HK1257578A1

HK1257578A1 - Heteroaryl compounds and their use as therapeutic drugs

Info

Publication number: HK1257578A1
Application number: HK18116664.1A
Authority: HK
Inventors: Myeong-Seop Kim; Sumin Kim; Jin Kwan Kim; Hadong Kim; Ki Moon Ryu; Seong Jin Park; Taesun Park; Joon-Ho SHEEN; Taeyoung Yoon; Mi Yeon Jang
Original assignee: Dong-A Socio Holdings Co., Ltd.
Priority date: 2015-08-31
Filing date: 2016-08-31
Publication date: 2019-10-25

Description

TECHNICAL FIELD

The present invention relates to novel heterocyclic compounds having Mer kinase inhibitory activity, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, the use for preparing pharmaceutical compositions, pharmaceutical compositions comprising the same, methods of treating diseases using these compositions.

BACKGROUND ART

Transmembrane receptor tyrosine kinases (RTKs) comprise an evolutionarily conserved family of structurally related proteins. The gene Mer is a member of the Tyro3/Axl/Mer (TAM) receptor kinase family and a proto-oncogene. Its abnormal expression and activation is found in conjunction with human cancers such as pituitary adenomas, mantle cell lymphomas, and T-cell acute lymphoblastic leukemia.

The ATP-binding site is similar for all protein kinases. For this reason, it is challenging to find an inhibitor that is specific for the Mer. Compound-52, a 2,6,9-trisubstituted purine that occupies the ATP-binding site, was actually the first molecule that was found to be successful in inhibiting Mer (J Struct Biol. 2009 February; 165(2): 88-96). This inhibitor has, however, limited potency and lack of selectivity. Lately, several compounds have been unveiled mostly 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 July;65:83-93, J Med Chem. 2014 Aug 28;57(16):7031-41).

WO 2004/054977 discloses nicotinamide-based kinase inhibitors for treating tyrosine kinose-assocated disease states.

It is an object of the invention to provide reagents and methods of regulating a receptor tyrosine kinase Mer. This and other objects of the invention are provided by one or more of the embodiments described below.

DISCLOSURE Technical Problem

Several Mer kinase inhibitors have been previously described, but they have different moieties onto the scaffold from the present invention. Highly potent and selective Mer kinase inhibitors based on aminopyridine or aminopyrimidine scaffolds are described.

The present invention relates to compounds capable of inhibiting the activity of Mer, which compounds are useful for the prevention and/or the treatment of cancer and other immune-related diseases such as infection and sepsis.

Technical Solution Novel Mer Kinase Inhibitors

The present invention relates to a heterocyclic compound represented by the following Formula Ib, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof: wherein

X is CH, or N;
W is CH2, NR11, or O;
V1 and V2 each independently is CR13R13', NR13, or O;
at least one of V1 and V2 is CR13R13';
X1 to X5 are the same as or different from each other, and are each independently CR14 or N;
at least one of X1 to X5 is CR14;
R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl, or C(=O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
R9 is halogen, hydroxyl, -CN, -NO2, -COOH, -(C=O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, -CN, -NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or -(CH2)1-C(=O)-NR15R16;
R10 is C1-3 alkyl or C1-3 alkylaryl;
R11 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(=O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
R13 and R13' each independently is H, C1-3 alkyl, C2-3 hydroxyalkyl;
each R14 is independently selected from H, halogen, hydroxyl, -CN, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -NR15R16, - L-alkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, aryl, heteroaryl, heterocyclyl may optionally be substituted with one or more R9; or adjacent groups among a plurality of R14s are bonded to each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR11 O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
R17 is H, C1-3 alkyl or C1-3 alkylaryl;
L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, -(CH2)1-C(=O)-(CH2)m-, C(=O)O, -(CH2)1-C(=O)NH-(CH2)m-, -(CH2)1-NHC(=O)-(CH2)m-, -(CH2)1-NH-(CH2)m-, NR8, -NH-C(=O)-CR15R16-NH-C(=O)-, NHC(=O), O, O(C=O) S, S, S(=O), or SO2; and
1 and m each independently is an integer of 0 to 2.

Also disclosed herein is a heterocyclic compound represented by the following formula I, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptalt salt thereof: wherein:

X is CR7, or N;
Y is CHR8, NR8, or O;
Z is CH2, CH2O, C(=O), C(=O)O, C(=O)NH, NR8, NHC(=O), O or O(C=O);
R1 is H, halogen, C1-3 alkyl, NHR8 or OR8;
R2 is H, halogen, C1-4 alkyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl or - L-aryl, which C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl or -L-aryl may optionally be substituted with one or more R9;
R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
R4 and R5 each independently is H, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C(=O) R6, C1-2 alkylaryl, aryl; or
R4 and R5 may be combined with each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR8, O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
R5' is H or R5 and R5' may be combined with each other to form carbonyl;
R6 is H, C1-4 alkyl, C1-6 alkoxy, -NR15R16, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, which C1-4 alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted with one or more R9;
R7 is H, halogen or C1-3 alkyl;
R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(=O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
when Z is NR8, R8 and R6 may be combined with each other to form a 3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;
R9 is halogen, hydroxyl, -CN, -NO2, -COOH, -(C=O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, -CN, -NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or -(CH2)l-C(=O)-NR15R16;
R10 is C1-3 alkyl or C1-3 alkylaryl;
R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
R17 is H, C1-3alkyl or C1-3 alkylaryl;
L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, -(CH2)l-C(=O)-(CH2)m-, C(=O)O, -(CH2)l-C(=O)NH-(CH2)m-, -(CH2)l-NHC(=O)-(CH2)m-, -(CH2)l-NH-(CH2)m-, NR8,-NH-C(=O)-CR15R16-NH-C(=O)-, NHC(=O), O, O(C=O) S, S(=O), or SO2; and
1 and m each independently is an integer of 0 to 2.

Also disclosed herein in a heterocyclic compound represented by the following Formula Ia: wherein

X is CH, or N;
Y is NR8, or O;
W is CH2, (CH2)2, NR11, or O;
Z is CH2, CH2O, C(=O), C(=O)O, C(=O)NH, NR8, NHC(=O), O or O(C=O);
R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
R6 is H, C1-4 alkyl, C1-6 alkoxy, -NR15R16, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, which C1-4 alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted with one or more R9;
R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(=O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
when Z is NR8, R8 and R6 may be combined with each other to form a 3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;
R9 is halogen, hydroxyl, -CN, -NO2, -COOH, -(C=O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, -CN, -NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or -(CH2)l-C(=O)-NR15R16;
R10 is C1-3 alkyl or C1-3 alkylaryl;
R11 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(=O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
R17 is H, C1-3 alkyl or C1-3 alkylaryl;
R18 to R21 are the same as or different from each other, and are each independently H or halogen; or
R18 and R19; or R20 and R21 may be combined with each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR8, O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, -(CH2)l-C(=O) -(CH2)m-, C(=O)O, -(CH2)l-C(=O)NH-(CH2)m-, -(CH2)l-NHC(=O)-(CH2)m-, -(CH2)l-NH-(CH2)m-, NR8, -NH-C(=O)-CR15R16-NH-C(=O)- NHC(=O), O, O(C=O) S, S, S(=O), or SO2; and
1 and m each independently is an integer of 0 to 2.

In the present disclosure, a halogen may be fluorine, chlorine, bromine or iodine.

In the present disclosure, the alkyl may be straight or branched, and the number of carbon atoms thereof is not particularly limited, but is preferably 1 to 6. Specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, and the like, or a branched chain thereof, but are not limited thereto.

In the present disclosure, the cycloalkyl is not particularly limited, but has preferably 3 to 10 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a norbornyl group, an adamantly group, and the like, but are not limited thereto.

In the present disclosure, the alkoxy may be straight, branched, or cyclic. The number of carbon atoms of the alkoxy group is not particularly limited, but is preferably 1 to 6. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and the like, but are not limited thereto.

In the present disclosure, the alkenyl may be straight or branched, and the number of carbon atoms thereof is not particularly limited, but is preferably 2 to 6. Specific examples thereof include vinyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-methyl-1-butenyl, 1,3-butadienyl, and the like, but are not limited thereto.

In the present disclosure, the aryl may be monocyclic, or polycyclic and the number of carbon atoms is not particularly limited, but is preferably 6 to 60. Specific examples of the aryl group include a monocyclic aromatic group, such as a phenyl group and a polycyclic aromatic group, such as a naphthyl group, an anthracenyl group, a phenanthrenyl group, a pyrenyl group, a perylenyl group, a tetracenyl group, a chrysenyl group, a fluorenyl group, an acenaphthacenyl group, a triphenylene group, and a fluoranthene group, and the like, but are not limited thereto.

In the present disclosure, the biaryl may two or more monocyclics and/or polycyclics linked each other.

In the present disclosure, the aryl in the alkylaryl and biaryl is the same as the above-described examples of the aryl group.

In the present disclosure, a heterocyclic or a heteroaryl including one or more hetero atom, for example, a heterocyclic group including one or more of O, N, S, Si, Se and the like. Examples of the heterocyclic group include a thiophene group, a furan group, a pyrrole group, an imidazole group, a thiazole group, an oxazole group, an oxadiazole group, a triazole group, a pyridyl group, a bipyridyl group, a triazine group, an acridyl group, a pyridazine group, a pyrrolidine group, a morpholine group, a piperazin group, a piperidine group, a tetrahydrofuran group, a pyrazole group, a quinolinyl group, an isoquinoline group, an indole group, a carbazole group, a benzoxazole group, a benzimidazole group, a benzothiazole group, a benzocarbazole group, a benzothiophene group, a dibenzothiophene group, a benzofuranyl group, a phenanthroline group, a dibenzofuranyl group, and the like, but are not limited thereto.

In the present disclosure, the "adjacent" group may mean a substituent substituted with an atom directly linked to an atom in which the corresponding substituent is substituted, a substituent disposed sterically closest to the corresponding substituent, or another substituent substituted with an atom in which the corresponding substituent is substituted. For example, two substituents substituted at the ortho position in a benzene ring and two substituents substituted with the same carbon in an aliphatic ring may be interpreted as groups "adjacent" to each other.

In the present disclosure, the cyclic ring or heterocyclic ring formed by binding two or more R¹⁴s comprises cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl.

In accordance with specific embodiments of the present invention, there are provided the heterocyclic compounds represented formula Ib represented by the following compounds.

Example 1	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 2	2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 3	2-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 4	2-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 5	2-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 6	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamide
Example 7	2-amino-N-((1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 8	2-amino-N-((1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 9	2-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 10	2-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 11	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 12	2-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 13	2-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 14	2-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 15	2-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 16	2-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 17	2-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 18	2-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 19	2-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 20	2-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 21	2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 22	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamide
Example 23	2-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 24	2-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 25	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 26	2-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 27	2-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 28	2-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 29	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide
Example 30	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamide
Example 31	2-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 32	2-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 33	2-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 34	2-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 35	2-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 36	2-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 37	2-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 38	2-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 39	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamide
Example 40	2-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 41	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamide
Example 42	methyl 3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate
Example 43	2-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 44	2-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 45	2-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 46	2-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamid
Example 47	2-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 48	2-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 49	2-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 50	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamide
Example 51	2-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 52	2-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 53	2-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 54	2-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 57	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)oxy)cyclopentyl)nicotinamide
Example 61	N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 62	N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 63	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamide
Example 64	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamide
Example 65	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 66	N-(trans-2-([1,1'-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 67	N-((1S,2S)-2-([1,1'-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 68	N-((1S,2S)-2-([1,1'-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 76	2-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 77	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamide
Example 78	2-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 80	2-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 81	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamide
Example 82	2-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 83	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide
Example 84	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamide
Example 85	2-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 86	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)methyl)cyclopentyl)nicotinamide
Example 88	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamide
Example 89	2-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 93	2-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 94	2-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 129	3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide
Example 130	3-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide
Example 132	3-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide
Example 133	3-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine- 2-carboxamide
Example 134	2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 135	2-amino-N-((1S,2S)-2-((4'-amino-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 136	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(methylamino)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 137	2-amino-N-((1S,2S)-2-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 138	2-amino-N-((1S,2S)-2-((4'-((dimethylamino)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 139	2-amino-N-((1S,2S)-2-((3'-amino-2'-methyl-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 140	2-amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 141	2-amino-N-((1S,2S)-2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 142	2-amino-N-((1S,2S)-2-((4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 143	2-amino-N-((1S,2S)-2-((3'-(aminomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 144	2-amino-N-((1S,2S)-2-((4'-(aminomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 145	2-amino-N-((1S,2S)-2-((4'-(2-aminoethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 146	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 147	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 148	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 149	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-(piperazin-1-yl)-[ 1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 150	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-(4-methylpiperazin-1-yl)-[ 1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 151	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide
Example 152	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 153	2-amino-N-((1S,2S)-2-((4'-ethyl-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 154	2-amino-N-((1S,2S)-2-((4'-(cyanomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 155	2-amino-N-((1S,2S)-2-((4'-carbamoyl-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 156	2-amino-N-((1S,2S)-2-((3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 157	2-amino-N-((1S,2S)-2-((3-fluoro-4'-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 158	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 159	2-amino-N-((1S,2S)-2-((2-chloro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 160	2-amino-N-((1S,2S)-2-((3-fluoro-4'-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 161	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 162	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 163	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 164	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 165	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 166	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamide
Example 167	2-amino-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 168	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 169	2-amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 170	2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 171	2-amino-N-((1S,2S)-2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 172	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 173	2-amino-N-((1S,2S)-2-((4'-(((2-hydroxyethyl)amino)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 174	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(morpholinomethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide
Example 175	2-amino-N-((1S,2S)-2-((4'-((3,3-difluoropiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 176	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 177	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(piperazin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 178	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-phenylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 179	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 180	2-amino-N-((1S,2S)-2-((4'-((4-hydroxypiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 181	2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 182	2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 183	2-amino-N-((1S,2S)-2-((4'-((4-ethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 184	2-amino-N-((1S,2S)-2-((4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 185	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(((R)-3-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 186	2-amino-N-((1S,2S)-2-((4'-(((R)-3,4-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 187	2-amino-N-((1S,2S)-2-((4'-(((R)-2,4-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 188	2-amino-N-((1S,2S)-2-((4'-((3-ethyl-4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 189	2-amino-N-((1S,2S)-2-((4'-((cis-3,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 190	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 191	2-amino-N-((1S,2S)-2-((4'-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 192	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 193	2-amino-N-((1S,2S)-2-((4'-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 194	3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)pyrazine-2-carboxamide
Example 195	2-amino-N-((1S,2S)-2-((3'-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 196	2-amino-N-((1S,2S)-2-((3',5'-difluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 197	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 198	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 199	2-amino-N-((1S,2S)-2-((3'-hydroxy-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 200	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-nitro-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 201	2-amino-N-((1S,2S)-2-((3'-methoxy-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 202	2-amino-N-((1S,2S)-2-((2'-chloro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 203	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 204	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamide
Example 205	2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 206	2-amino-N-((1S,2S)-2-((2'-chloro-4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 207	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 208	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 209	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 210	2-amino-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 211	2-amino-N-((1S,2S)-2-((4'-(1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 212	2-amino-N-((1S,2S)-2-((3',5'-difluoro-4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 213	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((R)-1-(piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 214	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 215	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 216	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 217	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 218	2-amino-N-((1S,2S)-2-((4'-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 219	2-amino-N-((1S,2S)-2-((4'-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 220	2-amino-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 221	2-amino-N-((1S,2S)-2-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 222	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 223	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 224	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 225	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 226	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 227	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 228	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 229	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 230	6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 231	2-amino-5-chloro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 232	2-amino-5-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 233	2-amino-5-cyano-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 235	2-amino-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 236	6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 237	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 238	6-amino-2'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 239	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-yl)methyl)-[ 1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 240	2-amino-N-((1S,2S)-2-((4'-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 242	2-amino-N-((1S,2S)-2-((4'-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 243	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotin amide
Example 244	2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 245	2-amino-N-((1S,2S)-2-((4'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 246	2-amino-N-((1S,2S)-2-((4'-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 247	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-yl)oxy)-[ 1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 253	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide
Example 254	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 255	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 256	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 257	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 258	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 259	2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 260	2-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 261	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 262	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 263	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 264	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)nicotinamide
Example 265	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)nicotinamide
Example 266	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)phenyl)nicotinamide
Example 267	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)nicotinamide
Example 268	2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide
Example 269	6-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6'-(hydroxymethyl)-[3,3'-bipyridine]-5-carboxamide
Example 270	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide
Example 271	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide
Example 272	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide
Example 273	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide
Example 274	2-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide
Example 275	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide
Example 276	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide
Example 277	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide
Example 278	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide
Example 279	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamide
Example 280	2-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide
Example 281	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide
Example 282	2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamide
Example 283	2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide
Example 284	2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide
Example 285	2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 286	2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 287	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamide
Example 288	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide
Example 289	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide
Example 290	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide
Example 291	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide
Example 292	2-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 293	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide
Example 294	6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2'-methoxy-[3,3'-bipyridine]-5-carboxamide
Example 295	2-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 296	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxyphenyl)nicotinamide
Example 297	2-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 298	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methylsulfonamido)phenyl)nicotinamide
Example 299	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxymethyl)phenyl)nicotinamide
Example 300	2-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 301	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxypropyl)phenyl)nicotinamide
Example 302	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide
Example 303	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide
Example 304	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamide
Example 305	3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acid
Example 306	4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)-2-methylbenzoic acid
Example 307	2-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 308	3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid
Example 309	3-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid
Example 310	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide
Example 311	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide
Example 312	2-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 313	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide
Example 314	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formylphenyl)nicotinamide
Example 315	4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid
Example 316	3-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)phenyl)propanoic acid
Example 317	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxyphenyl)nicotinamide
Example 318	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide
Example 319	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamide
Example 320	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide
Example 321	6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6'-(hydroxymethyl)-[3,3'-bipyridine]-5-carboxamide
Example 322	2-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid
Example 323	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamide
Example 324	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamide
Example 325	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide
Example 326	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamide
Example 327	2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 328	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide
Example 329	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamide
Example 330	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide
Example 331	2-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 332	2-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 333	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamide
Example 334	2-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 335	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)nicotinamide
Example 336	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamide
Example 337	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide
Example 338	2-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 339	2-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 340	2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 341	2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 342	2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 343	2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 344	2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 345	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide
Example 346	2-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 347	2-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 348	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide
Example 349	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide
Example 350	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide
Example 351	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamide
Example 352	2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamide
Example 353	2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 354	amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamide
Example 355	2-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide
Example 356	2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide
Example 357	2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide
Example 358	2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide
Example 359	2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamide
Example 360	2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamide
Example 361	3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide
Example 363	2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 364	2-amino-5-(3,4-difluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 365	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide
Example 366	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 367	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide
Example 368	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide
Example 369	2-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 370	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide
Example 371	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide
Example 372	2-amino-5-(4-hydroxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 373	2-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 374	2-amino-5-methyl-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 375	6-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 376	2-amino-5-(4-methoxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 377	6-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4'-bipyridine]-5-carboxamide
Example 378	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide
Example 379	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide
Example 380	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 381	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamide
Example 382	2-amino-5-(-cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin 1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 383	2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide
Example 384	6-amino-2',6'-difluoro-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4'-bipyridine]-5-carboxamide
Example 385	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide
Example 386	6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide
Example 387	2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)nicotinamide
Example 388	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 389	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamide
Example 390	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide
Example 391	2-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 392	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamide
Example 393	4-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoic acid
Example 394	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamide
Example 395	6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4'-bipyridine]-5-carboxamide
Example 396	6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3'-bipyridine]-5-carboxamide
Example 397	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamide
Example 398	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamide
Example 399	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamide
Example 400	2-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 401	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamide
Example 402	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamide
Example 403	5-([1,1'-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 404	2-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 405	2-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 406	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamide
Example 407	2-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 408	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamide
Example 409	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide
Example 410	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamide
Example 411	2-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 412	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 413	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 414	2-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 415	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 416	2-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 417	2-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 418	2-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 419	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide
Example 420	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide
Example 421	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonyl)phenyl)nicotinamide
Example 422	2-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 423	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide
Example 424	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide
Example 425	2-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide
Example 426	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 427	2-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 428	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 429	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 430	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 431	2-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 432	2-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 433	2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide
Example 434	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[ 1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide
Example 435	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-((4-methylpiperazin-1-yl)methyl)-[ 1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide
Example 436	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamid
Example 437	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide
Example 438	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide
Example 439	2-ammo-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide
Example 440	2-amino-N-((3S,4S)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 441	2-amino-N-((3S,4S)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 442	2-amino-N-((3S,4S)-4-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 443	2-amino-N-((3S,4S)-4-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 444	2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 445	2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 446	2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 447	2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 448	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide
Example 449	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide
Example 450	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide
Example 451	2-amino-N-((3S,4R)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 452	2-amino-N-((3S,4R)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 453	2-amino-N-((3S,4R)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide
Example 454	2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide
Example 455	2-amino-N-(trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

Pharmaceutical Compositions Comprising of Novel Mer Kinase Inhibitors

The present invention provides pharmaceutical compositions comprising the heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers.

The carriers that are used in the present invention may be those that are conventionally used in the art, and examples thereof include, but are not limited to, sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous dibasic calcium phosphate, or mixtures thereof.

Further, according to another embodiment of the present invention, the pharmaceutical compositions may contain additives such as binders, disintegrants, lubricants, pH-adjusting agents, antioxidants, and the like.

Examples of the binders that may be used in the present invention include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or mixtures thereof.

Examples of the disintegrants that may be used in the present invention include, but are not limited to, starches or modified starches such as sodium starch glyconate, maize starch, potato starch or pregelatinized starch; clays such as bentonite, montmorillonite, or veegum; celluloses such as microcrystalline cellulose, hydroxypropylcellulose or carboxymethylcellulose; algins such as sodium alginate or alginic acid; crosslinked celluloses such as croscarmellose sodium; gums such as guar gum or xanthan gum; crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); effervescent formulations such as sodium bicarbonate or citric acid; or mixtures thereof.

Examples of the lubricants that may be used in the present invention include, but are not limited to, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide, or mixtures thereof.

Examples of the pH-adjusting agents that may be used in the present invention include, but are not limited to, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etherate, malic acid, succinic acid, tartaric acid, fumaric acid or citric acid, and basifying agents such as precipitated calcium carbonate, ammonia water, meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, or tribasic calcium phosphate.

Examples of the antioxidants that may be used in the present invention include, but are not limited to, dibutyl hydroxytoluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, and the like.

The present invention provides the pharmaceutical compositions comprise, as active ingredients, the heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof and are used for prevention or treatment of a disease which is influenced by inhibition of Mer kinase.

The present invention provides the disease which is influenced by inhibition of Mer kinase is cancer or immune-related diseases.

The cancer is selected from the group consisting of: glioma, gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, small cell lung carcinoma, cervical carcinoma, colon cancer, rectal cancer, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, colorectal cancer, endometrium cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladder carcinoma, angiosarcoma, endotheliosarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenosarcoma, cystadenosarcoma, bronchogenic carcinoma, medullary carcinoma, mastocytoma, mesotheliorma, synovioma, melanoma, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodentroglioma, acoustic neuroma, hemangioblastoma, meningioma, pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma, embryonal carcinoma, squamous cell carcinoma, base cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, leukemia and metastatic lesions secondary to these primary tumors.

The immune-related disease is selected from the group consisting of infection and sepsis.

The term "treatment" is used to refer to both prevention of diseases and treatment of pre-existing conditions.

The therapeutic amount varies according to the specific disease and can be determined by the person skilled in the art without undue effort.

In addition, the subject to be treated (including by way of prevention) includes mammals, particularly humans.

The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.

Compound for use in Prevention or Treatment of Immune-Related Diseases or Cancer

The present invention provides heterocyclic compounds, isomers thereof or pharmaceutically acceptable salts thereof according to the invention for use in a method of treating or preventing immune-related diseases or cancer.

A pharmaceutical composition as described in the specification may be used for preventing or treating immune-related diseases or cancer.

Methods for Preparing of Novel Mer Kinase Inhibitors

The compounds of this invention can be prepared in accordance with one or more of schemes discussed below.

These methods can be used either directly or with obvious variations to trained chemists to prepare key intermediates and certain compounds of this invention.

Suitable synthetic sequences are readily selected per specific structures of this invention, but within the art known to individuals practicing organic synthesis, such as methods summarized in available chemistry data bases, as in CAS Scifinder and Elesevier Reaxys. Based on these general methods, the enablement for making the compounds of this invention is straightforward and can be practiced within a common professional knowledge. Some general synthetic methods to prepare the compounds of this invention are illustrated below in Schemes 1-2 (non-limiting, for illustration only).

One general approach to the compounds of this invention is illustrated in general a) NBS, CH₃CN, H₂O; b) R¹-B(OH)₂ or its pinacol ester, Pd(PPh₃)₄, aq. K₃PO₄, Dioxane, heat; c) NaOH, MeOH, heat; d) HATU, TEA, DMF

Another general approach to the compounds of this invention is illustrated in general a) NaOH, MeOH, heat; b) HATU, TEA, DMF; c) R¹-B(OH)₂ or its pinacol ester, Pd(PPh₃)₄, aq. K₃PO₄, Dioxane, heat

Advantageous Effects

Novel heterocyclic compounds according to the present invention, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof exhibit the effect of effectively inhibiting Mer kinase.

Novel heterocyclic compounds according to the present invention, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt can be used for the prevention or treatment of cancer or immune-related disease.

MODE FOR INVENTION

Based on the studies conducted and the results obtained so far, it is believed that the following compounds (numbered 1 to 458), including isomers, mixtures of isomer as well as pharmaceutically acceptable salts and solvates thereof, are particularly interesting.

General Synthetic Methods Examples

Embodiments of the present invention are described in the following examples, which are meant to illustrate and not limit the scope of this invention. Common abbreviations well known to those with ordinary skills in the synthetic art used throughout. Any Examples which do not fall within the claims are described for reference purposes only.

All chemical reagents were commercially available. Flash column chromatography means silica gel chromatography unless specified otherwise, which was performed on Teledyne Combiflash-RF200 System. ¹H NMR spectra (δ, ppm) are recorded on 400 MHz or 600 MHz instrument. Mass spectroscopy data for a positive ionization method are provided. Preparative HPLC was performed on Agilent technologies G1361A.

