) 7.83 (d, J=8.33 Hz, 1H).

[0198] Intermediate 17B 1-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)piperazine To a solution of Intermediate 17A (30 g, 45.5 mmol) in ethyl acetate (60 mL) was added a solution of HCl (16.60 g, 455 mmol) in ethyl acetate (180 mL), and the resulting mixture was stirred at 25 °C for 4 h under a nitrogen atmosphere. This reaction was repeated twice on the same scale, and all reaction mixtures were combined and filtered. The resulting solid was washed with ethyl acetate (300 mL) and diluted with water (800 mL). The mixture was adjusted to pH 10 by the slow addition of saturated K2CO3 (100 mL) and extracted with ethyl acetate. The organic layer was washed with brine, filtered, and concentrated under reduced pressure to give the title compound (80 g). 1 H NMR (400 MHz, methanol-d4) δ 1.70–1.72 (m, 2H), 1.98–2.01 (m, 2H), 2.72–2.81 (m, 6H), 3.20–3.24 (m, 4H), 3.90–3.91 (m, 1H), 7.25 (s, 1H), 7.28 (dd, J=8.31, 1.96 Hz, 1H), 7.55 (d, J=8.31 ​​Hz, 1H).

[0199] Intermediate 17C 1-[(1R)-6-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl]piperazine Intermediate 17B (80 g, 135 mmol) was purified by supercritical fluid chromatography using a ChiralPak AD-H (250 × 50 mm id) column to give the crude title compound as the first eluting peak. This crude product was dissolved in ethyl acetate (100 mL), and 4 N HCl in ethyl acetate (100 mL) was added. The resulting mixture was stirred at 25 °C for 2 hours and filtered. The filter cake was triturated with 10 / 1 ethyl acetate / methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure and purified a second time by supercritical fluid chromatography to give 10.8 g of the title compound. The filter cake was dissolved in 1 N K2CO3, adjusted to pH 10, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (17 g), which, combined with the title compound obtained above, gave a total of 27.8 g of the title compound. 1 H NMR (400 MHz, methanol-d4) δ 1.69 - 1.71 (m, 2H) 1.95 - 1.98 (m, 2H) 2.48 - 2.51 (m, 2H) 2.52 - 2.62 (m, 2H) 2.64 - 2.87 (m, 6H) 3.73 (br dd, J=9.05, 4.77 Hz, 1H) 7.21 (s, 1H) 7.24 (dd, J=8.38, 2.02 Hz, 1H) 7.57 (d, J=8.44 Hz, 1H).

[0200] Intermediate 18 1-[(1S)-6-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl]piperazine Purification by supercritical fluid chromatography as in the preparation of Intermediate 17C gave the title compound (26 g) as the second eluting peak. 1H NMR (400 MHz, methanol-d4) δ 1.69 - 1.71 (m, 2H) 1.95 - 1.98 (m, 2H) 2.48 - 2.51 (m, 2H) 2.52 - 2.62 (m, 2H) 2.64 - 2.88 (m, 6H) 3.73 (br dd, J=9.05, 4.77 Hz, 1H) 7.21 (s, 1H) 7.24 (dd, J=8.38, 2.02 Hz, 1H) 7.57 (d, J=8.44 Hz, 1H).

[0201] Intermediate 19 6-Amino-2'-fluoro-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl][3,3'-bipyridine]-5-carboxamide Intermediate 19A 6-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide To a solution of Intermediate 6 (5.5 g, 23.59 mmol) in N,N-dimethylformamide (100 mL) were added Intermediate 1 (6.57 g, 21.44 mmol), 1-hydroxybenzotriazole hydrate (4.93 g, 32.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.11 g, 21.44 mmol), and the resulting mixture was stirred at 25 °C for 5 min. N,N-Diisopropylethylamine (9.36 mL, 53.6 mmol) was added, and the resulting mixture was stirred at 25 °C for 18 h. This reaction was repeated five times on the same scale. All reaction mixtures were combined, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 10 / 1 to 1 / 1 petroleum ether / ethyl acetate to give the title compound (35 g). 1H NMR (400 MHz, DMSO-d6) δ 1.54 - 1.71 (m, 4H) 1.88 - 1.94 (m, 1H) 2.00 - 2.05 (m, 1H) 3.84 - 3.88 (m, 1H) 4.25 - 4.28 (m, 1H) 4.51 - 4.56 (m, 2H) 7.27 (d, J=8.31 ​​Hz, 2H) 7.31 (s, 2H) 7.47 - 7.50 (m, 3H) 8.09 (d, J=1.83 Hz, 1H) 8.11 - 8.18 (m, 1H) 8.19 - 8.20 (m, 1H) 8.34 - 8.38 (m, 2H).

[0202] Intermediate 19B 6-Amino-2'-fluoro-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl][3,3'-bipyridine]-5-carboxamide To a solution of Intermediate 19A (7 g, 14.42 mmol) in tetrahydrofuran (70 mL) was added potassium acetate (2.83 g, 28.8 mmol), and the resulting mixture was stirred for 1 h under a nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium(0) (0.132 g, 0.144 mmol) and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.275 g, 0.577 mmol) were added, and the resulting mixture was stirred at 75 °C for 18 h. This reaction was repeated five times on the same scale. All reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 10 / 1 to 1 / 1 petroleum ether / ethyl acetate to give the title compound (22.23 g). 1H NMR (400 MHz, methanol-d4) δ 1.27 - 1.41 (m, 12H) 1.53 - 1.67 (m, 1H) 1.69 - 1.86 (m, 3H) 1.93 - 2.00 (m, 1H) 2.09 - 2.22 (m, 1H) 3.94 (dt, J=6.51, 4.33 Hz, 1H) 4.39 (td, J=7.24, 4.59 Hz, 1H) 4.60 - 4.69 (m, 2H) 7.34 (d, J=7.95 Hz, 2H) 7.40 (ddd, J=7.27, 5.07, 1.83 Hz, 1H) 7.67 (d, J = 7.95 Hz, 2H) 8.02 - 8.11 (m, 2H) 8.12 - 8.21 (m, 1H) 8.32 (t, J = 2.08 Hz, 1H). The corresponding boronic acid was also obtained (1.64 g). 1 H NMR (400 MHz, methanol-d4) δ 1.30 - 1.36 (m, 1H) 1.53 - 1.65 (m, 1H) 1.69 - 1.85 (m, 3H) 1.94 - 2.06 (m, 1H) 2.10 - 2.23 (m, 1H) 3.36 (s, 1H) 3.95 (dt, J=6.57, 4.42 Hz, 1H) 4.34 - 4.44 (m, 1H) 4.58 - 4.69 (m, 2H) 7.29 - 7.37 (m, 2H) 7.40 (ddd, J=7.27, 5.07, 1.83 Hz, 1H) 7.52 - 7.70 (m, 2H) 8.01 - 8.10 (m, 2H) 8.12 - 8.22 (m, 1H) 8.33 (t, J=2.02 Hz, 1H).

[0203] Intermediate 20 6-Amino-6'-methoxy-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl][3,3'-bipyridine]-5-carboxamide Intermediate 20A 6-amino-6'-methoxy[3,3'-bipyridine]-5-carboxylic acid Under a nitrogen atmosphere, (6-methoxypyridin-3-yl)boronic acid (8.46 g, 55.3 mmol) and K2CO3 (7.64 g, 55.3 mmol) were added to a solution of 2-amino-5-bromopyridine-3-carboxylic acid (6 g, 27.6 mmol) in dioxane (60 mL) / water (20 mL), followed by tetrakis(triphenylphosphine)palladium(0) (1.597 g, 1.382 mmol). The resulting mixture was stirred at 110 °C for 12 h and then cooled to 25 °C. This reaction was repeated four times on the same scale. All reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The aqueous layer was acidified with 6 M HCl to a pH of approximately 5–6. The precipitate was collected and dried under reduced pressure to give the title compound (26.5 g), which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 6.75-6.92 (m, 1H), 6.87 (d, J=8.77 Hz, 1H), 7.13-7.85 (m, 2H), 7.95 (dd, J=8.77, 2.63 Hz, 1H), 8.23 ​​(d, J=2.63 Hz, 1H), 8.40 (d, J=2.19 Hz, 1H), 8.48 (d, J=2.63 Hz, 1H).

[0204] Intermediate 20B 6-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-6'-methoxy[3,3'-bipyridine]-5-carboxamide A solution of Intermediate 20A (5.3 g, 21.61 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (HATU, 9.86 g, 25.9 mmol), and triethylamine (4.52 mL, 32.4 mmol) in N,N-dimethylformamide (50 mL) was stirred at 20 °C until the solution became clear. A solution of Intermediate 1 (7.95 g, 25.9 mmol) in N,N-dimethylformamide (10 mL) was added, and the resulting mixture was stirred at 20 °C for 12 h. This reaction was repeated four times on the same scale. All reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (30 g), which was used directly in the next step.

[0205] Intermediate 20C 6-Amino-6'-methoxy-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl][3,3'-bipyridine]-5-carboxamide A solution of Intermediate 20B (5 g, 10 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.85 g, 19.1 mmol) in dioxane (100 mL) was treated with potassium acetate (2.96 g, 30.2 mmol) followed by 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.588 g, 0.804 mmol). The mixture was heated at 100 °C under a nitrogen atmosphere for 12 h and then cooled to ambient temperature. This reaction was repeated 14 times on the same scale. All reaction mixtures were combined, diluted with ethyl acetate, and washed with water. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with a gradient of 50% / 1% petroleum ether / ethyl acetate to 100% ethyl acetate to give the title compound (16.21 g). 1H NMR (400 MHz, methanol-d4) δ 1.20 (s, 1H), 1.31 (s, 12H), 1.54-1.63 (m, 1H), 1.72-1.83 (m, 3H), 1.96-2.04 (m, 1H), 2.11-2.20 (m, 1H), 3.94 (s, 4H), 4.36-4.45 (m, 1H), 4.65 (s, 2H), 6.88 (d, J=8.60 Hz, 1H), 7.34 (d, J=7.94 Hz, 2H), 7.66 (d, J=7.94 Hz, 2H), 7.89 (dd, J=8.60, 2.43 Hz, 1H), 8.03 (d, J=2.20 Hz, 1H), 8.24-8.40 (m, 2H). LCMS (ESI+): m / z 545.2 (M+H) + .

[0206] Intermediate 21 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-indole Intermediate 21A 3,3-Dimethyl-1,3-dihydro-2H-indol-2-one To a solution of indolin-2-one (20 g, 150 mmol) and LiCl (22.29 g, 526 mmol) in tetrahydrofuran (400 mL) was added n-butyllithium (120 mL, 300 mmol) at -78 °C, and the resulting mixture was stirred at -78 °C for 20 min. Iodomethane (18.78 mL, 300 mmol) was added, and the resulting mixture was stirred at 25 °C for 12 h. This reaction was repeated four times on the same scale. All reaction mixtures were combined, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Silica gel flash chromatography, eluting with 50:1 to 5:1 petroleum ether / ethyl acetate, followed by precipitation, afforded the title compound (62 g). 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 6H), 6.84 (d, J=7.72 Hz, 1H), 6.95 (td, J=7.50, 0.88 Hz, 1H), 7.15 (td, J=7.66, 1.21 Hz, 1H), 7.26 (d, J=7.50 Hz, 1H), 10.30 (br s, 1H).

[0207] Intermediate 21B 5-Bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one To a solution of Intermediate 21A (10 g, 58.9 mmol) and sodium acetate (4.83 g, 58.9 mmol) in acetic acid (80 mL), a solution of Br2 (3.04 mL, 58.9 mmol) in acetic acid (80 mL) was added dropwise at 25 °C, and the resulting mixture was stirred at 25 °C for 50 min. This reaction was repeated five times on the same scale. All reaction mixtures were combined, added to water, and the pH was adjusted to approximately 7-8 with aqueous Na2CO3. This mixture was extracted with ethyl acetate, and the organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (80 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.25 (s, 6H), 6.80 (d, J=8.16 Hz, 1H), 7.33 (dd, J=8.27, 2.09 Hz, 1H), 7.53 (d, J=1.98 Hz, 1H), 10.44 (s, 1H).

[0208] Intermediate 21C 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-indole To a solution of Intermediate 21B (10 g, 39.6 mmol) in tetrahydrofuran (20 mL) was added borane-tetrahydrofuran (396 mL, 396 mmol) dropwise at 0 °C, and the resulting mixture was stirred at 50 °C for 2 h. The mixture was cooled to 0 °C and slowly diluted with methanol (41.5 mL, 1026 mmol), followed by the addition of HCl (11 mL, 132 mmol). The resulting mixture was stirred at 25 °C for 1 h and adjusted to pH 8–9 with 10% NaOH (125 mL). This reaction was repeated seven times on the same scale, and all reaction mixtures were combined and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 1000:1 to 50:1 petroleum ether / ethyl acetate to give the title compound (32 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.21 (s, 6H), 3.18 (d, J=1.76 Hz, 2H), 5.63 (br s, 1H), 6.42 (d, J=8.16 Hz, 1H), 7.02 (dd, J=8.16, 1.98 Hz, 1H), 7.10 (d, J=1.98 Hz, 1H. LCMS (ESI+) m / z 225.9, 227.9 (M+H) + .

[0209] Intermediate 22 5-Bromo-3,3-dimethyl-1-(piperidin-4-yl)-2,3-dihydro-1H-indole-hydrogen chloride (1 / 1) Intermediate 22A tert-Butyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylate To a solution of 5-bromo-3,3-dimethylindoline (18 g, 80 mmol) in methanol (200 mL), tert-butyl 4-oxopiperidine-1-carboxylate (31.7 g, 159 mmol) and acetic acid (10 mL, 175 mmol) were added, and the resulting mixture was stirred at 25 °C for 2 h and then cooled to 0 °C. NaCNBH (12.51 g, 199 mmol) was added, and the resulting mixture was stirred at 25 °C for 12 h. This reaction was repeated four times on the same scale. All reaction mixtures were combined, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography eluting with 10 / 1 petroleum ether / ethyl acetate to give the title compound (92 g). 1 H NMR (400 MHz, methanol-d4) δ 1.24 (s, 6H) 1.44 - 1.46 (m, 9H) 1.49 - 1.56 (m, 2H) 1.74 (br d, J=12.35 Hz, 2H) 2.84 (br s, 2H) 3.11 (s, 2H) 3.56 (tt, J=11.74, 3.69 Hz, 1H) 4.17 (br d, J=13.23 Hz, 2H) 6.38 (d, J=8.38 Hz, 1H) 7.02 (d, J=1.98 Hz, 1H) 7.08 (dd, J=8.38, 1.98 Hz, 1H).

[0210] Intermediate 22B 5-Bromo-3,3-dimethyl-1-(piperidin-4-yl)-2,3-dihydro-1H-indole-hydrogen chloride (1 / 1) To a solution of Intermediate 22A (20 g, 48.9 mmol) in methanol (100 mL) was added 4 M HCl in methanol (100 mL, 400 mmol), and the resulting mixture was stirred at 25° C. for 4 hours. This reaction was repeated three times on the same scale. All reaction mixtures were combined, concentrated, and washed with ethyl acetate to give the title compound as the HCl salt (70 g). 1H NMR (400 MHz, methanol-d4) δ 1.31 (s, 6H) 1.85 - 2.09 (m, 4H) 3.08 - 3.22 (m, 2H) 3.28 (s, 2H) 3.52 (br d, J=12.79 Hz, 2H) 3.83 - 3.98 (m, 1H) 6.64 - 6.71 (m, 1H) 7.19 (d, J=1.98 Hz, 1H) 7.22 (dd, J=8.27, 1.87 Hz, 1H).

[0211] Intermediate 23 2-[4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]ethan-1-ol-hydrogen chloride (1 / 1) To a solution of intermediate 22 (15 g, 39.3 mmol) in methanol (150 mL) were added K2CO3 (27.1 g, 196 mmol) and 2-bromoethanol (12.26 g, 98 mmol), and the resulting mixture was stirred at 60 °C for 16 h and then cooled to 25 °C. This reaction was repeated three times on the same scale. All reaction mixtures were combined, filtered, and the solid was washed with methanol. The filtrate was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was poured into a 4 M HCl solution in ethyl acetate (200 mL), concentrated, washed with methanol, and dried under reduced pressure to give the title compound as the HCl salt (33 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.22 (s, 6H) 1.81 (br d, J=12.79 Hz, 2H) 1.92 - 2.15 (m, 2H) 3.04 - 3.36 (m, 6H) 3.58 (br d, J=11.91 Hz, 2H) 3.65 - 3.83 (m, 3H) 6.29 - 6.59 (m, 1H) 7.03 - 7.25 (m, 2H) 10.39 (br s, 1H).

[0212] Intermediate 24 [4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]boronic acid The flask was dried in a vacuum oven at 50 °C for 1 hour, cooled under a nitrogen atmosphere, then charged with ethylene glycol (34 mL) and methanol (136 mL) and sparged with nitrogen for 1 hour. A separate flask was charged with oven-dried potassium acetate (13.37 g, 136 mmol), dried in a vacuum oven at 50 °C for 1 hour, and cooled to ambient temperature under a nitrogen atmosphere. This flask was charged with Intermediate 3 (32.05 g, 68.1 mmol), diboronic acid (12.22 g, 136 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (1.746 g, 3.41 mmol) and sparged with nitrogen for 1 hour. Both flasks were cooled to 0 °C, and the contents of the first flask were transferred to the second flask via cannula under a nitrogen atmosphere. The resulting mixture was stirred at 10-20°C for 2 hours and then quenched by cannulation into vigorously stirred water. After stirring for 10 minutes, the solid was collected by filtration and washed with water. This solid was dissolved in 10% methanol in dichloromethane (4 L), and the resulting solution was washed with brine, dried over MgSO4, and filtered. After concentration, the mixture was filtered through a silica gel plug using 15% methanol in dichloromethane to give the title compound (21.3 g). 1H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 7.7 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.96 (s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.30 - 7.23 (m, 2H), 4.63 - 4.43 (m, 2H), 4.27 (qd, J = 7.6, 3.8 Hz, 1H), 3.89 (dt, J = 6.4, 4.0 Hz, 1H), 3.83 (s, 3H), 2.02 (qq, J = LCMS (APCI) m / z 435.38 (M+H) + .

[0213] Intermediate 25 [4-({[(1S,2S)-2-{[2-amino-5-(trifluoromethyl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]boronic acid Intermediate 25A 2-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide Under a nitrogen atmosphere, N,N-diisopropylethylamine (4.45 mL, 25.5 mmol) was added to a solution of 2-amino-5-(trifluoromethyl)pyridine-3-carboxylic acid (5.25 g, 25.5 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 10.65 g, 28.0 mmol) in N,N-dimethylformamide (42.5 mL), and the resulting mixture was stirred for 1 h. Intermediate 1 (7.89 g, 25.7 mmol) was added, followed by N,N-diisopropylethylamine (9.34 mL, 53.5 mmol), and the resulting mixture was stirred for 1 h. The mixture was partitioned with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was triturated with dichloromethane and filtered to give the title compound (8.52g). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 7.6 Hz, 1H), 8.39 (dt, J = 2.3, 0.9 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.72 (s, 2H), 7.54 - 7.44 (m, 2H), 7.35 - 7.22 (m, 2H), 4.52 (d, J = 1.9 Hz, 2H), 4.25 (qd, J = 7.5, 3.8 Hz, 1H), 3.92 - 3.82 (m, 1H), 2.07 - 1.96 (m, 1H), 1.95 - 1.85 (m, 1H), 1.78 - 1.47 (m, 4H). MS (DCI+) m / z 458.0 (M+H) + .

[0214] Intermediate 25B [4-({[(1S,2S)-2-{[2-amino-5-(trifluoromethyl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]boronic acid A mixture of Intermediate 25A product (8.52 g, 18.59 mmol) and potassium acetate (3.65 g, 37.2 mmol) was dried in a vacuum oven at 50 °C for 1 hour. The mixture was cooled under a nitrogen atmosphere, and diboronic acid (3.33 g, 37.2 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.476 g, 0.930 mmol) were added under a nitrogen atmosphere. A 30% ethylene glycol / methanol mixture (100 mL) was sparged with nitrogen for 1 hour, then cooled to 0 °C and transferred via cannula. After 30 minutes, a thick slurry formed. 30% ethylene glycol / methanol (100 mL) was added. After 1 hour, the mixture was poured into water, and the precipitate was collected by filtration and washed with water. The precipitate was dissolved in 2% methanol / dichloromethane (400 mL) and ammonium pyrrolidinedithiocarbamate (1 g) was added. The resulting mixture was stirred for 15 minutes, then dried over MgSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-5% methanol / dichloromethane to give the title compound (3.36 g). 1 H NMR (501 MHz, DMSO-d6-D2O) δ 8.36 (dd, J = 2.4, 1.0 Hz, 1H), 8.14 (dd, J = 2.5, 0.7 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.28 - 7.21 (m, 2H), 4.57 - 4.45 (m, 2H), 4.24 (ddd, J = 8.0, 6.4, 4.1 Hz, 1H), 3.86 (dt, J = 6.3, 4.0 Hz, 1H), 2.00 (dtd, J = 12.9, 7.9, 5.1 Hz, 1H), 1.93 - 1.83 (m, 1H), 1.75 - 1.58 (m, 3H), 1.52 (ddt, J = 13.1, 8.5, 6.9 Hz, 1H). MS (ESI-) m / z 422.1 (MH) - .

[0215] Intermediate 26 [4-({[(3R,4S)-4-{[2-amino-5-(trifluoromethyl)pyridine-3-carbonyl]amino}oxolan-3-yl]oxy}methyl)phenyl]boronic acid Intermediate 26A 2-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-5-(trifluoromethyl)pyridine-3-carboxamide To a solution of 2-amino-5-(trifluoromethyl)pyridine-3-carboxylic acid (14.24 g, 44.5 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (18.61 g, 48.9 mmol) in N,N-dimethylformamide (37.1 mL) was added N-ethyl-N-isopropylpropan-2-amine (16.32 mL, 93 mmol), and the resulting mixture was stirred for 1 h. A solution of Intermediate 28 (12.35 g, 45.4 mmol) in N,N-dimethylformamide (37.1 mL) was added via cannula, followed by N-ethyl-N-isopropylpropan-2-amine (7.77 mL, 44.5 mmol), and the resulting mixture was stirred for 2 h. 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (18 g, 47.3 mmol) and N-ethyl-N-isopropylpropan-2-amine (40 mL, 230 mmol) were added, and the resulting mixture was stirred for 2 h. The mixture was partitioned with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over MgSO, filtered, and concentrated, and the residue was purified by silica gel flash chromatography eluting with 0–5% methanol / dichloromethane to give the title compound (14.3 g). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 6.7 Hz, 1H), 8.44 - 8.37 (m, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.74 (s, 2H), 7.56 - 7.52 (m, 2H), 7.34 - 7.28 (m, 2H), 4.67 (d, J = 12.4 Hz, 1H), 4.57 (d, J = 12.4 Hz, 1H), 4.43 (dddd, J = 6.5, 5.2, 3.3, 1.5 Hz, 1H), 4.09 (dt, J = 4.7, 1.8 Hz, 1H), 4.01 (dd, J = MS (ESI+) m / z 461.8 (M+H) + .