Examples 55, 56, 58-60, 69-75, 79, 85, 87, 90-92, 95-128, 131, 173, 234, 241, 248-252, 362 and 456-458 are reference examples.

Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Scheme for the preparation of the Compound of Example 1:

Intermediate 1 To a mixture of methyl 2-amino-5-bromonicotinate (1.5 g, 6.5 mmol) and 1-Methylpyrazole-4-boronic acid pinacol ester (1.76 g, 8.5 mmol) in 24 ml of 1,4-dioxane was added 8 ml of aq. 2N K3PO4 followed by Pd(PPh3)4 (370 mg, 0.32 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude product was purified by silicagel column chromatography to give 1.25 g of off-white solid. 1H NMR (400 MHz, CD3OD) δ 3.90(s, 3H), 3.91(s, 3H), 7.74(s, 1H), 7.91(s, 1H), 8.29(d, J = 2.4 Hz, 1H), 8.35(d, J = 2.4 Hz, 1H); MS (ESI, m/z): 233.1 [M+H]+
Intermediate 2 To a suspension of intermediate 1 (1.2 g, 5.17 mmol) in 26 ml of MeOH was added 2N NaOH (4.3 ml, 8.63 mmol) and the mixture was heated at 65 °C for 1 hr, cooled to room temperature, neutralized (4.3 ml of 2N HCl), and the resulting precipitate was filtered, washed with MeOH, and dried to give 0.97 g of off-white solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 3.82(s, 3H), 5.73(s, 2H), 7.77(s, 1H), 8.05(s, 1H), 8.13(d, J = 2.4 Hz, 1H), 8.42(d, J = 2.4 Hz, 1H); MS (ESI, m/z): 219.1 [M+H]+

Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 2 (43 mg, 0.2 mmol) and triethylamine (24 mg, 0.24 mmol) in 2 ml of DMF was added HATU (91 mg, 0.24 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine(38 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 46 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.57 - 1.69 (m, 1H) 1.72 - 1.86 (m, 3H) 1.90 - 2.08 (m, 1H) 2.11 - 2.21 (m, 1H) 3.93 (s, 3H) 3.96 (dt, J=6.75, 4.26 Hz, 1H) 4.39 (td, J=7.34, 4.11 Hz, 1H) 4.61 (s, 2H) 7.13 - 7.24 (m, 1H) 7.27 (t, J=7.46 Hz, 2H) 7.32 (d, J=7.04 Hz, 2H) 7.79 - 7.90 (m, 1H) 8.00 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.46 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 392.2 [M+H]⁺

Example 2 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 392.2 [M+H]⁺

Example 3 2-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 392.2 [M+H]⁺

Example 4 2-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2S)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 392.2 [M+H]⁺

Example 5 2-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using cis-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 392.2 [M+H]⁺

Example 6 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((2-methylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 406.2 [M+H]⁺

Example 7 2-amino-N-((1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 8 2-amino-N-((1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 9 2-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((4-ethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 10 2-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 11 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 12 2-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 13 2-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 14 2-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Example 15 2-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 16 2-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 17 2-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 18 2-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 19 2-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 20 2-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 448.3 [M+H]⁺

Example 21 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 22 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-propylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 23 2-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 460.3 [M+H]⁺

Example 24 2-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 25 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 432.2 [M+H]⁺

Example 26 2-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 432.2 [M+H]⁺

Example 27 2-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 446.3 [M+H]⁺

Example 28 2-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 416.2 [M+H]⁺

Example 29 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 460.2 [M+H]⁺

Example 30 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 437.2 [M+H]⁺

Example 31 2-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzonitrile, the title compound was obtained as described for the example 1.¹H NMR (400 MHz, CD₃OD) δ ppm 1.58 - 1.70 (m, 1H) 1.73 - 1.90 (m, 3H) 1.95 - 2.07 (m, 1H) 2.11 - 2.22 (m, 1H) 3.88 - 3.98 (m, 4H) 4.36 - 4.44 (m, 1H) 4.61 - 4.72 (m, 2H) 7.43 - 7.51 (m, 1H) 7.57 (br d, J=7.43 Hz, 1H) 7.63 (br d, J=7.43 Hz, 1H) 7.70 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.23 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 417.2 [M+H]⁺

Example 32 2-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 408.2 [M+H]⁺

Example 33 2-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.¹H NMR (400 MHz, CD₃OD) δ ppm 1.54 - 1.65 (m, 1H) 1.68 - 1.88 (m, 3H) 1.95 - 2.07 (m, 1H) 2.09 - 2.22 (m, 1H) 3.65 - 3.74 (m, 3H) 3.88 - 3.98 (m, 4H) 4.33 - 4.43 (m, 1H) 4.51 - 4.66 (m, 2H) 6.74 (dd, J=8.41, 1.76 Hz, 1H) 6.83 - 6.93 (m, 2H) 7.12 - 7.22 (m, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 422.2 [M+H]⁺

Example 34 2-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 422.2 [M+H]⁺

Example 35 2-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 422.2 [M+H]⁺

Example 36 2-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 422.2 [M+H]⁺

Example 37 2-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 452.2 [M+H]⁺

Example 38 2-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 452.2 [M+H]⁺

Example 39 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 484.2 [M+H]⁺

Example 40 2-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-yl-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 436.2 [M+H]⁺

Example 41 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 438.2 [M+H]⁺

Example 42 methyl 3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate

Using methyl 3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzoate, the title compound was obtained as described for the example 1. MS (ESI, m/z): 450.2 [M+H]⁺

Example 43 2-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.50, 6.46 Hz, 1H) 1.72 - 1.87 (m, 3H) 1.94 - 2.05 (m, 1H) 2.16 (br d, J=6.65 Hz, 1H) 3.89 - 3.97 (m, 4H) 4.38 (br d, J=4.70 Hz, 1H) 4.55 - 4.66 (m, 2H) 7.20 (br s, 1H) 7.22 - 7.28 (m, 2H) 7.34 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.44 (br d, J=2.35 Hz, 1H); MS (ESI, m/z): 426.2 [M+H]⁺

Example 44 2-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3-chlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 426.2 [M+H]⁺

Example 45 2-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((4-chlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 426.2 [M+H]⁺

Example 46 2-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3,4-dichlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 460.1 [M+H]⁺

Example 47 2-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((2-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 410.2 [M+H]⁺

Example 48 2-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (dq, J=13.69, 7.17 Hz, 1H) 1.70 - 1.88 (m, 3H) 1.93 - 2.06 (m, 1H) 2.15 (dt, J=13.69, 6.85 Hz, 1H) 3.87 - 4.00 (m, 4H) 4.34 - 4.42 (m, 1H) 4.62 (s, 2H) 6.92 (td, J=8.61, 1.96 Hz, 1H) 7.03 - 7.16 (m, 2H) 7.27 (dd, J=8.02, 6.06 Hz, 1H) 7.85 (s, 1H) 8.00 (s, 1H) 8.22 (d, J=1.96 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 410.2 [M+H]⁺

Example 49 2-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 488.1/490.1 [M+H]⁺

Example 50 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamide

Using trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 446.2 [M+H]⁺

Example 51 2-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-bromobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 470.1/472.1 [M+H]⁺

Example 52 2-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 488.1/490.1 [M+H]⁺

Example 53 2-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 488.1/490.1 [M+H]⁺

Example 54 2-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 484.1/486.1 [M+H]⁺

Example 55 methyl (3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoyl)glycinate

Using methyl (3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzoyl)glycinate, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58 - 1.70 (m, 1H) 1.73 - 1.90 (m, 3H) 1.95 - 2.07 (m, 1H) 2.11 - 2.22 (m, 1H) 3.88 - 3.98 (m, 4H) 4.36 - 4.44 (m, 1H) 4.61 - 4.72 (m, 2H) 7.43 - 7.51 (m, 1H) 7.57 (br d, J=7.43 Hz, 1H) 7.63 (br d, J=7.43 Hz, 1H) 7.70 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.23 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 507.2[M+H]⁺

Example 56 2-amino-N-((1S,2S)-2-((3-((2-hydroxyethyl)carbamoyl)benzyl)-oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using methyl (3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)-N-(2-hydroxyethyl)-benzamide, the title compound was obtained as described for the example 1. MS (ESI, m/z): 479.2[M+H]⁺

Example 57 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)-oxy)cyclopentyl)nicotinamide

Using tert-butyl 4-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)carbamoyl)-piperidine-1-carboxylate, the title compound was obtained as described for the example 1 and following deprotection with TFA. MS (ESI, m/z): 518.3[M+H]⁺

Example 58 2-amino-N-((1S,2S)-2-((3-((S)-2-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl ((S)-1-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)carbamate, the title compound was obtained as described for the example 1 and following deprotection with TFA. MS (ESI, m/z): 478.3[M+H]⁺

Example 59 N-((1S,2S)-2-((3-((S)-2-acetamidopropanamido)benzyl)oxy)-cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-acetamido-N-(3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)-propanamide, the title compound was obtained as described for the example 1. MS (ESI, m/z): 520.3[M+H]⁺

Example 60 2-amino-N-((1S,2S)-2-((3-(3-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)amino)-3-oxopropyl)carbamate, the title compound was obtained as described for the example 1 and following deprotection with TFA. MS (ESI, m/z): 478.3[M+H]⁺

Example 61 N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 459.2 [M+H]⁺

Example 62 N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 459.2 [M+H]⁺

Example 63 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 442.2 [M+H]⁺

Example 64 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 443.2 [M+H]⁺

Example 65 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((2',3',4',5'-tetrahydro-[1,1-biphenyl]-4-yl)methoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br d, J=5.87 Hz, 2H) 1.67 - 1.87 (m, 5H) 1.93 - 2.09 (m, 2H) 2.14 (br s, 3H) 2.28 (br s, 2H) 3.92 (s, 3H) 4.37 (br d, J=5.48 Hz, 1H) 4.49 - 4.65 (m, 2H) 6.00 (br s, 1H) 7.18 - 7.30 (m, 2H) 7.54 (br s, 1H) 7.59 - 7.69 (m, 1H) 7.84 (s, 1H) 7.98 (s, 1H) 8.23 (s, 1H) 8.38 (s, 1H); MS (ESI, m/z): 472.3 [M+H]⁺

Example 66 N-(trans-2-([1,1'-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-([1,1'-biphenyl]-2-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 468.2 [M+H]⁺

Example 67 N-((1S,2S)-2-([1,1'-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-([1,1'-biphenyl]-3-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 468.2 [M+H]⁺

Example 68 N-((1S,2S)-2-([1,1'-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-3-([1,1'-biphenyl]-4-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.59 (br d, J=1.17 Hz, 1H) 1.79 (br s, 3H) 1.97 (br s, 1H) 2.11 - 2.21 (m, 1H) 3.62 (s, 2H) 3.87 (s, 3H) 3.97 (br s, 1H) 4.39 (br s, 1H) 4.65 (br d, J=13.69 Hz, 2H) 7.34 - 7.42 (m, 2H) 7.50 (br t, J=7.43 Hz, 2H) 7.80 (s, 1H) 7.90 (s, 1H) 8.17 (br s, 1H) 8.29 - 8.34 (m, 1H); MS (ESI, m/z): 468.2 [M+H]⁺

Example 69 2-amino-N-((1S,2S)-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-aminocyclopentan-1-ol, the title compound was obtained as described for the example 1. MS (ESI, m/z): 302.2 [M+H]⁺

Example 70 2-amino-N-(cis-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using cis-2-aminocyclopentan-1-ol, the title compound was obtained as described for the example 1. MS (ESI, m/z): 302.2 [M+H]⁺

Example 71 N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 72 N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-((3,4-dimethylbenzyl-)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-((3,4-dimethylbenzyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid, the title compound was obtained as described for the example 1. MS (ESI, m/z): 510.3 [M+H]⁺

Example 73 2-amino-N-((6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 450.2 [M+H]⁺

Example 74 2-amino-N-(trans-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2-(benzyloxy)cyclohexan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 406.2 [M+H]⁺

Example 75 2-amino-N-((1S,2S)-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(benzyloxy)cyclohexan-1-amine, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.28 - 1.47 (m, 4H) 1.77 (br s, 1H) 1.83 (br s, 1H) 1.97 (s, 1H) 2.29 (br s, 1H) 3.38 (br d, J=9.39 Hz, 1H) 3.92 (s, 3H) 3.99 (br d, J=10.17 Hz, 1H) 4.41 - 4.47 (m, 1H) 4.68 (br d, J=12.13 Hz, 1H) 7.13 (dt, J=14.57, 6.99 Hz, 3H) 7.25 (br d, J=7.43 Hz, 2H) 7.77 (s, 1H) 7.89 (s, 1H) 8.21 (s, 1H) 8.25 (br s, 1H); MS (ESI, m/z): 406.2 [M+H]⁺

Example 76 2-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-N1-benzyl-N1-methylcyclopentane-1,2-diamine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 405.2 [M+H]⁺

Example 77 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-(phenoxymethyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 392.2 [M+H]⁺

Example 78 2-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 420.2 [M+H]⁺

Example 79 2-amino-N-(trans-2,2-difluoro-5-(phenoxymethyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (trans-2,2-difluoro-5-(phenoxymethyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 428.2 [M+H]⁺

Example 80 2-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)-methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 432.2 [M+H]⁺

Example 81 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 82 2-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)-methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-(((1S,2S)-2-aminocyclopentyl)methoxy)-N,N-dimethylaniline, the title compound was obtained as described for the example 1. MS (ESI, m/z): 435.2 [M+H]⁺

Example 83 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide

Using (3-(((1S,2S)-2-aminocyclopentyl)methoxy)phenyl)(piperidin-1-yl)methanone, the title compound was obtained as described for the example 1. MS (ESI, m/z): 503.3 [M+H]⁺

Example 84 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 484.2 [M+H]⁺

Example 85 2-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((benzyloxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 406.2 [M+H]⁺

Example 86 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((lS,2S)-2-(((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)methyl)cyclopentyl)nicotinamide

Using (1S,2S)-2-(((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.56 - 1.65 (m, 1H) 1.67 - 1.75 (m, 1H) 1.79 (br d, J=6.46 Hz, 1H) 1.85 (br d, J=8.80 Hz, 1H) 2.03 - 2.12 (m, 1H) 2.16 (br dd, J=12.91, 5.87 Hz, 1H) 2.43 - 2.51 (m, 1H) 2.84 (s, 3H) 3.75 (s, 2H) 3.89 (s, 3H) 4.10 (d, J=5.87 Hz, 2H) 4.30 - 4.38 (m, 1H) 6.96 (d, J=8.80 Hz, 2H) 7.38 (br d, J=8.22 Hz, 2H) 7.50 (dd, J=16.43, 8.22 Hz, 4H) 7.86 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 580.3 [M+H]⁺

Example 87 (1S,2S)-2-(benzyloxy)cyclopentyl 2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinate

Using (1S,2S)-2-(benzyloxy)cyclopentan-1-ol, the title compound was obtained as described for the example 1. MS (ESI, m/z): 393.2 [M+H]⁺

Example 88 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamide

Using (1S,2R)-2-phenethylcyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 390.2 [M+H]⁺

Example 89 2-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 394.2 [M+H]⁺

Example 90 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-morpholinotetrahydrofuran-3-yl)nicotinamide

Using trans-4-morpholinotetrahydrofuran-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 373.2 [M+H]⁺

Example 91 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)nicotinamide

Using trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 357.2 [M+H]⁺

Example 92 2-amino-N-(cis-4-hydroxytetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using cis-4-aminotetrahydrofuran-3-ol, the title compound was obtained as described for the example 1. MS (ESI, m/z): 304.1 [M+H]⁺

Example 93 2-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-4-(benzyloxy)-1-methylpyrrolidin-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 407.2 [M+H]⁺

Example 94 2-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 435.2 [M+H]⁺

Example 95 (R)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-(benzyloxy)propan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 366.2 [M+H]⁺

Example 96 (S)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-(benzyloxy)propan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 366.2 [M+H]⁺

Example 97 (S)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 366.2 [M+H]⁺

Example 98 (R)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 366.2 [M+H]⁺

Example 99 2-ammo-N-(1-(benzyloxy)-2-methylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-(benzyloxy)-2-methylpropan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 380.2 [M+H]⁺

Example 100 (R)-2-amino-N-(1-((3,4-dimethylbenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((3,4-dimethylbenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 394.2 [M+H]⁺

Example 101 (S)-2-amino-N-(2-((3,4-dimethylbenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((3,4-dimethylbenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 394.2 [M+H]⁺

Example 102 (R)-2-amino-N-(1-((4-chlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((4-chlorobenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 400.2 [M+H]⁺

Example 103 (S)-2-amino-N-(2-((4-chlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((4-chlorobenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 400.2 [M+H]⁺

Example 104 (R)-2-amino-N-(1-((3,4-dichlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((3,4-dichlorolbenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.1 [M+H]⁺

Example 105 (S)-2-amino-N-(2-((3,4-dichlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((3,4-dichlorobenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 419.1 [M+H]⁺

Example 106 (R)-2-amino-N-(1-((3-methoxybenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-((3-methoxybenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 396.2 [M+H]⁺

Example 107 (S)-2-amino-N-(2-((3-methoxybenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-((3-methoxybenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 396.2 [M+H]⁺

Example 108 (R)-2-amino-N-(1-(benzyloxy)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)butan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 380.2 [M+H]⁺

Example 109 (S)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)-3-methylbutan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 394.2 [M+H]⁺

Example 110 (R)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)-3-methylbutan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 394.2 [M+H]⁺

Example 111 (S)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)-4-methylpentan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 408.2 [M+H]⁺

Example 112 (R)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)-4-methylpentan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 408.2 [M+H]⁺

Example 113 (R)-2-amino-N-(2-(benzyloxy)-1-cyclohexylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-(benzyloxy)-1-cyclohexylethan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 434.3 [M+H]⁺

Example 114 (R)-2-amino-N-(1-cyclohexyl-2-hydroxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-amino-2-cyclohexylethan-1-o1, the title compound was obtained as described for the example 1. MS (ESI, m/z): 344.3 [M+H]⁺

Example 115 (S)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-2-(benzyloxy)-1-phenylethan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 428.2 [M+H]⁺

Example 116 (R)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-2-(benzyloxy)-1-phenylethan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 428.2 [M+H]⁺

Example 117 (S)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (S)-1-(benzyloxy)-3-phenylpropan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 442.2 [M+H]⁺

Example 118 (R)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(benzyloxy)-3-phenylpropan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 442.2 [M+H]⁺

Example 119 (R)-2-amino-N-(1-(cyclobutylmethoxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (R)-1-(cyclobutylmethoxy)propan-2-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 344.2 [M+H]⁺

Example 120 methyl N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-serinate

Using methyl O-benzyl-L-serinate, the title compound was obtained as described for the example 1. MS (ESI, m/z): 410.2 [M+H]⁺

Example 121 methyl N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-threoninate

Using methyl O-benzyl-L-threoninate, the title compound was obtained as described for the example 1. MS (ESI, m/z): 424.2 [M+H]⁺

Example 122 2-amino-N-((2S,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide, the title compound was obtained as described for the example 1. MS (ESI, m/z): 423.2 [M+H]⁺

Example 123 2-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(propylamino)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-N-propylbutanamide, the title compound was obtained as described for the example 1. MS (ESI, m/z): 451.2 [M+H]⁺

Example 124 2-amino-N-((2S,3R)-3-(benzyloxy)-1-(cyclopentylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-N-cyclopentylbutanamide, the title compound was obtained as described for the example 1. MS (ESI, m/z): 477.3 [M+H]⁺

Example 125 2-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2S,3R)-2-amino-3-(benzyloxy)-1-(pyrrolidin-1-yl)butan-1-one, the title compound was obtained as described for the example 1. MS (ESI, m/z): 463.2 [M+H]⁺

Example 126 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-alaninate

Using benzyl L-alaninate, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.51 (d, J=7.43 Hz, 3H) 3.92 (s, 3H) 4.64 (d, J=7.43 Hz, 1H) 5.12 - 5.25 (m, 2H) 7.21 - 7.42 (m, 5H) 7.84 (s, 1H) 7.96 - 8.00 (m, 1H) 8.21 - 8.27 (m, 1H) 8.54 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 380.2 [M+H]⁺

Example 127 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-valinate

Using benzyl L-valinate, the title compound was obtained as described for the example 1. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.00 (dd, J=9.19, 6.85 Hz, 6H) 2.16 - 2.36 (m, 1H) 4.46 - 4.55 (m, 1H) 5.10 - 5.30 (m, 2H) 7.22 - 7.41 (m, 5H) 7.84 (d, J=0.78 Hz, 1H) 7.98 (s, 1H) 8.24 (d, J=1.96 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 408.2 [M+H]⁺

Example 128 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-serinate

Using benzyl L-serinate, the title compound was obtained as described for the example 1.¹H NMR (400 MHz, CD₃OD) δ ppm 3.94 - 4.07 (m, 2H) 4.78 (dd, J=5.48, 4.30 Hz, 1H) 5.21 (s, 2H) 7.23 - 7.43 (m, 5H) 7.86 (d, J=0.78 Hz, 1H) 8.01 (s, 1H) 8.24 (d, J=1.96 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 396.2 [M+H]⁺

Example 129 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and (1S,2S)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 393.2[M+H]⁺

Example 130 3-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 421.2 [M+H]⁺

Example 131 (S)-3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and (S)-1,2,3,4-tetrahydronaphthalen-1-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 349.2 [M+H]⁺

Example 132 3-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and trans-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 395.2 [M+H]⁺

Example 133 3-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and cis-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1. MS (ESI, m/z): 395.2 [M+H]⁺

Example 134 2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 134:

Intermediate 3

To a solution of methyl 2-amino-5-bromonicotinate (560 mg, 2.42 mmol) in 10 ml of MeOH was added 2N NaOH (2 ml, 4 mmol) and the mixture was heated at 65 °C for 1 hr, cooled to room temperature, neutralized (2 ml of 2N HCl), and the resulting precipitate was filtered, washed with MeOH, and dried to give 0.35 g of white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.17 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 217.0 [M+H]⁺

Intermediate 2

To a mixture of intermediate 3 (4.48 g, 20.6 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (5.5 g, 26.8 mmol) in 100 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (8.5 g, 61.9 mmol) followed by Pd(PPh₃)₄ (1.19 g, 1.03 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and partitioned between water and EtOAc. Water layer was separated and adjusted to pH value between 4 and 5. The precipitate was collected by filtration and dried to afford 4 g of the title compound. The crude product was used for the next step without further purification. ¹H NMR (600 MHz, DMSO-d ₆) δ ppm 3.82(s, 3H), 5.73(s, 2H), 7.77(s, 1H), 8.05(s, 1H), 8.13(d, J = 2.4 Hz, 1H), 8.42(d, J = 2.4 Hz, 1H); MS (ESI, m/z): 219.1 [M+H]⁺

Intermediate 4

To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine (0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol) followed by (1S,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine (475 mg, 1.76 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 650 mg of off-white solid. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.59 - 1.69 (m, 1H) 1.72 - 1.78 (m, 1H) 1.78 - 1.86 (m, 2H) 1.96 - 2.07 (m, 1H) 2.16 (dq, J=13.50, 6.85 Hz, 1H) 3.94 (s, 3H) 3.95 (br d, J=1.76 Hz, 1H) 4.33 - 4.42 (m, 1H) 4.53 - 4.62 (m, 2H) 7.25 (m, J=8.22 Hz, 2H) 7.41 (m, J=8.22 Hz, 2H) 7.87 (s, 1H) 8.01 (s, 1H) 8.22 (d, J=1.76 Hz, 1H) 8.52 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 470.1/472.1 [M+H]⁺

Example 134 2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 4 (33 mg, 0.07 mmol) and (3-aminophenyl)boronic acid (11 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60 - 1.69 (m, 1H) 1.73 - 1.90 (m, 3H) 2.05 (br d, J=7.04 Hz, 1H) 2.17 (s, 1H) 3.89 (s, 3H) 4.00 (br d, J=4.30 Hz, 1H) 4.36 - 4.46 (m, 2H) 4.67 (s, 2H) 7.24 (br d, J=7.43 Hz, 1H) 7.42 - 7.59 (m, 7H) 7.84 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 483.2 [M+H]⁺

Example 135. 2-amino-N-((1S,2S)-2-((4'-amino-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-aminophenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 483.2 [M+H]⁺

Example 136. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(methylamino)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-(methylamino)phenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br d, J=5.87 Hz, 1H) 1.73 - 1.94 (m, 3H) 2.05 (br s, 1H) 2.17 (br s, 1H) 3.55 (br t, J=11.15 Hz, 3H) 3.90 (s, 3H) 4.00 (br s, 1H) 4.43 (s, 4H) 4.67 (s, 2H) 7.45 (br d, J=8.22 Hz, 2H) 7.55 (br d, J=7.83 Hz, 2H) 7.60 (br d, J=7.83 Hz, 2H) 7.71 (br d, J=7.83 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.21 (s, 1H) 8.52 (s, 1H); MS (ESI, m/z): 497.3 [M+H]⁺

Example 137. 2-amino-N-((1S,2S)-2-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(dimethylamino)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 511.3 [M+H]⁺

Example 138. 2-amino-N-((1S,2S)-2-((4'-((dimethylamino)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using ((4-((dimethylamino)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.55 - 1.68 (m, 1H) 1.80 (br s, 3H) 2.04 (br d, J=7.43 Hz, 1H) 2.15 (br s, 1H) 3.49 (br s, 3H) 3.62 (br s, 3H) 3.75 (br s, 2H) 3.89 (s, 3H) 3.97 (br s, 1H) 4.39 (br s, 1H) 4.62 (br d, J=12.91 Hz,1H) 4.66 - 4.73 (m, 1H) 7.44 (br t,J=9.19 Hz, 4H) 7.56 (br d, J=8.22 Hz, 2H) 7.62 (br d, J=7.83 Hz, 2H) 7.82 (s, 1H) 7.94 (s, 1H) 8.16 (s, 1 H) 8.42 (s, 1H); MS (ESI, m/z): 525.3 [M+H]⁺

Example 139. 2-amino-N-((1S,2S)-2-((3'-amino-2'-methyl-[1,1'-biphenyl-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-amino-2-methylphenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 497.2 [M+H]⁺