[0216] Intermediate 26B [4-({[(3R,4S)-4-{[2-amino-5-(trifluoromethyl)pyridine-3-carbonyl]amino}oxolan-3-yl]oxy}methyl)phenyl]boronic acid A mixture of the product from Step 26A (4.84 g, 10.52 mmol) and potassium acetate (2.167 g, 22.08 mmol) was dried in a vacuum oven at 50°C for 30 minutes. The mixture was cooled under a nitrogen atmosphere, and tetrahydroxydiboron (1.886 g, 21.03 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.269 g, 0.526 mmol) were added. A 30% methanol / ethylene glycol mixture (35.1 mL) was sparged with nitrogen for 1 hour, then cooled to 0°C and transferred via cannula. The resulting mixture was stirred for 2 hours and poured into water. This mixture was extracted with 5% methanol / dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-20% methanol / dichloromethane to give the title compound (1.9 g). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 2.4, 1.0 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.80 - 7.68 (m, 2H), 7.29 (d, J = 7.8 Hz, 2H), 4.67 (d, J = 12.4 Hz, 1H), 4.56 (d, J = 12.4 Hz, 1H), 4.42 (ddd, J = 5.6, 3.5, 1.5 Hz, 1H), 4.07 (dt, J = 4.9, 1.9 Hz, 1H), 4.00 (dd, J = 9.4, 6.2 Hz, 1H), 3.91 (dd, J = 10.1, 4.8 Hz, 1H), 3.75 - 3.71 (m, 2H), 3.38 (s, 1H), 3.15 (s, 1H). MS (ESI+) m / z (M+H) + 426.3.

[0217] Intermediate 27 Bis(2-nitrobenzene-1-sulfonic acid) [(2-nitrobenzene-1-sulfonyl)azanediyl]di(ethane-2,1-diyl) To a solution of 2,2'-azanediyldiethanol (10 g, 95 mmol) in dichloromethane (700 mL) was added 2-nitrobenzene-1-sulfonyl chloride (65.3 g, 295 mmol) and triethylenediamine (33.1 g, 295 mmol) in several portions at 0 °C, and the resulting mixture was stirred at 25 °C for 1 h. The mixture was poured into water, and the organic phase was washed with 2 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 5 / 1 petroleum ether / ethyl acetate to give the title compound. 1H NMR (400 MHz, CDCl3) δ 3.84 (t, J=5.32 Hz, 4H), 4.42 (t, J=5.32 Hz, 4H), 7.59 - 7.68 (m, 1H), 7.70 - 7.76 (m, 2H), 7.77 - 7.88 (m, 6H), 8.05 (dd, J=5.81, 3.48 Hz, 1H), 8.12 (d, J=7.34 Hz, 2H).

[0218] Intermediate 28 (3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-amine To a solution of (3R,4S)-4-aminotetrahydrofuran-3-ol (7.5 g, 72.7 mmol) in N,N-dimethylformamide (145 mL) was added 1 M potassium tert-butoxide in tetrahydrofuran (100 mL, 100 mmol) via cannula at 17 °C, and the resulting mixture was stirred at 17 °C for 30 min. 1-Bromo-4-(bromomethyl)benzene (21.81 g, 87 mmol) was added in several portions, resulting in a slight exotherm and the formation of a precipitate. The cooling bath was removed, and the mixture was stirred at ambient temperature for 2 h. The reaction was quenched by the addition of methanol (10 mL) and stirred for 30 min. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0–10% methanol / dichloromethane, to give the title compound (14.7 g). MS (ESI+) m / z 272, 274 (M+H) + .

[0219] Intermediate 29 2-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide To a solution of Intermediate 28 (25.07 g, 92 mmol) in N,N-dimethylformamide (200 mL), Intermediate 2 (16.75 g, 77 mmol) and N-ethyl-N-isopropylpropan-2-amine (33.2 mL, 192 mmol) were added, and the mixture was stirred until most of the solids dissolved. 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (32.1 g, 84 mmol) was added, and the resulting mixture was stirred at ambient temperature overnight. The mixture was poured into water, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was treated with mercapto-modified silica gel (PhosPhonics SPM32, 3 g), stirred for 30 minutes, dried over Na2SO4, filtered, and concentrated to approximately 500 mL. The mixture was allowed to stand overnight, at which time a white precipitate formed. The resulting slurry was further concentrated to 400 mL, and heptane (100 mL) was added. The resulting mixture was allowed to stand for 30 minutes, and the precipitate was collected by filtration and rinsed with 1:1 ethyl acetate / heptane to give the first crop (17.7 g). Further concentration of the mother liquor yielded additional precipitate, which was precipitated in hot ethanol to give a second crop (3.93 g). A third crop was then recovered from the filtrate (862 mg), giving a total of 22.21 g of the title compound. MS (ESI+) m / z 472, 474 (M+H) + .

[0220] Intermediate 30 [4-({[(3R,4S)-4-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}oxolan-3-yl]oxy}methyl)phenyl]boronic acid A mixture of Intermediate 29 (1.0 g, 2.12 mmol), tetrahydroxydiboron (380 mg, 4.23 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (42 mg, 0.053 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1-1'-biphenyl]-2-yl)phosphine (61 mg, 127 mmol), and potassium acetate (436 mg, 4.45 mmol) was degassed with nitrogen for 30 minutes. Nitrogen-sparged ethanol (10 mL) was added, and the resulting mixture was heated at 80 °C for 1.5 hours. The mixture was cooled to ambient temperature, filtered, and rinsed with ethanol. The filtrate was concentrated, and the residue was dissolved in 0.1 N NaOH (100 mL). The resulting aqueous mixture was washed with CHCl, filtered, and the filtrate was adjusted to pH 7 by adding 10% citric acid. The resulting slurry was stirred for 2 h, and the precipitate was collected by filtration and rinsed with water to give the title compound (590 mg). MS (ESI+) m / z 438 (M+H) + .

[0221] Intermediate 31 6-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide To a suspension of Intermediate 7 (100 g, 429 mmol) in N,N-dimethylformamide (1600 mL) was added N-ethyl-N-isopropylpropan-2-amine (150 mL, 858 mmol), followed by N 1 -((ethylimino)methylene)-N 3 ,N 3To the resulting solution was added 1H-dimethylpropane-1,3-diamine hydrochloride (123 g, 643 mmol). 1H-Benzo[d][1,2,3]triazol-1-ol hydrate (8.21 g, 42.9 mmol) was added, and the resulting mixture was stirred for 10 minutes. Intermediate 1 (131 g, 429 mmol) was added, and the resulting mixture was stirred at ambient temperature for 12 hours. The mixture was transferred to the ethyl acetate layer, and this organic layer was washed sequentially with water, saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was suspended in methyl tert-butyl ether, and the resulting suspension was stirred vigorously for 2.5 hours, filtered, and dried under reduced pressure to give the title compound (92 g), which was used without further purification. 1 H NMR (501 MHz, DMSO-d6) δ 8.54 (d, J = 2.6 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.25 (td, J = 8.2, 2.7 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.32 - 7.14 (m, 5H), 4.59 - 4.46 (m, 2H), 4.27 (qd, J = 7.6, 3.8 Hz, 1H), 3.86 (dt, J = 6.3, 3.9Hz, 1H), 2.02 (dtd, J = 12.9, 7.9, 5.0 Hz, 1H), 1.95 - 1.84 (m, 1H), 1.79 - 1.46 (m, 4H). MS (ESI+) m / z 485.2 (M+H) + .

[0222] Intermediate 32 6-Amino-6'-fluoro-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl][3,3'-bipyridine]-5-carboxamide To a mixture of Intermediate 31 (50 g, 103 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (39.2 g, 155 mmol), and potassium acetate (20.22 g, 206 mmol), 2-methyltetrahydrofuran (500 mL) was added, and the resulting solution was degassed with nitrogen for 2 hours. Tris(dibenzylideneacetone)dipalladium(0) (0.943 g, 1.030 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.964 g, 4.12 mmol) were quickly added, and the resulting mixture was heated at 75 °C overnight. The mixture was cooled, filtered, and rinsed with tetrahydrofuran. The filtrate was transferred to the ethyl acetate layer, which was washed with water and brine, dried over MgSO4, and concentrated. Silica gel flash chromatography eluting with 45-90% ethyl acetate / heptane afforded the title compound (48 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.6 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.23 ​​(td, J = 8.2, 2.7 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.33 - 7.16 (m, 5H), 4.66 - 4.48 (m, 2H), 4.37 - 4.20 (m, 1H), 3.89 - 3.82 (m, 1H), 2.09 - 1.95 (m, 1H), 1.89 (dtd, J = 8.3, 6.6, 5.0 Hz, 1H), 1.76 - 1.45 (m, 4H), 1.23 (s, 12H). MS (ESI+) m / z 533.4 (M+H) + .

[0223] Intermediate 33 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]pyridine-3-carboxamide A solution of Intermediate 3 (0.86 g, 1.828 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.929 g, 3.66 mmol) in degassed dioxane (10 mL) was treated with potassium acetate (0.538 g, 5.49 mmol) followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.119 g, 0.146 mmol), and the mixture was heated at 105 °C for 2.5 h under a nitrogen atmosphere. After cooling to ambient temperature, the mixture was partitioned with ethyl acetate and water, and the solids were removed by filtration through diatomaceous earth. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel flash chromatography eluting with 0-10% methanol / ethyl acetate gave the title compound (620 mg). MS (ESI+) m / z 518.5 (M+H) + .

[0224] Intermediate 34 2-Amino-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]-5-(trifluoromethyl)pyridine-3-carboxamide A mixture of Intermediate 25A (200 mg, 0.436 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (222 mg, 0.873 mmol), tetrakis(triphenylphosphine)palladium(0) (25.2 mg, 0.022 mmol), and potassium acetate (128 mg, 1.309 mmol) was degassed and backfilled with nitrogen. Dioxane (2.2 mL) was added, and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was directly purified by silica gel flash chromatography eluting with 0–30% ethyl acetate / heptane to give the title compound (193 mg). 1 H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 2.3, 1.0 Hz, 1H), 7.86 - 7.70 (m, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 7.7 Hz, 2H), 6.77 (s, 2H), 5.88 (d, J = 7.1 Hz, 1H), 4.75 - 4.57 (m, 2H), 4.35 (qd, J = 7.0, 4.3 Hz, 1H), 3.84 (dt, J = 6.5, 4.4 Hz, 1H), 2.28 (dtd, J = 13.4, 7.8, 5.3Hz, 1H), 2.05 - 1.82 (m, 2H), 1.82 - 1.67 (m, 2H), 1.50 (tt, J = 13.6, 6.7 Hz, 1H), 1.34 (s, 12H). LCMS (ESI+) m / z 506.36 (M+H) + .

[0225] Intermediate 35 (3S,4S)-4-[(4-bromophenyl)methoxy]-1-methylpyrrolidin-3-amine Intermediate 35A (3S,4S)-tert-butyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-hydroxypyrrolidine-1-carboxylate A mixture of tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (5 g, 24.72 mmol), phthalic anhydride (3.66 g, 24.72 mmol), toluene (125 mL), and triethylamine (2.50 g, 24.72 mmol) was heated to reflux overnight in a Dean-Stark apparatus. The mixture was cooled to ambient temperature and diluted with ethyl acetate and 10% citric acid. The precipitate (4.48 g) was collected by filtration. The ethyl acetate layer was further washed with 1N NaOH, water, and brine, dried over Na2SO4, and concentrated to give additional product (2.46 g). An additional crop (518 mg) was recovered from the aqueous layer, yielding a combined total of 7.46 g. MS (ESI+) m / z 233.1 (M-Boc) + , 387.2 (M+methanol+Na) + .

[0226] Intermediate 35B 2-[(3S,4S)-4-Hydroxypyrrolidin-3-yl]-1H-isoindole-1,3(2H)-dione To a solution of Intermediate 35A (6.61 g, 19.89 mmol) in dioxane (40 mL) / methanol (10 mL) was added 4N HCl in dioxane (26 mL, 104 mmol), and the resulting mixture was stirred for 90 minutes (until gas evolution ceased). The mixture was diluted with methyl tert-butyl ether (50 mL) and allowed to stand at ambient temperature for 1.5 hours. The precipitate was collected and rinsed with methyl tert-butyl ether to give the title compound as the HCl salt (5.11 g). MS (ESI+) m / z 233.1 (M+H) + .

[0227] Intermediate 35C 2-[(3S,4S)-4-Hydroxy-1-methylpyrrolidin-3-yl]-1H-isoindole-1,3(2H)-dione To a solution of Intermediate 35B (2 g, 7.44 mmol) in acetonitrile (37.2 mL) was added 37% aqueous formaldehyde (2.79 mL, 37.2 mmol), followed by the addition of sodium triacetoxyborohydride (5.52 g, 26.1 mmol) in several portions, while maintaining the temperature below 25 °C. The reaction was stirred at ambient temperature for 3 h and poured into saturated NaHCO (150 mL). The mixture was stirred for 20 min, extracted with ethyl acetate, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0-15% methanol / dichloromethane, to give the title compound (1.37 g). MS (ESI+) m / z 247.3 (M+H) + .

[0228] Intermediate 35D 2-{(3S,4S)-4-[(4-bromophenyl)methoxy]-1-methylpyrrolidin-3-yl}-1H-isoindole-1,3(2H)-dione A solution of Intermediate 35C (500 mg, 2.030 mmol) in tetrahydrofuran (10 mL) was cooled in an ice bath, and 1 M potassium tert-butoxide in tetrahydrofuran (2.23 mL, 2.23 mmol) was added. The resulting mixture was stirred at 4-7 °C for 20 min, and 1-bromo-4-(bromomethyl)benzene (609 mg, 2.436 mmol) was added. The ice bath was removed, and the mixture was stirred for 30 min. The mixture was quenched with methanol, stirred for 1 h, and concentrated. Purification by silica gel flash chromatography, eluting with 0-7% methanol / CHCl, gave the title compound (440 mg). MS (ESI+) m / z 415.2, 417.2 (M+H). + , Br pattern.

[0229] Intermediate 35E (3S,4S)-4-[(4-bromophenyl)methoxy]-1-methylpyrrolidin-3-amine To a solution of Intermediate 35D (3.4 g, 8.19 mmol) in ethanol (80 mL) was added hydrazine hydrate (0.798 mL, 16.37 mmol), and the resulting mixture was heated to reflux for 3 hours, then cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was concentrated and partitioned with 1N NaOH and dichloromethane. The organic extract was dried over Na2SO4 and concentrated to give the title compound (2.16 g). MS (ESI+) m / z 285.2, 287.2 (M+H) + , Br pattern.

[0230] Intermediate 36 2-Amino-5-bromo-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}pyridine-3-carboxamide Intermediate 36A tert-Butyl {(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}carbamate A mixture of Intermediate 1 (10 g, 32.6 mmol), tetrahydrofuran (100 mL), di-tert-butyl dicarbonate (32.6 mL, 32.6 mmol), triethylamine (11.36 mL, 82 mmol), and 4-dimethylaminopyridine (0.398 g, 3.26 mmol) was stirred at ambient temperature for 2 days. The mixture was diluted with ethyl acetate, filtered, concentrated, and purified by silica gel flash chromatography eluting with 0-15% ethyl acetate / heptane to give the title compound (4.84 g). 1H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.42 (m, 2H), 7.32 - 7.19 (m, 2H), 6.88 (d, J = 7.7 Hz, 1H), 4.67 - 4.33 (m, 2H), 3.74 (d, J = 5.9 Hz, 1H), 3.68 (dt, J = 6.1, 3.5 Hz, 1H), 1.93 - 1.83 (m, 1H), 1.79 (ddd, J = 11.7, 7.9, 5.6 Hz, 1H), 1.68 - 1.48 (m, 3H), 1.45 - 1.32 (m, 10H). MS (DCI+) m / z 387.1 (M+NH4) + .

[0231] Intermediate 36B tert-Butyl [(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]carbamate A solution of Intermediate 36A (3.84 g, 10.37 mmol), potassium acetate (2.036 g, 20.74 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.95 g, 15.56 mmol) in 2-methyltetrahydrofuran (50 mL) was sparged with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) (0.095 g, 0.104 mmol) and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.203 g, 0.425 mmol) were added, and the resulting mixture was heated at 75 °C for 16 h and then cooled to ambient temperature. The mixture was diluted with methyl tert-butyl ether, filtered, and the filtrate was washed with water and brine, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-20% ethyl acetate / heptane to give the title compound (3.0 g). 1H NMR (501 MHz, DMSO-d6) δ 7.72 - 7.53 (m, 2H), 7.35 - 7.24 (m, 2H), 6.86 (d, J = 7.8 Hz, 1H), 4.63 - 4.46 (m, 2H), 3.75 (s, 1H), 3.68 (dt, J = 6.4, 3.6 Hz, 1H), 1.93 - 1.84 (m, 1H), 1.79 (ddd, J = 11.9, 7.9, 6.0 Hz, 1H), 1.68 - 1.49 (m, 3H), 1.43 - 1.36 (m, 10H), 1.28 (s, 12H). MS (DCI+) m / z 435.3 (M+NH4) + .

[0232] Intermediate 36C tert-Butyl {(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}carbamate A mixture of Intermediate 36B (3 g, 7.19 mmol), Intermediate 23 (2.54 g, 7.19 mmol), and Cs2CO3 (4.68 g, 14.38 mmol) in dioxane (30 mL) / water (10 mL) was sparged with nitrogen for 1 hour. Tris(dibenzylideneacetone)dipalladium(0) (0.066 g, 0.072 mmol) and 4-(di-tert-butylphosphino)-N,N-dimethylaniline (0.042 g, 0.158 mmol) were added, and the resulting mixture was heated at 75 °C for 6 hours and then cooled to ambient temperature. Ammonium pyrrolidinedithiocarbamate (200 mg) and water (10 mL) were added, and after stirring for 15 minutes, the mixture was partitioned with ethyl acetate and water. The aqueous layer was washed with ethyl acetate, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-5% methanol / dichloromethane to give the title compound (2.7 g). 1H NMR (500 MHz, DMSO-d6) δ 7.52 - 7.47 (m, 2H), 7.32 - 7.24 (m, 4H), 6.89 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H), 4.37 (s, 1H), 3.78 (h, J = 7.4, 6.7 Hz, 1H), 3.71 (dt, J = 6.4, 3.5 Hz, 1H), 3.49 (t, J = 6.4 Hz, 2H), 3.44 - 3.36 (m, 2H), 3.14 (s, 2H), 2.94 (dt, J = 12.8, 3.5 Hz, 2H), 2.40 (t, J = 6.3 Hz, 2H), 2.07 (td, J = 11.5, 2.8 Hz, 2H), 1.89 (m, 1H), 1.80 (dtt, J = 11.9, 7.3, 3.6 Hz, 1H), 1.71 - 1.50 (m, 7H), 1.40 (s, 9H), 1.26 (s, 6H). MS (DCI+) m / z 564.4 (M+H) + .

[0233] Intermediate 36D 2-(4-{5-[4-({[(1S,2S)-2-aminocyclopentyl]oxy}methyl)phenyl]-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl}piperidin-1-yl)ethan-1-ol A solution of Intermediate 36C (0.211 g, 0.374 mmol) in tetrahydrofuran (3.8 mL) was cooled to 0° C., and 4 M HCl in dioxane (0.936 mL, 3.74 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred until the reaction was complete. Concentration afforded the title compound as the HCl salt (0.23 g). 1H NMR (501 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.29 (s, 3H), 7.58 - 7.51 (m, 2H), 7.39 - 7.30 (m, 4H), 6.63 (d, J = 8.2 Hz, 1H), 4.52 (s, 2H), 3.98 (dt, J = 6.3, 4.2 Hz, 1H), 3.79 (dd, J = 6.3, 4.3 Hz, 2H), 3.72 - 3.63 (m, 1H), 3.55 - 3.36 (m, 2H), 3.23 - 3.03 (m, 6H), 2.18 - 1.93 (m, 4H), 1.86 (dt, J = 14.9, 7.4 Hz, 2H), 1.78 - 1.47 (m, 5H), 1.29 (s, 6H). MS (DCI+) m / z 464.4 (M+H) + .

[0234] Intermediate 36E 2-Amino-5-bromo-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}pyridine-3-carboxamide To Intermediate 36D (0.230 g, 0.401 mmol) were added 2-amino-5-bromopyridine-3-carboxylic acid (0.096 g, 0.442 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.115 g, 0.602 mmol), 1-hydroxybenzotriazole hydrate (0.092 g, 0.602 mmol), N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (0.351 mL, 2.007 mmol), and the resulting mixture was stirred for 16 hours. The mixture was partitioned with ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–5% methanol / dichloromethane to give the title compound (143 mg). 1H NMR (501 MHz, DMSO-d6) δ 8.41 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.56 - 7.41 (m, 2H), 7.32 - 7.24 (m, 4H), 7.20 (s, 2H), 6.50 (d, J = 8.1 Hz, 1H), 4.58 - 4.50 (m, 2H), 4.40 (s, 1H), 4.26 (qd, J = 7.6, 3.9 Hz, 1H), 3.87 (dt, J = 6.2, 3.9 Hz, 1H), 3.50 (q, J = 5.8 Hz, 3H), 3.14 (s, 2H), 2.96 (d, J = 11.0 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.11 (t, J = 11.0 Hz, 2H), 2.04 - 1.96 (m, 1H), 1.91 (dt, J = 12.3, 7.1 Hz, 1H), 1.75 - 1.45 (m, 8H), 1.26 (s, 6H). LCMS (APCI) 662.5 (M+H) + .

[0235] Intermediate 37 6-Amino-6'-fluoro-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl][3,3'-bipyridine]-5-carboxamide Intermediate 37A 6-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide To a solution of Intermediate 7 (0.25 g, 1.1 mmol) and triethylamine (217 g, 2.2 mmol) in N,N-dimethylformamide (5 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.45 g, 1.2 mmol) was added, followed by Intermediate 28 (0.29 mg, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and partitioned between water and ethyl acetate. The organic phase was dried over MgSO4, concentrated, and purified by silica gel flash chromatography eluting with 10% methanol / ethyl acetate to give the title compound (348 mg). 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.3 Hz, 1H), 8.16 (dt, J = 1.9, 0.9 Hz, 1H), 7.82 (ddd, J = 8.4, 7.5, 2.6 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.33 - 7.22 (m, 2H), 6.97 (ddd, J = 8.5, 3.0, 0.7 Hz, 1H), 6.76 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 4.83 (d, J = 12.3 Hz, 1H), 4.67 (d, J = 12.2 Hz, 1H), 4.62 (dd, J = 7.1, 4.3 Hz, 1H), 4.18 (t, J = 5.0 Hz, 1H), 4.13 (dd, J = 8.2, 6.0 Hz, 1H), 4.08 (dd, J = 9.9, 4.4 Hz, 1H), 3.94 (d, J = 9.9 Hz, 1H), 3.76 (dd, J = 9.9, 2.2 Hz, 1H). MS (DCI / NH3) m / z 488 (M+H) + .

[0236] Intermediate 37B 6-Amino-6'-fluoro-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl][3,3'-bipyridine]-5-carboxamide A mixture of Intermediate 37A (5 g, 10 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.2 g, 20 mmol), tetrakis(triphenylphosphine)palladium(0) (590 mg, 0.5 mmol), and potassium acetate (2 g, 21 mmol) was degassed with argon, and dioxane (40 mL) was added. The resulting mixture was stirred overnight at 110 °C under an argon atmosphere. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography on silica gel eluting with 10% methanol / ethyl acetate to give the title compound (5.2 g). 1 H NMR (501 MHz, CDCl3) δ 8.28 (d, J = 2.3 Hz, 1H), 8.13 (tt, J = 3.4, 0.9 Hz, 1H), 7.85 - 7.76 (m, 1H), 7.68 (dd, J = 5.6, 2.4 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.52 - 7.42 (m, 2H), 6.96 (tdd, J = 8.4, 3.0, 0.7 Hz, 1H), 6.87 (dd, J = 21.9, 7.1 Hz, 1H), 6.66 (d, J = 7.6 Hz, 2H), 4.92 (dd, J = 13.6, 12.2 Hz, 1H), 4.76 (t, J = 12.1 Hz, 1H), 4.73 - 4.64 (m, 1H), 4.25 - 4.08 (m, 3H), 4.01 - 3.93 (m, 1H), 3.85 - 3.76 (m, 1H), 1.36 (s, 9H). MS (DCI / NH3) m / z 535 (M+H) + .

[0237] Example 1 2-Amino-N-{(1S,2S)-2-[(4-{2-[3-(dimethylamino)propanoyl]-2,3-dihydro-1H-isoindol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 1A tert-Butyl 5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxylate Under a nitrogen atmosphere, a mixture of Intermediate 3 (0.15 g, 0.319 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (0.127 g, 0.367 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.021 g, 0.026 mmol), and K2CO3 (0.11 g, 0.797 mmol) in degassed dioxane (1.6 mL) / degassed water (0.5 mL) was heated at 100 °C for 3 h. The reaction was cooled to ambient temperature and partitioned with ethyl acetate and water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–10% methanol / ethyl acetate to give the title compound (143 mg). MS (ESI+) m / z 609.2 (M+H) + .

[0238] Process 1B 2-Amino-N-[(1S,2S)-2-{[4-(2,3-dihydro-1H-isoindol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A solution of the product of Step 1A (0.14 g, 0.230 mmol) and trifluoroacetic acid (0.354 mL, 4.60 mmol) in dichloromethane (2.5 mL) was stirred at ambient temperature for 3 hours. The mixture was concentrated, and the residue was dissolved in dichloromethane (60 mL) and washed with saturated NaHCO. The organic layer was dried over NaSO and concentrated to give the title compound (108 mg). MS (ESI+) m / z 509.2 (M+H) + .

[0239] Process 1C 2-Amino-N-{(1S,2S)-2-[(4-{2-[3-(dimethylamino)propanoyl]-2,3-dihydro-1H-isoindol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide To a mixture of 3-(dimethylamino)propanoic acid (6.08 mg, 0.052 mmol) and triethylamine (0.024 mL, 0.173 mmol) in N,N-dimethylformamide (0.3 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.019 g, 0.050 mmol), followed by the product of Step 1B (0.022 g, 0.043 mmol). The resulting mixture was stirred at ambient temperature for 4 h and purified directly by reverse-phase HPLC, eluting with 10–70% acetonitrile in water (0.1% trifluoroacetic acid), to give the title compound (10 mg) as the trifluoroacetate salt. 1H NMR (400 MHz, methanol-d4) δ 8.47 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.63 - 7.51 (m, 4H), 7.47 - 7.40 (m, 3H), 4.71 - 4.63 (m, 3H), 4.49 - 4.37 (m, 1H), 4.07 - 3.96 (m, 1H), 3.90 (s, 3H), 3.09 - 3.01 (m, 11H), 2.27 - 2.12 (m, 1H), 2.12 - 1.98 (m, 1H), 1.92 - 1.73 (m, 3H), 1.73 - 1.58 (m, 1H). MS (ESI+) m / z 607.4 (M+H) + .

[0240] Example 2 2-Amino-N-{(1S,2S)-2-[(4-{1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 2A 1-(5-Bromo-2,3-dihydro-1H-indol-1-yl)-2-(dimethylamino)ethan-1-one To a mixture of 5-bromoindoline (0.50 g, 2.52 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.387 g, 2.52 mmol), N,N-dimethylformamide (9.5 mL), N-methylmorpholine (1.11 mL, 10.10 mmol), and 2-(dimethylamino)acetic acid (0.299 g, 2.90 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.678 g, 3.53 mmol) was added, and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was diluted with water and extracted with 1:1 ether / ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0–5% methanol / dichloromethane, to give the title compound (580 mg). MS (DCI+) m / z 283.0 (M+H) + .

[0241] Process 2B 2-Amino-N-{(1S,2S)-2-[(4-{1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 33 (0.03 g, 0.058 mmol), the product of Step 2A (0.019 g, 0.067 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (3.79 mg, 4.64 μmol), and KCO (0.022 g, 0.162 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 95 °C for 1.5 h. The mixture was cooled to ambient temperature and purified directly by reverse-phase HPLC, eluting with 10–70% acetonitrile in water (0.1% trifluoroacetic acid) to give the title compound (29 mg) as the trifluoroacetate salt. 1H NMR (400 MHz, methanol-d4) δ 8.48 (d, J = 2.1 Hz, 1H), 8.21 - 8.11 (m, 2H), 7.96 (s, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.49 - 7.45 (m, 1H), 7.44 - 7.35 (m, 3H), 4.70 - 4.59 (m, 2H), 4.47 - 4.37 (m, 1H), 4.33 (s, 2H), 4.16 - 4.08 (m, 2H), 4.05 - 3.96 (m, 1H), 3.90 (s, 3H), 3.34 - 3.26 (m, 2H), 3.04 (s, 6H), 2.26 - 2.12 (m, 1H), 2.12 - 2.00 (m, 1H), 1.93 - 1.73 (m, 3H), 1.71 - 1.57 (m, 1H). MS (ESI+) m / z 594.3 (M+H) + .

[0242] Example 3 2-Amino-N-[(1S,2S)-2-{[4-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 2B, except 5-bromo-1-methylindolin-2-one was used in place of the product of Step 2A. 1H NMR (500 MHz, methanol-d4) δ 8.47 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.54 - 7.44 (m, 4H), 7.43 - 7.37 (m, 2H), 7.03 - 6.96 (m, 1H), 4.71 - 4.60 (m, 2H), 4.45 - 4.37 (m, 1H), 3.99 (dq, J = 6.5, 4.7 Hz, 1H), 3.89 (s, 3H), 3.58 (s, 2H), 3.24 (s, 3H), 2.24 - 2.12 (m, 1H), 2.11 - 2.00 (m, 1H), 1.89 - 1.73 (m, 3H), 1.69 - 1.58 (m, 1H). MS (ESI+) m / z 537.26 (M+H) + .

[0243] Example 4 tert-Butyl 4-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}piperidine-1-carboxylate Process 4A tert-Butyl 4-(5-bromo-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylate A solution of 5-bromoindoline (0.5 g, 2.52 mmol) in acetic acid (6 mL) was treated with tert-butyl 4-oxopiperidine-1-carboxylate (0.578 g, 2.90 mmol), followed by sodium triacetoxyborohydride (0.963 g, 4.54 mmol) added portionwise over 5 minutes. The resulting mixture was stirred at ambient temperature for 1 hour, poured into ethyl acetate and water, cooled in an ice bath, and adjusted to pH ∼10 by the addition of 6N NaOH. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0–30% ethyl acetate / hexanes, to give the title compound (720 mg). MS (ESI+) m / z 380.9 (M+H) + .

[0244] Process 4B tert-Butyl 4-(5-bromo-1H-indol-1-yl)piperidine-1-carboxylate A solution of the product of Step 4A (0.67 g, 1.757 mmol) in tetrahydrofuran (8 mL) at 0°C was treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.439 g, 1.933 mmol) in tetrahydrofuran (4 mL) dropwise over 5 min. The resulting mixture was stirred at 0°C for 1 h and then stored at 10°C for 16 h. After stirring at ambient temperature for 1 h, the mixture was partitioned between ethyl acetate and water. 6N NaOH was added to the aqueous layer to adjust the pH to 10, and the two layers were vigorously shaken. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0–26% ethyl acetate / hexanes, to give the title compound (530 mg). 1H NMR (400 MHz, methanol-d4) δ 7.67 (d, J = 1.9 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 3.3 Hz, 1H), 7.23 (dd, J = 8.8, 1.9 Hz, 1H), 6.43 (dd, J = 3.3, 0.8 Hz, 1H), 4.51 (tt, J = 11.8, 4.0 Hz, 1H), 4.34 - 4.20 (m, 2H), 3.11 - 2.87 (m, 2H), 2.11 - 1.98 (m, 2H), 1.89 (qd, J = 12.5, 4.4 Hz, 2H), 1.49 (s, 9H). MS (ESI+) m / z 379.1 (M+H) + .

[0245] Process 4C tert-Butyl 4-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}piperidine-1-carboxylate A mixture of Intermediate 33 (0.04 g, 0.077 mmol), the product of Step 4B (0.033 g, 0.088 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.28 mg, 4.64 μmol) and K2CO3 (0.032 g, 0.232 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 90 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0–8% methanol / ethyl acetate to give the title compound (36 mg). 1H NMR (400 MHz, methanol-d4) δ 8.35 - 8.16 (m, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.78 - 7.63 (m, 3H), 7.59 - 7.42 (m, 3H), 7.42 - 7.28 (m, 4H), 6.49 (d, J = 3.2 Hz, 1H), 4.65 (q, J = 12.4 Hz, 2H), 4.60 - 4.55 (m, 1H), 4.48 - 4.36 (m, 1H), 4.35 - 4.22 (m, 2H), 3.97 (q, J = 5.6 Hz, 1H), 3.75 (s, 3H), 3.15 - 2.90 (m, 2H), 2.24 - 1.69 (m, 9H), 1.68 - 1.53 (m, 1H), 1.50 (s, 9H). MS (ESI+) m / z 690.2 (M+H) + .

[0246] Example 5 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[1-(piperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide A solution of the product from Example 4 (0.024 g, 0.035 mmol) in methanol (0.696 mL) at 0° C. was treated with 4 M HCl in dioxane (0.078 mL, 0.313 mmol) dropwise over 3 minutes. The resulting mixture was stirred at ambient temperature for 20 hours and then partitioned with ethyl acetate and saturated Na2CO3. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (19 mg). 1H NMR (500 MHz, methanol-d4) δ 8.23 ​​(d, J = 2.3 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.67 (d, J = 1.7 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.49 - 7.44 (m, 1H), 7.41 - 7.29 (m, 4H), 6.49 (dd, J = 3.3, 0.7 Hz, 1H), 4.65 (q, J = 12.4 Hz, 2H), 4.51 - 4.39 (m, 2H), 4.00 - 3.94 (m, 1H), 3.74 (s, 3H), 3.26 - 3.17 (m, 2H), 2.85 (td, J = 12.6, 2.7 Hz, 2H), 2.21 - 2.10 (m, 1H), 2.10 - 1.89 (m, 5H), 1.87 - 1.69 (m, 3H), 1.65 - 1.52 (m, 1H). MS (ESI+) m / z 590.2 (M+H) + .

[0247] Example 6 2-Amino-N-[(1S,2S)-2-({4-[1-(1-methylpiperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 6A 5-Bromo-1-(piperidin-4-yl)-1H-indole The title compound was prepared in a manner similar to Example 5, except that the product of Step 4B was used instead of the product of Example 4. MS (ESI+) m / z 279.0 (M+H) + .

[0248] Process 6B 5-Bromo-1-(1-methylpiperidin-4-yl)-1H-indole A solution of the product of Step 6A (0.0385 g, 0.138 mmol) in methanol (0.8 mL) was treated with acetic acid (0.016 mL, 0.276 mmol) and formaldehyde (37 wt % aqueous solution, 0.016 mL, 0.221 mmol), and the resulting mixture was stirred at ambient temperature for 15 minutes. Sodium triacetoxyborohydride (0.088 g, 0.414 mmol) was added, and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated, dissolved in water, and adjusted to pH 10 with 6N NaOH. The suspension was extracted with dichloromethane, dried over Na2SO4, and concentrated to give the title compound. MS (ESI+) m / z 295.2 (M+H) + .

[0249] Process 6C 2-Amino-N-[(1S,2S)-2-({4-[1-(1-methylpiperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except that the product of Step 6B was used instead of the product of Step 4B. 1 H NMR (501 MHz, methanol- d4 ) δ 8.23 ​​(d, J = 2.2 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.40 - 7.29 (m, 4H), 6.49 (d, J = 3.2 Hz, 1H), 4.65 (q, J = 12.3 Hz, 2H), 4.45 - 4.33 (m, 2H), 4.01 - 3.93 (m, 1H), 3.75 (s, 3H), 3.11 - 3.02 (m, 2H), 2.43 - 2.31 (m, 5H), 2.19 - 2.01 (m, 6H), 1.87 - 1.70 (m, 3H), 1.63 - 1.53 (m, 1H). MS (ESI+) m / z 604.2 (M+H)+ .

[0250] Example 7 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 7A 2-[4-(5-bromo-1H-indol-1-yl)piperidin-1-yl]ethan-1-ol A solution of the product of Step 6A (0.06 g, 0.215 mmol) in methanol (1.6 mL) was treated with K2CO3 (0.089 g, 0.645 mmol) followed by 2-bromoethanol (0.036 mL, 0.429 mmol), and the resulting mixture was stirred at ambient temperature for 30 h and then at 60 °C for 24 h. The mixture was filtered through diatomaceous earth using dichloromethane, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound (22 mg). MS (ESI+) m / z 323.2 (M+H) + .

[0251] Process 7B 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except that the product of Step 7A was used instead of the product of Step 4B. 1H NMR (501 MHz, methanol-d4) δ 8.23 ​​(d, J = 2.3 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.67 (d, J = 1.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.42 - 7.29 (m, 4H), 6.49 (d, J = 3.2 Hz, 1H), 4.65 (q, J = 12.3 Hz, 2H), 4.48 - 4.30 (m, 2H), 4.01 - 3.93 (m, 1H), 3.79 - 3.71 (m, 5H), 3.16 (d, J = 12.4 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.38 (td, J = 12.0, 2.6 Hz, 2H), 2.22 - 2.02 (m, 6H), 1.86 - 1.70 (m, 3H), 1.64 - 1.53 (m, 1H). MS (APCI+) m / z 634.4 (M+H) + .

[0252] Example 8 2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 8A tert-Butyl 4-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (0.5 g, 2.369 mmol) in tetrahydrofuran (10 mL) was treated with tert-butyl piperazine-1-carboxylate (0.794 g, 4.26 mmol) followed by titanium(IV) isopropoxide (2.082 mL, 7.11 mmol), and the resulting mixture was stirred at 65° C. for 4 hours. The mixture was cooled to ambient temperature, and sodium cyanoborohydride (0.298 g, 4.74 mmol) was added. The resulting mixture was heated at 65° C. for 15 hours and then cooled to ambient temperature. The mixture was diluted with ethyl acetate and washed with saturated NaHCO. The bilayer was filtered through diatomaceous earth using ethyl acetate, and the organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-5% methanol / dichloromethane to give the title compound (360 mg). MS (ESI+) m / z 381.1 (M+H) + .

[0253] Process 8B 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine The title compound was prepared in a manner similar to Example 5, except that the product of Step 8A was used instead of the product of Example 4. MS (APCI+) m / z 283.1 (M+H) + .

[0254] Process 8C 2-[4-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl]ethan-1-ol A solution of the product of Step 8B (0.75 g, 2.67 mmol) in methanol (12 mL) was treated with K2CO3 (0.922 g, 6.67 mmol) followed by 2-bromoethanol (0.34 mL, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for 24 h. The mixture was diluted with dichloromethane and filtered through diatomaceous earth. The filtrate was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound (508 mg). MS (ESI+) m / z 325.2 (M+H) + .

[0255] Process 8D 2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 33 (0.025 g, 0.048 mmol), the product of Step 8C (0.017 g, 0.053 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.053 mg, 2.90 μmol) and KCO (0.020 g, 0.145 mmol) in degassed water (0.15 mL) / degassed dioxane (0.5 mL) was heated at 80 °C for 90 min. The mixture was cooled to ambient temperature and purified directly by reverse-phase HPLC, eluting with 10–70% acetonitrile in water (0.1% trifluoroacetic acid) to give the title compound (27 mg) as the trifluoroacetate salt. 1H NMR (500 MHz, methanol-d4) δ 8.51 (dd, J = 2.6, 1.3 Hz, 1H), 8.20 (dd, J = 2.2, 1.1 Hz, 1H), 7.98 (dd, J = 5.3, 0.8 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.58 - 7.52 (m, 2H), 7.52 - 7.39 (m, 5H), 4.74 - 4.62 (m, 3H), 4.46 - 4.38 (m, 1H), 4.06 - 3.99 (m, 1H), 3.91 (d, J = 3.0 Hz, 3H), 3.87 - 3.82 (m, 2H), 3.46 - 3.34 (m, 3H), 3.24 - 2.90 (m, 8H), 2.42 - 2.26 (m, 2H), 2.24 - 2.14 (m, 1H), 2.11 - 2.01 (m, 1H), 1.89 - 1.75 (m, 3H), 1.69 - 1.59 (m, 1H). MS (ESI+) m / z 636.3 (M+H) + .

[0256] Example 9 2-Amino-N-{(1S,2S)-2-[(4-{2-[2-(dimethylamino)acetamido]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 9A 2-(Dimethylamino)-N-(5-iodo-2,3-dihydro-1H-inden-2-yl)acetamide A solution of 2-(dimethylamino)acetic acid (0.048 g, 0.463 mmol) and triethylamine (0.19 mL, 1.35 mmol) in N,N-dimethylformamide (1.3 mL) was treated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.169 g, 0.444 mmol), and the resulting mixture was stirred for 5 min. A solution of 5-iodo-2,3-dihydro-1H-inden-2-amine (0.1 g, 0.386 mmol) in N,N-dimethylformamide (0.2 mL) was added, and the resulting mixture was stirred at ambient temperature for 16 h. The mixture was partitioned with ethyl acetate and water, and the organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound (94 mg). MS (ESI+) m / z 345.0 (M+H) + .

[0257] Process 9B 2-Amino-N-{(1S,2S)-2-[(4-{2-[2-(dimethylamino)acetamido]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 8D, except using the product of Step 9A instead of the product of Step 8C. 1H NMR (400 MHz, methanol-d4) δ 8.50 (t, J = 2.0 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.85 (dd, J = 5.5, 0.8 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.44 - 7.37 (m, 3H), 7.37 - 7.31 (m, 1H), 7.26 (d, J = 7.9 Hz, 1H), 4.73 - 4.58 (m, 3H), 4.46 - 4.36 (m, 1H), 4.05 - 3.97 (m, 1H), 3.93 - 3.87 (m, 5H), 3.39 - 3.33 (m, 1H), 2.96 - 2.90 (m, 8H), 2.88 (d, J = 5.2 Hz, 1H), 2.24 - 1.99 (m, 2H), 1.89 - 1.72 (m, 3H), 1.69 - 1.57 (m, 1H). MS (ESI+) m / z 608.3 (M+H) + .

[0258] Example 10 2-Amino-N-{(1S,2S)-2-[(4-{2-[(1-methylpiperidine-4-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 10A N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-1-methylpiperidine-4-carboxamide The title compound was prepared in a manner similar to Step 9A, except 1-methylpiperidine-4-carboxylic acid was used instead of 2-(dimethylamino)acetic acid. MS (ESI+) m / z 385.1 (M+H) + .

[0259] Process 10B 2-Amino-N-{(1S,2S)-2-[(4-{2-[(1-methylpiperidine-4-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 8D, except using the product of Step 10A instead of the product of Step 8C. 1 H NMR (400 MHz, methanol-d4) δ 8.31 - 8.17 (m, 1H), 7.96 - 7.90 (m, 1H), 7.80 (dd, J = 6.1, 0.8 Hz, 1H), 7.73 (dd, J = 7.6, 0.9 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.43 - 7.27 (m, 4H), 7.22 (d, J = 7.9 Hz, 1H), 4.72 - 4.51 (m, 4H), 4.46 - 4.34 (m, 1H), 4.04 - 3.92 (m, 1H), 3.84 (d, J = 8.7 Hz, 3H), 3.27 - 3.20 (m, 1H), 2.96 - 2.75 (m, 4H), 2.25 (s, 3H), 2.21 - 1.92 (m, 5H), 1.89 - 1.69 (m, 7H), 1.66 - 1.51 (m, 1H). MS (ESI+) m / z 648.3 (M+H) + .

[0260] Example 11 2-Amino-N-{(1S,2S)-2-[(4-{2-[(1-methylazetidine-3-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 11A N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-1-methylazetidine-3-carboxamide The title compound was prepared in a manner similar to Step 9A, except 1-methylazetidine-3-carboxylic acid was used instead of 2-(dimethylamino)acetic acid. MS (ESI+) m / z 385.1 (M+H) + .