Example 140. 2-amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-hydroxyphenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61 (br d, J=7.43 Hz, 1 H) 1.72 - 1.86 (m, 3 H) 1.95 - 2.08 (m, 1 H) 2.09 - 2.20 (m, 1 H) 3.87 (s, 3 H) 3.97 (br s, 1 H) 4.40 (br d, J=18.00 Hz, 1 H) 4.56 - 4.71 (m, 2 H) 6.70 - 6.75 (m, 1 H) 6.90 (br s, 1 H) 6.95 (br d, J=7.83 Hz, 1 H) 7.14 - 7.21 (m, 1 H) 7.32 - 7.41 (m, 2 H) 7.42 - 7.50 (m, 2 H) 7.78 - 7.83 (m, 1 H) 7.88 - 7.93 (m, 1 H) 8.16 (br d, J=1.96 Hz, 1 H) 8.36 (br d, J=2.35 Hz, 1 H); MS (ESI, m/z): 484.2 [M+H]⁺

Example 141. 2-amino-N-((1S,2S)-2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 498.2 [M+H]⁺

Example 142. 2-amino-N-((1S,2S)-2-((4'-(hydroxymethyl)-[1,1'-biphenyl-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using ((4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 498.2 [M+H]⁺

Example 143. 2-amino-N-((1S,2S)-2-((3'-(aminomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(aminomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.54 - 1.67 (m, 1 H) 1.71 - 1.90 (m, 3 H) 2.03 (br dd, J=12.33, 7.04 Hz, 1 H) 2.11 - 2.21 (m, 1 H) 3.88 (s, 3 H) 3.96 - 4.03 (m, 1 H) 4.16 (s, 2 H) 4.35 - 4.47 (m, 1 H) 4.67 (s, 2 H) 7.40 (br d, J=7.63 Hz, 1 H) 7.44 (d, J=8.22 Hz, 1 H) 7.49 (br t, J=7.63 Hz, 2 H) 7.58 (d, J=7.63 Hz, 1 H) 7.59 - 7.62 (m, 2 H) 7.61 (br d, J=7.63 Hz, 1 H) 7.66 (s, 1 H) 7.80 (s, 1 H) 7.92 (s, 1 H) 8.21 (d, J=2.35 Hz, 1 H) 8.29 (br s, 1 H); MS (ESI, m/z): 497.3 [M+H]⁺

Example 144. 2-amino-N-((1S,2S)-2-((4'-(aminomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(aminomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=14.09, 7.04 Hz, 1 H) 1.72 - 1.90 (m, 3 H) 2.03 (br dd, J=13.21, 6.16 Hz, 1 H) 2.14 - 2.23 (m, 1 H) 3.90 (s, 3 H) 4.01 (br d, J=7.04 Hz, 1 H) 4.14 (s, 2 H) 4.40 - 4.45 (m, 1 H) 4.63 - 4.70 (m, 2 H) 7.43 (d, J=8.22 Hz, 2 H) 7.49 (d, J=7.63 Hz, 2 H) 7.57 (d, J=7.63 Hz, 2 H) 7.65 (d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.21 (d, J=1.76 Hz, 1 H) 8.49 (br s, 1 H); MS (ESI, m/z): 497.3 [M+H]⁺

Example 145. 2-amino-N-((1S,2S)-2-((4'-(2-aminoethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(2-aminoethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 511.3 [M+H]⁺

Example 146. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-(4-methylpiperazin-1-yl)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 566.3 [M+H]⁺

Example 147. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (6-(piperazin-1-yl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br d, J=7.83 Hz, 1 H) 1.81 (br d, J=7.83 Hz, 3 H) 2.04 (br s, 1 H) 2.18 (br s, 1 H) 3.32 - 3.40 (m, 4 H) 3.84 (br s, 4 H) 3.90 (s, 3 H) 3.98 (br s, 1 H) 4.40 (br s, 1 H) 4.65 (s, 2 H) 6.98 - 7.02 (m, 1 H) 7.41 (br d, J=7.04 Hz, 2 H) 7.50 (br d, J=7.83 Hz, 2 H) 7.83 - 7.89 (m, 2 H) 7.96 (s, 1 H) 8.20 (s, 1 H) 8.35 (s, 1 H) 8.48 (s, 1 H); MS (ESI, m/z): 553.3 [M+H]⁺

Example 148. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.58 - 1.66 (m, 1 H) 1.73 - 1.87 (m, 3 H) 2.04 (dq, J=13.72, 6.77 Hz, 1 H) 2.16 (dt, J=13.35, 6.53 Hz, 1 H) 2.96 (s, 3 H) 3.90 (s, 3 H) 3.96 - 4.01 (m, 1 H) 4.37 - 4.45 (m, 1 H) 4.60 - 4.69 (m, 2 H) 6.99 (d, J=8.80 Hz, 1 H) 7.41 (d, J=8.22 Hz, 2 H) 7.50 (d, J=8.22 Hz, 2 H) 7.83 (s, 1 H) 7.85 (d, J=2.35 Hz, 1 H) 7.96 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.36 (d, J=2.35 Hz, 1 H) 8.45 (s, 1 H); MS (ESI, m/z): 567.3 [M+H]⁺

Example 149. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-(piperazin-1-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 3-(piperazin-1-yl)phenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br d, J=5.87 Hz, 2 H) 1.81 (br d, J=6.65 Hz, 3 H) 1.96 - 2.07 (m, 1 H) 2.17 (br s, 1 H) 3.40 (br dd, J=19.95, 5.87 Hz, 8 H) 3.88 (s, 3 H) 4.00 (br s, 1 H) 4.40 (br s, 1 H) 4.65 (s, 2 H) 6.99 (br d, J=7.43 Hz, 1 H) 7.10 (br d, J=6.65 Hz, 1 H) 7.16 (s, 1 H) 7.32 (t, J=7.60 Hz, 1 H) 7.40 (d, J=7.83 Hz, 2 H) 7.53 (d, J=8.61 Hz, 2 H) 7.84 (s, 1 H) 7.95 (s, 1 H) 8.19 (s, 1 H) 8.46 (s, 1 H); MS (ESI, m/z): 552.3 [M+H]⁺

Example 150. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (3-(4-methylpiperazin-1-yl)phenyl)boronic acid, the title compound was obtained as described for the example 134.¹H NMR (600 MHz, CD₃OD) δ ppm 1.66 (s, 1 H) 1.73 - 1.88 (m, 3 H) 1.99 - 2.08 (m, 1 H) 2.17 (br dd, J=13.50, 5.87 Hz, 1 H) 2.97 (s, 3 H) 3.06 (br s, 2 H) 3.60 (br s, 2 H) 3.88 (s, 3 H) 3.96 - 4.03 (m, 1 H) 4.41 (br d, J=4.70 Hz, 1 H) 4.61 - 4.70 (m, 2 H) 6.99 (br d, J=8.80 Hz, 1 H) 7.10 (br d, J=7.63 Hz, 1 H) 7.16 (s, 1 H) 7.32 (t, J=7.92 Hz, 1 H) 7.41 (d, J=8.22 Hz, 2 H) 7.53 (d, J=8.22 Hz, 2 H) 7.82 (s, 1 H) 7.93 (s, 1 H) 8.19 (d, J=1.76 Hz, 1 H) 8.35 - 8.41 (m, 1 H); MS (ESI, m/z): 566.3 [M+H]⁺

Example 151. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (3-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (br dd, J=13.30, 6.26 Hz, 1 H) 1.76 - 1.90 (m, 3 H) 1.99 - 2.10 (m, 1 H) 2.18 (br dd, J=14.09, 6.65 Hz, 1 H) 2.85 (s, 3 H) 3.78 (s, 2 H) 3.91 (s, 3 H) 4.02 (br s, 1 H) 4.43 (br dd, J=10.96, 7.83 Hz, 1 H) 4.68 (s, 2 H) 7.34 (br d, J=7.43 Hz, 1 H) 7.38 - 7.45 (m, 3 H) 7.51 (br d, J=7.83 Hz, 1 H) 7.54 - 7.60 (m, 3 H) 7.86 (s, 1 H) 7.99 (s, 1 H) 8.21 (d, J=1.96 Hz, 1 H) 8.51 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 579.3 [M+H]⁺

Example 152. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-(morpholine-4-carbonyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 581.3 [M+H]⁺

Example 153. 2-amino-N-((1S,2S)-2-((4'-ethyl-[1,1'-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-ethylphenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.24 (t, J=7.63 Hz, 3 H) 1.55 - 1.67 (m, 1 H) 1.73 - 1.86 (m, 3 H) 2.01 - 2.08 (m, 1 H) 2.16 (br dd, J=13.21, 5.58 Hz, 1 H) 2.66 (q, J=7.63 Hz, 2 H) 3.87 (s, 3 H) 3.93 - 3.99 (m, 1 H) 4.38 - 4.42 (m, 1 H) 4.61 (d, J=12.91 Hz, 1 H) 4.65-4.71 (m, 1 H) 7.21 (d, J=7.63 Hz, 2 H) 7.38 (d, J=8.22 Hz, 2 H) 7.41 (d, J=8.22 Hz, 2 H) 7.50 (d, J=8.22 Hz, 2 H) 7.82 (s, 1 H) 7.91 (s, 1 H) 8.16 (d, J=1.76 Hz, 1 H) 8.42 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 496.3 [M+H]⁺

Example 154. 2-amino-N-((1S,2S)-2-((4'-(cyanomethyl)-[1,1'-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(cyanomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134. MS (ESI, m/z): 507.2 [M+H]⁺

Example 155. 2-amino-N-((1S,2S)-2-((4'-carbamoyl-[1,1'-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-carbamoylphenyl)boronic acid, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (s, 1 H) 1.70 - 1.88 (m, 3 H) 2.05 (s, 1 H) 2.16 (td, J=13.06, 7.92 Hz, 1 H) 3.88 (s, 3 H) 3.98 (br d, J=6.46 Hz, 1 H) 4.40 (br d, J=4.70 Hz, 1 H) 4.63 (d, J=12.33 Hz, 1 H) 4.70 (d, J=12.91 Hz, 1 H) 7.44 (d, J=8.22 Hz, 2 H) 7.58 (d,J=8.22 Hz, 2 H) 7.61 (d, J=8.80 Hz, 2 H) 7.81 (s, 1 H) 7.89 (d, J=8.22 Hz, 2 H) 7.92 (s, 1 H) 8.17 (d, J=2.35 Hz, 1 H) 8.38 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 511.2 [M+H]⁺

Example 156. 2-amino-N-((1S,2S)-2-((3-fluoro-4'-((4-methylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.30, 7.04 Hz, 1 H) 1.74 - 1.92 (m, 3 H) 2.04 (br dd, J=12.72, 6.06 Hz, 1 H) 2.17 (br dd, J=13.50, 6.46 Hz, 1 H) 2.91 (s, 3 H) 3.25 (br s, 4 H) 3.47 (br s, 4 H) 3.90 (s, 3 H) 3.96 - 4.08 (m, 1 H) 4.12 (s, 2 H) 4.34 - 4.45 (m, 1 H) 4.64 - 4.78 (m, 2 H) 5.47 (s, 1 H) 7.32 (br d, J=11.35 Hz, 1 H) 7.40 (br d, J=7.83 Hz, 1 H) 7.47 - 7.57 (m, 3 H) 7.62 (br d, J=7.83 Hz, 2 H) 7.85 (s, 1 H) 7.99 (s, 1 H) 8.18 (s, 1 H) 8.55 (s, 1 H); MS (ESI, m/z): 598.4 [M+H]⁺

Example 157. 2-amino-N-((1S,2S)-2-((3-fluoro-4'-((cis-3,4,5-trimethypiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and (4-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134. MS (ESI, m/z): 626.4 [M+H]⁺

Example 158. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-methoxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((4-bromo-2-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.69 (dt, J=13.89, 6.75 Hz, 1 H) 1.77 - 1.93 (m, 3 H) 2.01 - 2.12 (m, 1 H) 2.13 - 2.30 (m, 1 H) 2.87 (s, 3 H) 3.75 (s, 2 H) 3.92 (s, 3 H) 4.00-4.08 (m, 1 H) 4.45 (br dd, J=11.54, 7.24 Hz, 1 H) 7.47 (d, J=8.22 Hz, 2 H) 7.62 (m, J=8.22 Hz, 2 H) 7.81 - 7.84 (m, 2 H) 7.86 (d, J=5.09 Hz, 2 H) 8.00 (s, 1 H) 8.23 (d, J=1.96 Hz, 1 H) 8.56 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 648.3[M+H]⁺

Example 159. 2-amino-N-((1S,2S)-2-((2-chloro-4'-((4-methylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (1S,2S)-2-((4-bromo-3-chlorobenzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.65 (br dd, J=13.50, 7.04 Hz, 1 H) 1.74 - 1.89 (m, 3H) 1.97 - 2.11 (m, 1 H) 2.15 - 2.22 (m, 1 H) 2.85 (s, 3 H) 3.72 (s, 2 H) 3.92 (s, 3 H) 3.98 (dt, J=6.46, 4.11 Hz, 1 H) 4.42 (td, J=7.34, 4.11 Hz, 1 H) 4.66 (d, J=2.35 Hz, 2 H) 7.27 (d, J=7.63 Hz, 1 H) 7.30 - 7.37 (m, 3 H) 7.40 (d, J=8.22 Hz, 2 H) 7.47 (d, J=1.17 Hz, 1 H) 7.86 (s, 1 H) 7.99 (s, 1 H) 8.22 (d, J=2.35 Hz, 1 H) 8.49 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 614.3[M+H]⁺

Example 160. 2-amino-N-((1S,2S)-2-((3-fluoro-4'-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and (4-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134. MS (ESI, m/z): 656.4 [M+H]⁺

Example 161. 2-amino-5-(-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-(2-(4-methylpiperazino)ethyl)phenylboronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.79, 6.75 Hz, 1 H) 1.74 - 1.87 (m, 3 H) 2.00 - 2.11 (m, 1 H) 2.11 - 2.23 (m, 1 H) 2.79 - 2.96 (m, 2 H) 3.02 (br s, 2 H) 3.24 (s, 2 H) 3.41 (br s, 4 H) 3.89 (s, 3 H) 3.97 - 4.03 (m, 1 H) 4.41 (br s, 1 H) 4.61 - 4.71 (m, 2 H) 7.31 (br d, J=8.22 Hz, 2 H) 7.40 (d, J=7.63 Hz, 2 H) 7.50 (br d, J=8.22 Hz, 2 H) 7.51 - 7.57 (m, 2 H) 7.84 (br d, J=2.93 Hz, 1 H) 7.96 (s, 1 H) 8.16 - 8.21 (m, 1 H) 8.50 (br d, J=4.70 Hz, 1 H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 162. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, the title compound was obtained as described for the example 134 and following deprotection with TFA.. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br s, 1 H) 1.80 (br d, J=6.65 Hz, 3 H) 2.03 (br s, 1 H) 2.15 (br s, 1 H) 2.28 (br d, J=13.69 Hz, 4 H) 3.14 - 3.25 (m, 2 H) 3.56 (br d, J=11.35 Hz, 2 H) 3.90 (s, 3 H) 3.97 (br s, 1 H) 4.39 (br s, 1 H) 4.53 (br s, 1 H) 4.60 (s, 2 H) 7.32 (br d, J=7.83 Hz, 2 H) 7.47 (br d, J=7.83 Hz, 2 H) 7.79 (s, 1 H) 7.85 (s, 1 H) 7.97 (br s, 2 H) 8.20 (br s, 1 H) 8.48 (s, 1 H); MS (ESI, m/z): 541.3 [M+H]⁺

Example 163. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-piperidine, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.57 - 1.66 (m, 1 H) 1.72 - 1.87 (m, 3 H) 2.03 (br dd, J=12.62, 6.75 Hz, 1 H) 2.17 (br s, 1 H) 2.24 - 2.42 (m, 4 H) 2.94 (s, 3 H) 3.19 - 3.27 (m, 2 H) 3.48 (br s, 1 H) 3.90 (s, 3 H) 3.98 (br d, J=6.46 Hz, 1 H) 4.36 - 4.45 (m, 1 H) 4.46 - 4.55 (m, 1 H) 4.57 - 4.64 (m, 2 H) 7.33 (br d, J=8.22 Hz, 2 H) 7.47 (br d, J=8.22 Hz, 2 H) 7.79 (br s, 1 H) 7.84 (s, 1 H) 7.97 (d, J=5.87 Hz, 2 H) 8.20 (br d, J=1.76 Hz, 1 H) 8.47 (s, 1 H); MS (ESI, m/z): 555.3 [M+H]⁺

Example 164. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (1S,2R)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.58 - 1.69 (m, 1 H) 1.82 - 1.97 (m, 4 H) 2.00 - 2.07 (m, 1 H) 2.83 - 2.90 (m, 3 H) 3.79 (s, 3 H) 3.80 - 3.87 (m, 2 H) 4.11 - 4.18 (m, 1 H) 4.36-4.43 (m, 1 H) 4.45 (d, J=11.74 Hz, 1 H) 4.67 (d, J=11.74 Hz, 1 H) 7.38 (d, J=8.22 Hz, 2 H) 7.40 - 7.44 (m, 2 H) 7.46 (d, J=8.22 Hz, 2 H) 7.49 (d, J=8.22 Hz, 2 H) 7.78 (s, 1 H) 7.83 (s, 1 H) 8.12 - 8.19 (m, 1 H) 8.44 (s, 1 H); MS (ESI, m/z): 580.3 [M+H]⁺

Example 165. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (1R,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.¹H NMR (600 MHz, CD₃OD) δ ppm 1.60 - 1.70 (m, 1 H) 1.81 - 1.98 (m, 4 H) 2.00 - 2.09 (m, 1 H) 2.87 (s, 3 H) 3.79 (s, 3 H) 3.80 - 3.85 (m, 2 H) 4.15 (d, J=4.70 Hz, 1 H) 4.36 - 4.42 (m, 1 H) 4.45 (d, J=11.74 Hz, 1 H) 4.67 (d, J=12.33 Hz, 1 H) 7.38 (d, J=8.22 Hz, 2 H) 7.42 (d, J=7.04 Hz, 2 H) 7.46 (d, J=8.22 Hz, 2 H) 7.48 - 7.50 (m, 2 H) 7.78 (s, 1 H) 7.83 (s, 1 H) 8.15 (d, J=1.76 Hz, 1 H) 8.44 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 580.3 [M+H]⁺

Example 166. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamide

Using (1S,2S)-2-((4-bromobenzyl)oxy)cyclohexan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.43 (br s, 4 H) 1.97 - 2.07 (m, 2 H) 2.18 (br s, 2 H) 2.32 (s, 3 H) 3.40 - 3.48 (m, 1 H) 3.58 (s, 2 H) 3.80 - 3.89 (m, 1 H) 3.90 (s, 3 H) 4.61 (s, 2 H) 7.41 (dd, J=14.09, 8.22 Hz, 4 H) 7.55 - 7.62 (m, 4 H) 7.78 (s, 1 H) 7.89 (s, 1 H) 8.03 (d, J=1.76 Hz, 1 H) 8.23 (br s, 1 H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 167. 2-amino-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid and (4-(2-(4-methylpiperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.47 (s, 6 H) 1.55 - 1.70 (m, 1 H) 1.82 (br d, J=7.04 Hz, 3 H) 2.03 (br s, 1 H) 2.12 - 2.25 (m, 1 H) 2.86 (s, 3 H) 4.00 (br s, 1 H) 4.40 (br s, 1 H) 4.66 (s, 2 H) 6.90 - 6.99 (m, 1 H) 7.38 - 7.46 (m, 2 H) 7.59 (br dd, J=10.96, 7.83 Hz, 6 H) 8.01 (d, J=5.09 Hz, 1 H) 8.33 (d, J=7.83 Hz, 1 H); MS (ESI, m/z): 528.3 [M+H]⁺

Example 168. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid, (1S,2S)-2-((4-bromo-2-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.¹H NMR (400 MHz, CD₃OD) δ ppm 1.66 (dt, J=13.60, 6.70 Hz, 1 H) 1.78 - 1.93 (m, 3 H) 1.97 - 2.12 (m, 1 H) 2.13 - 2.26 (m, 1 H) 2.87 (s, 3 H) 3.77 (s, 2 H) 4.00 - 4.05 (m, 1 H) 4.43 (br dd, J=10.76, 7.63 Hz, 1 H) 6.98 (dd, J=7.43, 6.26 Hz, 1 H) 7.48 (d, J=8.22 Hz, 2 H) 7.65 (d, J=8.22 Hz, 2 H) 7.77 - 7.93 (m, 3 H) 8.02 (br dd, J=6.26, 1.57 Hz, 1 H) 8.37 (dd, J=7.43, 1.57 Hz, 1 H): MS (ESI, m/z): 568.3[M+H]⁺

Example 169. amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-3-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 169:

Intermediate 5. To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine (0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol) followed by (1S,2S)-2-((3-bromobenzyl)oxy)cyclopentan-1-amine (475 mg, 1.76 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 680 mg of off-white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58 - 1.69 (m, 1 H) 1.72 - 1.88 (m, 3 H) 1.96 - 2.08 (m, 1 H) 2.16 (td, J=13.35, 7.92 Hz, 1 H) 3.86 - 4.00 (m, 3 H) 4.39 (td, J=7.48, 4.40 Hz, 1 H) 4.60 (q, J=12.72 Hz, 2 H) 7.20 (t, J=7.92 Hz, 1 H) 7.29 (d, J=7.63 Hz, 1 H) 7.35 (d, J=7.63 Hz, 1 H) 7.50 (s, 1 H) 7.45 - 7.53 (m, 1 H) 7.86 (s, 1 H) 8.00 (s, 1 H) 8.23 (d, J=2.35 Hz, 1 H) 8.46 (d, J=1.76 Hz, 1 H): MS (ESI, m/z): 470.1/472.1 [M+H]⁺

Example 169. 2-amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-3-yl)methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 5 (33 mg, 0.07 mmol) and (3-hydroxyphenyl)boronic acid (11 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. The crude residue was dissolved with 0.5 ml of CH₂Cl₂ / TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 27 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=12.62, 6.75 Hz, 1 H) 1.81 (br d, J=4.70 Hz, 3 H) 2.03 (br d, J=11.74 Hz, 1 H) 2.16 (br s, 1 H) 3.92 (s, 3 H) 3.94 - 4.01 (m, 1 H) 4.43 (br s, 1 H) 4.64 - 4.74 (m, 2 H) 7.13 (br d, J=6.46 Hz, 2 H) 7.34 - 7.43 (m, 3 H) 7.47 (br d, J=7.63 Hz, 2 H) 7.58 - 7.62 (m, 1 H) 7.81 (s, 1 H) 7.96 (s, 1 H) 8.17 (br d, J=1.76 Hz, 1 H) 8.36 (br d, J=2.35 Hz, 1 H); MS (ESI, m/z): 484.2 [M+H]⁺

Example 170. 2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-3-yl)methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-aminophenyl)boronic acid, the title compound was obtained as described for the example 169. MS (ESI, m/z): 483.2 [M+H]⁺

Example 171. 2-amino-N-((1S,2S)-2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 169. MS (ESI, m/z): 498.2 [M+H]⁺

Example 172. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 172:

Intermediate 6. To a mixture of intermediate 4 (33 mg, 0.07 mmol) and (4-formylphenyl)boronic acid (12 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.52 - 1.62 (m, 1 H) 1.74 - 1.85 (m, 3 H) 1.85 - 1.93 (m, 1 H) 1.97 - 2.06 (m, 1 H) 2.27 (br dd, J=13.30, 5.48 Hz, 1 H) 3.87 (s, 3 H) 3.97 - 4.03 (m, 1 H) 4.36 - 4.46 (m, 1 H) 4.69 (s, 2 H) 6.90 (br s, 1 H) 7.12 (br s, 1 H) 7.16 - 7.19 (m, 1 H) 7.43 - 7.48 (m, 2 H) 7.50 (s, 1 H) 7.54 - 7.60 (m, 2 H) 7.68 (m, J=8.22 Hz, 2 H) 7.79 (s, 1 H) 7.90 (m, J=8.22 Hz, 2 H) 7.98 (s, 1 H) 10.02 (s, 1 H);MS (ESI, m/z): 496.2 [M+H]⁺

Example 172. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To intermediate 6 (30 mg, 0.06 mmol) in 0.4 ml of dichloroethane was added 1-methylpiperazine (12 mg, 0.12 mmol) followed by NaBH(OAc)₃ (26 mg, 0.18 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 27 mg of the title compound. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.52 - 1.67 (m, 1 H) 1.69 - 1.86 (m, 3 H) 2.01 (br dd, J=12.52, 5.87 Hz, 1 H) 2.08 - 2.21 (m, 1 H) 2.28 (s, 3 H) 2.51 (br s, 8 H) 3.54 (s, 2 H) 3.84 (s, 3 H) 3.91 - 3.99 (m, 1 H) 4.40 (br d, J=4.70 Hz, 1 H) 4.64 (br d, J=3.13 Hz, 2 H) 7.34 (br d, J=7.83 Hz, 2 H) 7.39 (br d, J=8.22 Hz, 2 H) 7.47 (br d, J=7.83 Hz, 1 H) 7.50 (br d, J=7.83 Hz, 2 H) 7.73 (s, 1 H) 7.81 (s, 1 H) 7.96 (s, 1 H) 8.23 (s, 1 H); MS (ESI, m/z): 580.3 [M+H]⁺

Example 173. 2-amino-N-((1S,2S)-2-((4'-(((2-hydroxyethyl)amino)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-aminoethan-1-ol, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.59 - 1.69 (m, 1 H) 1.74 - 1.88 (m, 3 H) 1.99 - 2.11 (m, 1 H) 2.18 (td, J=12.91, 7.04 Hz, 1 H) 3.11 - 3.12 (m, 1 H) 3.11 - 3.16 (m, 1 H) 3.77 - 3.86 (m, 2 H) 3.90 (s, 3 H) 3.93 (br d, J=5.87 Hz, 1 H) 3.97 - 4.05 (m, 1 H) 4.26 (s, 2 H) 4.39-4.48 (m, 1 H) 4.67 (s, 2 H) 7.44 (d, J=8.22 Hz, 2 H) 7.53 (m, J=8.22 Hz, 2 H) 7.55 - 7.62 (m, 2 H) 7.66 (d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.20 (s, 1 H) 8.49 (br s, 1 H); MS (ESI, m/z): 541.3 [M+H]⁺

Example 174. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using morpholine, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.57 - 1.69 (m, 1 H) 1.74 - 1.90 (m, 3 H) 2.04 (s, 1 H) 2.14 - 2.23 (m, 1 H) 2.19 (br d, J=7.63 Hz, 1 H) 3.31 - 3.46 (m, 2 H) 3.90 (s, 3 H) 3.99-4.03 (m, 1 H) 4.39 (s, 2 H) 4.42 (br d, J=5.28 Hz, 1 H) 4.67 (d, J=3.52 Hz, 2 H) 7.45 (d, J=8.22 Hz, 2 H) 7.56 (d, J=8.22 Hz, 2 H) 7.59 (d, J=8.22 Hz, 2 H) 7.71 (d, J=7.63 Hz, 2 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.21 (d, J=1.76 Hz, 1 H) 8.49 (br s, 1 H); MS (ESI, m/z): 567.3 [M+H]⁺

Example 175. 2-amino-N-((1S,2S)-2-((4'-((4-(3,3-difluoropiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3,3-difluoropiperidine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 601.3 [M+H]⁺

Example 176. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-methylpiperidine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 579.3 [M+H]⁺

Example 177. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(piperazin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using piperazine, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.50, 7.04 Hz, 1 H) 1.73 - 1.88 (m, 3 H) 2.00 - 2.08 (m, 1 H) 2.13 - 2.22 (m, 1 H) 2.96 (br s, 4 H) 3.32 (br d, J=9.98 Hz, 4 H) 3.50 (s, 1 H) 3.84 - 3.89 (m, 2 H) 3.90 (s, 3 H) 4.00 (br s, 1 H) 4.38 - 4.44 (m, 1 H) 4.66 (d, J=2.93 Hz, 2 H) 7.38 - 7.47 (m, 4 H) 7.52 - 7.60 (m, 4 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.19 (d, J=2.35 Hz, 1 H) 8.50 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 566.3 [M+H]⁺

Example 178. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-phenylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 1-phenylpiperazine, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.61 - 1.69 (m, 1 H) 1.76 - 1.87 (m, 3 H) 2.00 - 2.07 (m, 1 H) 2.15 - 2.23 (m, 1 H) 3.90 (s, 3 H) 3.98 - 4.04 (m, 1 H) 4.39 - 4.44 (m, 1 H) 4.45 (s, 2 H) 4.68 (s, 2 H) 6.92 (t, J=7.34 Hz, 1 H) 7.00 (d, J=8.22 Hz, 2 H) 7.27 (t, J=7.92 Hz, 2 H) 7.45 (d, J=8.22 Hz, 2 H) 7.60 (dd, J=9.68, 8.51 Hz, 4 H) 7.72 (br d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.21 (d, J=1.76 Hz, 1 H) 8.51 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 642.4 [M+H]⁺

Example 179. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-(pyrrolidin-1-yl)piperidine, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.60 - 1.69 (m, 1 H) 1.74 - 1.88 (m, 3 H) 1.96 - 2.23 (m, 8 H) 2.43 (br d, J=13.50 Hz, 2 H) 3.06 - 3.21 (m, 4 H) 3.44 (br s, 2 H) 3.66 (br d, J=12.91 Hz, 4 H) 3.90 (s, 3 H) 3.99 - 4.03 (m, 1 H) 4.37 (s, 2 H) 4.39 - 4.45 (m, 1 H) 4.67 (s, 2 H) 7.41 - 7.48 (m, 2 H) 7.51 - 7.57 (m, 2 H) 7.58 (d, J=8.22 Hz, 2 H) 7.68 (br d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.50 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 634.4 [M+H]⁺

Example 180. 2-amino-N-((1S,2S)-2-((4'-((4-hydroxypiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using piperidin-4-ol, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.59 - 1.68 (m, 1 H) 1.74 - 1.87 (m, 3 H) 1.92 (br s, 1 H) 2.03 (dt, J=13.35, 6.53 Hz, 1 H) 2.10 - 2.23 (m, 1 H) 3.07 (br s, 1 H) 3.51 (br d, J=10.56 Hz, 1 H) 3.82 (br s, 1 H) 3.89 - 3.92 (m, 3 H) 3.98 - 4.03 (m, 1 H) 4.08 (br s, 1 H) 4.34 (br s, 2 H) 4.39 - 4.45 (m, 1 H) 4.67 (s, 2 H) 7.45 (d, J=8.22 Hz, 2 H) 7.54 (br s, 2 H) 7.57 - 7.61 (m, 2 H) 7.59 (d, J=8.22 Hz, 2 H) 7.69 (br d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.99 (s, 1 H) 8.21 (s, 1 H) 8.52 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 581.3 [M+H]⁺

Example 181. 2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.50, 7.04 Hz, 1 H) 1.76 - 1.86 (m, 3 H) 2.00 - 2.08 (m, 1 H) 2.14 - 2.22 (m, 1 H) 3.19 (br s, 2 H) 3.82 - 3.85 (m, 2 H) 3.90 (s, 3 H) 3.98 - 4.02 (m, 1 H) 4.39 - 4.44 (m, 1 H) 4.66 (s, 2 H) 7.40 - 7.47 (m, 4 H) 7.53 - 7.61 (m, 4 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.52 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 610.3 [M+H]⁺

Example 182. 2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxy-2-methylpropyl)-piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-methyl-1-(piperazin-1-yl)propan-2-ol, the title compound was obtained as described for the example 172. MS (ESI, m/z): 638.4 [M+H]⁺

Example 183. 2-amino-N-((1S,2S)-2-((4'-((4-ethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-ethylpiperazine, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.32 (t, J=7.34 Hz, 3 H) 1.59 - 1.68 (m, 1 H) 1.74-1.88 (m, 3 H) 2.04 (dq, J=13.50, 6.85 Hz, 1 H) 2.13 - 2.21 (m, 1 H) 3.18 (br d, J=7.63 Hz, 2 H) 3.78 - 3.87 (m, 2 H) 3.90 (s, 3 H) 3.98 - 4.02 (m, 1 H) 4.38 - 4.44 (m, 1 H) 4.66 (d, J=1.76 Hz, 2 H) 7.38 - 7.46 (m, 4 H) 7.51 - 7.60 (m, 4 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.19 (d, J=2.35 Hz, 1 H) 8.51 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 184. 2-amino-N-((1S,2S)-2-((4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-cyclopropylpiperazine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 606.4 [M+H]⁺

Example 185. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(((R)-3-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentil)nicotinamide

Using tert-butyl(R)-2-methylpiperazine-1-carboxylate, the title compound was obtained as described for the example 172 and following deprotection with TFA. MS (ESI, m/z): 580.3 [M+H]⁺

Example 186. 2-amino-N-((1S,2S)-2-((4'-(((R)-3,4-1imethylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (R)-1,2-dimethylpiperazine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 594.4 [M+H]⁺

Example 187. 2-amino-N-((1S,2S)-2-((4'-(((R)-2,4-dimethylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (R)-1,3-dimethylpiperazine, the title compound was obtained as described for the example 172.¹H NMR (400 MHz, CD₃OD) δ ppm 1.34 (br d, J=5.09 Hz, 3 H) 1.63 (br dd, J=15.06, 6.46 Hz, 1 H) 1.81 (br d, J=7.43 Hz, 3 H) 2.03 (br d, J=6.26 Hz, 1 H) 2.18 (s, 1 H) 2.55 (br s, 1 H) 2.82 (s, 3 H) 2.92 (br s, 1 H) 3.02 (br d, J=12.52 Hz, 1 H) 3.89 (s, 3 H) 4.00 (br s, 1 H) 4.30 (br d, J=11.35 Hz, 1 H) 4.42 (br s, 1 H) 4.65 (s, 2 H) 7.41 (br d, J=7.43 Hz, 4 H) 7.54 (br dd, J=7.63, 3.33 Hz, 4 H) 7.84 (s, 1 H) 7.96 (s, 1 H) 8.19 (s, 1 H) 8.50 (s, 1 H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 188. 2-amino-N-((1S,2S)-2-((4'-((3-ethyl-4-methylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using 2-ethyl-1-methylpiperazine, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.96 (br t, J=7.24 Hz, 3 H) 1.62 (br d, J=14.48 Hz, 3 H) 1.81 (br d, J=7.43 Hz, 3 H) 1.92 (br s, 1 H) 2.04 (br s, 1 H) 2.16 (br d, J=7.04 Hz, 1 H) 2.87 (s, 3 H) 3.20 (br d, J=14.09 Hz, 1 H) 3.45 (br d, J=13.30 Hz, 1 H) 3.70 (br d, J=13.30 Hz, 1 H) 3.81 (br d, J=12.91 Hz, 1 H) 3.89 (s, 3 H) 3.99 (br s, 1 H) 4.42 (br s, 1 H) 4.65 (s, 2 H) 7.41 (br d, J=8.22 Hz, 4 H) 7.55 (br d, J=7.43 Hz, 4 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.19 (s, 1 H) 8.51 (s, 1 H); MS (ESI, m/z): 608.4 [M+H]⁺

Example 189. 2-amino-N-((1S,2S)-2-((4'-((cis-3,5-dimethylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate, the title compound was obtained as described for the example 172 and following deprotection with TFA. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.27 (br d, J=6.26 Hz, 6 H) 1.64 (br d, J=5.87 Hz, 1 H) 1.81 (br d, J=7.04 Hz, 3 H) 1.96 - 2.24 (m, 3 H) 3.09 (d, J=12.91 Hz, 2 H) 3.62 (br s, 5 H) 3.68 (s, 3 H) 3.89 (s, 3 H) 4.00 (br s, 1 H) 4.37 - 4.45 (m, 1 H) 4.65 (s, 2 H) 7.34 - 7.46 (m, 4 H) 7.53 (br d, J=7.43 Hz, 4 H) 7.83 (s, 1 H) 7.95 (s, 1 H) 8.20 (s, 1 H) 8.45 (s, 1 H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 190. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using cis-1,2,6-trimethylpiperazine, the title compound was obtained as described for the example 172.¹H NMR (600 MHz, CD₃OD) δ ppm 1.30 (br d, J=6.46 Hz, 6 H) 1.64 (br dd, J=13.50, 7.04 Hz, 1 H) 1.74 - 1.90 (m, 3 H) 2.00 - 2.09 (m, 1 H) 2.18 (br dd, J=12.91, 5.87 Hz, 1 H) 2.30 (br d, J=12.91 Hz, 3 H) 3.22 (br s, 3 H) 3.45 (br s, 2 H) 3.84 (br d, J=19.37 Hz, 2 H) 3.90 (s, 3 H) 3.97 - 4.03 (m, 1 H) 4.38 - 4.45 (m, 1 H) 4.66 (s, 2 H) 4.69 (s, 1 H) 7.42 (br d, J=7.63 Hz, 4 H) 7.49 - 7.62 (m, 4 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.52 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 608.4 [M+H]⁺

Example 191. 2-amino-N-((1S,2S)-2-((4'-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using trans-2,5-dimethylpiperazine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 594.4 [M+H]⁺

Example 192. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using trans-1,2,5-trimethylpiperazine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 608.4 [M+H]⁺

Example 193. 2-amino-N-((1S,2S)-2-((4'-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using N,N-Dimethyl-3-pyrrolidinamine, the title compound was obtained as described for the example 172. MS (ESI, m/z): 594.4 [M+H]⁺

Example 194. 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)pyrazine-2-carboxamide

Using 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.60 - 1.69 (m, 1 H) 1.70 - 1.78 (m, 1 H) 1.78 - 1.87 (m, 2 H) 2.03 - 2.20 (m, 3 H) 2.88 (d, J=1.76 Hz, 3 H) 3.00 (br s, 4 H) 3.34 (br d, J=11.74 Hz, 3 H) 3.85 (s, 3 H) 3.91 (br d, J=11.74 Hz, 2 H) 3.99 - 4.06 (m, 1 H) 4.33 - 4.40 (m, 1 H) 4.59 - 4.70 (m, 2 H) 7.38 (d, J=8.22 Hz, 2 H) 7.42 (br d, J=8.22 Hz, 2 H) 7.47 (d, J=8.22 Hz, 2 H) 7.52 (br d, J=8.22 Hz, 2 H) 7.99 (s, 1 H) 8.12 (s, 1 H) 8.41 (s, 1 H); MS (ESI, m/z): 581.3 [M+H]⁺

Example 195. 2-amino-N-((1S,2S)-2-((3'-fluoro-4'-((4-methylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (3-fluoro-4-formylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.69, 7.04 Hz, 1 H) 1.72 - 1.90 (m, 3 H) 1.96 - 2.09 (m, 1 H) 2.10 - 2.23 (m, 1 H) 2.90 (s, 3 H) 3.05 - 3.27 (m, 4 H) 3.34 - 3.51 (m, 4 H) 3.89 (s, 3 H) 3.94 - 4.01 (m, 1 H) 4.07 (s, 2 H) 4.34 - 4.47 (m, 1 H) 4.60 - 4.73 (m, 2 H) 5.47 (s, 1 H) 7.35 (br d, J=11.35 Hz, 1 H) 7.42 (br d, J=7.83 Hz, 3 H) 7.50 (br t, J=7.83 Hz, 1 H) 7.55 (d, J=8.22 Hz, 2 H) 7.83 (s, 1 H) 7.97 (s, 1 H) 8.17 (d, J=1.96 Hz, 1 H) 8.50 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 598.7 [M+H]⁺

Example 196. 2-amino-N-((1S,2S)-2-((3',5'-difluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using ((3,5-difluoro-4-formylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.30, 7.04 Hz, 1 H) 1.71 - 1.91 (m, 3 H) 2.03 (br dd, J=12.91, 5.48 Hz, 1 H) 2.12 - 2.23 (m, 1 H) 2.87 (s, 3 H) 2.94 (br d, J=18.00 Hz, 3 H) 3.32 (br s, 4 H) 3.90 (s, 3 H) 3.99 (br s, 1 H) 4.40 (br d, J=3.91 Hz, 1 H) 4.62 - 4.77 (m, 2 H) 7.24 (br d, J=8.61 Hz, 2 H) 7.44 (m, J=7.83 Hz, 2 H) 7.57 (m, J=7.83 Hz, 2 H) 7.83 (s, 1 H) 7.98 (s, 1 H) 8.19 (s, 1 H) 8.50 (s, 1 H); MS (ESI, m/z): 616.8 [M+H]⁺

Example 197. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.59 - 1.71 (m, 1 H) 1.75 - 1.89 (m, 3 H) 1.99 - 2.10 (m, 1 H) 2.13 - 2.25 (m, 1 H) 2.91 (s, 3 H) 3.47 (br d, J=1.57 Hz, 2 H) 3.81 (s, 2 H) 3.91 (s, 3 H) 4.02 (br d, J=4.30 Hz, 1 H) 4.39 - 4.46 (m, 1 H) 4.69 (s, 2 H) 7.47 (m, J=8.22 Hz, 2 H) 7.60 (m, J=8.22 Hz, 2 H) 7.83 (d, J=8.22 Hz, 4 H) 7.98 (s, 1 H) 8.21 (d, J=1.96 Hz, 1 H) 8.50 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 648.32 [M+H]⁺

Example 198. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-formyl-3-methylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.11, 6.85 Hz, 2 H) 1.72 - 1.90 (m, 3 H) 1.82 (br s, 1 H) 1.94 - 2.09 (m, 2 H) 2.10 - 2.24 (m, 2 H) 2.43 (s, 1 H) 2.88 (s, 3 H) 3.29 - 3.31 (m, 11 H) 3.69 (s, 1 H) 3.90 (s, 2 H) 3.93 - 3.96 (m, 1 H) 4.01 (br d, J=4.70 Hz, 1 H) 4.16 (s, 1 H) 4.37 - 4.47 (m, 1 H) 4.66 (d, J=3.13 Hz, 1 H) 7.37 - 7.43 (m, 2 H) 7.51 - 7.55 (m, 1 H) 7.52 - 7.59 (m, 1 H) 7.85 (d, J=0.78 Hz, 1 H) 7.96 (s, 1 H) 8.19 (d, J=1.96 Hz, 1 H) 8.49 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 594.4 [M+H]⁺

Example 199. 2-amino-N-((1S,2S)-2-((3'-hydroxy-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-formyl-3-hydroxyphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (br dd, J=12.72, 6.85 Hz, 1 H) 1.74 - 1.90 (m, 3 H) 2.05 (br s, 1 H) 2.12 - 2.26 (m, 1 H) 2.82 (d, J=3.13 Hz, 3 H) 3.13 (br s, 5 H) 3.91 (s, 3 H) 4.01 (br d, J=6.26 Hz, 1 H) 4.05 (s, 1 H) 4.08 (s, 1 H) 4.38 - 4.46 (m, 1 H) 4.66 (s, 2 H) 7.05 (s, 1 H) 7.28 (br d, J=8.61 Hz, 1 H) 7.25 - 7.34 (m, 1 H) 7.32 (br d, J=7.83 Hz, 1 H) 7.41 (d, J=8.22 Hz, 2 H) 7.52 (d, J=8.22 Hz, 2 H) 7.54 - 7.59 (m, 1 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.48 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 596.3 [M+H]⁺

Example 200. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-nitro-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using (4-formyl-3-nitrophenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (dt, J=13.89, 7.14 Hz, 1 H) 1.74 - 1.91 (m, 3 H) 2.00 - 2.10 (m, 1 H) 2.13 - 2.24 (m, 1 H) 2.88 (s, 3 H) 3.35 - 3.39 (m, 2 H) 3.91 (s, 3 H) 3.92 - 3.95 (m, 2 H) 3.99 - 4.03 (m, 1 H) 4.39 - 4.47 (m, 1 H) 4.69 (d, J=3.13 Hz, 2 H) 7.48 (d, J=8.22 Hz, 2 H) 7.60 - 7.65 (m, 4 H) 7.83 (s, 1 H) 7.97 (s, 1 H) 8.02 (d, J=1.96 Hz, 1 H) 8.21 (d, J=2.35 Hz, 1 H) 8.48 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 625.3 [M+H]⁺

Example 201. 2-amino-N-((1S,2S)-2-((3'-methoxy-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-formyl-3-methoxyphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (br dd, J=13.50, 6.46 Hz, 1 H) 1.74 - 1.91 (m, 3 H) 1.99 - 2.10 (m, 1 H) 2.19 (br d, J=6.65 Hz, 1 H) 2.81 (s, 3 H) 3.91 (s, 3 H) 3.92 (s, 3 H) 3.98 - 4.07 (m, 1 H) 4.43 (br d, J=3.52 Hz, 1 H) 4.68 (s, 2 H) 7.15 - 7.24 (m, 2 H) 7.37 - 7.47 (m, 3 H) 7.59 (d, J=8.22 Hz, 2 H) 7.86 (s, 1 H) 7.98 (s, 1 H) 8.21 (d, J=1.96 Hz, 1 H) 8.51 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 610.3 [M+H]⁺

Example 202. 2-amino-N-((1S,2S)-2-((2'-chloro-4'-((4-methylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (2-chloro-4-formylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. MS (ESI, m/z): 614.3 [M+H]⁺

Example 203. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using ((6-formylpyridin-3-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (dt, J=13.60, 7.09 Hz, 1 H) 1.74 - 1.90 (m, 3 H) 2.05 (br dd, J=13.11, 6.46 Hz, 1 H) 2.13 - 2.26 (m, 1 H) 2.90 (s, 3 H) 3.91 - 3.94 (m, 3 H) 3.99 - 4.06 (m, 1 H) 4.43 (br dd, J=11.93, 6.85 Hz, 1 H) 7.52 (d, J=8.22 Hz, 2 H) 7.64 - 7.68 (m, 2 H) 7.72 (br dd, J=12.33, 8.41 Hz, 2 H) 7.85 (s, 1 H) 7.99 (s, 1 H) 8.22 (d, J=2.35 Hz, 1 H) 8.51 (d, J=1.96 Hz, 1 H) 8.82 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 581.3 [M+H]⁺

Example 204. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamide

Using (5-formylpyridin-2-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.¹n NMR (400 MHz, CD₃OD) δ ppm 1.66 (td, J=14.09, 7.04 Hz, 1 H) 1.76 - 1.92 (m, 3 H) 1.98 - 2.11 (m, 1 H) 2.19 (br s, 1 H) 2.90 (s, 3 H) 3.64 (s, 1 H) 3.76 (s, 3 H) 3.98 - 4.07 (m, 1 H) 4.38 - 4.48 (m, 1 H) 7.52 (d, J=8.22 Hz, 2 H) 7.84 (s, 1 H) 7.90 (dd, J=8.41, 1.76 Hz, 3 H) 7.98 (s, 1 H) 8.02 (br d, J=8.61 Hz, 1 H) 8.21 (d, J=1.96 Hz, 1 H) 8.50 (d, J=1.96 Hz, 1 H) 8.60 (s, 1 H); MS (ESI, m/z): 581.3 [M+H]⁺

Example 205. 2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester and 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.57 - 1.72 (m, 1 H) 1.75 - 1.90 (m, 3 H) 2.04 (dt, J=12.81, 6.70 Hz, 1 H) 2.13 - 2.26 (m, 1 H) 3.82 (s, 2 H) 3.86 - 3.90 (m, 2 H) 3.91 (s, 3 H) 3.97 - 4.05 (m, 1 H) 4.43 (br dd, J=11.93, 6.46 Hz, 1 H) 4.69 (s, 2 H) 7.48 (d, J=8.22 Hz, 2 H) 7.60 (d, J=8.22 Hz, 2 H) 7.81 - 7.87 (m, 3 H) 7.99 (s, 1 H) 8.22 (d, J=2.35 Hz, 1 H) 8.51 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 678.3[M+H]⁺

Example 206. 2-amino-N-((1S,2S)-2-((2'-chloro-4'-((4-(2-hydroxyethyl)-piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (2-chloro-4-formylphenyl)boronic acid pinacol ester and 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 172. MS (ESI, m/z): 644.3 [M+H]⁺

Example 207. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid and (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.53 - 1.69 (m, 1 H) 1.76 - 1.89 (m,3 H) 2.01 (s, 1 H) 2.18 (br dd, J=13.30, 5.87 Hz, 1 H) 2.48 (br s, 2 H) 2.91 (s, 3 H) 3.82 (s, 2 H) 3.99 (br d,J=4.30 Hz, 1 H) 4.40 (br d, J=5.09 Hz, 1 H) 4.68 (d, J=4.30 Hz, 2 H) 6.95 (dd, J=7.43, 6.26 Hz, 1 H) 7.47 (d, J=8.22 Hz, 2 H) 7.62 (d, J=8.22 Hz, 2 H) 7.84 - 7.92 (m, 3 H) 7.98 - 8.05 (m, 1 H) 8.32 (dd, J=7.43, 1.56 Hz, 1 H); MS (ESI, m/z): 568.3 [M+H]⁺

Example 208. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 208:

Intermediate 7. To a mixture of intermediate 4 (100 mg, 0.21 mmol) and (4-acetylphenyl)boronic acid (52 mg, 0.32 mmol) in 1.2 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (88 mg, 0.64 mmol) followed by Pd(PPh₃)₄ (12 mg, 0.01 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 80 mg of off-white solid ¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1 H) 1.74 - 1.88 (m, 3 H) 2.05 (br dd, J=12.62, 7.34 Hz, 1 H) 2.17 (br dd, J=13.21, 5.58 Hz, 1 H) 2.62 (s, 3 H) 3.89 (s, 3 H) 3.96 - 4.01 (m, 1 H) 4.38 - 4.45 (m, 1 H) 4.61 - 4.73 (m, 2 H) 7.45 (d, J=8.22 Hz, 2 H) 7.60 (d, J=8.22 Hz, 2 H) 7.66 (d, J=8.22 Hz, 2 H) 7.82 (s, 1 H) 7.94 (s, 1 H) 8.01 (d, J=8.22 Hz, 2 H) 8.18 (d, J=1.76 Hz, 1 H) 8.44 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 510.8[M+H]⁺

Example 208. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To a mixture of intermediate 7 (30 mg, 0.06 mmol) in 0.4 ml of methanol was added 1-methylpiperazine (14 µl, 0.12 mmol) followed by NaBH₃CN(11 mg, 0.18 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 17 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.40 (d, J=6.46 Hz, 3 H) 1.59 (br dd, J=13.21, 7.34 Hz, 1 H) 1.73 - 1.85 (m, 3 H) 1.98 - 2.05 (m, 1 H) 2.15 (br dd, J=13.21, 5.58 Hz, 1 H) 2.31 (s, 3 H) 2.35 - 2.77 (m, 8 H) 3.41 - 3.48 (m, 1 H) 3.86 (s, 3 H) 3.90 - 3.99 (m, 1 H) 4.37 - 4.44 (m, 1 H) 4.61 - 4.70 (m, 2 H) 7.34 (d, J=7.63 Hz, 2 H) 7.39 (br d, J=7.63 Hz, 2 H) 7.48 (br d, J=7.63 Hz, 2 H) 7.50 (br d, J=8.22 Hz, 2 H) 7.74 (s, 1 H) 7.82 (d, J=2.93 Hz, 1 H) 7.96 (s, 1 H) 8.22 - 8.26 (m, 1 H); MS (ESI, m/z): 594.7 [M+H]⁺

Example 209. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamide

Using (2S,6R)-1,2,6-trimethylpiperazine, title compound was obtained as described for the example 208. MS (ESI, m/z): 622.4 [M+H]⁺

Example 210. 2-amino-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)-ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using 1-(2-hydroxyethyl)piperazine, title compound was obtained as described for the example 208. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.50, 7.04 Hz, 1 H) 1.69 (d, J=7.04 Hz, 3 H) 1.75 - 1.88 (m, 3 H) 2.00 - 2.08 (m, 1 H) 2.18 (br dd, J=13.50, 5.87 Hz, 1 H) 3.16 - 3.23 (m, 2 H) 3.23 - 3.27 (m, 2 H) 3.53 (br s, 4 H) 3.84 (br t, J=4.99 Hz, 2 H) 3.90 (s, 3 H) 3.98 - 4.03 (m, 1 H) 4.25 (br d, J=7.04 Hz, 1 H) 4.38 - 4.45 (m, 1 H) 4.64 - 4.70 (m, 2 H) 7.43 (d, J=7.63 Hz, 2 H) 7.51 (m, J=8.22 Hz, 2 H) 7.56 (m, J=8.22 Hz, 2 H) 7.64 (d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.19 (s, 1 H) 8.53 (s, 1 H); MS (ESI, m/z): 624.4 [M+H]⁺

Example 211. 2-amino-N-((1S,2S)-2-((4'-((1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)ethyl)-[1.1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 2-(cis-2,6-dimethylpiperazin-1-yl)ethan-1-ol, title compound was obtained as described for the example 208. MS (ESI, m/z): 652.4 [M+H]⁺