[0261] Process 11B 2-Amino-N-{(1S,2S)-2-[(4-{2-[(1-methylazetidine-3-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 8D, except using the product of Step 11A instead of the product of Step 8C. 1 H NMR (400 MHz, methanol-d4) δ 8.29 - 8.20 (m, 1H), 7.98 - 7.91 (m, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.43 - 7.32 (m, 3H), 7.32 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 4.73 - 4.58 (m, 3H), 4.46 - 4.36 (m, 1H), 4.01 - 3.91 (m, 1H), 3.84 (d, J = 12.3 Hz, 3H), 3.61 - 3.50 (m, 2H), 3.37 - 3.32 (m, 2H), 3.29 - 3.19 (m, 3H), 2.83 (dd, J = 15.8, 5.5 Hz, 2H), 2.33 (s, 3H), 2.22 - 2.10 (m, 1H), 2.09 - 2.01 (m, 1H), 1.87 - 1.69 (m, 3H), 1.66 - 1.53 (m, 1H). MS (ESI+) m / z 620.3 (M+H) + .

[0262] Example 12 2-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 12A tert-Butyl 4-(5-bromo-3,3-dimethylindolin-1-yl)piperidine-1-carboxylate A solution of 5-bromo-3,3-dimethylindoline (0.455 g, 2.012 mmol) in acetic acid (5.7 mL) was treated with tert-butyl 4-oxopiperidine-1-carboxylate (0.441 g, 2.213 mmol), followed by sodium triacetoxyborohydride (0.682 g, 3.22 mmol) added over 5 minutes. After stirring at ambient temperature for 2 hours, the mixture was poured into ethyl acetate and water, cooled in an ice bath, and adjusted to pH 10 by dropwise addition of 6N NaOH. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0-25% ethyl acetate / heptane, to give the title compound (670 mg). MS (ESI+) m / z 408.9 (M+H) + .

[0263] Process 12B 5-Bromo-3,3-dimethyl-1-(piperidin-4-yl)-2,3-dihydro-1H-indole The title compound was prepared in a manner similar to Example 5, except that the product of Step 12A was used instead of the product of Example 4. MS (ESI+) m / z 309.2 (M+H) + .

[0264] Process 12C 5-Bromo-3,3-dimethyl-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-indole The title compound was prepared similarly to Step 6B, except that the product of Step 12B was used instead of the product of Step 6A. MS (ESI+) m / z 323.3 (M+H) + .

[0265] Process 12D 2-Amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 24 (0.030 g, 0.069 mmol), the product of Step 12C (0.023 g, 0.072 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.93 mg, 4.14 μmol) and K2CO3 (0.029 g, 0.207 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 75 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane, followed by 0-100% dichloromethane solution (dichloromethane / methanol / NH4OH=89:10:1) to give the title compound (15 mg). 1H NMR (501 MHz, methanol-d4) δ 8.25 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.47 - 7.40 (m, 2H), 7.37 - 7.30 (m, 2H), 7.24 - 7.10 (m, 2H), 6.48 (d, J = 8.3 Hz, 1H), 4.67 - 4.62 (m, 2H), 4.46 - 4.36 (m, 1H), 4.01 - 3.92 (m, 1H), 3.83 (s, 3H), 3.53 - 3.40 (m, 1H), 3.18 (s, 2H), 3.03 - 2.92 (m, 2H), 2.31 (s, 3H), 2.25 - 2.10 (m, 3H), 2.09 - 1.97 (m, 1H), 1.84 - 1.68 (m, 7H), 1.65 - 1.53 (m, 1H), 1.28 (d, J = 6.5 Hz, 6H). MS (APCI+) m / z 634.41 (M+H) + .

[0266] Example 13 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 13A 2-[4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]ethan-1-ol A solution of the product of Step 12B (0.77 g, 2.490 mmol) in methanol (15 mL) was treated with K2CO3 (1.032 g, 7.47 mmol) followed by 2-bromoethanol (0.529 mL, 7.47 mmol), and the resulting mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-100% dichloromethane solution (dichloromethane / methanol / NH4OH = 89:10:1) to give the title compound (543 mg). MS (ESI+) m / z 353.2 (M+H) + .

[0267] Process 13B 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except using the product of Step 13A instead of the product of Step 12C. 1H NMR (501 MHz, methanol-d4) δ 8.25 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 8.2, 1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 4.69 - 4.58 (m, 2H), 4.48 - 4.37 (m, 1H), 4.01 - 3.92 (m, 1H), 3.83 (s, 3H), 3.71 (t, J = 6.1 Hz, 2H), 3.48 (p, J = 8.7, 7.5 Hz, 1H), 3.19 (s, 2H), 3.11 (d, J = 11.7 Hz, 2H), 2.59 (t, J = 6.1 MS (ESI+) m / z 664.0 (M+H) + .

[0268] Example 14 2-Amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 30 (0.037 g, 0.085 mmol), the product of Step 7A (0.029 g, 0.089 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphinedichloropalladium(II)) (3.59 mg, 5.08 μmol) and K2CO3 (0.029 g, 0.212 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 75 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0–10% methanol / dichloromethane to give the title compound (16 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 6.8 Hz, 1H), 8.47 - 8.35 (m, 2H), 8.10 (s, 1H), 7.99 - 7.81 (m, 2H), 7.78 - 7.60 (m, 3H), 7.60 - 7.38 (m, 3H), 6.57 (d, J = 3.2 Hz, 1H), 4.84 - 4.61 (m, 3H), 4.56 - 4.46 (m, 1H), 4.22 - 4.14 (m, 1H), 4.12 - 3.91 (m, 3H), 3.87 (s, 3H), 3.83 - 3.69 (m, 6H), 3.27 - 3.18 (m, 3H), 2.44 - 2.10 (m, 4H). MS (APCI+) m / z 636.32 (M+H) + .

[0269] Example 15 2-Amino-N-[(1S,2S)-2-({4-[3-(1-methylpiperidin-4-yl)-1H-indol-6-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 15A 6-chloro-3-(1-methylpiperidin-4-yl)-1H-indole A solution of 6-chloro-3-(piperidin-4-yl)-1H-indole (0.10 g, 0.426 mmol) in methanol (2 mL) was treated with acetic acid (0.049 mL, 0.852 mmol) and formaldehyde (37 wt% aqueous solution, 0.063 mL, 0.852 mmol). After 10 min, sodium triacetoxyborohydride (0.271 g, 1.278 mmol) was added, and the resulting mixture was stirred at ambient temperature for 5 h. The mixture was concentrated, and the residue was dissolved in water and adjusted to pH 9 with 3N NaOH. The suspension was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (97 mg). MS (ESI+) m / z 249.1 (M+H) + .

[0270] Process 15B 2-Amino-N-[(1S,2S)-2-({4-[3-(1-methylpiperidin-4-yl)-1H-indol-6-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 24 (0.034 g, 0.078 mmol), the product of Step 15A (0.019 g, 0.078 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.32 mg, 4.69 μmol), and K2CO3 (0.027 g, 0.195 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 130 °C for 30 min in a microwave reactor. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane, followed by 0-100% dichloromethane solution (dichloromethane / methanol / NH4OH=89:10:1) to give the title compound (22 mg). 1H NMR (501 MHz, methanol-d4) δ 8.22 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.47 (d, J = 1.7 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.19 (dd, J = 8.3, 1.6 Hz, 1H), 7.05 (d, J = 0.7 Hz, 1H), 4.65 (q, J = 12.4 Hz, 2H), 4.42 (td, J = 7.7, 4.8 Hz, 1H), 3.97 (dt, J = 6.7, 4.7 Hz, 1H), 3.73 (s, 3H), 3.05 - 2.96 (m, 2H), 2.90 - 2.79 (m, 1H), 2.25 (td, J = 12.0, 2.5 Hz, 2H), 2.19 - 2.10 (m, 1H), 2.10 - 1.98 (m, 3H), 1.94 - 1.69 (m, 5H), 1.64 - 1.53 (m, 1H). MS (ESI+) m / z 604.1 (M+H) + .

[0271] Example 16 2-Amino-N-[(3S,4R)-4-{[4-(1-methyl-1H-indol-5-yl)phenyl]methoxy}oxolan-3-yl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Example 14, except 5-bromo-1-methyl-1H-indole was used in place of the product of Step 7A. 1H NMR (501 MHz, DMSO-d6) δ 8.58 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.70 - 7.62 (m, 2H), 7.55 - 7.48 (m, 1H), 7.47 - 7.40 (m, 3H), 7.35 (d, J = 3.0 Hz, 1H), 7.01 (s, 2H), 6.47 (dd, J = 3.1, 0.8 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.18 - 4.12 (m, 1H), 4.06 (dd, J = 9.4, 6.2 Hz, 1H), 3.98 (dd, J = 10.0, 4.8 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.79 - 3.71 (m, 2H). MS (ESI+) m / z 523.2 (M+H) + .

[0272] Example 17 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-{[4-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]pyridine-3-carboxamide Process 17A 5-Bromo-1,3,3-trimethyl-2,3-dihydro-1H-indole A suspension of 5-bromo-3,3-dimethylindoline (0.13 g, 0.575 mmol) in N,N-dimethylformamide (3.4 mL) at 0 °C was treated with 60% sodium hydride (0.057 g, 1.437 mmol), and the resulting mixture was stirred at ambient temperature for 2 h and then cooled to 0 °C. Iodomethane (0.144 mL, 2.3 mmol) was added, and the resulting mixture was stirred at ambient temperature for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography, eluting with 0–15% ethyl acetate / heptane, to give the title compound (25 mg). MS (ESI+) m / z 240.2 (M+H) + .

[0273] Process 17B 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-{[4-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except using the product of Step 17A instead of the product of Step 12C. 1H NMR (501 MHz, DMSO-d6) δ 8.41 - 8.28 (m, 2H), 8.06 - 7.95 (m, 2H), 7.78 (d, J = 0.8 Hz, 1H), 7.57 - 7.45 (m, 2H), 7.36 - 7.23 (m, 4H), 6.96 (s, 2H), 6.54 (d, J = 8.0 Hz, 1H), 4.63 - 4.51 (m, 2H), 4.36 - 4.25 (m, 1H), 3.95 - 3.89 (m, 1H), 3.83 (s, 3H), 3.07 (s, 2H), 2.73 (s, 3H), 2.12 - 2.00 (m, 1H), 2.00 - 1.87 (m, 1H), 1.80 - 1.62 (m, 3H), 1.63 - 1.50 (m, 1H), 1.27 (d, J = 2.0 Hz, 6H). MS (ESI+) m / z 551.2 (M+H) + .

[0274] Example 18 2-Amino-N-{(3S,4R)-4-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Example 14, except using the product of Step 8C instead of the product of Step 7A. 1H NMR (501 MHz, DMSO-d6) δ 8.25 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.49 - 7.36 (m, 5H), 4.79 - 4.68 (m, 2H), 4.63 - 4.56 (m, 1H), 4.33 (dd, J = 7.7, 5.3 Hz, 1H), 4.23 - 4.17 (m, 1H), 4.13 (dd, J = 9.5, 5.9 Hz, 1H), 4.07 (dd, J = 10.1, 5.2 Hz, 1H), 3.89 (s, 3H), 3.86 - 3.77 (m, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.00 (dt, J = 15.2, 7.2 Hz, 1H), 2.93 - 2.80 (m, 1H), 2.75 - 2.47 (m, 10H), 2.26 - 2.08 (m, 2H). MS (ESI+) m / z 638.2.2 (M+H) + .

[0275] Example 19 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide A mixture of Intermediate 32 (0.027 g, 0.051 mmol), the product of Step 8C (0.017 g, 0.053 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.154 mg, 3.04 μmol) and K2CO3 (0.018 g, 0.127 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 75 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–10% methanol in dichloromethane followed by a gradient of 0–100% dichloromethane (dichloromethane / methanol / NH4OH = 89:10:1) to give the title compound (21 mg). 1 H NMR (501 MHz, DMSO-d6) δ 8.42 - 8.26 (m, 2H), 8.11 - 8.02 (m, 1H), 7.98 (t, J = 2.3 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.42 - 7.35 (m, 3H), 7.35 - 7.24 (m, 2H), 7.08 - 6.97 (m, 1H), 4.73 - 4.57 (m, 2H), 4.46 - 4.37 (m, 1H), 4.33 (dd, J = 7.6, 5.4 Hz, 1H), 4.01 - 3.91 (m, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.05 - 2.92 (m, 1H), 2.91 - 2.77 (m, 1H), 2.77 - 2.41 (m, 10H), 2.25 - 2.01 (m, 4H), 1.88 - 1.69 (m, 3H), 1.65 - 1.50 (m, 1H). MS (ESI+) m / z 651.4 (M+H) + .

[0276] Example 20 6-Amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Example 19, except that Intermediate 37 (0.035 g, 0.065 mmol) was used instead of Intermediate 32. 1 H NMR (400 MHz, methanol-d4) δ 8.45 - 8.37 (m, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.60 - 7.51 (m, 2H), 7.49 - 7.35 (m, 5H), 7.09 (dd, J = 8.5, 2.7 Hz, 1H), 4.80 - 4.69 (m, 2H), 4.64 - 4.57 (m, 1H), 4.34 (dd, J = 7.6, 5.3 Hz, 1H), 4.22 - 4.17 (m, 1H), 4.13 (dd, J = 9.5, 6.0 Hz, 1H), 4.07 (dd, J = 10.0, 5.2 Hz, 1H), 3.86 - 3.76 (m, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.07 - 2.94 (m, 1H), 2.92 - 2.81 (m, 1H), 2.75 - 2.48 (m, 10H), 2.26 - 2.10 (m, 2H). MS (ESI+) m / z 653.4 (M+H) + .

[0277] Example 21 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except using Intermediate 25 instead of Intermediate 33 and the product of Step 7A instead of the product of Step 4B. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J = 7.7 Hz, 1H), 8.41 (dd, J = 2.4, 1.1 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.84 - 7.73 (m, 3H), 7.66 - 7.57 (m, 3H), 7.53 (d, J = 3.2 Hz, 1H), 7.44 - 7.32 (m, 3H), 6.51 (d, J = 3.3 Hz, 1H), 4.66 - 4.54 (m, 2H), 4.44 (t, J = 5.3 Hz, 1H), 4.41 - 4.25 (m, 2H), 4.11 (q, J = 5.3 Hz, 1H), 3.92 (dt, J = 6.3, 3.8 Hz, 1H), 3.60 - 3.48 (m, 2H), 3.18 (d, J = 4.7 Hz, 2H), 3.03 (dt, J = 12.2, 3.2 Hz, 2H), 2.25 (td, J = 11.8, 2.5 Hz, 2H), 2.08 - 1.90 (m, 5H), 1.80 - 1.52 (m, 4H). MS (ESI+) m / z 622 (M+H) + .

[0278] Example 22 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 4C, except using Intermediate 32 instead of Intermediate 33 and the product of Step 7A instead of the product of Step 4B. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.27 (td, J = 8.2, 2.7 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.52 (d, J = 3.2 Hz, 1H), 7.41 - 7.34 (m, 3H), 7.29 (s, 2H), 7.22 (dd, J = 8.6, 2.8 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 4.60 (d, J = 1.9 Hz, 2H), 4.46 (d, J = 5.4 Hz, 1H), 4.35 (ddt, J = 10.3, 7.7, 5.0 Hz, 2H), 3.93 (dt, J = 6.3, 4.0 Hz, 1H), 3.55 (td, J = 6.3, 3.1 Hz, 2H), 3.04 (dt, J = 12.7, 3.4 Hz, 2H), 2.48 (t, J = 6.3 Hz, 2H), 2.26 (td, J = 11.8, 2.5 Hz, 2H), 2.14 - 1.86 (m, 6H), 1.83 - 1.50 (m, 4H). MS (ESI+) m / z 649 (M+H) + .

[0279] Example 23 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2,3-dihydroxypropyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 23A 5-Bromo-1-{1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperidin-4-yl}-3,3-dimethyl-2,3-dihydro-1H-indole A solution of the product of Step 12B (0.075 g, 0.243 mmol) and (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (0.032 g, 0.243 mmol) in dichloromethane (2.5 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (0.129 g, 0.606 mmol) was added in several portions, and the resulting mixture was stirred at ambient temperature for 2 days. The mixture was diluted with dichloromethane, washed with saturated Na2CO3, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-4% methanol / dichloromethane to give the title compound (66 mg). MS (ESI+) m / z 425.2 (M+H) + .

[0280] Process 23B 2-Amino-N-[(1S,2S)-2-{[4-(1-{1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperidin-4-yl}-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except that the product of Step 23A was used instead of the product of Step 12C. MS (APCI+) m / z 734.48 (M+H) + .

[0281] Process 23C 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2,3-dihydroxypropyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A solution of the product of Step 23B (0.034 g, 0.046 mmol) and trifluoroacetic acid (0.071 mL, 0.927 mmol) in dichloromethane (0.4 mL) was stirred at ambient temperature for 16 h. This mixture was partitioned with saturated NaHCO and ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–10% methanol / dichloromethane followed by 0–100% dichloromethane (dichloromethane / methanol / NHOH=89:10:1) to give the title compound (13 mg). 1 H NMR (501 MHz, methanol-d4) δ 8.25 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.47 - 7.41 (m, 2H), 7.36 - 7.31 (m, 2H), 7.20 (dd, J = 8.1, 1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 4.67 - 4.59 (m, 2H), 4.41 (td, J = 7.8, 4.8 Hz, 1H), 3.96 (dt, J = 6.7, 4.7 Hz, 1H), 3.86 - 3.78 (m, 4H), 3.57 - 3.41 (m, 3H), 3.19 (s, 2H), 3.17 - 3.05 (m, 2H), 2.56 - 2.43 (m, 2H), 2.33 - 2.11 (m, MS (ESI+) m / z 694.3 (M+H) + .

[0282] Example 24 2-Amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(trifluoromethyl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except using Intermediate 26 instead of Intermediate 33 and the product of Step 7A instead of the product of Step 4B. 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 6.7 Hz, 1H), 8.37 (dd, J = 2.4, 1.0 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.84 - 7.69 (m, 3H), 7.65 - 7.52 (m, 3H), 7.49 (d, J = 3.2 Hz, 1H), 7.42 - 7.31 (m, 3H), 6.47 (d, J = 3.2 Hz, 1H), 4.73 - 4.52 (m, 2H), 4.45 (td, J = 6.6, 3.8 Hz, 1H), 4.40 - 4.24 (m, 2H), 4.10 (dt, J = 4.9, 1.8 Hz, 1H), 3.97 (ddd, J = 25.6, 9.7, 5.4 Hz, 2H), 3.81 - 3.62 (m, 2H), 3.51 (q, J = 6.0 Hz, 2H), 3.09 - 2.90 (m, MS (ESI+) m / z 624 (M+H) + .

[0283] Example 25 6-Amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 4C, except using Intermediate 37 instead of Intermediate 33 and the product of Step 7A instead of the product of Step 4B. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 6.9 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.25 (tq, J = 4.4, 2.6 Hz, 2H), 7.76 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 16.5, 8.4 Hz, 3H), 7.48 (d, J = 3.3 Hz, 1H), 7.43 - 7.34 (m, 3H), 7.27 (s, 2H), 7.22 (dd, J = 8.6, 2.9 Hz, 1H), 6.47 (d, J = 3.2 Hz, 1H), 4.78 - 4.55 (m, 2H), 4.54 - 4.28 (m, 4H), 4.11 (dt, J = 4.3, 1.9 Hz, 1H), 3.99 (ddd, J = 29.9, 9.7, 5.4 Hz, 2H), 3.73 MS (ESI+) m / z 651 (M+H) + .

[0284] Example 26 2-Amino-N-{(1S,2S)-2-[(4-{3-[1-(2-hydroxyethyl)piperidin-4-yl]-1-methyl-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 26A tert-Butyl 4-(6-chloro-1H-indol-3-yl)piperidine-1-carboxylate A solution of 6-chloro-3-(piperidin-4-yl)-1H-indole (0.15 g, 0.639 mmol) and di-tert-butyl dicarbonate (0.139 g, 0.639 mmol) in tetrahydrofuran (2.5 mL) was stirred at ambient temperature for 16 hours. The resulting mixture was concentrated, and the residue was purified by silica gel flash chromatography eluting with 0-30% ethyl acetate / heptane to give the title compound (182 mg). MS (ESI+) m / z 333.0 (MH). + .

[0285] Process 26B tert-Butyl 4-(6-chloro-1-methyl-1H-indol-3-yl)piperidine-1-carboxylate A suspension of the product of Step 26A (0.179 g, 0.535 mmol) in N,N-dimethylformamide (3.3 mL) at 0 °C was treated with 60% sodium hydride (0.053 g, 1.336 mmol) in one portion. The resulting mixture was stirred at ambient temperature for 1 hour and then cooled to 0 °C. Iodomethane (0.134 mL, 2.138 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the title compound (210 mg). MS (ESI+) m / z 349.2 (M+H) + .

[0286] Process 26C 6-chloro-1-methyl-3-(piperidin-4-yl)-1H-indole The title compound was prepared in a manner similar to Example 5, except that the product of Step 26B was used instead of the product of Example 4. MS (ESI+) m / z 249.2 (M+H) + .

[0287] Process 26D 2-[4-(6-chloro-1-methyl-1H-indol-3-yl)piperidin-1-yl]ethan-1-ol The title compound was prepared in a manner similar to Step 13A, except that the product of Step 26C was used instead of the product of Step 12B. MS (ESI+) m / z 293.3 (M+H) + .

[0288] Process 26E 2-Amino-N-{(1S,2S)-2-[(4-{3-[1-(2-hydroxyethyl)piperidin-4-yl]-1-methyl-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 24 (0.029 g, 0.067 mmol), the product of Step 26D (0.018 g, 0.060 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.83 mg, 4.00 μmol), and K2CO3 (0.023 g, 0.167 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 110 °C for 30 min in a microwave reactor. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane, followed by 0-100% dichloromethane solution (dichloromethane / methanol / NH4OH=89:10:1) to give the title compound (22 mg). 1H NMR (501 MHz, methanol-d4) δ 8.21 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.72 - 7.68 (m, 2H), 7.61 - 7.56 (m, 3H), 7.44 - 7.35 (m, 3H), 7.20 (dd, J = 8.3, 1.5 Hz, 1H), 6.96 (s, 1H), 4.70 - 4.59 (m, 2H), 4.42 (td, J = 7.7, 4.8 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.77 - 3.70 (m, 8H), 3.14 - 3.06 (m, 2H), 2.85 (tt, J = 11.9, 3.8 Hz, 1H), 2.62 (t, J = 6.2 Hz, 2H), 2.30 (td, J = 12.0, 2.5 Hz, 2H), 2.19 - 2.10 (m, 1H), 2.08 - 1.99 (m, 3H), 1.91 - 1.69 (m, 5H), 1.62 - 1.53 (m, 1H). MS (ESI+) m / z 648.8 (M+H) + .

[0289] Example 27 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-amino-2-oxoethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 27A 2-(4-(5-bromo-3,3-dimethylindolin-1-yl)piperidin-1-yl)acetamide A solution of the product of Step 12B (0.103 g, 0.270 mmol) and triethylamine (0.188 mL, 1.348 mmol) in N,N-dimethylformamide (1.684 mL) was treated with 2-bromoacetamide (0.043 g, 0.310 mmol), and the resulting mixture was heated at 75 °C for 3 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over NaSO, and concentrated to give the title compound (86 mg). MS (ESI+) m / z 366.2 (M+H) + .

[0290] Process 27B 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-amino-2-oxoethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 24 (0.035 g, 0.080 mmol), the product of Step 27A (0.028 g, 0.076 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.42 mg, 4.82 μmol) and K2CO3 (0.028 g, 0.201 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 70 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by reverse-phase HPLC using a Phenomenex® Luna® C8(2) column eluting with 10-70% acetonitrile in water with 0.1% trifluoroacetic acid to give the title compound (38 mg) as the trifluoroacetic acid salt. 1H NMR (400 MHz, methanol-d4) δ 8.48 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.50 - 7.43 (m, 2H), 7.40 - 7.32 (m, 2H), 7.28 - 7.20 (m, 2H), 6.58 (d, J = 8.2 Hz, 1H), 4.70 - 4.58 (m, 2H), 4.46 - 4.36 (m, 1H), 4.06 - 3.95 (m, 3H), 3.92 - 3.79 (m, 4H), 3.79 - 3.64 (m, 2H), 3.29 - 3.16 (m, 4H), 2.24 - 2.12 (m, 1H), 2.11 - 1.97 (m, 5H), 1.90 - 1.72 (m, 3H), 1.69 - 1.57 (m, 1H), 1.31 (d, J = 1.3 Hz, 6H). MS (ESI+) m / z 677.3 (M+H) + .

[0291] Example 28 2-Amino-N-{(1S,2S)-2-[(4-{1'-[1-(2-hydroxyethyl)piperidin-4-yl]-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-5'-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 28A tert-Butyl 4-(5'-bromospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl)piperidine-1-carboxylate The title compound was prepared in a manner similar to Step 12A, except that 5'-bromospiro[cyclopropane-1,3'-indoline] was used instead of 5-bromo-3,3-dimethylindoline. MS (ESI+) m / z 407.0 (M+H) + .

[0292] Process 28B 5'-Bromo-1'-(piperidin-4-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole] The title compound was prepared in a manner similar to Example 5, except that the product of Step 28A was used instead of the product of Example 4. MS (ESI+) m / z 307.1 (M+H) + .

[0293] Process 28C 2-[4-(5'-bromospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl)piperidin-1-yl]ethan-1-ol The title compound was prepared in a manner similar to Step 13A, except that the product of Step 28B was used instead of the product of Step 12B. MS (ESI+) m / z 351.2 (M+H) + .

[0294] Process 28D 2-Amino-N-{(1S,2S)-2-[(4-{1'-[1-(2-hydroxyethyl)piperidin-4-yl]-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-5'-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except using the product of Step 28C instead of the product of Step 12C. 1H NMR (400 MHz, methanol-d4) δ 8.24 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.16 (dd, J = 8.1, 1.9 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 4.61 (q, J = 12.3 Hz, 2H), 4.40 (td, J = 7.6, 4.8 Hz, 1H), 3.94 (dt, J = 6.7, 4.7 Hz, 1H), 3.83 (s, 3H), 3.70 (t, J = 6.1 Hz, 2H), 3.56 - 3.48 (m, 1H), 3.46 (s, 2H), 3.13 - 3.06 (m, 2H), 2.57 (t, J = 6.1 Hz, 2H), 2.23 (td, J = 11.6, 3.5 Hz, 2H), 2.18 - 2.09 (m, 1H), 2.07 - 1.98 (m, 1H), 1.83 - 1.71 (m, 7H), 1.63 - 1.53 (m, 1H), 1.00 - 0.92 (m, 4H). MS (APCI+) m / z 662.37 (M+H) + .

[0295] Example 29 2-Amino-N-[(1S,2S)-2-{[4-(1H-indol-7-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 7-bromo-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.29 (t, J = 2.3 Hz, 1H), 8.05 - 7.87 (m, 2H), 7.76 (d, J = 0.9 Hz, 1H), 7.60 - 7.40 (m, 5H), 7.28 - 7.18 (m, 1H), 7.10 - 7.01 (m, 2H), 6.94 (s, 2H), 6.47 (dd, J = 3.1, 1.8 Hz, 1H), 4.70 - 4.56 (m, 2H), 4.31 (dt, J = 11.5, 7.7 MS (ESI+) m / z 507 (M+H) + .

[0296] Example 30 6-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide Process 30A 6-amino-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxylic acid The title compound was prepared in a manner similar to that of Intermediate 2, except that (1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid was used instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (APCI) m / z 246 (M+H) + .

[0297] Process 30B 6-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that of Intermediate 3, except that the product of Step 30A was used instead of Intermediate 2. MS (APCI) m / z 499 (M+H) + .

[0298] Process 30C 6-Amino-1'-methyl-2'-oxo-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 30B was used instead of Intermediate 19A. MS (ESI+) m / z 545 (M+H) + .

[0299] Process 30D 6-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 12D, except that the product of Step 30C was used in place of Intermediate 24 and Intermediate 13 was used in place of the product of Step 12C. 1H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.40 (m, 2H), 8.18 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.43 (dd, J = 7.3, 5.3 Hz, 4H), 7.27 (d, J = 8.1 Hz, 2H), 7.24 - 7.14 (m, 2H), 6.78 (d, J = 2.1 Hz, 1H), 6.60 (dd, J = 7.2, 2.1 Hz, 1H), 6.49 - 6.41 (m, 1H), 4.64 - 4.44 (m, 2H), 4.38 - 4.21 (m, 2H), 3.89 (dt, J = 6.3, 4.0 Hz, 1H), 3.45 (q, J = 6.0 Hz, 2H), 3.39 (s, 3H), 3.10 (s, 2H), 2.91 (d, J = 11.0 Hz, 2H), 2.37 (t, J = 6.3 Hz, MS (ESI+) m / z 691 (M+H) + .

[0300] Example 31 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Example 19, except using the product of Step 13A instead of the product of Step 8C. 1H NMR (501 MHz, methanol-d4) δ 8.35 (d, J = 2.7 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.03 (ddd, J = 8.5, 7.6, 2.7 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 - 7.30 (m, 2H), 7.18 - 7.12 (m, 2H), 6.98 (dd, J = 8.5, 2.6 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 4.68 - 4.57 (m, 2H), 4.41 (td, J = 7.7, 5.0 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.71 (t, J = 6.1 Hz, 2H), 3.52 - 3.43 (m, 1H), 3.19 (s, 2H), 3.14 - 3.06 (m, 2H), 2.58 (t, J = 6.1 Hz, 2H), 2.29 - 2.20 (m, 2H), 2.19 - 2.10 (m, 1H), 2.08 - 1.99 (m, 1H), 1.84 - 1.72 (m, 7H), 1.61 - 1.52 (m, 1H), 1.28 (d, J = 8.5 Hz, 6H). MS (ESI+) m / z 679.2 (M+H) + .

[0301] Example 32 2-Amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Example 14, except using the product of Step 13A instead of the product of Step 7A. 1H NMR (501 MHz, methanol-d4) δ 8.28 - 8.24 (m, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.25 (dd, J = 8.1, 2.0 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 6.49 (d, J = 8.3 Hz, 1H), 4.79 - 4.63 (m, 3H), 4.22 - 4.16 (m, 1H), 4.16 - 4.02 (m, 2H), 3.88 (s, 3H), 3.84 - 3.76 (m, 2H), 3.70 (t, J = 6.1 Hz, 2H), 3.53 - 3.41 (m, 1H), 3.19 (s, 2H), 3.13 - 3.05 (m, 2H), 2.57 (t, J = MS (ESI+) m / z 666.3 (M+H) + .

[0302] Example 33 2-Amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 33A 2-{4-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}ethan-1-ol Chiral preparative supercritical fluid chromatography was performed on racemic 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine (Step 8C, 500 mg) using a ChiralPak AD-H column to give the title compound (205 mg) as the first compound to elute. 1 H NMR (400 MHz, methanol-d4) δ 7.38 (d, J = 1.8 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.27 (d, J = 8.1 Hz, 1H), 4.56 (brs, 1H), 4.27 (dd, J = 7.8, 5.4 MS (APCI+) m / z 325.0 (M+H) + .

[0303] Process 33B 2-Amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except using the product of Step 33A instead of the product of Step 12C. 1H NMR (400 MHz, methanol-d4) δ 8.23 ​​(d, J = 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.54 - 7.47 (m, 2H), 7.43 - 7.31 (m, 5H), 4.71 - 4.60 (m, 2H), 4.41 (td, J = 7.5, 4.6 Hz, 1H), 4.32 (dd, J = 7.6, 5.3 Hz, 1H), 4.00 - 3.92 (m, 1H), 3.85 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.04 - 2.93 (m, 1H), 2.89 - 2.78 (m, 1H), 2.73 - 2.46 (m, 10H), 2.25 - 2.09 (m, 3H), 2.09 - 1.97 (m, 1H), 1.88 - 1.69 (m, 3H), 1.66 - 1.53 (m, 1H). MS (ESI+) m / z 636.3 (M+H) + .

[0304] Example 34 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 34A 2-{4-[(1S)-5-Bromo-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}ethan-1-ol In a similar manner to Step 33A, the title compound (203 mg) was obtained as the second eluting compound by chiral preparative supercritical fluid chromatography on racemic 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine (Step 8C, 500 mg). 1H NMR (501 MHz, methanol-d4) δ 7.38 (d, J = 1.7 Hz, 1H), 7.32 (dd, J = 8.1, 1.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.56 (brs, 1H), 4.27 (dd, J = MS (APCI+) m / z 325.0 (M+H) + .

[0305] Process 34B 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except using the product of Step 34A instead of the product of Step 12C. 1H NMR (400 MHz, methanol-d4) δ 8.23 ​​(d, J = 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.54 - 7.47 (m, 2H), 7.44 - 7.31 (m, 5H), 4.71 - 4.61 (m, 2H), 4.41 (td, J = 7.5, 4.6 Hz, 1H), 4.33 (dd, J = 7.7, 5.3 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.86 (s, 3H), 3.67 (t, J = 6.1 Hz, 2H), 3.03 - 2.92 (m, 1H), 2.91 - 2.79 (m, 1H), 2.72 - 2.48 (m, 10H), 2.25 - 2.09 (m, 3H), 2.08 - 1.96 (m, 1H), 1.87 - 1.70 (m, 3H), 1.65 - 1.53 (m, 1H). MS (ESI+) m / z 636.2 (M+H) + .

[0306] Example 35 6-Amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide A mixture of Intermediate 37 (0.045 g, 0.084 mmol), the product of Step 13A (0.031 g, 0.088 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.58 mg, 5.05 μmol) and K2CO3 (0.029 g, 0.211 mmol) in degassed water (0.25 mL) / degassed dioxane (0.7 mL) was heated at 70 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–8% dichloromethane solution (dichloromethane / methanol / NH4OH = 89:10:1) to give the title compound (25 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 6.9 Hz, 1H), 8.57 (d, J = 2.6 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.32 - 8.24 (m, 2H), 7.55 - 7.49 (m, 2H), 7.39 - 7.33 (m, 2H), 7.32 - 7.22 (m, 5H), 6.53 - 6.47 (m, 1H), 4.71 (d, J = 12.1 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.36 (t, J = 5.4 Hz, 1H), 4.15 - 4.10 (m, 1H), 4.08 - 4.01 (m, 1H), 3.97 (dd, J = 9.9, 4.9 Hz, 1H), 3.80 - 3.70 (m, 2H), 3.49 (q, J = 6.2 Hz, 2H), 3.44 - 3.37 (m, 1H), 3.15 (s, 2H), 2.99 - 2.91 (m, 2H), 2.40 (t, J = 6.3 Hz, 2H), 2.14 - 2.03 (m, 2H), 1.71 - 1.54 (m, 4H), 1.26 (d, J = 1.2 Hz, 6H). MS ((ESI+) m / z 681.5 (M+H) + .

[0307] Example 36 6-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-6'-oxo-1',6'-dihydro[3,3'-bipyridine]-5-carboxamide A solution of Intermediate 36 (65 mg, 0.098 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (34.6 mg, 0.147 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.41 mg, 7.85 μmol), and cesium carbonate (96 mg, 0.294 mmol) in dioxane (1.6 mL) / water (0.4 mL) was degassed and heated in a microwave oven at 120 °C for 20 min. After adding water, the resulting mixture was extracted with ethyl acetate, washed with brine, dried over MgSO, and purified by silica gel flash chromatography eluting with 0–12% methanol / dichloromethane containing 1% NHOH to give the title compound (41 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 15.3, 2.6 Hz, 2H), 7.74 (dd, J = 9.3, 2.7 Hz, 1H), 7.53 - 7.36 (m, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.20 (dp, J = 4.7, 2.2 Hz, 2H), 7.04 (s, 2H), 6.44 (dd, J = 9.2, 5.9 Hz, 2H), 4.60 - 4.46 (m, 2H), 4.38 - 4.19 (m, 2H), 4.07 (q, J = 5.2 Hz, 1H), 3.87 (dt, J = 6.4, 3.8 Hz, 1H), 3.45 (m, 5H), 3.19 - 3.04 (m, 3H), 2.91 (d, J = 11.3 Hz, MS (ESI+) m / z 691 (M+H) + .

[0308] Example 37 6-Amino-6'-fluoro-N-{(3S,4S)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]-1-methylpyrrolidin-3-yl}[3,3'-bipyridine]-5-carboxamide Process 37A 6-Amino-N-{(3S,4S)-4-[(4-bromophenyl)methoxy]-1-methylpyrrolidin-3-yl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that of Intermediate 31, except that Intermediate 35 was used instead of Intermediate 1. MS (ESI+) m / z 500 (M+H) + .

[0309] Process 37B 6-Amino-6'-fluoro-N-[(3S,4S)-1-methyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pyrrolidin-3-yl][3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 37A was used instead of Intermediate 19A. MS (ESI+) m / z 548 (M+H) + .

[0310] Process 37C 6-Amino-6'-fluoro-N-{(3S,4S)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]-1-methylpyrrolidin-3-yl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 12D, except using the product of Step 37B instead of Intermediate 24 and Intermediate 13 instead of the product of Step 12C. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.31 - 8.12 (m, 2H), 7.51 - 7.36 (m, 2H), 7.30 - 7.22 (m, 3H), 7.23 - 7.11 (m, 3H), 6.48 - 6.41 (m, 1H), 4.65 - 4.45 (m, 2H), 4.43 - 4.21 (m, 2H), 4.15 - 3.92 (m, 2H), 3.46 (q, J = 5.7 Hz, 2H), 3.12 (d, J = 15.6 Hz, 3H), 2.96 - 2.73 (m, 4H), 2.38 (q, J = 7.4, 6.3 Hz, 3H), 2.22 (s, 3H), 2.05 (td, J = 11.4, 3.1 Hz, 2H), 1.59 (qd, J = 11.8, 10.2, 4.5 Hz, 4H), 1.22 (d, J = 3.5 Hz, 6H). MS (ESI+) m / z 694 (M+H) + .

[0311] Example 38 rel-2-Amino-N-{(1S,2S,4S)-4-hydroxy-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 38A tert-Butyl[(cyclopent-3-en-1-yl)oxy]dimethylsilane To a mixture of cyclopent-3-enol (5.0 g, 59.4 mmol) and 1H-imidazole (8.09 g, 119 mmol) in tetrahydrofuran (200 mL) was added tert-butylchlorodimethylsilane (10.75 g, 71.3 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and then at ambient temperature overnight. Water was added, and the resulting mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel flash chromatography eluting with 0–10% ethyl acetate / heptane gave the title compound (8.63 g). 1 H NMR (400 MHz, DMSO-d6) δ 5.57 (s, 1H), 4.42 (tt, J = 6.7, 3.3 Hz, 1H), 2.50 - 2.43 (m, 2H), 2.11 - 2.00 (m, 2H), 0.77 (s, 10H), -0.05 (s, 6H).

[0312] Process 38B rel-tert-butyl(dimethyl){[(1,3r,5)-6-oxabicyclo[3.1.0]hexan-3-yl]oxy}silane To the degassed and refilled with nitrogen product of Step 38A (2.04 g, 10.28 mmol), dichloromethane (10 mL) was added, and the resulting mixture was cooled to 0 °C. A solution of 3-chloroperbenzoic acid (2.484 g, 14.40 mmol) in dichloromethane (25 mL) was added, and the resulting mixture was stirred at ambient temperature for 2.5 h. 10% sodium bisulfite solution (30 mL) and dichloromethane (30 mL) were added, and the resulting mixture was stirred for 20 min and poured into saturated NaHCO3. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, dried over MgSO4, filtered, and concentrated. Purification by silica gel flash chromatography, eluting with 100% heptane followed by 0–10% ethyl acetate / heptane, gave the title compound (452 ​​mg) and diastereoisomeric isomers (1.02 g). MS (DCI+) m / z 215.1 (M+H) + .

[0313] Process 38C rel-(1S,2S,4S)-2-Azido-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentan-1-ol A mixture of the product of Step 38B (500 mg, 2.332 mmol), NH₄Cl (387 mg, 7.23 mmol), and sodium azide (455 mg, 7.00 mmol) in ethanol (20 mL) / water (4 mL) was heated at 75 °C for 23 h. Water was added, and the resulting mixture was extracted with diethyl ether, washed with brine, dried over MgSO₄, filtered, and concentrated. Purification by silica gel flash chromatography eluting with 0-30% ethyl acetate in heptane gave the title compound. MS (ESI+) m / z 258.1 (M+H) + .

[0314] Process 38D rel-(1S,2S,4S)-2-amino-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentan-1-ol In a 20 mL Barnstead Hast C reactor, a solution of the product from Step 38C (325 mg, 1.263 mmol) in tetrahydrofuran (4 mL) was added to an aqueous slurry of Ra-Ni 2800 (165 mg, 1.263 mmol). The reactor was purged with argon, and the mixture was stirred at 24 °C under 54 psi H pressure for 3.5 h. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography, eluting with 0-12% methanol in dichloromethane containing 1% NHOH, to give the title compound (207 mg). MS (DCI+) m / z 232.1 (M+H) + .

[0315] Step 38E rel-(1S,2S,4S)-2-[(4-bromophenyl)methoxy]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentan-1-amine To a solution of the product of Step 38D (2.78 g, 12.01 mmol) in tetrahydrofuran (40 mL) was added 1 M potassium tert-butoxide in tetrahydrofuran (18.02 mL, 18.02 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 20 minutes. A solution of 1-bromo-4-(bromomethyl)benzene (3.15 g, 12.61 mmol) in tetrahydrofuran (10 mL) was added, and the resulting mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel flash chromatography, eluting with 0-12% methanol / dichloromethane, gave the title compound (4.02 g). MS (ESI+) m / z 402.2 (M+H) + .

[0316] Process 38F rel-2-Amino-N-[(1S,2S,4S)-2-[(4-bromophenyl)methoxy]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 2 (0.807 g, 3.70 mmol), triethylamine (1.288 mL, 9.24 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.827 g, 4.8 mmol) in N,N-dimethylformamide (12 mL) was stirred for 15 min, followed by the addition of a solution of the product of Step 38E (1.48 g, 3.70 mmol) in N,N-dimethylformamide (5 mL). After stirring at ambient temperature for 16 h, water was added, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography, eluting with 0–10% methanol / dichloromethane, afforded the title compound (1.38 g). MS (APCI+) m / z 600.3 (M+H) + .

[0317] Process 38G rel-2-amino-N-{(1S,2S,4S)-2-[(4-bromophenyl)methoxy]-4-hydroxycyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide To a solution of the product of Step 38F (1.38 g, 2.298 mmol) in tetrahydrofuran (10 mL) was added 1 M tetrabutylammonium fluoride in tetrahydrofuran (9.19 mL, 9.19 mmol), and the resulting mixture was stirred at ambient temperature overnight. Water was added, and the resulting mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel flash chromatography eluting with 0-12% methanol in dichloromethane gave the title compound (1.04 g). MS (ESI+) m / z 486.3 (M+H) + .

[0318] Process 38H rel-2-Amino-N-[(1S,2S,4S)-4-hydroxy-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of tetrakis(triphenylphosphine)palladium (314 mg, 0.271 mmol), the product of Step 38G (220 mg, 0.452 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (230 mg, 0.905 mmol), and potassium acetate (133 mg, 1.357 mmol) was purged with nitrogen for 10 minutes, and dioxane (10 mL) was added. The resulting mixture was purged with nitrogen for 5 minutes and heated at 100 °C for 16 hours. The mixture was cooled, diluted with ethyl acetate, filtered, and concentrated. Purification by silica gel flash chromatography, eluting with 0-12% methanol / dichloromethane, gave the title compound (94 mg). MS (ESI+) m / z 534.4 (M+H) + .

[0319] Process 38I rel-2-Amino-N-{(1S,2S,4S)-4-hydroxy-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of the product of Step 38H (59 mg, 0.111 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl adduct (9.03 mg, 0.011 mmol), Intermediate 23 (39.1 mg, 0.111 mmol), and cesium carbonate (108 mg, 0.332 mmol) was purged with nitrogen for 5 minutes. Dioxane (2 mL) and water (0.5 mL) were added, and the resulting mixture was purged with nitrogen for 5 minutes and stirred at 120 °C for 30 minutes in a Biotage Initiator microwave synthesizer. The mixture was diluted with ethyl acetate, washed with brine, dried over MgSO, filtered, and concentrated. Purification by silica gel flash chromatography, eluting with 0–14% methanol in dichloromethane containing 1% NHOH, gave the title compound (11 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.49 - 7.42 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.26 - 7.19 (m, 2H), 6.98 (s, 2H), 6.48 (d, J = 8.9 Hz, 1H), 4.70 (d, J = 4.1 Hz, 1H), 4.59 - 4.47 (m, 3H), 4.35 (t, J = 5.4 Hz, 1H), 4.19 (q, J = 5.2 Hz, 1H), 3.93 (dt, J = 7.9, 6.1 Hz, 1H), 3.82 (s, 3H), 3.49 (dt, J = 9.6, 4.3 Hz, 2H), 3.39 (s, 1H), 3.14 (s, 2H), 2.99 - 2.90 (m, 2H), 2.40 (t, J = 6.3 Hz, 2H), 2.37 - 2.29 (m, 1H), 2.08 (td, J = 11.4, 3.1 Hz, 2H), 1.91 (ddd, J = 12.8, 8.2, 4.1Hz, 1H), 1.75 (ddd, J = 13.5, 8.2, 6.1 Hz, 1H), 1.69 - 1.51 (m, 5H), 1.25 (d, J = 2.5 Hz, 6H). MS (ESI+) m / z 680.1 (M+H) + .