Example 212. 2-amino-N-((1S,2S)-2-((3',5'-difluoro-4'-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-acetyl-3,5-difluorophenyl)boronic acid pinacol ester and 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 208. MS (ESI, m/z): 660.32 [M+H]⁺

Scheme for the preparation of the intermediate 9:

Intermediate 8. A mixture of (S)-1-(4-Bromophenyl)ethylamine (300 mg, 1.50 mmol) and (N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (533 mg, 1.80 mmol) in 3 ml of DIPEA was heated at 120 °C for 24 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 500 mg of off-white solid ¹H NMR (600 MHz, DMSO-d ₆) δ ppm 1.16 (d, J=6.46 Hz, 3 H) 2.27 - 2.33 (m, 2 H) 2.39 (s, 5 H) 2.78 (br s, 4 H) 3.37 - 3.44 (m, 1 H) 7.16 (d, J=7.87 Hz, 2 H) 7.43 (t, J=7.59 Hz, 4 H) 7.55 - 7.60 (m, 2 H) : MS (ESI, m/z): 423.1/ 425.2[M+H]⁺

Intermediate 9. (S)-1-(1-(4-bromophenyl)ethyl)piperazine

Intermediate 8 (0.5 g, 1.1 mmol) in 5 ml of HBr in AcOH was stirred at room temperature for 24 hrs. After concentration under vacuum, the crude product was diluted with EtOAC and the solid was collected by filtration to give 0.5 g of off-white solid ¹H NMR (600 MHz, DMSO-d ₆) δ ppm 1.63 (br s, 3 H) 3.40 (br s, 1 H) 3.47 - 3.72 (br s, 8 H) 7.54 (br s, 2 H) 7.69 (br d, J=7.63 Hz, 2 H); MS (ESI, m/z): 269.1/ 271.4 [M+H]⁺

Intermediate 10. (R)-1-(1-(4-bromophenyl)ethyl)piperazine

Using (R)-1-(4-Bromophenyl)ethylamine, the title compound was obtained as described for the intermediate 9. MS (ESI, m/z): 269.1/ 271.4 [M+H]⁺

Intermediate 11. 1-(1-(4-bromophenyl)cyclopropyl)piperazine

Using 1-(4-Bromophenyl)cyclopropan-1-amine, the title compound was obtained as described for the intermediate 9. MS (ESI, m/z): 281.1/ 283.4 [M+H]⁺

Intermediate 12. 1-(2-(4-bromophenyl)propan-2-yl)piperazine

Using 2-(4-Bromophenyl)propan-2-amine, the title compound was obtained as described for the intermediate 9. MS (ESI, m/z): 283.1/ 285.4 [M+H]⁺

Example 213 and 214

Scheme for the preparation of the Compounds of Example 213 and 214;

Intermediate 13. To a mixture of intermediate 4 (0.56 g, 1.19 mmol) and bis(pinacalato)diboron (0.6 g, 2.38 mmol) in 6 ml of 1,4-dioxane was added KOAc(0.35 g, 3.57 mmol) followed by Pd(PPh₃)₄ (69 mg, 0.06 mmol). The reaction mixture was heated at 110 °C for 5 hrs, cooled to room temperature, and partitioned between water and EtOAc, dried over anhydrous MgSO₄. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 0.5 g of light yellow solid ¹H NMR (400 MHz, CD₃OD) δ ppm 1.19 (s, 6 H) 1.30 (s, 6 H) 1.60 (br dd, J=13.30, 7.04 Hz, 1 H) 1.68 - 1.88 (m, 3 H) 1.93 - 2.06 (m, 1 H) 2.15 (br dd, J=13.11, 6.06 Hz, 1 H) 3.90 (s, 3 H) 3.92 - 3.99 (m, 1 H) 4.32 - 4.44 (m, 1 H) 4.64 (s, 2 H) 7.33 (m, J=7.83 Hz, 2 H) 7.66 (m, J=7.83 Hz, 2 H) 7.75 (s, 1 H) 7.85 (s, 1 H) 7.97 (d, J=1.96 Hz, 1 H) 8.20 - 8.30 (m, 1 H); MS (ESI, m/z): 518.3 [M+H]⁺

Example 213. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((R)-1-(piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To a mixture of intermediate 13 (150 mg, 0.29 mmol) and intermediate 10 (100 mg, 0.29 mmol) in 1.5 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (120 mg, 0.87 mmol) followed by Pd(PPh₃)₄(17 mg, 0.01 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 130 mg of off-white solid ¹H NMR (600 MHz, CD₃OD) δ ppm 1.40 (d, J=6.46 Hz, 3 H) 1.54 - 1.63 (m, 1 H) 1.73 - 1.86 (m, 3 H) 1.98 - 2.05 (m, 1 H) 2.12 - 2.19 (m, 1 H) 2.40 (br s, 2 H) 2.82 (t, J=4.99 Hz, 4 H) 3.40 (q, J=6.46 Hz, 1 H) 3.86 (s, 3 H) 3.95 (dt, J=6.90, 4.48 Hz, 1 H) 4.41 (td, J=7.63, 4.70 Hz, 1 H) 4.61 - 4.70 (m, 2 H) 5.48 (s, 1 H) 7.33 (d, J=8.22 Hz, 2 H) 7.39 (d, J=8.22 Hz, 2 H) 7.44 - 7.49 (m, 2 H) 7.49 - 7.55 (m, 2 H) 7.74 (s, 1 H) 7.83 (s, 1 H) 7.97 (d, J=2.35 Hz, 1 H) 8.23 (d, 1=2.35 Hz, 1 H); MS (ESI, m/z): 580.6[M+H]⁺

Example 214. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To compound 213 (20 mg, 0.03 mmol) in 0.2 ml of 1,2-dichloroethane was added formaldehyde (0.005 ml, 0.06 mmol) followed by NaBH(OAc)₃ (13 mg, 0.09 mmol). The mixture was stirred at room temperature for 1 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 15 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (dd, J=13.50, 7.04 Hz, 1 H) 1.71 (d, J=7.04 Hz, 3 H) 1.75 - 1.88 (m, 3 H) 2.00 - 2.10 (m, 1 H) 2.12 - 2.23 (m, 1 H) 2.91 (s, 3 H) 3.20 - 3.28 (m, 2 H) 3.52 (br s, 4 H) 3.90 (s, 3 H) 4.00 (dt, J=6.46, 4.40 Hz, 1 H) 4.32 (q, J=6.65 Hz, 1 H) 4.42 (td, J=7.34, 4.11 Hz, 1 H) 4.63 - 4.71 (m, 2 H) 7.43 (d, J=8.22 Hz, 2 H) 7.52 (d, J=8.22 Hz, 2 H) 7.56 (d, J=8.22 Hz, 2 H) 7.64 (d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.20 (d, J=1.76 Hz, 1 H) 8.53 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 594.8 [M+H]⁺

Example 215. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using intermediate 9, the title compound was obtained as described for the example 214.¹H NMR (600 MHz, CD₃OD) δ ppm 1.51 (d, J=7.04 Hz, 3 H) 1.64 (br dd, J=13.21, 6.75 Hz, 1 H) 1.76 - 1.85 (m, 3 H) 2.01 - 2.06 (m, 1 H) 2.14 (s, 1 H) 2.15 - 2.20 (m, 1 H) 2.84 (s, 3 H) 3.82 (br d, J=6.46 Hz, 1 H) 3.90 (s, 3 H) 3.98 - 4.02 (m, 1 H) 4.42 (br dd, J=6.75, 3.23 Hz, 1 H) 4.66 (s, 2 H) 7.42 (dd, J=8.22, 1.76 Hz, 4 H) 7.54 - 7.59 (m, 4 H) 7.86 (s, 1 H) 7.98 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.53 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 594.8 [M+H]⁺

Example 216. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using intermediate 11, the title compound was obtained as described for the example 214. ¹H NMR (600 MHz, CD₃OD) δ ppm 0.85 - 0.88 (m, 1 H) 0.89 - 0.92 (m, 1 H) 0.99 - 1.01 (m, 1 H) 1.01 - 1.04 (m, 1 H) 1.64 (br dd, J=13.50, 6.46 Hz, 1 H) 1.75 - 1.88 (m, 3 H) 2.01 - 2.07 (m, 1 H) 2.16 - 2.24 (m, 2 H) 2.79 (d, J=1.76 Hz, 3 H) 3.00 (br s, 2 H) 3.15 - 3.21 (m, 2 H) 3.34 - 3.43 (m, 4 H) 3.90 (s, 3 H) 4.00 (dt, J=6.46, 4.11 Hz, 1 H) 4.42 (td, J=7.34, 4.70 Hz, 1 H) 4.66 (s, 2 H) 7.26 (d, J=8.31 Hz, 2 H) 7.37 - 7.40 (m, 2 H) 7.40 - 7.43 (m, 2 H) 7.49 - 7.52 (m, 1 H) 7.86 (s, 1 H) 7.98 (s, 1 H) 8.20 (d, J=1.76 Hz, 1 H) 8.54 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 606.3 [M+H]⁺

Example 217. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamide

Using intermediate 12, the title compound was obtained as described for the example 214. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.49 (s, 5 H) 1.60 - 1.61 (m, 1 H) 1.60 - 1.66 (m, 1 H) 1.80 - 1.88 (m, 3 H) 2.02 - 2.08 (m, 1 H) 2.17 (br s, 1 H) 2.87 (s, 3 H) 3.90 (s, 3 H) 4.02 (br s, 1 H) 4.40 - 4.47 (m, 1 H) 4.67 (s, 2 H) 7.42 (d, J=8.22 Hz, 2 H) 7.51 - 7.58 (m, 4 H) 7.58 - 7.62 (m, 2 H) 7.85 (d, J=0.78 Hz, 1 H) 7.98 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.51 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 608.2 [M+H]⁺

Example 218. 2-amino-N-((1S,2S)-2-((4'-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Scheme for the preparation of the Compound of Example 218;

To a mixture of compound 213 (20 mg, 0.03 mmol) and K₂CO₃ (14 mg, 0.1 mmol) in 0.3 ml of methanol was added 2-bromothanol (4 µl, 0.05 mmol). The reaction mixture was stirred at room temperature for 3 hrs, After concentration under vacuum, the crude product was purified by HPLC to give 10 mg of off-white solid ¹H NMR (600 MHz, CD₃OD) δ ppm 1.60 - 1.71 (m, 1 H) 1.75 (d, J=7.04 Hz, 3 H) 1.76 - 1.85 (m, 3 H) 2.00 - 2.09 (m, 1 H) 2.14 - 2.23 (m, 1 H) 3.33 - 3.44 (m, 2 H) 3.56 - 3.73 (m, 4 H) 3.83 - 3.87 (m, 2 H) 3.90 (s, 3 H) 4.00 (dt, J=6.60, 4.33 Hz, 1 H) 4.38 - 4.45 (m, 2 H) 4.64 - 4.70 (m, 2 H) 7.43 (d, J=8.22 Hz, 2 H) 7.54 (d, J=8.22 Hz, 2 H) 7.56 - 7.61 (m, 2 H) 7.64 - 7.71 (m, 2 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.20 (d, J=1.76 Hz, 1 H) 8.53 (s, 1 H); MS (ESI, m/z): 624.8 [M+H]⁺

Example 219. 2-amino-N-((1S,2S)-2-((4'-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using intermediate 9, the title compound was obtained as described for the example 213 and 218. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.58 (d, J=7.04 Hz, 3 H) 1.64 (br dd, J=13.21, 6.75 Hz, 1 H) 1.72 - 1.87 (m, 3 H) 2.00 - 2.07 (m, 1 H) 2.15 - 2.23 (m, 1 H) 2.99 (br s, 2 H) 3.17 - 3.22 (m, 3 H) 3.35 - 3.44 (m, 4 H) 3.80 - 3.85 (m, 3 H) 3.90 (s, 3 H) 3.96 - 4.03 (m, 2 H) 4.42 (td, J=7.34, 4.11 Hz, 1 H) 4.66 (s, 2 H) 7.42 (d, J=8.22 Hz, 2 H) 7.46 (d, J=8.22 Hz, 2 H) 7.55 - 7.57 (m, 2 H) 7.60 (d, J=8.22 Hz, 2 H) 7.86 (s, 1 H) 7.98 (s, 1 H) 8.20 (d, J=2.35 Hz, 1 H) 8.52 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 624.8 [M+H]⁺

Example 220. 2-amino-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using intermediate 11, the title compound was obtained as described for the example 213 and 218. ¹H NMR (600 MHz, CD₃OD) δ ppm 0.85 - 0.88 (m, 1 H) 0.91 - 0.94 (m, 1 H) 1.00 - 1.03 (m, 1 H) 1.05 - 1.07 (m, 1 H) 1.64 (dd, J=13.21, 6.75 Hz, 1 H) 1.74 - 1.86 (m, 2 H) 1.99 - 2.07 (m, 1 H) 2.15 - 2.21 (m, 1 H) 3.13 - 3.18 (m, 3 H) 3.76 - 3.81 (m, 2 H) 3.90 (s, 3 H) 3.97 - 4.04 (m, 1 H) 4.39 - 4.45 (m, 1 H) 4.61 - 4.71 (m, 2 H) 7.25 - 7.28 (m, 1 H) 7.35 - 7.43 (m, 3 H) 7.49 - 7.58 (m, 4 H) 7.85 (s, 1 H) 7.98 (s, 1 H) 8.19 (d, J=1.76 Hz, 1 H) 8.53 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 636.5 [M+H]⁺

Example 221. 2-amino-N-((1S,2S)-2-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using intermediate 12, the title compound was obtained as described for the example 213 and 218. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.35 - 1.44 (m, 6 H) 1.60 (br dd, J=12.91, 7.43 Hz, 1 H) 1.73 - 1.89 (m, 3 H) 2.03 (br dd, J=13.50, 6.46 Hz, 1 H) 2.11 - 2.21 (m, 1 H) 2.48 - 2.62 (m, 9 H) 3.67 (t, J=6.06 Hz, 2 H) 3.86 (s, 3 H) 3.96 (dt, J=6.95, 4.55 Hz, 1 H) 4.36 - 4.46 (m, 1 H) 4.59 - 4.72 (m, 2 H) 7.40 (d, J=7.83 Hz, 2 H) 7.43 - 7.49 (m, 2 H) 7.53 (dd, J=12.72, 8.41 Hz, 4 H) 7.75 (s, 1 H) 7.83 (s, 1 H) 7.97 (d, J=2.35 Hz, 1 H) 8.24 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 624.8 [M+H]⁺

Example 222. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 222:

Intermediate 14.

Using 6-fluoropyridine-3-boronic acid, the title compound was obtained as described for the intermediate 2. ¹H NMR (600 MHz, DMSO-d ₆) δ ppm 7.20 (dd, J=8.51, 2.64 Hz, 1 H) 8.20 (td, J=8.22, 2.35 Hz, 1 H) 8.27 (d, J=2.93 Hz, 1 H) 8.45 (d, J=2.93 Hz, 1 H) 8.48 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 234.1 [M+H]⁺

Intermediate 15.

Using intermediate 14, the title compound was obtained as described for the intermediate 4. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60 (br dd, J=13.30, 7.04 Hz, 1 H) 1.71 - 1.84 (m, 3 H) 2.00 (br dd, J=13.30, 6.26 Hz, 1 H) 2.10 - 2.21 (m, 1 H) 3.92 (dt, J=6.55, 4.35 Hz, 1 H) 4.39 (td, J=7.34, 4.50 Hz, 1 H) 4.58 (s, 2 H) 7.15 (dd, J=8.41, 2.54 Hz, 1 H) 7.26 (d, J=8.22 Hz, 2 H) 7.38 - 7.43 (m, 2 H) 8.08 (d, J=2.35 Hz, 1 H) 8.12 - 8.21 (m, 1 H) 8.35 (d, J=2.35 Hz, 1 H) 8.43 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 485.2/ 487.3 [M+H]⁺

Intermediate 16.

Using intermediate 15, the title compound was obtained as described for the intermediate 13. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.18 (s, 12 H) 1.58 (br dd, J=13.21, 7.34 Hz, 1 H) 1.69 - 1.84 (m, 3 H) 1.96 - 2.03 (m, 1 H) 2.15 (br d, J=7.63 Hz, 1 H) 3.93 (br d, J=6.46 Hz, 1 H) 4.39 (br d, J=4.70 Hz, 1 H) 4.63 (s, 2 H) 7.13 (dd, J=8.51, 2.64 Hz, 1 H) 7.32 (d, J=7.63 Hz, 2 H) 7.49 - 7.57 (m, 1 H) 7.64 (d, J=7.63 Hz, 2 H) 8.07 (d, J=2.35 Hz, 1 H) 8.10 - 8.18 (m, 1 H) 8.33 (d, J=1.76 Hz, 1 H) 8.41 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 533.3 [M+H]⁺

Intermediate 17.

Using intermediate 16, the title compound was obtained as described for the compound 213. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61 (d, J=6.65 Hz, 3 H) 1.64 (br s, 1 H) 1.77 - 1.86 (m, 3 H) 2.02 - 2.08 (m, 1 H) 2.16 - 2.22 (m, 1 H) 3.02 (br s, 2 H) 3.13 (br s, 2 H) 3.32 - 3.40 (m, 4 H) 3.97 - 4.02 (m, 2 H) 4.05 (br d, J=6.26 Hz, 1 H) 4.41 - 4.46 (m, 1 H) 4.67 (d, J=3.91 Hz, 2 H) 7.16 (br dd, J=8.41, 2.54 Hz, 1 H) 7.43 (br d, J=8.22 Hz, 2 H) 7.48 (d, J=8.22 Hz, 2 H) 7.55 (d, J=7.83 Hz, 2 H) 7.60 (d, J=7.83 Hz, 2 H) 8.19 (td, J=8.02, 2.74 Hz, 1 H) 8.35 (d, J=2.35 Hz, 1 H) 8.47 (br d, J=2.74 Hz, 1 H) 8.52 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 595.3 [M+H]⁺

Example 222. 6-amino-6'-fluoro-N-((1S,2S)-2-(4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 17, the title compound was obtained as described for the example 214. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.57 (d, J=6.65 Hz, 3 H) 1.63 (br dd, J=13.50, 6.85 Hz, 1 H) 1.72 - 1.89 (m, 3 H) 2.00 - 2.08 (m, 1 H) 2.14 - 2.23 (m, 1 H) 2.87 (s, 3 H) 3.90 - 3.97 (m, 1 H) 3.97 - 4.05 (m, 1 H) 4.40 - 4.47 (m, 1 H) 4.63 - 4.71 (m, 2 H) 7.16 (dd, J=8.61, 2.74 Hz, 1 H) 7.32 - 7.50 (m, 4 H) 7.55 (br d, J=8.22 Hz, 2 H) 7.58 (br d, J=8.22 Hz, 2 H) 8.19 (ddd, J=8.61, 7.43, 2.74 Hz, 1 H) 8.35 (d, J=2.35 Hz, 1 H) 8.48 (d, J=2.74 Hz, 1 H) 8.56 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 609.3 [M+H]⁺

Example 223. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 10, the title compound was obtained as described for the example 222. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.49 (d, J=7.04 Hz, 3 H) 1.63 (br d, J=6.65 Hz, 1 H) 1.84 (br d, J=15.65 Hz, 3 H) 2.06 (br s, 1 H) 2.19 (br d, J=8.61 Hz, 1 H) 2.84 (s, 3 H) 3.74 (br d, J=6.26 Hz, 1 H) 4.00 (br s, 1 H) 4.43 (br s, 1 H) 4.67 (d, J=3.13 Hz, 2 H) 7.15 (br dd, J=9.00, 2.74 Hz, 1 H) 7.42 (dd, J=7.83, 3.52 Hz, 4 H) 7.54 (br dd, J=7.83, 5.09 Hz, 4 H) 8.15 - 8.22 (m, 1 H) 8.35 (br d, J=2.35 Hz, 1 H) 8.46 (s, 1 H) 8.50 (br d, J=1.96 Hz, 1 H); MS (ESI+) m/z 609.4 [M+H]⁺

Example 224. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 11, the title compound was obtained as described for the example 222.¹H NMR (400 MHz, CD₃OD) δ ppm 0.91 - 0.95 (m, 2 H) 1.01 - 1.06 (m, 2 H) 1.64 (br dd, J=13.21, 6.75 Hz, 1 H) 1.76 - 1.85 (m, 3 H) 2.01 - 2.06 (m, 1 H) 2.14 (s, 1 H) 2.15 - 2.20 (m, 1 H) 2.80 (s, 3 H) 3.34 (s, 2 H) 3.99 (br d, J=4.30 Hz, 1 H) 4.43 (br d, J=4.70 Hz, 1 H) 4.67 (d, J=3.52 Hz, 2 H) 7.12 - 7.16 (m, 1 H) 7.40 (dd, J=14.28, 8.41 Hz, 4 H) 7.52 (br dd, J=8.22, 3.91 Hz, 4 H) 8.18 (s, 1 H) 8.35 (d, J=2.35 Hz, 1 H) 8.42 (d, J=2.35 Hz, 1 H) 8.45 (s, 1 H); MS (ESI+) m/z 621.5 [M+H]⁺

Example 225. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 12, the title compound was obtained as described for the example 222. MS (ESI+) m/z 623.3 [M+H]⁺

Example 226. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 226:

Using intermediate 17, the title compound was obtained as described for the example 218. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58 - 1.68 (m, 4 H) 1.77 - 1.87 (m, 3 H) 2.02 - 2.09 (m, 1 H) 2.15 - 2.23 (m, 1 H) 3.13 (br s, 2 H) 3.17 - 3.26 (m, 2 H) 3.46 (br s, 4 H) 3.77 (br s, 1 H) 3.82 - 3.87 (m, 2 H) 4.02 (br d, J=4.70 Hz, 2 H) 4.11 (br d, J=6.26 Hz, 1 H) 4.44 (br dd, J=11.74, 7.43 Hz, 1 H) 4.67 (d, J=2.74 Hz, 2 H) 7.17 (dd, J=8.61, 2.74 Hz, 1 H) 7.43 (d, J=8.22 Hz, 2 H) 7.49 (d, J=8.22 Hz, 2 H) 7.56 (d, J=8.22 Hz, 2 H) 7.62 (d, J=8.61 Hz, 2 H) 8.20 (td, J=8.02, 2.74 Hz, 1 H) 8.36 (d, J=2.35 Hz, 1 H) 8.48 (br d, J=2.74 Hz, 1 H) 8.57 (d, J=1.96 Hz, 1 H); MS (ESI+) m/z 639.4 [M+H]⁺

Example 227. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((R)-1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 10, the title compound was obtained as described for the example 226. MS (ESI+) m/z 639.1 [M+H]+

Example 228. 6-amino-6'-fluoro-N-al S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 11, the title compound was obtained as described for the example 226. MS (ESI+) m/z 651.6 [M+H]⁺

Example 229. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(2-(4-(2-hydroxyethyl)-piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 12, the title compound was obtained as described for the example 226. MS (ESI+) m/z 653.4 [M+H]+

Example 230. 6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 230:

Intermediate 18.

Using (1S,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the intermediate 7. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.58 - 1.65 (m, 1 H) 1.74 - 1.85 (m, 3 H) 2.01 - 2.08 (m, 1 H) 2.12 - 2.18 (m, 1 H) 2.60 (s, 3 H) 3.41 - 3.48 (m, 1 H) 3.92 (q, J=5.87 Hz, 1 H) 4.45 - 4.55 (m, 2 H) 7.27 (d, J=8.22 Hz, 2 H) 7.43 - 7.50 (m, 3 H) 7.65 (d, J=8.22 Hz, 1 H) 7.73 (d, J=8.22 Hz, 1 H) 8.03 (d, J=8.22 Hz, 1 H); MS (ESI+) m/z 310.1 [M+H]⁺

Intermediate 19.

Using intermediate 18, the title compound was obtained as described for the intermediate 4. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.45 - 1.54 (m, 1 H) 1.71 - 1.82 (m, 2 H) 1.84 - 1.92 (m, 1 H) 1.92 - 2.02 (m, 1 H) 2.23 - 2.33 (m, 1 H) 2.63 (s, 3 H) 3.81 - 3.91 (m, 1 H) 4.29 - 4.44 (m, 1 H) 4.63 - 4.75 (m, 2 H) 5.90 (br d, J=6.46 Hz, 1 H) 6.35 (br s, 2 H) 7.44 (d, J=8.22 Hz, 2 H) 7.56 - 7.62 (m, 3 H) 7.66 (d, J=8.22 Hz, 2 H) 8.01 (d, J=8.22 Hz, 2 H) 8.15 (d, J=1.76 Hz, 1 H); MS (ESI+) m/z 508.1/510.2 [M+H]⁺

Intermediate 20.

To intermediate 19 (300 mg, 0.59 mmol) in 3 ml of THF was added 1-methylpiperazine (0.13 ml, 1.18 mmol) followed by Ti(OiPr)₄ (0.7 ml, 2.36 mmol). The mixture was stirred at 60 °C for 4 hr and then NaBH₃CN(0.11 g, 1.18 mmol) was added. The mixture was stirred for 1 h and extracted with EtOAc, washed with brine, dried over MgSO₄. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 200 mg of off-white solid. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.55 - 1.61 (m, 1 H) 1.64 (d, J=7.04 Hz, 3 H) 1.72 - 1.84 (m, 3 H) 1.97 - 2.05 (m, 1 H) 2.09 - 2.17 (m, 1 H) 2.88 (s, 3 H) 3.11 (br s, 2 H) 3.36 - 3.49 (m, 4 H) 3.95 (dt, J=6.75, 4.26 Hz, 1 H) 4.14 (br d, J=6.46 Hz, 1 H) 4.35 (td, J=7.34, 4.70 Hz, 1 H) 4.61 - 4.68 (m, 2 H) 7.42 (d, J=8.22 Hz, 2 H) 7.50 (d, J=8.22 Hz, 2 H) 7.57 (d, J=8.22 Hz, 2 H) 7.65 (d, J=8.22 Hz, 2 H) 8.13 (d, J=2.35 Hz, 1 H) 8.20 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 592.2/594.3 [M+H]⁺

Example 230. 6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 20 and 5-fluoropyridine-3-boronic acid, the title compound was obtained as described for the intermediate 14. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.54 (d, J=7.04 Hz, 3 H) 1.63 (br dd, J=13.21, 6.75 Hz, 1 H) 1.77 - 1.86 (m, 3 H) 2.04 (br dd, J=12.91, 7.04 Hz, 1 H) 2.16 - 2.23 (m, 1 H) 2.85 (s, 3 H) 3.88 (br d, J=7.04 Hz, 1 H) 3.97 - 4.03 (m, 1 H) 4.43 (br d, J=4.70 Hz, 1 H) 4.64 - 4.70 (m, 2 H) 7.42 (br dd, J=8.22, 4.11 Hz, 4 H) 7.53 (br d, J=8.22 Hz, 2 H) 7.56 (br d, J=8.22 Hz, 2 H) 7.96 (br d, J=9.39 Hz, 1 H) 8.42 (s, 1 H) 8.50 (d, J=2.35 Hz, 1 H) 8.56 (s, 1 H) 8.70 (br s, 1 H); MS (ESI+) m/z 609.3 [M+H]⁺

Example 231. 2-amino-5-chloro-N-((1S,2S)-2-((4'-((1-(4-methylpiperazin-1-yl)-ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-5-chloronicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60 (dt, J=13.60, 7.09 Hz, 1 H) 1.66 (d, J=6.65 Hz, 3 H) 1.73 - 1.87 (m, 3 H) 1.98 - 2.06 (m, 1 H) 2.10 - 2.20 (m, 1 H) 2.90 (s, 2 H) 3.15 (br s, 2 H) 3.45 (br s, 4 H) 3.96 (dt, J=6.65, 4.30 Hz, 1 H) 4.18 (q, J=6.65 Hz, 1 H) 4.37 (td, J=7.24, 4.30 Hz, 1 H) 4.61 - 4.71 (m, 2 H) 7.43 (m, J=8.22 Hz, 2 H) 7.52 (d, J=8.22 Hz, 2 H) 7.59 (d, J=8.22 Hz, 2 H) 7.67 (m, J=8.22 Hz, 2 H) 8.09 (d, J=2.74 Hz, 1 H) 8.14 (d, J=2.74 Hz, 1 H); MS (ESI+) m/z 548.3 [M+H]⁺

Example 232. 2-amino-5-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-5-fluoronicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20. MS (ESI, m/z): 532.3 [M+H]⁺

Example 233. 2-amino-5-cyano-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)-ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-5-cyanonicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20. MS (ESI, m/z): 539.3 [M+H]⁺

Example 234. 2-amino-6-chloro-N-((1S,2S)-2-((4'-((1-(4-methylpiperazin-1-yl)-ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-amino-6-chloronicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.56 (br dd, J=13.11, 7.24 Hz, 1 H) 1.66 (d, J=7.04 Hz, 3 H) 1.70 - 1.85 (m, 3 H) 2.01 (br dd, J=13.11, 6.46 Hz, 1 H) 2.07 - 2.19 (m, 2 H) 2.90 (s, 3 H) 3.09 - 3.21 (m, 2 H) 3.39 - 3.58 (m, 4 H) 3.87 - 3.96 (m, 1 H) 4.19 (br d, J=6.65 Hz, 1 H) 4.35 (br d, J=4.70 Hz, 1 H) 4.57 - 4.73 (m, 2 H) 6.56 (d, J=7.83 Hz, 1 H) 7.42 (m, J=8.22 Hz, 2 H) 7.52 (d, J=8.22 Hz, 2 H) 7.56 (d, J=8.22 Hz, 2 H) 7.66 (m, J=8.22 Hz, 2 H) 7.73 (d, J=8.22 Hz, 1 H) ; MS (ESI, m/z): 548.3 [M+H]⁺

Example 235. 2-amino-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 2-aminonicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.58 - 1.64 (m, 1 H) 1.66 (d, J=7.04 Hz, 3 H) 1.74 - 1.85 (m, 3 H) 1.97 - 2.05 (m, 1 H) 2.13 - 2.20 (m, 1 H) 2.89 (s, 3 H) 3.02 - 3.27 (m, 4 H) 3.46 (br s, 4 H) 3.93 - 4.00 (m, 1 H) 4.20 (q, J=6.46 Hz, 1 H) 4.35 - 4.42 (m, 1 H) 4.65 (s, 2 H) 6.95 (t, J=6.75 Hz, 1 H) 7.43 (d, J=8.22 Hz, 2 H) 7.52 (m, J=8.22 Hz, 2 H) 7.58 (m, J=8.22 Hz, 2 H) 7.67 (d, J=8.22 Hz, 2 H) 7.99 (dd, J=6.46, 1.17 Hz, 1 H) 8.33 (dd, J=7.34, 1.47 Hz, 1H); MS (ESI, m/z): 514.3 [M+H]⁺

Example 236. 6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Scheme for the preparation of the Compound of Example 236:

Intermediate 21. Using 1-(2-hydroxyethyl)piperazine, the title compound was obtained as described for the intermediate 20. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.42 (d, J=6.46 Hz, 2 H) 1.51 - 1.58 (m, 1 H) 1.71 - 1.81 (m, 3 H) 1.97 - 2.04 (m, 1 H) 2.08 - 2.15 (m, 1 H) 2.61 (br s, 2 H) 3.47 (br d, J=5.28 Hz, 1 H) 3.67 (t, J=5.87 Hz, 2 H) 3.91 (dt, J=6.46, 4.70 Hz, 1 H) 4.35 (td, J=7.34, 4.70 Hz, 1 H) 4.59 - 4.67 (m, 2 H) 7.37 (br d, J=8.22 Hz, 2 H) 7.39 (br d, J=8.22 Hz, 2 H) 7.54 (d, J=7.63 Hz, 4 H) 7.90 (d, J=2.35 Hz, 1 H) 8.05 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 622.2/624.2 [M+H]⁺

Example 236. 6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using intermediate 21, the title compound was obtained as described for the example 230. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.89, 6.85 Hz, 1 H) 1.72 (br d, J=6.65 Hz, 3 H) 1.76 - 1.87 (m, 3 H) 2.04 (br dd, J=12.72, 6.46 Hz, 1 H) 2.13 - 2.23 (m, 1 H) 3.52 - 3.68 (m, 4 H) 3.84 (br t, J=4.89 Hz, 2 H) 4.00 (br d, J=3.91 Hz, 1 H) 4.35 (br d, J=6.65 Hz, 1 H) 4.39 - 4.49 (m, 2 H) 4.61 - 4.73 (m, 2 H) 7.43 (br d, J=7.83 Hz, 2 H) 7.53 (br t, J=9.39 Hz, 4 H) 7.63 (br d, J=8.22 Hz, 2 H) 7.98 (br d, J=9.78 Hz, 1 H) 8.43 (s, 1 H) 8.52 (s, 1 H) 8.61 (s, 1 H) 8.71 (s, 1 H); MS (ESI+) m/z 639.3 [M+H]⁺

Example 237. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using 6-fluoropyridine-3-boronic acid, the title compound was obtained as described for the example 236.¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.30, 6.65 Hz, 1 H) 1.68 (br d, J=7.04 Hz, 3 H) 1.81 (br d, J=7.43 Hz, 3 H) 1.98 - 2.08 (m, 1 H) 2.12 - 2.23 (m, 1 H) 3.17 - 3.28 (m, 4 H) 3.53 (br s, 4 H) 3.84 (br d, J=4.30 Hz, 2 H) 3.99 (br s, 1 H) 4.25 (br d, J=7.04 Hz, 1 H) 4.42 (br d, J=4.70 Hz, 1 H) 4.62 - 4.72 (m, 2 H) 7.16 (br d, J=7.83 Hz, 1H) 7.42 (br d, J=7.83 Hz, 2 H) 7.47 - 7.59 (m, 4 H) 7.62 (br d, J=7.83 Hz, 2 H) 8.19 (br t, J=8.02 Hz, 1 H) 8.34 (s, 1 H) 8.47 (br s, 1 H) 8.56 (s, 1 H); MS (ESI+) m/z 639.3 [M+H]⁺

Example 238. 6-amino-2'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1'-biphenyl)-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using 2-fluoropyridine-3-boronic acid, the title compound was obtained as described for the example 236. MS (ESI+) m/z 639.3 [M+H]⁺

Example 239. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 239:

Intermediate 22.

Using 4-(4-(1-trifluoroacetylpiperidino)methyl)phenylboronic acid pinacol ester, the title compound was obtained as described for the example 134. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.39 - 1.48 (m, 2 H) 1.63 (br dd, J=13.50, 7.04 Hz, 1 H) 1.76 - 1.86 (m, 4 H) 1.86 - 1.95 (m, 3 H) 2.04 (br dd, J=13.21, 6.75 Hz, 1 H) 2.18 (br dd, J=13.50, 5.87 Hz, 1 H) 2.64 (br d, J=6.46 Hz, 2 H) 2.90 - 2.98 (m, 2 H) 3.33 (s, 3 H) 3.36 (br d, J=12.33 Hz, 3 H) 3.89 (s, 3 H) 3.97 - 4.03 (m, 1 H) 4.37 - 4.45 (m, 1 H) 4.63 - 4.70 (m, 2 H) 7.23 (br d, J=8.22 Hz, 2 H) 7.40 (d, J=8.22 Hz, 2 H) 7.48 (d, J=8.22 Hz, 2 H) 7.52 (d, J=8.22 Hz, 2 H) 7.85 (s, 1 H) 7.97 (s, 1 H) 8.19 (d, J=1.76 Hz, 1 H) 8.51 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 564.8 [M+H]⁺

Example 239. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using intermediate 22 and formaldehyde, the title compound was obtained as described for the example 214. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.42 - 1.54 (m, 2 H) 1.63 (br dd, J=13.50, 7.04 Hz, 1 H) 1.75 - 1.88 (m, 4 H) 1.92 (br d, J=14.67 Hz, 2 H) 2.00 - 2.08 (m, 1 H) 2.17 (br dd, J=13.50, 5.87 Hz, 1 H) 2.64 (br d, J=7.04 Hz, 2 H) 2.82 (s, 3 H) 2.89 - 2.98 (m, 2 H) 3.47 (br d, J=12.33 Hz, 2 H) 3.89 (s, 3 H) 3.94 - 4.05 (m, 1 H) 4.36 - 4.46 (m, 1 H) 4.61 - 4.69 (m, 2 H) 7.22 (d, J=8.22 Hz, 2 H) 7.39 (br d, J=8.22 Hz, 2 H) 7.47 (br d, J=8.22 Hz, 2 H) 7.51 (br d, J=8.22 Hz, 2 H) 7.84 (s, 1 H) 7.96 (s, 1 H) 8.18 (d, J=1.76 Hz, 1 H) 8.49 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 579.8 [M+H]⁺

Example 240. 2-amino-N-((1S,2S)-2-((4'-((1-(2-hydroxyethyl)piperidin-4-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Scheme for the preparation of the Compound of Example 240:

To a mixture of intermediate 22 (30 mg, 0.05 mmol) and K₂CO₃ (22 mg, 0.16 mmol) in 0.4 ml of DMF was added 2-bromoethanol (6 µl, 0.08 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 27 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.26 (br d, J=13.50 Hz, 2 H) 1.56 - 1.74 (m, 4 H) 1.74 - 1.89 (m, 4 H) 2.04 (br dd, J=13.21, 6.16 Hz, 1 H) 2.20 (br dd, J=13.50, 7.04 Hz, 1 H) 2.64 (br d, J=7.04 Hz, 2 H) 2.77 (br t, J=12.62 Hz, 2 H) 3.05 - 3.13 (m, 2 H) 3.47 (br d, J=12.33 Hz, 2 H) 3.75 - 3.81 (m, 2 H) 3.92 (s, 3 H) 4.01 - 4.07 (m, 1 H) 4.40 - 4.47 (m, 1 H) 4.62 - 4.72 (m, 2 H) 7.10 (br d, J=7.63 Hz, 1 H) 7.20 - 7.26 (m, 3 H) 7.27 - 7.33 (m, 2 H) 7.41 (br d, J=7.63 Hz, 2 H) 7.87 - 7.90 (m, 1 H) 7.88 (s, 1 H) 8.03 (s, 1 H) 8.23 (d, J=1.76 Hz, 1 H) 8.60 (br s, 1 H); MS (ESI, m/z): 609.8 [M+H]⁺

Example 241. methyl 2-(4-((4'-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)-[1,1'-biphenyl]-4-yl)methyl)piperidin-1-yl)-acetate

Using intermediate 22 and methyl bromoacetate, the title compound was obtained as described for the example 240. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.32 (br s, 2 H) 1.61 - 1.71 (m, 4 H) 1.79 - 1.89 (m, 4 H) 2.01 - 2.06 (m, 1 H) 2.20 (br dd, J=13.79, 6.75 Hz, 1 H) 2.66 (br s, 2 H) 2.85 (br s, 2 H) 3.49 (br s, 2 H) 3.79 (s, 3 H) 3.92 (s, 3 H) 4.01 (br s, 2 H) 4.02 - 4.06 (m, 1 H) 4.44 (br dd, J=11.15, 7.04 Hz, 1 H) 4.63 - 4.73 (m, 2 H) 7.11 (br d, J=7.63 Hz, 1 H) 7.23 - 7.30 (m, 4 H) 7.41 (br d, J=8.22 Hz, 2 H) 7.88 (s, 1 H) 8.02 - 8.04 (m, 1 H) 8.23 (d, J=1.76 Hz, 1 H) 8.60 (s, 1 H); MS (ESI, m/z): 637.7 [M+H]⁺

Example 242. 2-amino-N-((1S,2S)-2-((4'-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using intermediate 22 and bromoacetamide, the title compound was obtained as described for the example 240. MS (ESI, m/z): 622.8 [M+H]⁺

Example 243. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 243

Intermediate 23.

A mixture of intermediate 4 (300 mg, 0.64 mmol), Pd(dba)₂ (7 mg, 0.01 mmol), P(t-bu)₃ (8 mg, 0,04 mmol) in DMF (3 ml) was degassed with nitrogen and TEA (0.133 ml, 0.96 mmol), allyl alcohol (0.11 ml, 1.28 mmol) were added. The mixture was heated at 100°C for 1 h. After cooling, the mixture was partitioned between EA and water. The organic layer was separated and washed with water, brine dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with Et₂O-hexane mixtures as eluents to give 150 mg of off-white solid. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.21, 6.75 Hz, 1 H) 1.75 (br d, J=7.63 Hz, 1 H) 1.79 - 1.85 (m, 2 H) 1.94 - 2.04 (m, 3 H) 2.16 (br d, J=6.46 Hz, 1 H) 2.64 (br t, J=7.63 Hz, 2 H) 2.89 (s, 3 H) 3.02 - 3.07 (m, 2 H) 3.40 (br s, 2 H) 3.46 (br s, 4 H) 3.93 (s, 3 H) 3.96 - 4.00 (m, 1 H) 4.36 - 4.42 (m, 1 H) 4.54 - 4.65 (m, 3 H) 7.16 (d, J=8.22 Hz, 2 H) 7.27 (d, J=8.22 Hz, 2 H) 7.84 - 7.89 (m, 1 H) 8.03 (s, 1 H) 8.23 (d, J=1.76 Hz, 1 H) 8.56 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 532.5 [M+H]⁺

Example 243. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide

Using intermediate 23, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=13.21, 6.75 Hz, 1 H) 1.75 (br d, J=7.63 Hz, 1 H) 1.79 - 1.85 (m, 2 H) 1.94 - 2.04 (m, 3 H) 2.16 (br d, J=6.46 Hz, 1 H) 2.64 (br t, J=7.63 Hz, 2 H) 2.89 (s, 3 H) 3.02 - 3.07 (m, 2 H) 3.40 (br s, 2 H) 3.46 (br s, 4 H) 3.93 (s, 3 H) 3.96 - 4.00 (m, 1 H) 4.36 - 4.42 (m, 1 H) 4.54 - 4.65 (m, 3 H) 7.16 (d, J=8.22 Hz, 2 H) 7.27 (d, J=8.22 Hz, 2 H) 7.84 - 7.89 (m, 1 H) 8.03 (s, 1 H) 8.23 (d, J=1.76 Hz, 1 H) 8.56 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 532.4 [M+H]⁺

Example 244. 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using intermediate 23 and dimethylamine (50% in THF), the title compound was obtained as described for the example 243. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 - 1.68 (m, 1 H) 1.73 - 1.78 (m, 1 H) 1.80 - 1.83 (m, 3 H) 1.96 - 2.05 (m, 3 H) 2.17 (br d, J=6.46 Hz, 1 H) 2.65 (br t, J=7.63 Hz, 2 H) 2.84 (s, 6 H) 3.06 - 3.14 (m, 2 H) 3.94 (s, 3 H) 3.98 (br s, 1 H) 4.39 (br s, 1 H) 4.55 - 4.67 (m, 3 H) 7.18 (br d, J=7.63 Hz, 2 H) 7.29 (br d, J=7.63 Hz, 2 H) 7.87 - 7.89 (m, 1 H) 8.04 (s, 1 H) 8.23 (d, J=1.76 Hz, 1 H) 8.57 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 477.5 [M+H]⁺

Example 245. 2-amino-N-((1S,2S)-2-((4'-(2-(dimethvlamino)ethoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 245

Intermediate 24.

To a mixture of intermediate 4 (300 mg, 0.64 mmol) and (4-hydroxyphenyl)boronic acid (132 mg, 0.96 mmol) in 4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (264 mg, 1.91 mmol) followed by Pd(PPh₃)₄ (37 mg, 0.03 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. After concentration under vacuum, the crude material was purified by flash chromatography on silica gel with DCM-MeOH mixtures as eluents to give 250 mg of off-white solid. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.60 (br dd, J=13.21, 7.34 Hz, 1 H) 1.74 - 1.87 (m, 3 H) 2.04 (br dd, J=12.62, 7.34 Hz, 1 H) 2.10 - 2.20 (m, 1 H) 3.88 (s, 3 H) 3.92 - 4.00 (m, 1 H) 4.35 - 4.44 (m, 1 H) 4.57 (d, J=12.33 Hz, 1 H) 4.66 (d, J=12.33 Hz, 2 H) 6.78 (m, J=8.22 Hz, 2 H) 7.33 (t, J=9.10 Hz, 4 H) 7.43 (m, J=8.22 Hz, 2 H) 7.82 (s, 1 H) 7.91 (s, 1 H) 8.15 (d, J=2.35 Hz, 1 H) 8.43 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 484.3 [M+H]⁺

Example 245. 2-amino-N-((1S,2S)-2-((4'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

A mixture of intermediate 24 (30 mg, 0.06 mmol) and K₂CO₃ (43 mg, 0.31 mmol) was heated at 60 °C for 12 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound ¹H NMR (400 MHz, CD₃OD) δ ppm 1.57 - 1.68 (m, 1 H) 1.81 (br d, J= 7.83 Hz, 3 H) 2.01 (br d, J=19.56 Hz, 1 H) 2.16 (br d, J=12.91 Hz, 1 H) 2.99 (s, 6 H) 3.61 (br s, 2 H) 3.89 (s, 3 H) 3.99 (br s, 1 H) 4.37 (br d, J=3.52 Hz, 3 H) 4.64 (s, 2 H) 7.05 (br d, J=8.22 Hz, 2 H) 7.38 (br d, J= 7.83 Hz, 2 H) 7.50 (br t, J=7.43 Hz, 3 H) 7.84 (s, 1 H) 7.96 (s, 1 H) 8.19 (br s, 1 H) 8.48 (s, 1 H); MS (ESI, m/z): 555.4 [M+H]⁺

Example 246. 2-amino-N-((1S,2S)-2-((4'-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-chloropropyl)dimethylamine, title compound was obtained as described for the example 245. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1 H) 1.73 - 1.86 (m, 3 H) 2.04 (br dd, J=12.91, 7.63 Hz, 1 H) 2.16 (br dd, J=13.21, 6.16 Hz, 1 H) 2.19 - 2.28 (m, 2 H) 2.94 (s, 6 H) 3.32 - 3.41 (m, 2 H) 3.88 (s, 3 H) 3.93 - 4.05 (m, 1 H) 4.13 (t, J=5.87 Hz, 2 H) 4.36 - 4.43 (m, 1 H) 4.58 - 4.68 (m, 2 H) 6.97 (d, J=8.80 Hz, 2 H) 7.37 (d, J=8.22 Hz, 2 H) 7.46 (t, J=8.51 Hz, 4 H) 7.82 (s, 1 H) 7.93 (s, 1 H) 8.17 (d, J=2.35 Hz, 1 H) 8.43 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 569.4 [M+H]⁺

Example 247. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-ly)oxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-bromo-1-methylpiperidine, title compound was obtained as described for the example 245. MS (ESI, m/z): 581.5 [M+H]⁺

Example 248. 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)prop-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 248

A mixture of intermediate 4 (40 mg, 0.09 mmol), Pd(dba)₂ (1 mg, 2 mol %), P(t-bu)₃ (1 mg, 6 mol %) in DMF (3 ml) was degassed with nitrogen and TEA (0.018 ml, 0.13 mmol), N,N-dimethylpropargylamine (0.016 ml, 0.17 mmol) were added. The mixture was heated at 100 °C for 12 hrs. After cooling, the mixture was partitioned between EA and water. The organic layer was separated and washed with water, brine dried over MgSO₄ and concentrated in vacuo. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 10 mg of the title compound. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63 (s, 2 H) 1.78 (br dd, J=14.28, 6.85 Hz, 2 H) 1.99 (br dd, J=12.91, 6.65 Hz, 1 H) 2.09 - 2.18 (m, 1 H) 2.35 (s, 3 H) 3.12 - 3.18 (m, 1 H) 3.32 - 3.34 (m, 4 H) 3.42 - 3.50 (m, 2 H) 3.58 (br d, J=7.04 Hz, 1 H) 3.90 (s, 3 H) 4.32 - 4.42 (m, 1 H) 4.61 (s, 2 H) 7.27 - 7.40 (m, 4 H) 7.76 (s, 1 H) 7.87 (s, 1 H) 7.98 (s, 1 H) 8.24 (s, 1 H); MS (ESI, m/z): 473.4 [M+H]⁺

Example 249. 2-amino-N-((1S,2S)-2-((4-(4-hydroxybut-1-yn-1-yn-yl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-butyn-1-ol, title compound was obtained as described for the example 248. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1 H) 1.70 - 1.77 (m, 1 H) 1.77 - 1.84 (m, 3 H) 2.01 (br dd, J=12.62, 7.34 Hz, 1 H) 2.15 (br dd, J=13.21, 6.16 Hz, 1 H) 2.57 (t, J=6.75 Hz, 2 H) 3.69 (t, J=6.75 Hz, 2 H) 3.94 (s, 3 H) 4.32 - 4.40 (m, 1 H) 4.54 - 4.63 (m, 2 H) 7.23 - 7.31 (m, 4 H) 7.87 (s, 1 H) 8.01 (s, 1 H) 8.23 (d, J=2.35 Hz, 1 H) 8.50 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 460.6 [M+H]⁺

Example 250. 2-amino-N-((1S,2S)-2-((4-(5-hydroxypent-1-yn-1-yl)-benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 4-pentyn-1-ol, title compound was obtained as described for the example 248. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.62 (br dd, J=12.91, 7.04 Hz, 1 H) 1.69 - 1.78 (m, 3 H) 1.78 - 1.86 (m, 2 H) 2.01 (br dd, J=12.91, 7.63 Hz, 1 H) 2.16 (br d, J=5.87 Hz, 1 H) 2.45 (t, J=7.04 Hz, 2 H) 3.66 (t, J=6.46 Hz, 2 H) 3.88 - 4.00 (m, 4 H) 4.31 - 4.41 (m, 1 H) 4.51 - 4.65 (m, 2 H) 7.26 (s, 4 H) 7.87 (s, 1 H) 8.01 (s, 1 H) 8.23 (d, J=1.76 Hz, 1 H) 8.51 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 474.2 [M+H]⁺

Example 251. 2-amino-N-((1S,2S)-2-((4-(6-hydroxyhex-1-yn-1-yl)benzyl)oxy-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 5-hexyn-1-ol, title compound was obtained as described for the example 248. ¹H NMR (600 MHz, CD₃OD) δ ppm 0.00 - 0.00 (m, 1 H) 1.54 - 1.69 (m, 8 H) 1.72 - 1.78 (m, 1 H) 1.78 - 1.86 (m, 3 H) 1.91 (br d, J=7.63 Hz, 1 H) 1.97 - 2.05 (m, 1 H) 2.12 - 2.20 (m, 1 H) 2.24 - 2.30 (m, 2 H) 2.32 (br d, J=3.52 Hz, 1 H) 2.40 (t, J=7.04 Hz, 1 H) 2.45 (t, J=6.75 Hz, 1 H) 2.43 - 2.43 (m, 1 H) 3.55 (t, J=6.46 Hz, 2 H) 3.56 - 3.60 (m, 1 H) 3.94 (d, J=1.17 Hz, 3 H) 4.35 - 4.41 (m, 2 H) 4.43 (t, J=6.46 Hz, 1 H) 4.54 - 4.65 (m, 2 H) 4.68 - 4.68 (m, 1 H) 4.69 - 4.69 (m, 1 H) 7.26 (d, J=7.04 Hz, 3 H) 7.87 (s, 1 H) 8.01 (s, 1 H) 8.19 - 8.26 (m, 1 H) 8.48 - 8.53 (m, 1 H); MS (ESI, m/z): 488.3 [M+H]⁺

Example 252. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)benzyl)oxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 252

To a mixture of compound 249 (30 mg, 0.07 mmol) and triethylamine (27 µL, 0.2 mmol) in DCM (0.3 mL) was added methanesulfonyl chloride (12 µL, 0.16 mmol). The mixture was stirred at room temperature for 2 hrs. After completion of conversion, the volatile was removed under reduced pressure. The crude residue was diluted with EtOH (0.3 mL) and 1-methylpiperazine (16 µL, 0.13 mmol) was added. The mixture was refluxed for 2 hrs. After cooling, the crude residue was purified by preparative HPLC to afford 20 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.63 (br dd, J=13.21, 6.75 Hz, 1 H) 1.75 (br d, J=5.28 Hz, 1 H) 1.80 - 1.84 (m, 2 H) 1.98 - 2.02 (m, 1 H) 2.16 (br dd, J=13.79, 6.75 Hz, 1 H) 2.78 (br s, 2 H) 2.89 - 2.93 (m, 3 H) 3.44 (br s, 4 H) 3.55 (br s, 2 H) 3.94 (s, 3 H) 3.95 - 3.99 (m, 1 H) 4.38 (br dd, J=11.15, 7.04 Hz, 1 H) 4.60 (s, 2 H) 7.26 - 7.35 (m, 4 H) 7.88 (s, 1 H) 8.02 (s, 1 H) 8.23 (d, J=2.35 Hz, 1 H) 8.55 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 542.5 [M+H]⁺

Example 253. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Scheme for the preparation of the Compound of Example 253:

Intermediate 25.