[0320] Example 39 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-3-propyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 39A 5-Bromo-3-methyl-3-propyl-2,3-dihydro-1H-indole Under a nitrogen atmosphere, a mixture of (4-bromophenyl)hydrazine hydrochloride (2 g, 8.95 mmol), acetic acid (15 mL), and 2-methylvaleraldehyde (0.896 g, 8.95 mmol) was heated at 60 °C for 3 h. The resulting mixture was diluted with 1,2-dichloroethane (15 mL) and cooled to 0 °C. Sodium triacetoxyborohydride (2.84 g, 13.42 mmol) was added, and the resulting mixture was stirred for 20 min. The mixture was concentrated, and the residue was dissolved in ethyl acetate and washed with saturated Na2CO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–50% ethyl acetate / heptane to give the title compound (740 mg). 1 H NMR (400 MHz, DMSO-d6) δ 7.04 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.2, 2.1 Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 5.59 (d, J = 1.9 Hz, 1H), 3.29 (dd, J = 9.1, 1.8 Hz, 1H), 3.12 (dd, J = 9.1, 2.1 Hz, 1H), 1.48 (dddd, J = 29.6, 13.2, 11.7, 4.7 Hz, 2H), 1.36 - 1.21 (m, 1H), 1.19 (s, 3H), 1.17 - 1.00 (m, 1H), 0.84 (t, J = 7.3 Hz, 3H). LCMS (APCI) m / z 254.83 (M+H) + .

[0321] Process 39B tert-Butyl 4-(5-bromo-3-methyl-3-propyl-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylate A mixture of the product of Step 39A (740 mg, 2.91 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (638 mg, 3.20 mmol), acetic acid (8.3 mL), and sodium triacetoxyborohydride (1.23 g, 5.82 mmol) was stirred at ambient temperature overnight. This mixture was diluted with dichloromethane and washed with saturated Na2CO3. The organic layer was dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel flash chromatography eluting with 0-10% ethyl acetate / heptane to give the title compound (1.03 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 4.13 - 3.95 (m, 2H), 3.55 (tt, J = 11.7, 3.7 Hz, 1H), 3.21 (d, J = 9.0 Hz, 1H), 3.02 (d, J = 9.0 Hz, 1H), 2.79 (s, 2H), 1.63 (dd, J = 10.8, 6.7 Hz, 2H), 1.57 - 1.42 (m, 4H), 1.40 (s, 9H), 1.27 (dp, J = 17.1, 6.0, 5.5 Hz, 1H), 1.18 (s, 3H), 1.14 - 1.01 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H). LCMS (APCI) m / z 437.24 (M+H) + .

[0322] Process 39C 5-Bromo-3-methyl-1-(piperidin-4-yl)-3-propyl-2,3-dihydro-1H-indole A solution of the product of Step 39B (1.03 g, 2.3 mmol) and a mixture of tetrahydrofuran (10 mL) and 4 M HCl in dioxane (5.89 mL, 23.55 mmol) was stirred at ambient temperature overnight. After concentration, the residue was dissolved in ethyl acetate and washed with saturated NaHCO. The organic layer was dried over MgSO, filtered, and concentrated to give the title compound (631 mg), which was used without further purification. 1 H NMR (501 MHz, DMSO-d6) δ 7.08 (dd, J = 8.3, 2.1 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 3.41 (tt, J = 11.9, 4.0 Hz, 1H), 3.22 (d, J = 9.0 Hz, 1H), 3.04 (d, J = 9.0 Hz, 1H), 3.00 (ddd, J = 12.1, 4.1, 2.2 Hz, 2H), 2.59 - 2.52 (m, 2H), 1.65 - 1.36 (m, 7H), 1.34 - 1.22 (m, 1H), 1.19 (s, 3H), 1.08 (tdd, J = 12.3, 7.0, 4.6 Hz, 1H), 0.83 (t, J = 7.3 Hz, 3H). LCMS (APCI) m / z 336.97 (M+H) + .

[0323] Process 39D 2-[4-(5-bromo-3-methyl-3-propyl-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]ethan-1-ol A mixture of the product of Step 39C (631 mg, 1.87 mmol), methanol (10 mL), 2-bromoethanol (701 mg, 5.6 mmol), and KCO (517 mg, 3.74 mmol) was stirred at ambient temperature for 48 h. The mixture was diluted with ethyl acetate, and the solid was filtered. Purification by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane gave the title compound (474 ​​mg). 1H NMR (400 MHz, DMSO-d6) δ 7.08 (dd, J = 8.4, 2.1 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.36 (d, J = 8.4 Hz, 1H), 4.40 (dt, J = 34.5, 5.4 Hz, 2H), 3.48 (q, J = 5.7 Hz, 2H), 3.39 (t, J = 2.1 Hz, 2H), 3.23 (d, J = 9.0 Hz, 1H), 3.04 (d, J = 9.0 Hz, 1H), 2.93 (d, J = 11.2 Hz, 2H), 2.39 (t, J = 6.4 Hz, 2H), 2.05 (td, J = 11.1, 5.5 Hz, 2H), 1.67 - 1.37 (m, 5H), 1.35 - 1.21 (m, 1H), 1.19 (s, 3H), 1.07 (dt, J = 12.4, 7.3 Hz, 1H), 0.83 (t, J = 7.2 Hz, 3H). LCMS (APCI) m / z 381.08 (M+H) + .

[0324] Step 39E 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-3-propyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of the product of Step 39D (474 ​​mg, 1.24 mmol), Intermediate 33 (643 mg, 1.24 mmol), cesium carbonate (1.21 g, 3.73 mmol), and dioxane / water (3 / 1) (8.29 mL) was sparged with argon for 20 minutes, and tris(dibenzylideneacetone)dipalladium (23 mg, 0.025 mmol) and 4-(di-tert-butylphosphino)-N,N-dimethylaniline (16 mg, 0.062 mmol) were added. The reaction vial containing this mixture was heated at 70 °C for 16 hours, cooled to ambient temperature, and diluted with ethyl acetate. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–10% methanol / dichloromethane to give the title compound (306 mg) as a diastereomeric mixture. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.25 (dt, J = 8.2, 1.4 Hz, 1H), 7.19 (d, J = 1.7 Hz, 1H), 6.96 (s, 2H), 6.46 (d, J = 8.3 Hz, 1H), 4.64 - 4.49 (m, 2H), 4.35 (t, J = 5.3 Hz, 1H), 3.96 - 3.88 (m, 1H), 3.83 (s, 3H), 3.49 (q, J = 6.0 Hz, 2H), 3.26 (d, J = 8.9 Hz, 1H), 3.08 (d, J = 5.3 Hz, 2H), 2.94 (d, J = 11.2 Hz, 2H), 2.40 (t, J = 6.4 Hz, 2H), 2.06 (d, J = 9.9 Hz, 3H), 1.93 (dt, J = 12.0, 7.0 Hz, 1H), 1.81 - 1.40 (m, 11H), 1.38 - 1.18 (m, 4H), 1.11 (s, 3H), 0.83 (td, J = 7.2, 2.9 Hz, 3H). LCMS (APCI) m / z 692.62 (M+H) + .

[0325] Example 40 2-Amino-N-{(1S,2S)-2-[(4-{3-ethyl-1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 40A tert-Butyl 4-(5-bromo-3-ethyl-3-methyl-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylate A mixture of 4-bromophenylhydrazine hydrochloride (14.27 g, 63.9 mmol), acetic acid (200 mL), and 2-methylbutyraldehyde (5 g, 58.1 mmol) was heated at 60 °C for 3 hours and cooled to ambient temperature overnight. This mixture was diluted with dichloromethane (100 mL), cooled to 0 °C, and sodium triacetoxyborohydride (36.9 g, 174 mmol) was added. The cooling bath was removed and the reaction stirred until complete. tert-Butyl 4-oxopiperidine-1-carboxylate (13.6 g, 68.3 mmol) was added, and the resulting mixture was stirred overnight. The mixture was poured into saturated NaHCO3, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–50% ethyl acetate / heptane to give the title compound (2.06 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.10 (dd, J = 8.3, 2.1 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 4.04 (dd, J = 9.5, 5.1 Hz, 2H), 3.56 (tt, J = 11.6, 3.7 Hz, 1H), 3.01 (d, J = 9.1 Hz, 1H), 2.80 (s, 2H), 1.63 (td, J = 7.8, 6.1, 3.0 Hz, 2H), 1.59 - 1.47 (m, 2H), 1.45 (dd, J = 7.8, 4.5 Hz, 1H), 1.42 - 1.37 (m, 11H), 1.17 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H). MS (DCI+) m / z 423.1 (M+H) + .

[0326] Process 40B 5-Bromo-3-ethyl-3-methyl-1-(piperidin-4-yl)-2,3-dihydro-1H-indole A mixture of the product of Step 40A (2.06 g, 4.87 mmol), dichloromethane (10 mL), and trifluoroacetic acid (7.5 mL, 97 mmol) was stirred at ambient temperature overnight. The mixture was quenched with saturated NaHCO3 and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (1.5 g), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 3.68 (tt, J = 11.3, 4.3 Hz, 1H), 3.40 - 3.30 (m, 3H), 3.20 (d, J = 8.8 Hz, 1H), 3.03 (d, J = 8.9 Hz, 1H), 2.95 (td, J = 12.6, 3.5 Hz, 2H), 1.86 - 1.65 (m, 4H), 1.64 - 1.47 (m, 2H), 1.20 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H). MS (APCI+) m / z 322.97 (M+H) + .

[0327] Process 40C 2-[4-(5-bromo-3-ethyl-3-methyl-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]ethan-1-ol A mixture of the product of Step 40B (1.57 g, 4.87 mmol), methanol (49 mL), 2-bromoethanol (1.83 g, 14.6 mmol), K2CO3 (2.02 g, 14.6 mmol), and glass beads (2 g) was stirred overnight. The mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound (718 mg). 1H NMR (501 MHz, DMSO-d6) δ 7.10 (dd, J = 8.4, 2.1 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.57 (s, 1H), 3.54 (t, J = 6.1 Hz, 2H), 3.22 (d, J = 9.0 Hz, 1H), 3.12 - 3.06 (m, 2H), 3.04 (d, J = 9.0 Hz, 1H), 2.57 (s, 2H), 2.29 (s, 2H), 1.66 (p, J = 4.4 Hz, 4H), 1.61 - 1.45 (m, 2H), 1.18 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H). MS (APCI+) m / z 367.02 (M+H) + .

[0328] Process 40D 2-Amino-N-{(1S,2S)-2-[(4-{3-ethyl-1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 33 (1.01 g, 1.96 mmol), the product of Step 40C (0.718 g, 1.96 mmol), cesium carbonate (1.91 g, 5.86 mmol), dioxane (10 mL), and water (3 mL) was sparged with argon for 20 minutes. 4-(Di-tert-butylphosphino)-N,N-dimethylaniline (26 mg, 0.098 mmol) and tris(dibenzylideneacetone)dipalladium (0.036 g, 0.039 mmol) were added, and the reaction vial was heated at 70 °C for 16 hours. The mixture was cooled to ambient temperature, and ammonium pyrrolidinedithiocarbamate (70 mg) was added. The resulting mixture was stirred for 15 minutes. The mixture was partitioned between ethyl acetate and water, and the aqueous layer was washed with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound (505 mg) as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.29 (m, 2H), 8.00 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.78 (d, J = 0.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.25 (dd, J = 8.4, 1.9 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.95 (s, 2H), 6.47 (d, J = 8.3 Hz, 1H), 4.65 - 4.46 (m, 2H), 4.36 (t, J = 5.4 Hz, 1H), 4.34 - 4.23 (m, 1H), 3.94 - 3.88 (m, 1H), 3.83 (d, J = 1.3 Hz, 3H), 3.49 (q, J = 6.0 Hz, 2H), 3.25 (d, J = 8.9 Hz, 1H), 3.13 - 3.01 (m, 1H), 2.94 (d, J = 11.0 Hz, 2H), 2.39 (t, J = 6.3 Hz, 2H), 2.06 (td, J = 13.0, 9.0 Hz, 3H), 1.92 (dt, J = 11.9, 7.0 Hz, 1H), 1.83 - 1.44 (m, 10H), 1.22 (d, J = 2.5 Hz, 3H), 1.10 (s, 1H), 0.79 (td, J = 7.5, 2.2 Hz, 3H). MS (DCI+) m / z 678.4 (M+H) + .

[0329] Example 41 3-Amino-6-(6-fluoropyridin-3-yl)-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}pyrazine-2-carboxamide Process 41A 3-amino-6-(6-fluoropyridin-3-yl)pyrazine-2-carboxylic acid methyl ester In a degassed and backfilled microwave vial, a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (503 mg, 2.2 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (537 mg, 2.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex dichloromethane adduct (93 mg, 0.11 mmol), and potassium phosphate (1.41 g, 6.6 mmol) in dioxane (10 mL) was heated at 75 °C for 18 h. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth, concentrated, and purified by silica gel flash chromatography eluting with 0-100% ethyl acetate / hexane to give the title compound (367 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.85 - 8.79 (m, 1H), 8.56 - 8.46 (m, 1H), 7.55 (s, 2H), 7.30 (dd, J = 8.6, 2.8 Hz, 1H), 3.91 (s, 3H). MS (ESI+) m / z 255.1 (M+H) + .

[0330] Process 41B 3-amino-6-(6-fluoropyridin-3-yl)pyrazine-2-carboxylic acid To a solution of the product of Step 41A (367 mg, 1.5 mmol) in tetrahydrofuran (13 mL) was added a solution of LiOH (95 mg, 2.3 mmol) in water (2 mL), and the resulting mixture was stirred at ambient temperature for 18 h. 1 M HCl (2.3 mL, 2.3 mmol) was added, and the precipitate was collected, washed with water, and dried under vacuum to give the title compound (347 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.66 (td, J = 8.3, 2.6 Hz, 1H), 7.61 (s, 2H), 7.30 (dd, J = 8.6, 2.8 Hz, 1H). MS (ESI+) m / z 253.2 (M+H) + .

[0331] Process 41C 3-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-6-(6-fluoropyridin-3-yl)pyrazine-2-carboxamide To a solution of the product of Step 41B (253.7 mg, 1.083 mmol), Intermediate 1 (381.8 mg, 1.413 mmol), and N,N-diisopropylethylamine (0.5 mL, 2.86 mmol) in N,N-dimethylformamide (6 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 470.3 mg, 1.237 mmol), and the resulting mixture was stirred for 72 h. The mixture was then concentrated and purified by silica gel flash chromatography, eluting with 0-40% ethyl acetate / hexanes, to give the title compound (385 mg). 1 H NMR (501 MHz, DMSO-d6) δ 9.05 (dd, J = 2.6, 0.8 Hz, 1H), 8.90 (s, 1H), 8.74 - 8.66 (m, 2H), 7.46 - 7.40 (m, 2H), 7.33 - 7.22 (m, 3H), 4.52 (s, 2H), 4.30 (td, J = 8.4, 5.2 Hz, 1H), 4.03 (dt, J = 6.7, 4.8 Hz, 1H), 2.06 - 1.94 (m, 2H), 1.68 (dddd, J = 20.3, 18.1, 10.0, 3.7 Hz, 4H). MS (ESI+) m / z 488.2 (M+H) + .

[0332] Process 41D 3-Amino-6-(6-fluoropyridin-3-yl)-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]pyrazine-2-carboxamide A mixture of the product of Step 41C (385.4 mg, 0.792 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (411.6 mg, 1.621 mmol), tetrakis(triphenylphosphine)palladium(0) (46.9 mg, 0.041 mmol), potassium acetate (247.8 mg, 2.52 mmol), and dioxane (4 mL) in a microwave vial was degassed, refilled with nitrogen, and heated at 110° C. for 18 h. The mixture was concentrated and purified by silica gel flash chromatography eluting with 0 to 50% ethyl acetate / hexane to give the title compound (254 mg). 1 H NMR (501 MHz, DMSO-d6) δ 9.03 (d, J = 2.6 Hz, 1H), 8.90 (s, 1H), 8.77 - 8.62 (m, 2H), 7.58 - 7.52 (m, 2H), 7.33 - 7.24 (m, 3H), 4.57 MS (ESI+) m / z 534.1 (M+H) + .

[0333] Process 41E 3-Amino-6-(6-fluoropyridin-3-yl)-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}pyrazine-2-carboxamide A mixture of the product of Step 41D (128 mg, 0.24 mmol), Intermediate 23 (113 mg, 0.32 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (8 mg, 0.011 mmol), and potassium phosphate (104 mg, 0.49 mmol) was combined with dioxane / water (3:1) (2 mL), degassed, and refilled with nitrogen. This mixture was heated at 100 °C for 18 h. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and concentrated. The residue was purified by reverse-phase HPLC using a gradient elution of 5 / 95 to 90 / 10 acetonitrile / 0.1% aqueous trifluoroacetic acid to give the title compound as the trifluoroacetate salt. This trifluoroacetate salt was dissolved in methanol and loaded onto an Agilent Bond Elut SCX column. The free base was eluted from the column using 1 M NH3 in methanol and concentrated. The residue was dissolved in methanol, filtered through a 0.22 μM PTFE syringe filter, and concentrated to give the title compound (31 mg). 1 H NMR (400 MHz, methanol-d4) δ 8.72 (dd, J = 2.6, 0.9 Hz, 1H), 8.63 (s, 1H), 8.42 (ddd, J = 8.6, 7.6, 2.6 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.15 - 7.06 (m, 2H), 6.99 (ddd, J = 8.6, 2.6, 0.7 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.63 (d, J = 12.3 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.36 (td, J = 8.1, 5.5 Hz, 1H), 4.08 - 3.96 (m, 1H), 3.70 (t, J = 6.1 Hz, 2H), 3.18 (s, 2H), 3.15 - 3.04 (m, 2H), 2.58 (t, J = 6.1 MS (ESI+) m / z 680.3 (M+H) + .

[0334] Example 42 2-Amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide Process 42A 2-Amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxylic acid The title compound was prepared in a manner similar to that of Intermediate 2, except that 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI+) m / z 233 (M+H) + .

[0335] Process 42B 2-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 29, except that the product of Step 42A was used instead of Intermediate 2. MS (ESI+) m / z 486 (M+H) + .

[0336] Process 42C 2-Amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl]pyridine-3-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 42B was used instead of Intermediate 19A. MS (ESI+) m / z 534 (M+H)+ .

[0337] Process 42D 2-Amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 12D, except that the product of Step 42C was used in place of Intermediate 24 and Intermediate 13 was used in place of the product of Step 12C. 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 6.8 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.59 - 7.42 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.95 (s, 2H), 6.52 - 6.44 (m, 1H), 4.75 - 4.51 (m, 2H), 4.50 - 4.23 (m, 2H), 4.07 (dt, J = 4.4, 1.9 Hz, 1H), 4.00 (dd, J = 9.3, 6.2 Hz, 1H), 3.89 (dd, J = 10.0, 4.8 Hz, 1H), 3.79 - 3.58 (m, 4H), 3.46 (q, J = 5.7 Hz, 2H), 3.36 (s, 2H), 3.09 (d, J = 18.0 Hz, 2H), 2.92 (d, J = 11.1 Hz, 2H), 2.37 (t, J = 6.3 Hz, 2H), 2.20 (s, 3H), 2.06 (td, J = 11.3, 3.1 Hz, 2H), 1.59 (dtt, J = 19.7, 11.7, 5.7 Hz, 4H), 1.23 (s, 6H). MS (ESI+) m / z 680 (M+H) + .

[0338] Example 43 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1,2-dihydrospiro[indole-3,3'-oxolan]-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 43A tert-Butyl 4-(5-bromospiro[indol-3,3'-oxolan]-1(2H)-yl)piperidine-1-carboxylate The title compound was prepared in a manner similar to Step 12A, except that 5'-bromo-4,5-dihydro-2H-spiro[furan-3,3'-indoline] was used instead of 5-bromo-3,3-dimethylindoline. MS (ESI+) m / z 437.1 (M+H) + .

[0339] Process 43B 5-Bromo-1-(piperidin-4-yl)-1,2-dihydrospiro[indole-3,3'-oxolane] The title compound was prepared in a manner similar to Example 5, except that the product of Step 43A was used instead of the product of Example 4. MS (ESI+) m / z 337.3 (M+H) + .

[0340] Process 43C 2-[4-(5-bromospiro[indol-3,3'-oxolan]-1(2H)-yl)piperidin-1-yl]ethan-1-ol The title compound was prepared in a manner similar to Step 13A, except that the product of Step 43B was used instead of the product of Step 12B. MS (ESI+) m / z 337.3 (M+H) + .

[0341] Process 43D 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1,2-dihydrospiro[indole-3,3'-oxolan]-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 33 (30 mg, 0.057 mmol), the product of Step 43C (23 mg, 0.06 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2 mg, 2.84 μmol) and K2CO3 (24 mg, 0.170 mmol) in degassed water (0.2 mL) / degassed dioxane (0.6 mL) was heated at 70 °C for 1 h. The mixture was cooled to ambient temperature and partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with 0–15% methanol / dichloromethane to give the title compound (19 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.40 - 8.30 (m, 2H), 8.04 - 7.96 (m, 2H), 7.78 (d, J = 0.8 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.39 - 7.26 (m, 4H), 6.96 (s, 2H), 6.55 (d, J = 8.3 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.51 - 4.36 (m, 1H), 4.36 - 4.25 (m, 1H), 4.03 - 3.85 (m, 3H), 3.83 (s, 3H), 3.75 (d, J = 8.3 Hz, 1H), 3.63 (dd, J = 8.4, 4.6 Hz, 1H), 3.56 - 3.43 (m, 3H), 2.99 (d, J = 10.9 Hz, 2H), 2.46 (brs, 2H), 2.28 - 1.85 (m, 6H), 1.80 - 1.52 (m, 8H). MS (ESI+) m / z 692.0 (M+H) + .

[0342] Example 44 6-Amino-5'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide Process 44A 6-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-5'-fluoro[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that for intermediate 29, except that intermediate 5 was used instead of intermediate 2. MS (ESI+) m / z 487 (M+H) + .

[0343] Process 44B 6-Amino-5'-fluoro-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl][3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 44A was used instead of Intermediate 19A. MS (ESI+) m / z 535 (M+H) + .