To a mixture of intermediate 3 (300 mg, 1.38 mmol) and triethylamine (168 mg, 1.66 mmol) in 7 ml of DMF was added HATU (524 mg, 1.66 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine(263 mg, 1.38 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 326 mg of off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.47 (dt, J=13.99, 6.90 Hz, 1 H) 1.72 - 1.82 (m, 2 H) 1.83 - 1.92 (m, 1 H) 1.92 - 2.01 (m, 2 H) 2.22 - 2.34 (m, 1 H) 3.79 - 3.88 (m, 1 H) 4.32 (dd, J=7.04, 4.70 Hz, 1 H) 4.56 - 4.68 (m, 2 H) 5.81 (br d, J=6.65 Hz, 1 H) 6.35 (br s, 2 H) 7.26 - 7.38 (m, 4 H) 7.53 (d, J=2.35 Hz, 1 H) 8.17 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 390.2/392.2 [M+H]⁺

Example 253. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

To a mixture of intermediate 25 (40 mg, 0.1 mmol) and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester (51 mg, 0.16 mmol) in 1 ml of 1,4-dioxane was added 0.15 ml of aq. 2N K₃PO₄ followed by Pd(PPh₃)₄ (8 mg, 0.007 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. The crude residue was purified by preparative HPLC to afford 23 mg of the title compound. ¹H NMR (400 MHz, METHANOL-d ₄) δ ppm 1.57 (br dd, J=13.30, 7.04 Hz, 1 H) 1.66 - 1.87 (m, 3 H) 1.97 (dt, J=13.01, 6.60 Hz, 1 H) 2.13 (br dd, J=13.11, 6.85 Hz, 1 H) 2.95 (s, 3 H) 3.44 - 3.62 (m, 4 H) 3.87 - 3.97 (m, 1 H) 4.17 (s, 2 H) 4.31 - 4.39 (m, 1 H) 4.60 (s, 2 H) 6.25 (d, J= 9.00 Hz, 1 H) 7.21 - 7.35 (m, 5 H) 7.43 (d, J=8.22 Hz, 2 H) 7.58 (d, J=8.61 Hz, 2 H) 8.08 (d, J=9.00 Hz, 1 H); MS (ESI, m/z): 500.3 [M+H]⁺

Example 254. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 201. MS (ESI, m/z): 461.3 [M+H]⁺

Example 255. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-methylpipendin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 475.3 [M+H]⁺

Example 256. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-ethy1piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 489.3 [M+H]⁺

Example 257. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 503.3 [M+H]⁺

Example 258. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 544.3 [M+H]⁺

Example 259. 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1R,2R)-2-(benzyloxy)cyclopentan-1-amine and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 461.3 [M+H]⁺

Example 260. 2-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using (1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentan-1-amine and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 529.2 [M+H]⁺

Example 261. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymeth-yl)-1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 422.2 [M+H]⁺

Example 262. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 465.3 [M+H]⁺

Example 263. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 505.3 [M+H]⁺

Example 264. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)-nicotinamide

Using (4-cyanophenyl)boronic acid, the title compound was obtained as described for the example 253. ¹H NMR (400 MHz, CDCl₃) δ 1.59 (m, 2 H) 1.85 (m, 4 H) 2.10 (m, 2 H) 2.24 (m, 1 H) 4.17 (br d, J=7.04 Hz, 1 H) 4.28 (br d, J=7.04 Hz, 1 H) 4.43 - 4.54 (m, 1 H) 4.56 - 4.67 (m, 2 H) 7.13 - 7.19 (m, 1 H) 7.13 - 7.19 (m, 1 H) 7.13 - 7.19 (m, 2 H) 7.19 - 7.24 (m, 2 H) 7.35 (br d, J=7.43 Hz, 2 H) 7.64 (m, J=8.22 Hz, 2 H) 7.73 (m, J=8.22 Hz, 2 H) 7.80 (s, 1 H) 7.85 - 7.91 (m, 1 H) 8.27 (s, 1 H) 8.58 (br s, 2 H) 11.76 - 11.97 (m, 2 H); MS (ESI, m/z): 413.2 [M+H]⁺

Example 265. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophen-yl)-nicotinamide

Using (3-cyanophenyl)boronic acid, the title compound was obtained as described for the example 253. ¹H NMR (400 MHz, CDCl₃) 1.54 - 1.70 (m, 2 H) 1.70 - 1.95 (m, 4 H) 2.07 (br s, 2 H) 2.23 (br s, 2 H) 4.08 (br d, J=5.87 Hz, 1 H) 4.33 (br s, 1 H) 4.61 (q, J=11.74 Hz, 2 H) 7.14 - 7.20 (m, 1 H) 7.20 - 7.29 (m, 2 H) 7.29 - 7.38 (m, 2 H) 7.53 - 7.63 (m, 1 H) 7.70 (br d, J=7.43 Hz, 1 H) 7.75 (br d, J=7.43 Hz, 1 H) 7.87 (s, 1 H) 7.91 (s, 1 H) 8.26 (s, 1 H) 8.87 (br s, 2 H) 11.40 - 11.54 (m, 1 H); MS (ESI, m/z): 413.2 [M+H]⁺

Example 266. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)phenyl)nicotinamide

Using (4-(cyanomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. ¹H NMR (400 MHz, CDCl₃) 1.54 - 1.64 (m, 1 H) 1.70 (br s, 1 H) 1.83 (br s, 2 H) 1.97 - 2.05 (m, 2 H) 3.11 (br s, 1 H) 3.79 (s, 2 H) 4.35 (br s, 1 H) 4.64 (s, 2 H) 7.14 (br s, 1 H) 7.18 - 7.24 (m, 3 H) 7.39 (br t, J=7.83 Hz, 2 H) 7.55 (br d, J=7.83 Hz, 1 H) 7.59 (s, 1 H) 8.00 (br s, 1 H) 8.34 (s, 1 H) 8.55 - 8.67 (m, 1 H); MS (ESI, m/z): 427.2 [M+H]⁺

Example 267. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)nicotinamide

Using (4-phenoxyphenyl)boronic acid, the title compound was obtained as described for the example 253. ¹H NMR (400 MHz, CDCl₃) 1.23 (m, 2 H) 1.56 (m, 2 H) 1.75 (m, 4 H) 2.07 (br s, 2 H) 2.24 (br s, 2 H) 4.12 (br d, J=5.87 Hz, 1 H) 4.29 (br s, 1 H) 4.56 - 4.66 (m, 2 H) 7.04 (br t, J=6.85 Hz, 3 H) 7.17 (br d, J=7.43 Hz, 1 H) 7.22 - 7.26 (m, 4 H) 7.30 - 7.39 (m, 3 H) 7.39 - 7.44 (m, 2 H) 7.50 (s, 1 H) 7.74 (s, 1 H) 8.18 (s, 1 H) 8.45 (br s, 2 H) 11.28 (br s, 1 H); MS (ESI, m/z): 480.2 [M+H]⁺

Example 268. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

Using (3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 269. 6-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6'-(hydroxymethyl)-[3,3'-bipyridine]-5-carboxamide

Using (6-(hydroxymethyl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 420.2 [M+H]⁺

Example 270. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotiriamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 514.3 [M+H]⁺

Example 271. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-methylpiperazin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 272. 2-amino-N-((1S,2S)-2-((3-methybenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-(pyrrolidin-1-yl)piperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 582.3 [M+H]⁺

Example 273. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopent)yl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 514.3 [M+H]⁺

Example 274. 2-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methylpiperazine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 532.3 [M+H]⁺

Example 275. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 4-(pyrrolidin-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 568.4 [M+H]⁺

Example 276. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 277. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 582.3 [M+H]⁺

Example 278. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and N-(1-methylpiperidin-4-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide, the title compound was obtained as described for the example 253. MS (ESI, m/z): 556.3 [M+H]⁺

Example 279. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 2-(4-methylpiperazin-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 280. 2-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)-methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide

(1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(pyrrolidin-1-yl)piperidine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 586.4 [M+H]⁺

Example 281. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 611.4 [M+H]⁺

Example 282. 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 500.3 [M+H]⁺

Example 283. 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((4-methylbenzyl)oxy)cyclopentan-1-amine and (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 284. 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((4-methylbenzyl)oxy)cyclopentan-1-amine and (4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 582.3 [M+H]⁺

Example 285. 2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 434.3 [M+H]⁺

Example 286. 2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 434.3 [M+H]⁺

Example 287. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hidroxipropan-2-yl)-4-methylthiazol-5-yl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 495.2 [M+H]⁺

Example 288. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 523.2 [M+H]⁺

Example 289. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 290. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopenty)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-methylpiperazin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one, the title compound was obtained as described for the example 253. MS (ESI, m/z): 556.3 [M+H]⁺

Example 291. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopent)yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 515.3 [M+H]⁺

Example 292. 2-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-((dimethylamino)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 473.3 [M+H]⁺

Example 293. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 558.3 [M+H]⁺

Example 294. 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2'-methoxy-[3,3'-bipyridine]-5-carboxamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methoxypyridin-3-yl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 447.2 [M+H]⁺

Example 295. 2-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(dimethylamino)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 459.3 [M+H]⁺

Example 296. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-hydroxyphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 432.2 [M+H]⁺

Example 297. 2-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-aminophenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 431.2 [M+H]⁺

Example 298. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methylsulfonamido)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(methylsulfonamido)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 509.2 [M+H]⁺

Example 299. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 446.2 [M+H]⁺

Example 300. 2-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(aminomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 445.3 [M+H]⁺

Example 301. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxyroprophenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(3-hydroxypropyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 474.3 [M+H]⁺

Example 302. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (1r,4r)-4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)cyclohexan-1-ol, the title compound was obtained as described for the example 253 MS (ESI, m/z): 543.3 [M+H]⁺

Example 303. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 304. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (S)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 305. 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-borono-5-hydroxybenzoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 476.2 [M+H]⁺

Example 306. 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-2-methylbenzoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-borono-2-methylbenzoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 474.2 [M+H]⁺

Example 307. 2-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-aminophenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 431.2 [M+H]⁺

Example 308. 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-boronobenzoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 460.2 [M+H]⁺

Example 309. 3-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-amino-5-boronobenzoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 475.2 [M+H]⁺

Example 310. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 610.4 [M+H]⁺

Example 311. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-methylpiperazin-1-yl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 556.3 [M+H]⁺

Example 312. 2-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 611.4 [M+H]⁺

Example 313. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 446.2 [M+H]⁺

Example 314. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formylphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-formylphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 444.2 [M+H]⁺

Example 315. 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-boronobenzoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 460.2 [M+H]⁺

Example 316. 3-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)phenyl)propanoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-(4-boronophenyl)propanoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 488.3 [M+H]⁺

Example 317. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-hydroxyphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 432.22 [M+H]⁺

Example 318. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

Using (1S,2S)-2-(3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and N-(1-methylpiperidin-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, the title compound was obtained as described for the example 253. MS (ESI, m/z): 556.3 [M+H]⁺

Example 319. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(dimethylcarbamoyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 487.3 [M+H]⁺

Example 320. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 321. 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6'-(hydroxymethyl)-[3,3'-bipyridine]-5-carboxamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (6-(hydroxymethyl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 447.2 [M+H]⁺

Example 322. 2-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 2-amino-4-boronobenzoic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 475.2 [M+H]⁺

Example 323. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 476.3 [M+H]⁺

Example 324. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-fluoro-4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 464.2 [M+H]⁺

Example 325. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(pyrrolidin-1-yl)piperidine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 600.4 [M+H]⁺

Example 326. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(1-hydroxyethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 460.3 [M+H]⁺

Example 327. 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 328. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 529.3 [M+H]⁺

Example 329. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(1-methylpiperidin-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanamine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 556.4 [M+H]⁺

Example 330. 2-amino-N-((1S,2S)-2-(3,4-d:methylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 610.4 [M+H]⁺

Example 331. 2-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253. MS (ESI, m/z): 611.4 [M+H]⁺

Example 332. 2-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 2-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline, the title compound was obtained as described for the example 253. MS (ESI, m/z): 597.4 [M+H]⁺

Example 333. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 460.3 [M+H]⁺

Example 334. 2-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-chlorophenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 450 [M+H]⁺

Example 335. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and m-tolylboronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 430.2 [M+H]⁺

Example 336. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3,5-dimethylphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 444.3 [M+H]⁺

Example 337. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-yl)morpholine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 584.4 [M+H]⁺

Example 338. 2-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 339. 2-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 528.3 [M+H]⁺

Example 340. 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 514.3 [M+H]⁺

Example 341. 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 532.3 [M+H]⁺

Example 342. 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3,5-difluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 550.3 [M+H]⁺

Example 343. 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 344. 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-N,N-dimethylpyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 572.4 [M+H]⁺

Example 345. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidin-3-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 501.3 [M+H]⁺

Example 346. 2-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (R)-N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 347. 2-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (S)-N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 542.3 [M+H]⁺

Example 348. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 515.3 [M+H]⁺

Example 349. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 515.3 [M+H]⁺

Example 350. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 529.3 [M+H]⁺

Example 351. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-hydroxyphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 432.2 [M+H]⁺

Example 352. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-hydroxy-3-methoxyphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 462.23 [M+H]⁺

Example 353. 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3,4-dimethoxyphenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 476.3 [M+H]⁺

Example 354. 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(pyrrolidin-1-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 485.3 [M+H]⁺

Example 355. 2-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 435.2 [M+H]⁺

Example 356. 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and (4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253. MS (ESI, m/z): 460.3 [M+H]⁺

Example 357. 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253. MS (ESI, m/z): 556.4 [M+H]⁺

Example 358. 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol, the title compound was obtained as described for the example 253. MS (ESI, m/z): 529.3 [M+H]⁺

Example 359. 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperazine, the title compound was obtained as described for the example 253. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.11 (t, J=7.63 Hz, 3 H) 1.50 (s, 6 H) 1.58 - 1.67 (m, 1 H) 1.70 - 1.88 (m, 3 H) 1.98 - 2.06 (m, 1 H) 2.10-2.17 (m, 1H) 2.17 (s, 3 H) 2.49 - 2.57 (q, J=7.63 Hz, 2 H) 2.84 (br s, 4 H) 3.24 (t, J=4.70 Hz, 4 H) 3.91 - 4.00 (m, 1 H) 4.40 (br d, J=4.70 Hz, 1 H) 4.49 - 4.61 (m, 2 H) 6.98 - 7.05 (m, 2 H) 7.09 (s, 1 H) 7.64 - 7.80 (m, 4 H) 8.31 (d, J=2.35 Hz, 1 H) 8.57 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 556.4 [M+H]⁺

Example 360. 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamide

Using (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and 2-(4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 253. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.11 (t, J=7.43 Hz, 3 H) 1.57 (s, 3 H) 1.61-1.64 (m, 1H) 1.64 (s, 3 H) 1.69 - 1.89 (m, 3 H) 2.01 (br dd, J=13.11, 6.06 Hz, 1 H) 2.10 - 2.29 (m, 4 H) 2.53 (q, J=7.56 Hz, 2 H) 2.88 - 3.13 (m, 4 H) 3.22 - 3.28 (m, 1 H) 3.33 - 3.39 (m, 2 H) 3.43 (br s, 2 H) 3.83 - 3.90 (m, 1 H) 3.92 - 4.00 (m, 1 H) 4.35 - 4.45 (m, 1 H) 4.47 - 4.62 (m, 2 H) 6.95 - 7.07 (m, 2 H) 7.09 (s, 1 H) 7.65 - 7.84 (m, 4 H) 8.29 - 8.36 (m, 1 H) 8.56 - 8.64 (m, 1 H); MS (ESI, m/z): 600.3 [M+H]⁺

Example 361. 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide

Using 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-bromopyrazine-2-carboxamide and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 462.3 [M+H]⁺

Example 362. (S)-3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide

Using (S)-3-amino-6-bromo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253. MS (ESI, m/z): 418.2 [M+H]⁺

Example 363. 2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Scheme for the preparation of the Compound of Example 363:

Intermediate 26.

To a solution of trans-(1S,2S)-2-Aminocyclopentanol hydrochloride (8.0 mmol) in DMF (5 ml) was added 1M potassium tert-butoxide in THF (20 ml) at room temperature. The mixture was allowed to stir for 30 min. After being allowed to stir for 30 min, 4-bromobenzyl bromide (9.6 mmol) was added to the mixture, and then allowed to stir for additional 2 h at room temperature. The reaction mixture was then quenched with water and extracted with EtOAc. The separated organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The concentrated residue was used in the next step without further purification. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.29 - 1.35 (m, 1 H) 1.57 - 1.65 (m, 1 H) 1.65 - 1.77 (m, 2 H) 1.96 (br dd, J=12.62, 6.75 Hz, 2 H) 3.20 - 3.27 (m, 1 H) 3.51 (br d, J=5.28 Hz, 1 H) 4.40 - 4.46 (m, 1 H) 4.46 - 4.54 (m, 1 H) 7.21 (br t, J=7.63 Hz, 2 H) 7.40 - 7.48 (m, 2 H); MS (ESI+) m/z 270 [M+H]⁺

Intermediate 27.

To a solution of intermediate 26 (0.851 mmol) in 1,4-dioxane (4 ml) and water (1 ml) was added 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (0.851 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0851 mmol) and potassium carbonate (0.851 mmol). The mixture was heated to 100 °C and allowed to stir for overnight. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The separated organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The concentrated residue was purified by flash column chromatography to afford the desired compound (265 mg, 0.7 mmol). ¹H NMR (600 MHz, CD₃OD) δ ppm 1.36 - 1.45 (m, 1 H) 1.63 - 1.78 (m, 3 H) 1.97 - 2.07 (m, 2 H) 2.26 (s, 3 H) 2.30 - 2.71 (br s, 8 H) 3.24 (td, J=7.48, 4.99 Hz, 1 H) 3.55 (s, 2 H) 3.67 - 3.74 (m, 1 H) 4.53 (d, J=11.74 Hz, 1 H) 4.60 (d, J=11.74 Hz, 1 H) 7.38 (d, J=8.22 Hz, 2 H) 7.42 (d, J=8.22 Hz, 2 H) 7.55 - 7.58 (m, 2 H) 7.58 - 7.61 (m, 2 H); MS (ESI+) m/z 380 [M+H]⁺

Intermediate 28.

To a solution of intermediate 27 (0.685 mmol) and 2-amino-5-bromonicotinic acid (0.685 mmol) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (3.425 mmol) and HATU (1.027 mmol) at room temperature. The reaction mixture was allowed to stir for overnight, concentrated in vacuo, diluted with EtOAc and washed with brine. The separated organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The concentrated residue was purified by flash column chromatography to afford the desired compound (0.653 mmol) as a pale yellow oil. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.49 - 1.57 (m, 1 H) 1.68 - 1.78 (m, 3 H) 1.95 - 2.01 (m, 1 H) 2.07 - 2.13 (m, 1 H) 2.41 (s, 3 H) 2.49 - 2.79 (br s, 8 H) 3.56 (s, 2 H) 3.91 (dt, J=6.90, 4.48 Hz, 1 H) 4.34 (td, J=7.48, 4.40 Hz, 1 H) 4.57 - 4.65 (m, 2 H) 7.35 (br d, J=8.22 Hz, 2 H) 7.37 (br d, J=8.22 Hz, 2 H) 7.52 (d, J=7.63 Hz, 4 H) 7.90 (d, J=2.35 Hz, 1 H) 8.04 (d, J=2.35 Hz, 1 H); MS (ESI+) m/z 579 [M+H]⁺

Example 363. 2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

To a solution of intermediate 28 (0.076 mmol) in 1,4-dioxane (4 ml) and water (1 ml) was added (4-fluorophenyl)boronic acid (0.076 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0076 mmol) and potassium carbonate (0.076 mmol). The mixture was heated to 100 °C and allowed to stir for overnight. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The separated organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The concentrated residue was purified by preparative HPLC to afford the compound of Example 363. ¹H NMR (400MHz, CD₃OD) δ 8.57 (s, 1H), 8.23 (s, 1H), 7.64-7.47 (m, 8H), 7.42 (d, 2H), 7.17 (t, 2H), 4.66 (qd, 2H), 4.45-4.39 (m, 1H), 4.25 (s, 1H), 4.09-3.90 (m, 1H), 3.62 (s, 1H), 3.53 (br s, 2H), 3.39 (br s, 2H), 2.94 (s, 3H), 2.19-2.12 (m, 1H), 2.05-1.97 (m, 1H), 1.83-1.75 (m, 3H), 1.66-1.57 (m, 1H); MS (ESI+) m/z 594 [M+H]⁺

Example 364. 2-amino-5-(3,4-difluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 3,4-difluorophenylboronic acid, the title compound was obtained as described for the example 363.¹H NMR (400MHz, CD₃OD) δ 8.54 (s, 1H), 8.26 (s, 1H), 7.71-7.52 (m, 8H), 7.42-7.33 (m, 3H), 4.65 (qd, 2H), 4.41 (m, 1H), 4.32 (s, 2H), 3.98 (m, 1H), 3.57 (br s, 2H), 3.48 (br s, 2H), 2.94 (s, 3H), 2.18-2.05 (m, 1H), 2.04-1.99 (m, 1H), 1.81-1.73 (m, 3H), 1.66-1.59 (m, 1H); MS (ESI+) m/z 612 [M+H]⁺

Example 365. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide

Using 4-trifluoromethylphenylboronic acid, the title compound was obtained as described for the example 363. ¹H NMR (400MHz, CD₃OD) δ 8.65 (s, 1H), 8.36 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 12.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.54-7.50 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H), 4.69-4.62 (qd, 2H), 4.44-4.39 (m, 1H), 4.27 (s, 2H), 4.02-4.00 (m, 1H), 3.54 (br s, 2H), 3.42 (br s, 2H), 2.94 (s, 3H), 2.21-2.05 (m, 1H), 2.05-1.97 (m, 1H), 1.87-1.76 (m, 3H), 1.68-1.59 (m, 1H); MS (ESI+) m/z 644 [M+H]⁺

Example 366. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-methyl-4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine, the title compound was obtained as described for the example 363. ¹H NMR (400MHz, CD₃OD) δ 8.57 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.57-7.50 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H), 4.59-4.53 (m, 1H), 4.43-4.38 (m, 1H), 4.25 (s, 2H), 4.12-4.01 (m, 2H), 3.69-3.66 (d, 2H), 3.53 (br s, 2H), 3.39 (br s, 2H), 3.25-3.20 (m, 1H), 2.93 (s, 3H), 2.92 (s, 3H), 2.41-2.33 (m, 4H), 2.19-1.97 (m, 2H), 1.84-1.76 (m, 3H), 1.69-1.60 (m, 1H); MS (ESI+) m/z 663 [M+H]⁺

Example 367. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide

Using 4-(4-Methylpiperazin-1-yl)phenylboronic acid, the title compound was obtained as described for the example 363. ¹H NMR (400MHz, CD₃OD) δ 8.59 (s, 1H), 8.18 (s, 1H), 7.64-7.50 (m, 8H), 7.43 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H), 4.43-4.39 (m, 1H), 4.25 (s, 2H), 4.03-4.00 (m, 1H), 3.92 (d, J = 1.2 Hz, 2H), 3.62 (d, J = 1.2 Hz, 2H), 3.52 (br s, 2H), 3.39 (br s, 2H), 3.26-3.20 (m, 2H), 3.12-3.06 (m, 2H), 2.96 (s, 3H), 2.93 (s, 3H), 2.18-2.13 (m, 1H), 2.05-1.92 (m, 1H), 1.83-1.76 (m, 3H), 1.66-1.59 (m, 1H); MS (ESI+) m/z 674 [M+H]⁺

Example 368. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid, the title compound was obtained as described for the example 363. ¹H NMR (400MHz, CD₃OD) δ 8.66 (s, 1H), 8.29 (s, 1H). 7.73 (d, J = 8.0 Hz, 2H), 7.65-7.52 (m, 8H), 7.43 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H), 4.42 (m, 1H), 4.31 (s, 2H), 4.21 (s, 2H), 4.02 (m, 1H), 3.53 (br, 8H), 3.46 (br, 4H), 3.29 (br, 4H), 2.94 (s, 3H), 2.93 (s, 3H), 2.23-2.10 (m, 1H), 2.04-1.98 (m, 1H), 1.88-1.75 (m, 3H), 1.67-1.60 (m, 1H); MS (ESI+) m/z 688 [M+H]⁺

Example 369. 2-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopent-yl)nicotinamide

Using 4-(Hydroxymethyl)phenylboronic acid, the title compound was obtained as described for the example 363.¹H NMR (400MHz, CD₃OD) δ 8.63 (s, 1H), 8.26 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61-7.53 (m, 5H), 7.46-7.41 (m, 6H), 4.66 (s, 2H), 4.64 (s, 2H), 4.42 (m, 1H), 3.99 (m, 1H), 3.91 (s, 2H), 3.35 (br s, 2H), 3.00 (br s, 2H), 2.88 (s, 3H), 2.22-2.10 (m, 1H), 2.04 (m, 1H), 1.85-1.74 (m, 3H), 1.63 (m, 1H); MS (ESI+) m/z 606 [M+H]⁺

Example 370. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide

Using 3-tolylboronic acid, the title compound was obtained as described for the example 363. ¹H NMR (400MHz, CD₃OD) δ 8.62 (s, 1H), 8.23 (s, 1H), 7.72-7.32 (m, 11H), 7.24 (d, J = 8.0 Hz, 1H), 4.66 (s, 2H), 4.41 (m, 1H), 4.06 (s, 2H), 4.00 (m, 1H), 3.43 (br s, 2H), 3.17 (br s, 2H), 2.90 (s, 3H), 2.39 (s, 3H), 2.18 (m, 1H), 2.04 (m, 1H), 1.89-1.75 (m, 3H), 1,65-1.60 (m, 1H); MS (ESI+) m/z 590 [M+H]⁺

Example 371. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide

Using phenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 576 [M+H]⁺

Example 372. 2-amino-5-(4-hydroxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-hydroxyphenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 592 [M+H]⁺

Example 373. 2-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopent-yl)nicotinamide

Using 4-chloro-3-fluorophenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 629 [M+H]⁺

Example 374. 2-amino-5-methyl-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using trimethylboroxine, the title compound was obtained as described for the example 363. MS (ESI+) m/z 514 [M+H]⁺

Example375. 6-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using 3-pyridylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 577 [M+H]⁺

Example 376. 2-amino-5-(4-methoxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 4-methoxyphenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 606 [M+H]⁺

Example 377. 6-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4'-bipyridine]-5-carboxamide

Using 4-pyridylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 577 [M+H]⁺

Example 378. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-nicotinamide

Using (4-((4-methylpiperidin-1-yl)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 687 [M+H]⁺

Example 379. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide

Using (4-(morpholinomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 675 [M+H]⁺

Example 380. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-(Tetrahydro-pyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester, the title compound was obtained as described for the example 363. MS (ESI+) m/z 650 [M+H]⁺

Example 381. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamide

Using 4-morpholinophenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 661 [M+H]⁺

Example 382. 2-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 1-cyclohexenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 580 [M+H]⁺

Example383. 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide

Using 3,4-dimethoxyphenylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 636 [M+H]⁺

Example384. 6-amino-2',6'-difluoro-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4'-bipyridine]-5-carboxamide

Using 2,6-difluoropyridine-4-boronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 613 [M+H]⁺

Example 385. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide

Using 4-Methyl-3-thienylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 596 [M+H]⁺

Example 386. 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide

Using 6-fluoro-3-pyridinylboronic acid, the title compound was obtained as described for the example 363. MS (ESI+) m/z 595 [M+H]⁺

Example 387. 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)nicotinamide

Using (1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)boronic acid, the title compound was obtained as described for the example 363. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.64 (br dd, J=14.09, 7.04 Hz, 1 H) 1.75 - 1.88 (m, 3 H) 2.04 (br dd, J=12.33, 7.63 Hz, 1 H) 2.15 - 2.23 (m, 1 H) 2.87 (s, 3 H) 2.90 - 3.06 (m, 4 H) 3.33 (br s, 4 H) 3.86 (s, 2 H) 3.98 - 4.04 (m, 1 H) 4.39 - 4.44 (m, 1 H) 4.62 - 4.69 (m, 2 H) 6.75 - 6.98 (m, 1 H) 7.39 - 7.45 (m, 4 H) 7.55 (br d, J=8.22 Hz, 2 H) 7.57 (br d, J=8.22 Hz, 2 H) 8.20 (s, 1 H) 8.33 (d, J=1.76 Hz, 1 H) 8.58 (d, J=1.76 Hz, 1 H) 8.60 (s, 1 H); MS (ESI+) m/z 666.3 [M+H]⁺

Example 388. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 388:

Intermediate 29.