[0344] Process 44C 6-Amino-5'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 4C, except that the product of Step 44B was used in place of Intermediate 33 and Intermediate 13 was used in place of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (t, J = 1.8 Hz, 1H), 8.67 (d, J = 6.9 Hz, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.05 (dt, J = 10.6, 2.4 Hz, 1H), 7.59 - 7.42 (m, 2H), 7.43 - 7.28 (m, 4H), 7.28 - 7.21 (m, 2H), 6.52 - 6.36 (m, 1H), 4.77 - 4.53 (m, 2H), 4.53 - 4.44 (m, 1H), 4.38 (s, 1H), 4.10 (dt, J = 4.4, 1.9 Hz, 1H), 3.98 (ddd, J = 27.7, 9.6, 5.4 Hz, 2H), 3.73 (dt, J = 9.9, 3.0 Hz, 2H), 3.47 (t, J = 6.3 Hz, 2H), 3.10 (s, 2H), 3.05 (m, 1H), 2.94 (d, J = 11.0 Hz, 2H), 2.40 (t, J = 6.3 Hz, 2H), 2.09 (dt, J = 11.6, 5.8 Hz, 2H), 1.60 (dp, J = 11.7, 4.5, 3.8 Hz, 4H), 1.23 (s, 6H). MS (ESI+) m / z 681 (M+H) + .

[0345] Example 45 2-Amino-N-{(3S,4R)-4-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Example 14, except using the product of Step 34A instead of the product of Step 7A. 1H NMR (501 MHz, methanol-d4) δ 8.25 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.46 - 7.38 (m, 5H), 4.79 - 4.68 (m, 2H), 4.62 - 4.57 (m, 1H), 4.34 (dd, J = 7.7, 5.2 Hz, 1H), 4.22 - 4.17 (m, 1H), 4.16 - 4.03 (m, 2H), 3.89 (s, 3H), 3.85 - 3.78 (m, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.04 - 2.96 (m, 1H), 2.91 - 2.83 (m, 1H), 2.74 - 2.50 (m, 10H), 2.25 - 2.11 (m, 2H). MS (ESI+) m / z 638.40 (M+H) + .

[0346] Example 46 6-Amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Example 19, except using the product of Step 34A instead of the product of Step 8C. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.25 (td, J = 8.2, 2.7 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.45 - 7.35 (m, 4H), 7.33 - 7.20 (m, 4H), 4.60 (s, 2H), 4.38 - 4.23 (m, 3H), 3.96 - 3.89 (m, 1H), 3.47 (q, J = 6.1 MS (ESI+) m / z 651.3 (M+H) + .

[0347] Example 47 2-Amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide Process 47A 2-Amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxylic acid The title compound was prepared in a manner similar to that of Intermediate 2, except that 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI+) m / z 233 (M+H) + .

[0348] Process 47B 2-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 29, except that the product of Step 47A was used instead of Intermediate 2. MS (ESI+) m / z 486 (M+H) + .

[0349] Process 47C 2-Amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl]pyridine-3-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 47B was used instead of Intermediate 19A. MS (ESI+) m / z 534 (M+H) + .

[0350] Process 47D 2-Amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except that the product of Step 47C was used in place of Intermediate 33 and Intermediate 13 was used in place of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.34 - 7.28 (m, 2H), 7.28 - 7.18 (m, 2H), 7.18 - 7.05 (m, 1H), 6.97 (s, 2H), 6.49 - 6.44 (m, 1H), 4.70 - 4.51 (m, 2H), 4.49 - 4.39 (m, 1H), 4.33 (s, 1H), 4.08 (dt, J = 4.3, 1.9 Hz, 1H), 4.00 (dd, J = 9.3, 6.2 Hz, 1H), 3.89 (dd, J = 10.0, 4.8 Hz, 1H), 3.76 - 3.63 (m, 4H), 3.50 - 3.42 (m, 3H), 3.11 (s, 2H), 2.99 - 2.86 (m, 2H), 2.37 (t, J = 6.3 Hz, 2H), 2.27 (s, 3H), 2.05 (td, J = 11.4, 3.1 Hz, 2H), 1.60 (qd, J = 11.8, 3.6 Hz, 5H), 1.23 (d, J = 4.3 Hz, 6H). MS (ESI+) m / z 680 (M+H) + .

[0351] Example 49 6-amino-2'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide Process 49A 6-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19A, except that Intermediate 28 was used instead of Intermediate 1. MS (ESI+) m / z 487 (M+H) + .

[0352] Process 49B 6-Amino-2'-fluoro-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl][3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 49A was used instead of Intermediate 19A. MS (ESI+) m / z 535 (M+H) + .

[0353] Process 49C 6-amino-2'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 4C, except that the product of Step 49B was used in place of Intermediate 33 and Intermediate 13 was used in place of the product of Step 4B. 1H NMR (501 MHz, DMSO-d6) δ 8.62 (d, J = 6.9 Hz, 1H), 8.35 (t, J = 2.3 Hz, 1H), 8.25 - 8.03 (m, 3H), 7.59 - 7.46 (m, 2H), 7.43 (ddd, J = 7.0, 4.8, 1.9 Hz, 1H), 7.37 - 7.16 (m, 5H), 6.53 - 6.42 (m, 1H), 4.72 - 4.53 (m, 2H), 4.52 - 4.41 (m, 1H), 4.35 (d, J = 5.4 Hz, 1H), 4.09 (dt, J = 4.2, 1.9 Hz, 1H), 4.01 (dd, J = 9.3, 6.1 Hz, 1H), 3.92 (dd, J = 10.0, 4.9 Hz, 1H), 3.71 (ddd, J = 13.0, 9.6, 2.7 Hz, 2H), 3.47 (dt, J = 9.8, 4.8 Hz, 2H), 3.38 (s, 1H), 3.13 (s, 2H), 3.00 - 2.83 (m, 2H), 2.38 (t, J = 6.4 Hz, 2H), 2.07 (td, J = 11.5, 2.8 Hz, 2H), 1.60 (dtd, J = 27.7, 12.1, 3.7Hz, 4H), 1.25 (s, 6H). MS (ESI+) m / z 681 (M+H) + .

[0354] Example 50 2-Amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 50A 5-Bromo-2-fluoro-2,3-dihydro-1H-inden-1-one To a solution of 5-bromo-1-indanone (200 mg, 0.948 mmol) in acetonitrile (4.7 mL) was added NaSO (269 mg, 1.895 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (839 mg, 2.369 mmol), and the resulting mixture was stirred at 80 °C for 16 h. The mixture was diluted with ethyl acetate and water and extracted with dichloromethane. The organic layer was washed with water, dried over MgSO, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0–10% ethyl acetate / heptane to give the title compound (202 mg). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.9 Hz, 2H), 7.58 (dt, J = 7.4, 1.3 Hz, 1H), 5.25 (ddd, J = 50.8, 7.7, 4.3 Hz, 1H), 3.68 - 3.52 (m, 1H), 3.22 (dddd, J = 22.9, 17.2, 4.3, 1.2 Hz, 1H).

[0355] Process 50B 5-Bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-one To a solution of the product of Step 50A (202.2 mg, 0.883 mmol) in dichloromethane (5.9 mL) were added triethylamine (0.37 mL, 2.65 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (350 mg, 1.32 mmol), and the resulting mixture was stirred at 0 °C for 5 hours. The mixture was diluted with ethyl acetate and water and extracted with dichloromethane. The organic layer was washed with water, dried over MgSO, filtered, and concentrated. The crude product was dissolved in acetonitrile (5.9 mL), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (344 mg, 0.97 mmol) was added. The resulting mixture was stirred at ambient temperature overnight. The mixture was concentrated, diluted with dichloromethane, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 0-10% ethyl acetate / heptane to give the title compound (154 mg). 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 1H), 7.70 - 7.60 (m, 2H), 3.55 (td, J = 12.5, 1.1 Hz, 2H).

[0356] Process 50C tert-Butyl 4-(5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate A mixture of the product of Step 50B (150 mg, 0.607 mmol), triethylamine (0.25 mL, 1.82 mmol), 1-Boc-piperazine (226 mg, 1.214 mmol), and titanium(IV) chloride (0.3 mL, 0.304 mmol) in dichloromethane (4.6 mL) was stirred at ambient temperature for 16 hours. A solution of sodium cyanoborohydride (153 mg, 2.429 mmol) in methanol (1.5 mL) was added, and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with saturated NaHCO3 and ethyl acetate. The insoluble material was removed by filtration, and the organic layer was concentrated. The residue was purified by silica gel flash chromatography, eluting with 0-50% ethyl acetate / heptane, to give the title compound (218 mg). LCMS (APCI+) m / z 417.20 (M+H). + .

[0357] Process 50D 1-(5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)piperazine To a solution of the product of Step 50C (0.26 g, 0.622 mmol) in dichloromethane (3.11 mL) at 0° C. was added 4 M HCl in dioxane (1.56 mL, 6.22 mmol), and the resulting mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated to give the crude title compound, which was used without further purification.

[0358] Process 50E 2-[4-(5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl]ethan-1-ol To a solution of the product of Step 50D (243 mg, 0.62 mmol) in acetonitrile (3.1 mL) was added 2-bromoethanol (0.11 mL, 1.56 mmol), followed by K2CO3 (430 mg, 3.11 mmol), and the resulting mixture was stirred at 70 °C for 18 h. The solution was purified directly by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound (18 mg). LCMS (APCI+) m / z 361.05 (M+H) + .

[0359] Process 50F 2-Amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide A mixture of Intermediate 33 (25 mg, 0.048 mmol), the product of Step 50E (17.5 mg, 0.048 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.71 mg, 2.416 μmol) and KCO (20 mg, 0.145 mmol) in dioxane (0.24 mL) / water (0.08 mL) was sparged with nitrogen and heated at 100 °C for 2 h. The mixture was cooled to ambient temperature and purified directly by silica gel flash chromatography, eluting with 0–10% methanol / dichloromethane containing 3% NHOH. The product was then further purified by reverse-phase HPLC (C18 column) using a gradient elution of 10–75% acetonitrile / water containing 0.1% trifluoroacetic acid to give the title compound (22 mg). 1H NMR (400 MHz, methanol-d4) δ 8.48 (dd, J = 2.2, 1.4 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 4.4 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.63 - 7.40 (m, 7H), 4.77 - 4.57 (m, 3H), 4.51 - 4.41 (m, 1H), 4.05 (dt, J = 6.5, 4.3 Hz, 1H), 3.97 - 3.87 (m, 5H), 3.65 (d, J = 12.0 Hz, 1H), 3.57 (d, J = 8.5 Hz, 1H), 3.46 (dd, J = 15.9, 13.2 Hz, 2H), 3.34 - 2.99 (m, 7H), 2.21 (dt, J = 14.2, 6.9 Hz, 1H), 2.08 (ddd, J = 12.4, 7.8, 5.7 Hz, 1H), 1.95 - 1.76 (m, 3H), 1.76 - 1.60 (m, 1H). MS (ESI+) m / z 672.2 (M+H) + .

[0360] Example 51 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(prop-1-en-2-yl)pyridine-3-carboxamide Process 51A 2-Amino-5-(prop-1-en-2-yl)pyridine-3-carboxylic acid The title compound was prepared in a manner similar to that of Intermediate 2, except that 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane was used instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI+) m / z 179 (M+H) + .

[0361] Process 51B 2-Amino-N-{(1S,2S)-2-[(4-bromophenyl)methoxy]cyclopentyl}-5-(prop-1-en-2-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to that of Intermediate 3, except that the product of Step 51A was used instead of Intermediate 2. MS (ESI+) m / z 430 (M+H) + .

[0362] Process 51C 2-Amino-5-(prop-1-en-2-yl)-N-[(1S,2S)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}cyclopentyl]pyridine-3-carboxamide The title compound was prepared in a manner similar to that for the preparation of Intermediate 19B, except that the product of Step 51B was used instead of Intermediate 19A. MS (ESI+) m / z 478 (M+H) + .

[0363] Process 51D 2-Amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(prop-1-en-2-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except that the product of Step 51C was used in place of Intermediate 33 and Intermediate 13 was used in place of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.36 - 7.15 (m, 4H), 7.04 (s, 2H), 6.46 (d, J = 8.2 Hz, 1H), 5.32 (s, 1H), 4.91 (t, J = 1.6 Hz, 1H), 4.62 - 4.41 (m, 2H), 4.43 - 4.12 (m, 2H), 3.87 (dt, J = 6.3, 3.9 Hz, 1H), 3.52 - 3.43 (m, 2H), 3.11 (s, 2H), 2.97 - 2.72 (m, 2H), 2.38 (td, J = 6.3, 3.7 Hz, 2H), 2.16 - 1.79 (m, 7H), 1.75 - 1.34 (m, 9H), 1.20 (d, J = 24.4 Hz, 6H). MS (ESI+) m / z 624 (M+H) + .

[0364] Example 52 3-Amino-6-(6-fluoropyridin-3-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyrazine-2-carboxamide Process 52A 3-Amino-N-{(3S,4R)-4-[(4-bromophenyl)methoxy]oxolan-3-yl}-6-(6-fluoropyridin-3-yl)pyrazine-2-carboxamide The title compound was prepared in a manner similar to Step 41C, except that Intermediate 28 was used instead of Intermediate 1. MS (ESI+) m / z 487.9 (M+H) + .

[0365] Process 52B 3-Amino-6-(6-fluoropyridin-3-yl)-N-[(3S,4R)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}oxolan-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Step 41D, except that the product of Step 52A was used instead of the product of Step 41C. MS (ESI+) m / z 536.4 (M+H) + .

[0366] Process 52C 3-Amino-6-(6-fluoropyridin-3-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyrazine-2-carboxamide The title compound was prepared in a manner similar to Step 41E, except using the product of Step 52B instead of the product of Step 41D. 1H NMR (400 MHz, methanol-d4) δ 8.69 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.41 (td, J = 8.1, 2.6 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.15 - 7.05 (m, 2H), 6.99 (dd, J = 8.6, 2.6 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 4.65 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.50 (td, J = 4.1, 2.1 Hz, 1H), 4.16 (dt, J = 5.3, 2.6 Hz, 1H), 4.02 (ddd, J = 13.7, 9.7, 5.8 Hz, 2H), 3.71 (ddd, J = 9.3, 6.0, 3.5 Hz, 2H), 3.61 (t, J = 6.1 Hz, 2H), 3.10 (s, 2H), 3.02 (d, J = 11.5 Hz, 2H), 2.50 (t, J = 6.1 Hz, 2H), 2.17 (s, 2H), 1.84 (s, 1H), 1.69 (td, J = 10.8, 9.5, 3.3 Hz, 4H), 1.20 (s, 6H).MS (ESI+) m / z 682.2 (M+H) + .

[0367] Example 53 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[2-(trifluoromethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-2-(trifluoromethyl)-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.37 - 8.23 ​​(m, 2H), 7.97 (dd, J = 7.4, 1.6 Hz, 2H), 7.86 (t, J = 1.2 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.61 - 7.44 (m, 4H), 7.41 - 7.29 (m, 2H), 6.98 (d, J = 32.4 Hz, 3H), 4.58 (d, J = 2.9 Hz, 2H), 4.29 (dt, J = 11.4, 7.3 Hz, 1H), 3.90 (q, J = 3.2, 2.5 MS (ESI+) m / z 575 (M+H) + .

[0368] Example 54 2-Amino-N-[(1S,2S)-2-{[4-(1,3-dimethyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-1,3-dimethyl-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.42 - 8.14 (m, 2H), 7.96 (dd, J = 10.8, 1.5 Hz, 2H), 7.75 (d, J = 0.8 Hz, 1H), 7.67 (dd, J = 1.6, 0.8 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.47 - 7.24 (m, 4H), 7.06 (d, J = 1.1 Hz, 1H), 6.94 (s, 2H), 4.66 - 4.48 (m, 2H), 4.29 (dt, J = 11.5, 7.4 Hz, 1H), 3.90 (dt, J = 6.2, 3.7 MS (ESI+) m / z 535 (M+H) + .

[0369] Example 55 2-Amino-N-[(1S,2S)-2-{[4-(2,3-dimethyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-2,3-dimethyl-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.37 - 8.18 (m, 2H), 7.96 (dd, J = 11.3, 1.5 Hz, 2H), 7.75 (d, J = 0.8 Hz, 1H), 7.63 - 7.47 (m, 2H), 7.38 - 7.30 (m, 2H), 7.28 - 7.14 (m, 2H), 6.93 (s, 2H), 5.72 (s, 1H), 4.65 - 4.48 (m, 2H), 4.29 (p, J = 7.3 Hz, 1H), 3.90 (dt, J = 5.9, 3.7 Hz, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.22 - 2.07 (m, 3H), 2.09 - 1.82 (m, 2H), 1.84 - 1.43 (m, 4H). MS (ESI+) m / z 535 (M+H) + .

[0370] Example 56 2-Amino-N-[(1S,2S)-2-{[4-(2-methyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-2-methyl-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.0 Hz, 1H), 8.36 - 8.21 (m, 2H), 8.03 - 7.89 (m, 2H), 7.76 (d, J = 0.8 Hz, 1H), 7.65 - 7.47 (m, 3H), 7.37 - 7.17 (m, 4H), 6.94 (s, 2H), 6.12 (dt, J = 1.9, 1.0 Hz, 1H), 4.65 - 4.48 (m, 2H), 4.29 (qd, J = 7.6, 3.8 Hz, 1H), 3.90 (dt, J = 6.2, 3.8 Hz, 1H), 3.80 (s, 3H), 2.35 (d, J = 1.0 Hz, 3H), 2.05 - 1.86 (m, 2H), 1.73 - 1.50 (m, 4H). MS (ESI+) m / z 521 (M+H) + .

[0371] Example 57 2-Amino-N-[(1S,2S)-2-({4-[1-(2-hydroxyethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 2-(5-bromo-1H-indol-1-yl)ethanol was used in place of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.35 - 8.24 (m, 2H), 8.01 - 7.89 (m, 2H), 7.74 (dd, J = 12.6, 1.3 Hz, 2H), 7.62 - 7.53 (m, 2H), 7.49 (d, J = 8.6 Hz, 1H), 7.39 - 7.27 (m, 4H), 6.94 (s, 2H), 6.43 (dd, J = 3.1, 0.8 Hz, 1H), 4.85 (t, J = 5.3 Hz, 1H), 4.66 - 4.48 (m, 2H), 4.29 (qd, J = 7.5, 3.8 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.90 (dt, J = 6.0, 3.7 Hz, 1H), 3.79 (s, 3H), 3.70 (q, J = 5.5 Hz, 2H), 2.13 - 1.85 (m, 2H), 1.81 - 1.51 (m, 4H). MS (ESI+) m / z 551 (M+H) + .

[0372] Example 58 3-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}propanoic acid The title compound was prepared in a manner similar to Step 4C, except 3-(5-bromo-1H-indol-1-yl)propanoic acid was used in place of the product of Step 4B. 1H NMR (501 MHz, DMSO-d6) δ 8.36 - 8.26 (m, 2H), 8.00 (d, J = 2.3 Hz, 1H), 7.97 (s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.40 - 7.26 (m, 4H), 6.96 (s, 2H), 6.45 (dd, J = 3.2, 0.8 Hz, 1H), 4.69 - 4.51 (m, 2H), 4.40 (t, J = 6.8 Hz, 2H), 4.31 (qd, J = 7.6, 3.9 Hz, 1H), 3.92 (dt, J = 6.3, 3.8 Hz, 1H), 3.81 (s, 3H), 2.74 (t, J = 6.8 Hz, 2H), 2.08 - 1.87 (m, 2H), 1.78 - 1.52 (m, 4H). MS (ESI+) m / z 579 (M+H) + .

[0373] Example 59 2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,2-difluoro-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 59A 1-(5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazine To a solution of the product of Step 50D (388 mg, 1.097 mmol) in 1,2-dichloroethane (7.3 mL) / methanol (3.7 mL) was added (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (571 mg, 2.19 mmol), and the resulting mixture was stirred at ambient temperature for 15 minutes. Sodium triacetoxyborohydride (698 mg, 3.29 mmol) was added, and the resulting mixture was stirred at ambient temperature for 16 hours. Additional (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (571 mg, 2.19 mmol) was added, followed by sodium triacetoxyborohydride (698 mg, 3.29 mmol), and the resulting mixture was stirred for 16 hours. The reaction was quenched with water and extracted with dichloromethane. The organic extract was concentrated and purified by silica gel flash chromatography eluting with 0-10% methanol / dichloromethane to give the title compound as a racemic mixture (471 mg): LCMS (APCI+) m / z 431.00 (M+H). + .

[0374] Process 59B 3-[4-(5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl]propane-1,2-diol To a solution of the product of Step 59A (0.473 g, 1.097 mmol) in tetrahydrofuran (7.31 mL) was added 2 M HCl (10.97 mL, 21.94 mmol) and the resulting mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated to give the title compound, which was used without further purification. LCMS (ESI+) m / z 391.00 (M+H) + .

[0375] Process 59C 2-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,2-difluoro-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 50F except using the product of Step 59B instead of the product of Step 50E. 1 H NMR (501 MHz, methanol-d4) δ 8.50 (dd, J = 2.2, 1.2 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.60 - 7.52 (m, 3H), 7.50 (d, J = 1.6 Hz, 1H), 7.48 - 7.38 (m, 3H), 4.75 - 4.65 (m, 2H), 4.62 (t, J = 11.8 Hz, 1H), 4.44 (td, J = 7.3, 4.4 Hz, 1H), 4.12 - 4.00 (m, 2H), 3.93 (d, J = 2.2 Hz, 3H), 3.73 - 3.62 (m, 1H), 3.63 - 3.51 (m, 3H), 3.44 (dd, J = 15.8, 12.9 Hz, 3H), 3.32 - 2.97 (m, 7H), 2.27 - 2.14 (m, 1H), 2.14 - 2.02 (m, 1H), 1.83 (dddd, J = 22.7, 12.7, 6.7, 2.9 Hz, 3H), 1.67 (dq, J = 13.2, 7.5 Hz, 1H). MS (ESI+) m / z 702.5 (M+H) + .

[0376] Example 60 2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[1-(propan-2-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-1-isopropyl-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.25 (m, 2H), 8.02 - 7.87 (m, 2H), 7.74 (dd, J = 11.6, 1.3 Hz, 2H), 7.59 - 7.42 (m, 4H), 7.38 - 7.30 (m, 3H), 6.94 (s, 2H), 6.46 (d, J = 3.2 Hz, 1H), 4.73 (hept, J = 6.4 Hz, 1H), 4.61 - 4.51 (m, 2H), 4.32 - 4.25 (m, 1H), 3.98 - 3.89 (m, 1H), 3.79 (s, 3H), 2.05 - 1.88 (m, 2H), 1.74 - 1.52 (m, 4H), 1.44 (d, J = 6.6 Hz, 6H). MS (ESI+) m / z 549 (M+H) + .

[0377] Example 61 {5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}acetic acid The title compound was prepared in a manner similar to Step 4C, except 2-(5-bromo-1H-indol-1-yl)acetic acid was used in place of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 8.44 - 8.23 ​​(m, 2H), 8.05 - 7.88 (m, 2H), 7.84 - 7.68 (m, 2H), 7.64 - 7.47 (m, 2H), 7.46 - 7.16 (m, 5H), 6.94 (s, 2H), 6.44 (d, J = 3.2 Hz, 1H), 4.93 (s, 2H), 4.74 - 4.44 (m, 2H), 4.30 (pd, J = 7.1, 2.9 Hz, 1H), 3.90 (dt, J = 6.2, 3.8 Hz, 1H), 3.79 (s, 3H), 2.13 - 1.87 (m, 2H), 1.78 - 1.37 (m, 4H). MS (ESI+) m / z 565 (M+H) + .

[0378] Example 62 6-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,2-difluoro-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 50F, except that the product of Step 59B was used instead of the product of Step 50E and Intermediate 32 was used instead of Intermediate 33. 1H NMR (501 MHz, methanol-d4) δ 8.46 (dd, J = 8.1, 2.7 Hz, 1H), 8.40 (dt, J = 4.0, 2.1 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.18 (dddd, J = 8.7, 7.4, 2.6, 1.4 Hz, 1H), 7.57 - 7.51 (m, 3H), 7.51 - 7.39 (m, 4H), 7.16 (dt, J = 8.5, 2.2 Hz, 1H), 4.77 - 4.59 (m, 3H), 4.46 (td, J = 7.4, 4.6 Hz, 1H), 4.08 (ddt, J = 14.2, 11.0, 4.8 Hz, 1H), 4.02 (dt, J = 6.7, 4.6 Hz, 1H), 3.74 - 3.53 (m, 4H), 3.52 - 3.36 (m, 4H), 3.33 - 3.00 (m, 6H), 2.21 (dq, J = 13.5, 7.2 Hz, 1H), 2.09 (dq, J = 12.6, 7.1 Hz, 1H), 1.94 - 1.76 (m, 3H), 1.65 (dq, J = 14.8, 7.5 Hz, 1H). MS (ESI+) m / z 717.5 (M+H) + .

[0379] Example 63 6-Amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,2-difluoro-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide The title compound was prepared in a manner similar to Step 50F, except that the product of Step 59B was used in place of the product of Step 50E and the product of Step 30C was used in place of Intermediate 33. 1H NMR (400 MHz, methanol-d4) δ 8.47 - 8.37 (m, 2H), 7.73 (dd, J = 7.1, 5.9 Hz, 1H), 7.60 - 7.38 (m, 7H), 6.82 (d, J = 2.0 Hz, 1H), 6.70 (td, J = 6.9, 2.1 Hz, 1H), 4.76 - 4.60 (m, 3H), 4.45 (td, J = 7.4, 4.6 Hz, 1H), 4.13 - 3.98 (m, 2H), 3.73 - 3.53 (m, 7H), 3.52 - 3.37 (m, 3H), 3.30 (t, J = 2.7 Hz, MS (ESI+) m / z 729.4 (M+H) + .

[0380] Example 64 2-Amino-N-[(1S,2S)-2-({4-[1-(difluoromethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-1-(difluoromethyl)-1H-indole was used instead of the product of Step 4B. 1H NMR (501 MHz, DMSO-d6) δ 8.38 - 8.26 (m, 2H), 8.02 - 7.95 (m, 2H), 7.85 (d, J = 1.7 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.66 - 7.58 (m, 3H), 7.53 (dd, J = 8.5, 1.8 Hz, 1H), 7.42 - 7.35 (m, 2H), 6.96 (s, 2H), 6.72 (dd, J = 3.5, 0.8 Hz, 1H), 4.66 - 4.55 (m, 2H), 4.31 (qd, J = 7.6, 4.0Hz, 1H), 3.81 (s, 3H), 3.15 (d, J = 5.1 Hz, 1H), 2.10 - 1.90 (m, 2H), 1.78 - 1.52 (m, 4H). MS (ESI+) m / z 557 (M+H) + .

[0381] Example 65 2-Amino-N-{(1S,2S)-2-[(4-{(1R)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 65A 2-{4-[(1R)-5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}ethan-1-ol The title compound (31 mg) was separated from the product of Step 50E by chiral supercritical fluid chromatography using a YMC Amylose-C column (20 x 250 mm ID) as the first eluting peak. LCMS (APCI+) m / z 361.04 (M+H) + .

[0382] Process 65B 2-Amino-N-{(1S,2S)-2-[(4-{(1R)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 50F except using the product of Step 65A instead of the product of Step 50E. 1 H NMR (501 MHz, methanol-d4) δ 8.51 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 0.8 Hz, 1H), 7.60 - 7.52 (m, 3H), 7.50 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 15.0, 8.1 Hz, 3H), 4.75 - 4.65 (m, 2H), 4.62 (dd, J = 12.9, 10.7 Hz, 1H), 4.44 (ddd, J = 8.2, 6.8, 4.4 Hz, 1H), 4.04 (dt, J = 6.5, 4.4 Hz, 1H), 3.96 - 3.86 (m, 5H), 3.64 (d, J = 12.0 Hz, 1H), 3.56 (d, J = 8.8 Hz, 1H), 3.41 (ddd, J = 26.7, 15.8, 8.7 Hz, 3H), 3.31 (td, J = 4.7, 1.3 Hz, 3H), 3.29 - 3.18 (m, 1H), 3.09 (dd, J = 22.4, 10.8 Hz, 3H), 2.26 - 2.15 (m, 1H), 2.07 (ddd, J = 15.0, 7.7, 5.8 Hz, 1H), 1.92 - 1.75 (m, 3H), 1.72 - 1.61 (m, 1H). MS (ESI+) m / z 672.3 (M+H) + .

[0383] Example 66 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 66A 2-{4-[(1S)-5-Bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}ethan-1-ol Purification by supercritical fluid chromatography as in Step 65A gave the title compound (30 mg) as the second eluting peak. LCMS (APCI+) m / z 361.04 (M+H) + .

[0384] Process 66B 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 50F except using the product of Step 66A instead of the product of Step 50E. 1H NMR (400 MHz, methanol-d4) δ 8.50 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.99 (s, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.56 (td, J = 8.0, 1.8 Hz, 3H), 7.49 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 13.0, 8.1 Hz, 3H), 4.75 - 4.57 (m, 3H), 4.49 - 4.40 (m, 1H), 4.04 (dt, J = 6.4, 4.3 Hz, 1H), 3.97 - 3.87 (m, 5H), 3.64 (d, J = 12.0 Hz, 1H), 3.56 (d, J = 8.2 Hz, 1H), 3.44 (dd, J = 16.0, 13.2 Hz, 4H), 3.33 - 3.18 (m, 5H), 3.18 - 2.99 (m, 3H), 2.28 - 2.14 (m, 1H), 2.07 (ddd, J = 14.8, 7.6, 5.5 Hz, 1H), 1.94 - 1.76 (m, 3H), 1.67 (dq, J = 14.8, 7.5 Hz, 1H). MS (ESI+) m / z 672.4 (M+H) + .

[0385] Example 67 2-Amino-N-[(1S,2S)-2-({4-[1-(2-aminoethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 2-(5-chloro-1H-indol-1-yl)ethanamine was used in place of the product of Step 4B. 1H NMR (501 MHz, DMSO-d6) δ 8.44 - 8.17 (m, 2H), 8.11 - 7.91 (m, 2H), 7.85 - 7.71 (m, 2H), 7.63 - 7.47 (m, 3H), 7.42 - 7.28 (m, 4H), 6.96 (s, 2H), 6.45 (dd, J = 3.2, 0.8 Hz, 1H), 4.71 - 4.50 (m, 2H), 4.31 (qd, J = 7.6, 3.9 Hz, 1H), 4.14 (t, J = 6.5 Hz, 2H), 3.92 (dt, J = 6.4, 3.8 Hz, 1H), 3.81 (s, 3H), 2.88 (t, J = 6.5 Hz, 2H), 2.09 - 1.88 (m, 2H), 1.77 - 1.53 (m, 4H). MS (ESI+) m / z 550 (M+H) + .

[0386] Example 68 2-Amino-N-[(1S,2S)-2-{[4-(1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide The title compound was prepared in a manner similar to Step 4C, except 5-bromo-1H-indole was used instead of the product of Step 4B. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.40 - 8.19 (m, 2H), 8.05 - 7.88 (m, 2H), 7.82 - 7.69 (m, 2H), 7.61 - 7.50 (m, 2H), 7.47 - 7.23 (m, 5H), 6.94 (s, 2H), 6.44 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 4.67 - 4.50 (m, 2H), 4.29 (qd, J = 7.7, 4.0 Hz, 1H), 3.91 (q, J = 3.3, 2.5 Hz, 1H), 3.79 (s, MS (ESI+) m / z 507 (M+H) + .

[0387] Example 69 2-Amino-N-{(1S,2S)-2-[(4-{3-[4-(2-hydroxyethyl)piperazin-1-yl]-2-oxo-2,3-dihydro-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide Process 69A 6-Bromo-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1,3-dihydro-2H-indol-2-one To a mixture of 6-bromoisatin (500 mg, 2.21 mmol) and N-(2-hydroxyethyl)piperazine (374 mg, 2.88 mmol) in anhydrous dioxane (8 mL) was added titanium(IV) isopropoxide (1.31 mL). The resulting mixture was heated at 80 °C for 2 hours and then cooled to ambient temperature. NaCNBH (278 mg, 4.42 mmol) was added, and the resulting mixture was heated at 60 °C overnight. After cooling, ethyl acetate and aqueous NaOH were added to the mixture and stirred. The solid was filtered through diatomaceous earth, an...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Ring A is selected from the group consisting of benzofuran, benzimidazole, chroman, dihydroindene, dihydropyrrolopyridine, indazole, indole, indoline, isoindoline, pyrrolopyridine, tetrahydroisoquinoline, tetrahydronaphthalene, tetrahydronaphthyridine, and tetrahydroquinoline; W is N and CR 2 selected from the group consisting of: X is -CR 6 R 7 -, -O-, and -NR 8 - selected from the group consisting of; Y is selected from the group consisting of a bond, piperidinediyl, piperazinediyl, and octahydropyrrolopyrazinediyl; L 1 is a bond, -(CH 2 ) m -, -C(O)-(CH 2 ) n -, -N(R a )-, and -NHCO 2 -(CH 2 ) p - selected from the group consisting of; R a is C 1 ~C 4 is alkyl; R 1 is hydrogen, C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 selected from the group consisting of alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I; R 2 is hydrogen or C 1 ~C 4 is alkoxy; R 3 is hydrogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c , and -C(O)NH 2 R 3 Each of the azetidinyl and dioxolanyl groups may be one or more C 1 ~C 4 optionally substituted with alkyl substituents; R 3a and R 3b is hydrogen and C 1 ~C 4 are each independently selected from the group consisting of alkyl; R 3c is C 1 ~C 4 is alkyl; R 4 are F, Cl, Br, I, =O, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxyalkyl, and C 1 ~C 4 hydroxyalkyl; R 4 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; R 6 is hydrogen, C 1 ~C 4 selected from the group consisting of alkyl, and -OH; R 7 is hydrogen and C 1 ~C 4 selected from the group consisting of alkyl; R 8 is C 1 ~C 4 is alkyl; k is 1, 2, 3, or 4; m is 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3) or a pharmaceutically acceptable salt thereof.

2. W is CR 2 2. The compound of claim 1, wherein:

3. X is -CR 6 R 7 - and; R 1 But C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 selected from the group consisting of alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I; R 2 , R 6 and R 7 are each independently hydrogen, 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

4. 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of dihydroindene and tetrahydronaphthalene.

5. Formula (II): 【Chemistry 2】 (In the formula, Y is selected from the group consisting of a bond, piperidinediyl, piperazinediyl, and octahydropyrrolopyrazinediyl; L 1 is a bond, -(CH 2 ) m -, -C(O)-(CH 2 ) n -, -N(R a )-, and -NHCO 2 -(CH 2 ) p - selected from the group consisting of; R a is C 1 ~C 4 is alkyl; R 1 is C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 selected from the group consisting of alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I; R 3 is hydrogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c , and -C(O)NH 2 R 3 Each of the azetidinyl and dioxolanyl groups may be one or more C 1 ~C 4 optionally substituted with alkyl substituents; R 3a and R 3b is hydrogen and C 1 ~C 4 are each independently selected from the group consisting of alkyl; R 3c is C 1 ~C 4 is alkyl; R 5 are hydrogen, F, Cl, Br, I, =O, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxyalkyl, and C 1 ~C 4 hydroxyalkyl; More than three R 5 But at the same time, not hydrogen; R 5 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; m is 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 1 or 2) 5. The compound of claim 4, wherein:

6. L 1 is a bond; R 3 But hydrogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Hydroxyalkyl, -OH, and -NR 3a R 3b selected from the group consisting of: R 5 But F and C 1 ~C 4 selected from the group consisting of alkyl, 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof.

7. Formula (III): 【Transformation 3】 (In the formula, Y is selected from the group consisting of a bond, piperidinediyl, piperazinediyl, and octahydropyrrolopyrazinediyl; L 1 is a bond, -(CH 2 ) m -, -C(O)-(CH 2 ) n -, -N(R a )-, and -NHCO 2 -(CH 2 ) p - selected from the group consisting of; R a is C 1 ~C 4 is alkyl; R 1 is C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 selected from the group consisting of alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I; R 3 is hydrogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, azetidinyl, dioxolanyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c , and -C(O)NH 2 R 3 Each of the azetidinyl and dioxolanyl groups may be one or more C 1 ~C 4 optionally substituted with alkyl substituents; R 3a and R 3b is hydrogen and C 1 ~C 4 are each independently selected from the group consisting of alkyl; R 3c is C 1 ~C 4 is alkyl; R 5 are hydrogen, F, Cl, Br, I, =O, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxyalkyl, and C 1 ~C 4 hydroxyalkyl; More than three R 5 But at the same time, not hydrogen; R 5 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; m is 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; r is 1 or 2) 5. The compound of claim 4, wherein:

8. Y is piperazinediyl; L 1 is a bond, 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof.

9. Formula (IV): 【Chemistry 4】 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 selected from the group consisting of alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I; R 3 is hydrogen, C 1 ~C 4 Alkyl, and C 1 ~C 4 hydroxyalkyl; R 5 are hydrogen, F, Cl, Br, I, =O, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxyalkyl, and C 1 ~C 4 hydroxyalkyl; R 5 two substituents together with the atoms to which they are attached may form a cycloalkyl or heterocycloalkyl ring; r is 1 or 2) 9. The compound of claim 8, wherein: or a pharmaceutically acceptable salt thereof.

10. R 3 But C 1 ~C 4 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, which is hydroxyalkyl.

11. R 1 is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I.

12. R 1 but, 【Transformation 5】 12. The compound of claim 11, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

13. Y is octahydropyrrolopyrazinediyl; L 1 is a bond, 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof.

14. Formula (V): 【Transformation 6】 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 selected from the group consisting of alkenyl, pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl; R 1 Each of pyrazolyl, pyridinyl, pyridinonyl, and thiazolyl is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, CN, F, Cl, Br, and I; R 3 is C 1 ~C 4 Hydroxyalkyl, -OH, -NR 3a R 3b , -C(O)OH, C(O)OR 3c , and -C(O)NH 2 selected from the group consisting of: R 5 are hydrogen, F, Cl, Br, I, =O, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxyalkyl, and C 1 ~C 4 hydroxyalkyl; r is 1 or 2) 14. The compound of claim 13, wherein: or a pharmaceutically acceptable salt thereof.

15. The compound of claim 3 , wherein ring A is indole.

16. Y is piperidinediyl; L 1 is a bond, 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof.

17. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein ring A is indoline.

18. 2-amino-N-{(1S,2S)-2-[(4-{2-[3-(dimethylamino)propanoyl]-2,3-dihydro-1H-isoindol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; tert-Butyl 4-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}piperidine-1-carboxylate; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[1-(piperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(1-methylpiperidin-4-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{2-[2-(dimethylamino)acetamido]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{2-[(1-methylpiperidine-4-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{2-[(1-methylazetidine-3-carbonyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[3-(1-methylpiperidin-4-yl)-1H-indol-6-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(3S,4R)-4-{[4-(1-methyl-1H-indol-5-yl)phenyl]methoxy}oxolan-3-yl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-{[4-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]pyridine-3-carboxamide; 2-amino-N-{(3S,4R)-4-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2,3-dihydroxypropyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(trifluoromethyl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{3-[1-(2-hydroxyethyl)piperidin-4-yl]-1-methyl-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-amino-2-oxoethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1'-[1-(2-hydroxyethyl)piperidin-4-yl]-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-5'-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(1H-indol-7-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-6'-oxo-1',6'-dihydro[3,3'-bipyridine]-5-carboxamide; 6-amino-6'-fluoro-N-{(3S,4S)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]-1-methylpyrrolidin-3-yl}[3,3'-bipyridine]-5-carboxamide; rac-2-amino-N-{(1S,2S,4S)-4-hydroxy-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-3-propyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{3-ethyl-1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 3-amino-6-(6-fluoropyridin-3-yl)-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}pyrazine-2-carboxamide; 2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1,2-dihydrospiro[indole-3,3'-oxolan]-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-5'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(3S,4R)-4-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]oxolan-3-yl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(prop-1-en-2-yl)pyridine-3-carboxamide; 3-amino-6-(6-fluoropyridin-3-yl)-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}pyrazine-2-carboxamide; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[2-(trifluoromethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(1,3-dimethyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(2,3-dimethyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(2-methyl-1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(2-hydroxyethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 3-{5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}propanoic acid; 2-amino-N-[(1S,2S)-2-{[4-(1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[1-(propan-2-yl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide; {5-[4-({[(1S,2S)-2-{[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl]amino}cyclopentyl]oxy}methyl)phenyl]-1H-indol-1-yl}acetic acid; 6-amino-N-[(1S,2S)-2-{[4-(1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-{[4-(1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(difluoromethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1R)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(2-aminoethyl)-1H-indol-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(1H-indol-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{3-[4-(2-hydroxyethyl)piperazin-1-yl]-2-oxo-2,3-dihydro-1H-indol-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[2-(dimethylamino)ethyl]-1H-indol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 3-amino-N-{(3S,4R)-4-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl}phenyl)methoxy]oxolan-3-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{2'-[1-(2-hydroxyethyl)piperidin-4-yl]-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-6'-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{2'-[1-(2-hydroxyethyl)piperidin-4-yl]-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-6'-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-[(1S,2S)-2-{[4-(1-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-{[4-(1-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl)phenyl]methoxy}cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1R,2S)-2-fluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{2,2-difluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1R,2S)-2-fluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1R,2S)-2-fluoro-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-6'-oxo-1',6'-dihydro[3,3'-bipyridine]-5-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{3-[4-(2-hydroxyethyl)piperazin-1-yl]-1-benzofuran-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; rac-6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-1'-methyl-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[1-(dimethylamino)-2,2-dimethyl-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indazol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1,2,3,4-tetrahydroquinolin-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-1'-methyl-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-oxo-1',2'-dihydro[3,4'-bipyridine]-5-carboxamide; 6-amino-2'-fluoro-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-6'-fluoro-N-{(1S,2S)-2-[(4-{(1R)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[5-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide; 6-amino-5'-fluoro-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[(3,4-dihydroxybutyl)(methyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[(3,4-dihydroxybutyl)(methyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-fluoro[3,3'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[(3,4-dihydroxybutyl)(methyl)amino]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide; 6-amino-5'-fluoro-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}-5-(trifluoromethyl)pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-3,4-dihydro-2H-1-benzopyran-7-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-4-methoxypyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-4-methoxypyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-4-methoxypyridine-3-carboxamide; 2-amino-4-methoxy-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{1-[4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-[(1S,2S)-2-({4-[(5S)-5-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(5S)-5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(trifluoromethyl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(1S)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(1R)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[8,8-dimethyl-5-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[8,8-dimethyl-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[(1S)-3,3-dimethyl-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 6-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6'-methoxy[3,3'-bipyridine]-5-carboxamide; 6-amino-6'-methoxy-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide; 6-amino-6'-cyano-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-6'-cyano-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{1-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-benzimidazol-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-4-methoxy-N-[(1S,2S)-2-({4-[(1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{8-[1-(2-hydroxyethyl)piperidin-4-yl]-5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(1S)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{8-[1-(2-hydroxyethyl)piperidin-4-yl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}phenyl)methoxy]cyclopentyl}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-2'-fluoro-N-[(1S,2S)-2-({4-[(5S)-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl][3,3'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(5S)-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 6-amino-2'-fluoro-N-{(1S,2S)-2-[(4-{(5S)-5-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}phenyl)methoxy]cyclopentyl}[3,3'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2R)-2,3-dihydroxypropyl]piperazin-1-yl}-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(1S)-1-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(5R)-5-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-[(1S,2S)-2-({4-[(5S)-5-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(2-methyl-1,3-thiazol-5-yl)pyridine-3-carboxamide; 6-amino-N-[(1S,2S)-2-({4-[(5S)-5-{4-[(2S)-2,3-dihydroxypropyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalen-2-yl]phenyl}methoxy)cyclopentyl]-2'-fluoro[3,3'-bipyridine]-5-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1,2-thiazol-5-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(3-methyl-1,2-thiazol-5-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(1,3-thiazol-5-yl)pyridine-3-carboxamide; 6'-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}[2,3'-bipyridine]-5'-carboxamide; 6'-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-6-methoxy[2,3'-bipyridine]-5'-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(2-methoxy-1,3-thiazol-4-yl)pyridine-3-carboxamide; 2-amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(2-methyl-1,3-thiazol-4-yl)pyridine-3-carboxamide; and 2-Amino-N-{(1S,2S)-2-[(4-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-2,3-dihydro-1H-inden-5-yl}phenyl)methoxy]cyclopentyl}-5-(4-methyl-1,3-thiazol-2-yl)pyridine-3-carboxamide 2. The compound of claim 1 selected from the group consisting of:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. 1. A method of treating a disease, disorder, or condition, comprising:

20. A method comprising administering to a subject in need of treatment for a disease, disorder, or condition an effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, wherein the disease, disorder, or condition is cancer or an immune-related disease.

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