To a mixture of intermediate 3 (420 mg, 1.94 mmol) and triethylamine (0.40 ml, 2.90 mmol) in 10 ml of DMF was added HATU (884 mg, 2.32 mmol) followed by tert-butyl (3S,4S)-3-amino-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidine-1-carboxylate (647 mg, 1.94 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 800 mg of off-white solid. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.14 - 1.22 (t, 3 H) 1.41 (br s, 9 H) 2.27 (s, 3 H) 2.55 - 2.64 (q, 2 H) 3.37 - 3.66 (m, 4 H) 3.78 (dd, J=12.03, 5.58 Hz, 1 H) 4.10 (br s, 1 H) 4.50 - 4.79 (m, 2 H) 6.74 (br s, 2 H) 7.04 - 7.15 (m, 3 H) 7.98 (d, J=1.76 Hz, 1 H) 8.43 (br s, 1 H); MS (ESI, m/z): 534.3 [M+H]⁺

Example 388. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

To a mixture of intermediate 29 (40 mg, 0.07 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (23 mg, 0.11 mmol) in 0.4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (31 mg, 0.22 mmol) followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. The crude residue was dissolved with 0.5 ml of CH₂Cl₂ / TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 23 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) ppm 1.13 (t, J=7.34 Hz, 3 H) 2.23 (s, 2 H) 2.57 (q, J=7.24 Hz, 2 H) 2.91 (dd, J=12.03, 4.40 Hz, 1 H) 2.97 - 3.04 (m, 1 H) 3.16 - 3.22 (m, 1 H) 3.36 - 3.43 (m, 1 H) 3.91 (s, 3 H) 4.05 - 4.10 (m, 1 H) 4.48 (br s, 1 H) 4.57 (d, J=11.74 Hz, 1 H) 4.65 (d, J=11.74 Hz, 1 H) 7.06 (s, 2 H) 7.12 (s, 1 H) 7.76 (s, 1 H) 7.89 (s, 1 H) 8.02 (d, J=2.35 Hz, 1 H) 8.26 (d, J=2.35 Hz, 1 H), MS (ESI, m/z): 435.5 [M+H]⁺

Example 389. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamide

Using 4-hydroxymethylphenylboronic acid, the title compound was obtained as described for the example 388. MS (ESI, m/z): 461.6 [M+H]⁺

Example390. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide

Using (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 388. MS (ESI, m/z): 543.4 [M+H]⁺

Example 391. 2-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using (4-carbamoylphenyl)boronic acid, the title compound was obtained as described for the example 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.19 - 2.19 (m, 1 H) 2.60 (q, J=7.70 Hz, 2 H) 3.33 - 3.35 (m, 1 H) 3.43 - 3.64 (m, 2 H) 3.77 (br dd, J=12.72, 7.24 Hz, 1 H) 4.36 (br s, 1 H) 4.55 - 4.73 (m, 3 H) 7.10 (s, 2 H) 7.17 (s, 1 H) 7.78 (d, J=8.22 Hz, 2 H) 7.99 (d, J=8.61 Hz, 2 H) 8.44 (d, J=2.35 Hz, 1 H) 8.62 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 474.5 [M+H]⁺

Example 392. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamide

Using m-tolylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.43 Hz, 3 H) 2.25 (s, 3 H) 2.41 (s, 3 H) 2.60 (q, J=7.56 Hz, 2 H) 3.43 - 3.65 (m, 3 H) 3.77 (dd, J=12.52, 7.04 Hz, 1 H) 4.35 (br d, J=4.30 Hz, 1 H) 4.62 - 4.74 (m, 3 H) 7.09 (s, 2 H) 7.16 (s, 1 H) 7.25 (br d, J=7.43 Hz, 1 H) 7.36 (t, J=7.63 Hz, 1 H) 7.42 - 7.51 (m, 2 H) 8.31 (d, J=1.96 Hz, 1 H) 8.65 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 445.3 [M+H]⁺

Example 393. 4-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoic acid

Using 4-carboxyphenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.43 Hz, 3 H) 2.23 (s, 3 H) 2.59 (q, J=7.56 Hz, 2 H) 3.34 - 3.51 (m, 2 H) 3.52 - 3.67 (m, 1 H) 3.76 (br d, J=7.43 Hz, 1 H) 4.13 (br s, 1 H) 4.57 - 4.69 (m, 3 H) 7.02 - 7.10 (m, 2 H) 7.14 (s, 1 H) 7.79 (br d, J=8.22 Hz, 2 H) 8.13 (br d, J=8.22 Hz, 2 H) 8.37 - 8.45 (m, 1 H) 8.73 (d, J=1.56 Hz, 1 H); MS (ESI, m/z): 475.4 [M+H]⁺

Example 394. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamide

Using phenylboronic acid, the title compound was obtained as described for the example 388.¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.43 Hz, 2 H) 3.42 - 3.51 (m, 1 H) 3.51 - 3.65 (m, 2 H) 3.77 (dd, J=12.91, 7.04 Hz, 1 H) 4.35 (br d, J=4.30 Hz, 1 H) 4.57 - 4.76 (m, 3 H) 7.06 - 7.13 (m, 2 H) 7.17 (s, 1 H) 7.35 - 7.58 (m, 3 H) 7.68 (d, J=7.04 Hz, 2 H) 8.33 (d, J=2.35 Hz, 1 H) 8.74 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 431.5 [M+H]⁺

Example 395. 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4'-bipyridine]-5-carboxamide

Using pyridine-4-boronic acid, the title compound was obtained as described for the example 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.63 Hz, 3 H) 2.26 (s, 3 H) 2.62 (q, J=7.56 Hz, 2 H) 3.47 (br d, J=12.52 Hz, 1 H) 3.52 - 3.67 (m, 2 H) 3.77 (br dd, J=12.72, 6.85 Hz, 1 H) 4.34 (br d, J=3.91 Hz, 1 H) 4.61 - 4.78 (m, 3 H) 7.07 - 7.13 (m, 2 H) 7.13 - 7.19 (m, 1 H) 7.99 (dd, J=8.02, 5.67 Hz, 1 H) 8.56 (d, J=1.96 Hz, 1 H) 8.68 - 8.82 (m, 3 H) 9.14 (s, 1 H); MS (ESI, m/z): 432.3 [M+H]⁺

Example 396. 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3'-b]pyridine]-5-carboxamide

Using pyridine-3-boronic acid, the title compound was obtained as described for the example 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.63 Hz, 3 H) 2.26 (s, 3 H) 2.62 (q, J=7.56 Hz, 2 H) 3.47 (br d, J=12.52 Hz, 1 H) 3.52 - 3.67 (m, 2 H) 3.77 (br dd, J=12.72, 6.85 Hz, 1 H) 4.34 (br d, J=3.91 Hz, 1 H) 4.60 - 4.78 (m, 3 H) 7.07 - 7.13 (m, 2 H) 7.17 (d, J=7.06 Hz, 1 H) 7.18 (s, 1 H) 7.99 (dd, J=8.02, 5.67 Hz, 1 H) 8.56 (d, J=1.96 Hz, 1 H) 8.67 - 8.83 (m, 3 H) 9.14 (s, 1 H); MS (ESI, m/z): 432.3 [M+H]⁺

Example 397. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamide

Using potassium vinyltrifluoroborate, the title compound was obtained as described for the example 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.43 Hz, 3 H) 2.26 (s, 3 H) 2.61 (q, J=7.56 Hz, 2 H) 3.44 - 3.65 (m, 3 H) 3.76 (br dd, J=12.91, 7.04 Hz, 1 H) 4.33 (br d, J=3.91 Hz, 1 H) 4.59 - 4.74 (m, 3 H) 5.42 (d, J=10.96 Hz, 1 H) 5.94 (d, J=17.61 Hz, 1 H) 6.66 (dd,J=17.80, 11.15 Hz, 1 H) 7.10 (s, 2 H) 7.16 (s, 1 H) 8.02 - 8.08 (m, 1 H) 8.66 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 381.3 [M+H]⁺

Example 398. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamide

Using 4-fluorophenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.60 (q, J=7.63 Hz, 2 H) 3.44 - 3.59 (m, 2 H) 3.76 (dd, J=12.62, 7.34 Hz, 2 H) 4.25 - 4.38 (m, 1 H) 4.61 - 4.71 (m, 3 H) 7.03 - 7.12 (m, 2 H) 7.14 - 7.24 (m, 3 H) 7.60 - 7.69 (m, 2 H) 8.32 (d, J=2.35 Hz, 1 H) 8.48 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 499.3 [M+H]⁺

Example 399. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamide

Using 4-formylphenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.30 (t, J=7.63 Hz, 3 H) 2.26 (br s, 3 H) 2.58 (q, J=7.63 Hz, 2 H), 3.43 - 3.49 (m, 1 H) 3.50 - 3.65 (m, 2 H) 3.77 (dd, J=12.62, 6.75 Hz, 1 H), 4.17 (br s, 1 H) 4.64 (br s, 2 H) 4.77 (br s, 1 H) 6.59 (br s, 2 H) 7.05 - 7.20 (m, 3 H) 7.55 - 7.73 (m, 2 H) 7.86 (br d, J=5.28 Hz, 2 H) 8.04 (br s, 1 H) 8.46 (br s, 1 H) 9.86 (br s, 1 H); MS (ESI, m/z): 459.5 [M+H]⁺

Example 400. 2-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-cyanophenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.34 Hz, 3 H) 2.25 (s, 3 H) 2.60 (q, J=7.63 Hz, 2 H) 3.43 - 3.49 (m, 1 H) 3.50 - 3.65 (m, 2 H) 3.77 (dd, J=12.62, 6.75 Hz, 1 H) 4.35 (br d, J=4.11 Hz, 1 H) 4.62 - 4.74 (m, 3 H) 7.04 - 7.14 (m, 2 H) 7.16 (s, 1 H) 7.78 - 7.84 (m, 2 H) 7.84 - 7.88 (m, 2 H) 8.39 - 8.52 (m, 1 H) 8.59 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 456.3 [M+H]⁺

Example 401. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamide

Using 4-methylsulfonylphenylboronic acid, the title compound was obtained as described for the example 388.¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.34 Hz, 3 H) 2.25 (s, 3 H) 2.60 (q, J=7.63 Hz, 2 H) 2.98 (s, 3 H) 3.43 - 3.49 (m, 1 H) 3.50 - 3.65 (m, 2 H) 3.76 (dd, J=12.62, 7.34 Hz, 1 H) 4.33 - 4.38 (m, 1 H) 4.62 - 4.71 (m, 3 H) 7.05 - 7.13 (m, 2 H) 7.16 (s, 1 H) 7.36 (d, J=8.80 Hz, 2 H) 7.65 (d, J=8.22 Hz, 2 H) 8.32 (d, J=1.76 Hz, 1 H) 8.59 (d, J=1.76 Hz, 1 H); MS (ESI, m/z):524.6 [M+H]⁺

Example 402. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamide

Using 4-phenoxyphenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.56 - 2.65 (m, 2 H) 3.46 (br d, J=12.33 Hz, 1 H) 3.52 - 3.61 (m, 2 H) 3.76 (s, 1 H) 4.32 - 4.40 (m, 1 H) 4.62 - 4.73 (m, 3 H) 7.02 (d, J=7.63 Hz, 2 H) 7.04 - 7.12 (m, 4 H) 7.13 - 7.19 (m, 2 H) 7.38 (t, J=7.92 Hz, 2 H) 7.66 (d, J=8.80 Hz, 2 H) 8.29 - 8.34 (m, 1 H) 8.68 (d, J=1.76 Hz, 1 H); MS (ESI, m/z):523.7 [M+H]⁺

Example 403. 5-([1,1'-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-biphenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.60 (q, J=7.63 Hz, 2 H) 3.47 (br d, J=12.91 Hz, 1 H) 3.51 - 3.62 (m, 2 H) 3.77 (dd, J=12.33, 7.04 Hz, 1 H) 4.31 - 4.40 (m, 1 H) 4.63 - 4.73 (m, 3 H) 7.05 - 7.14 (m, 2 H) 7.17 (s, 1 H) 7.34 (s, 1 H) 7.36 (br d, J=7.63 Hz, 1 H) 7.45 (t, J=7.63 Hz, 2 H) 7.64 (d, J=7.63 Hz, 2 H) 7.70 - 7.79 (m, 3 H) 8.40 (d, J=1.76 Hz, 1 H) 8.64 (d, J=2.35 Hz, 1 H); MS (ESI, m/z):507.4 [M+H]⁺

Example 404. 2-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-benzyloxyphenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.24 (s, 3 H) 2.60 (q, J=7.63 Hz, 2 H) 3.46 (br d, J=12.91 Hz, 1 H) 3.49 - 3.60 (m, 2 H) 3.76 (dd, J=12.91, 7.04 Hz, 1 H) 4.28 - 4.36 (m, 1 H) 4.60 - 4.73 (m, 3 H) 5.13 (s, 2 H) 7.03 - 7.13 (m, 4 H) 7.16 (s, 1 H) 7.23 - 7.32 (m, 1 H) 7.36 (t, J=7.63 Hz, 2 H) 7.43 (d, J=7.04 Hz, 2 H) 7.59 (d, J=8.80 Hz, 2 H) 8.23 - 8.29 (m, 1 H) 8.60 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 537.8 [M+H]⁺

Example 405. 2-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-dimethylaminophenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.60 (q, J=7.24 Hz, 2 H) 3.07 (s, 6 H) 3.47 (br d, J=12.91 Hz, 1 H) 3.57 (ddd, J=18.78, 12.91, 3.52 Hz, 2 H) 3.76 (br dd, J=12.91, 7.04 Hz, 1 H) 4.32 - 4.37 (m, 1 H) 4.61 - 4.72 (m, 3 H) 7.02 - 7.12 (m, 4 H) 7.16 (s, 1 H) 7.62 (d, J=8.80 Hz, 2 H) 8.26 (d, J=1.76 Hz, 1 H) 8.69 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 474.4 [M+H]⁺

Example 406. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamide

Using quinoline-3-boronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.17 (t, J=7.34 Hz, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.24 Hz, 2 H) 3.48 (br d, J=12.91 Hz, 1 H) 3.57 - 3.69 (m, 2 H) 3.78 (br dd, J=12.91, 7.04 Hz, 1 H) 4.34 - 4.42 (m, 1 H) 4.61 - 4.75 (m, 3 H) 7.05 - 7.15 (m, 2 H) 7.18 (s, 1 H) 7.78 - 7.93 (m, 1 H) 7.93 - 8.09 (m, 1 H) 8.18 (br dd, J=8.22, 3.52 Hz, 2 H) 8.63 (d, J=1.76 Hz, 1 H) 8.86 (d, J=2.35 Hz, 1 H) 8.99 - 9.07 (m, 1 H) 9.37 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 482.6 [M+H]⁺

Example 407. 2-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using benzo[b]furan-2-boronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.63 Hz, 2 H) 3.48 (br d, J=12.33 Hz, 1 H) 3.53 (br dd, J=12.91, 2.93 Hz, 1 H) 3.60 (br dd, J=12.91, 4.70 Hz, 1 H) 3.78 (br dd, J=12.62, 7.34 Hz, 1 H) 4.37 (br s, 1 H) 4.63 - 4.72 (m, 3 H) 7.04 - 7.14 (m, 2 H) 7.15 - 7.20 (m, 2 H) 7.20 - 7.26 (m, 1 H) 7.29 (br t, J=7.63 Hz, 1 H) 7.51 (d, J=8.22 Hz, 1 H) 7.58 (br d, J=7.63 Hz, 1 H) 8.57 (d, J=1.76 Hz, 1 H) 8.60 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 471.5 [M+H]⁺

Example 408. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamide

Using 2-naphthyleneboronic acid, the title compound was obtained as described for the example 388.¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.24 (s, 3 H) 2.60 (q, J=7.43 Hz, 2 H) 3.48 (br d, J=12.91 Hz, 1 H) 3.53 - 3.69 (m, 2 H) 3.78 (dd, J=12.91, 7.04 Hz, 1 H) 4.31 - 4.46 (m, 1 H) 4.55 - 4.72 (m, 3 H) 7.05 - 7.14 (m, 2 H) 7.17 (s, 1 H) 7.47 - 7.58 (m, 2 H) 7.79 (dd, J=8.22, 1.76 Hz, 1 H) 7.85 - 8.02 (m, 3 H) 8.16 (s, 1 H) 8.47 (d, J=1.76 Hz, 1 H) 8.78 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 481.4 [M+H]⁺

Example 409. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide

Using 4-trifluoromethylbenzeneboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.24 Hz, 2 H) 3.45 (br d, J=12.32 Hz, 1 H) 3.49 - 3.62 (m, 2 H) 3.75 (dd, J=12.62, 6.75 Hz, 1 H) 4.26 - 4.38 (m, 1 H) 4.61 - 4.72 (m, 3 H) 7.03 - 7.13 (m, 2 H) 7.16 (s, 1 H) 7.33 (td, J=10.12, 6.75 Hz, 2 H) 7.53 - 7.69 (m, 2 H) 8.29 (s, 1 H) 8.48 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 499.6 [M+H]⁺

Example 410. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamide

Using 2,4,5-trifluorophenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.24 Hz, 2 H) 3.45 (br d, J=12.32 Hz, 1 H) 3.49 - 3.62 (m, 2 H) 3.75 (dd, J=12.62, 6.75 Hz, 1 H) 4.26 - 4.38 (m, 1 H) 4.61 - 4.72 (m, 3 H) 7.03 - 7.13 (m, 2 H) 7.16 (s, 1 H) 7.33 (td, J=10.12, 6.75 Hz, 1 H) 7.53 - 7.63 (m, 1 H) 8.29 (s, 1 H) 8.48 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 485.3 [M+H]⁺

Example 411. 2-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-eth-yl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 4-cyanomethylphenylboronic acid, the title compound was obtained as described for the example 388. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (td, J=7.63, 2.35 Hz, 3 H) 2.24 (d, J=4.11 Hz, 3 H) 2.59 (qd, J=7.53, 3.23 Hz, 2 H) 3.45 - 3.56 (m, 1 H) 3.67 - 3.74 (m, 1 H) 3.77 - 3.88 (m, 1 H) 3.93 (s, 2 H) 3.98 (br dd, J=11.44, 6.16 Hz, 1 H) 4.11 - 4.28 (m, 1 H) 4.58 - 4.70 (m, 3 H) 7.07 (s, 2 H) 7.14 (s, 1 H) 7.86 (d, J=2.93 Hz, 1 H) 8.02 (s, 1 H) 8.19 (d, J=11.15 Hz, 1 H) 8.24 (d, J=1.76 Hz, 1 H) 8.59 (dd, J=7.04, 2.35 Hz, 1 H); MS (ESI, m/z): 470.8 [M+H]⁺

Example 412. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-(4-N-Boc-piperidine)pyrazole-4-boronic acid, the title compound was obtained as described for the example 388 and following deprotection with TFA. MS (ESI, m/z): 504.3 [M+H]⁺

Example 413. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

Using 1-(4-N-methylpiperidine)pyrazole-4-boronic acid, the title compound was obtained as described for the example 388. MS (ESI, m/z): 518.3 [M+H]⁺

Example 414. 2-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-(benzyloxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388. MS (ESI, m/z): 393.2 [M+H]⁺

Example 415. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-((4-methylbenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388. MS (ESI, m/z): 407.2 [M+H]⁺

Example 416. 2-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-((3-ethylbenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388. MS (ESI, m/z): 421.2 [M+H]⁺

Example 417. 2-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388. MS (ESI, m/z): 439.2 [M+H]⁺

Example 418. 2-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using tert-butyl (3S,4S)-3-amino-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388. MS (ESI, m/z): 455.2 [M+H]⁺

Example 419. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

Scheme for the preparation of the Compound of Example 419:

Intermediate 30.

To a mixture of intermediate 29 (400 mg, 0.7 mmol) and 4-carboxyphenylboronic acid (230 mg, 1.10 mmol) in 4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (310 mg, 2.2 mmol) followed by Pd(PPh₃)₄ (40 mg, 0.03 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. The crude product was purified through silicagel column chromatography to give 350 mg of off-white solid ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.43 Hz, 3 H) 1.46 (br d, J=1.96 Hz, 9 H) 2.23 (s, 3 H) 2.59 (q, J=7.56 Hz, 2 H) 3.40 - 3.51 (m, 2 H) 3.52 - 3.65 (m, 1 H) 3.76 (br d, J=7.43 Hz, 1 H) 4.13 (br s, 1 H) 4.57 - 4.74 (m, 3 H) 7.06 (s, 2 H) 7.14 (s, 1 H) 7.79 (br d, J=8.22 Hz, 2 H) 8.13 (br d, J=8.22 Hz, 2 H) 8.37 - 8.45 (m, 1 H) 8.73 (d, J=1.56 Hz, 1 H); MS (ESI, m/z): 575.3 [M+H]⁺

Example 419. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide

To a mixture of intermediate 30 (12 mg, 0.02 mmol) and triethylamine (0.04 ml, 0.03 mmol) in 0.2 ml of DMF was added HATU (10 mg, 0.03 mmol) followed by 4-amino-1-methylpiperidine (0.03 ml, 0.02 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was dissolved with 0.5 ml of CH₂Cl₂ / TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 10 mg of the title compound. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 1.86 - 1.98 (m, 2 H) 2.23 (br s, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.70 Hz, 2 H) 2.89 (s, 3 H) 3.10 - 3.26 (m, 2 H) 3.47 (br d, J=12.52 Hz, 1 H) 3.52 - 3.66 (m, 3 H) 3.77 (dd, J=12.72, 6.85 Hz, 1 H) 4.11 - 4.23 (m, 1 H) 4.32 - 4.43 (m, 1 H) 4.53 - 4.77 (m, 3 H) 7.05 - 7.14 (m, 2 H) 7.17 (s, 1 H) 7.81 (d, J=8.22 Hz, 2 H) 7.88 - 7.99 (m, 2 H) 8.42 (d, J=1.96 Hz, 1 H) 8.74 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 571.4 [M+H]⁺

Example 420. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide

Using 4-methylcyclohexylamine, the title compound was obtained as described for the example 419. ¹H NMR (600 MHz, CD₃OD) δ ppm 0.93 (d, J=6.46 Hz, 1 H) 1.00 (d, J=6.46 Hz, 2 H) 1.09 (br d, J=14.09 Hz, 1 H) 1.16 (t, J=7.63 Hz, 3 H) 1.38 - 1.48 (m, 2 H) 1.59 - 1.73 (m, 3 H) 1.75 - 1.84 (m, 2 H) 1.96 (br d, J=11.15 Hz, 1 H) 2.25 (s, 3 H) 2.60 (q, J=7.63 Hz, 2 H) 3.32 - 3.36 (m, 1 H) 3.47 (br d, J=12.91 Hz, 1 H) 3.51 - 3.61 (m, 2 H) 3.76 (dd, J=12.91, 7.04 Hz, 2 H) 3.99 (br s, 1 H) 4.35 (br s, 1 H) 4.62 - 4.72 (m, 3 H) 7.03 - 7.14 (m, 2 H) 7.16 (s, 1 H) 7.76 (dd, J=8.51, 4.40 Hz, 2 H) 7.91 (dd, J=8.22, 2.35 Hz, 2 H) 8.42 (d, J=2.35 Hz, 1 H) 8.58 - 8.62 (m, 1 H); MS (ESI, m/z): 570.5 [M+H]⁺

Example 421. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonylphenyl)nicotinamide

Using 4-methylpiperidine, the title compound was obtained as described for the example 419. ¹H NMR (600 MHz, CD₃OD) δ ppm 0.98 (d, J=6.46 Hz, 3 H) 1.09-1.22 (m, 3H) 1.16 (t, , J=7.63, 3 H) 1.62 (br d, J=11.74 Hz, 1 H) 1.66 - 1.74 (m, 2 H) 1.79 (br d, J=12.91 Hz, 1 H) 2.23 (s, 3 H) 2.53 - 2.63 (q, J=7.63 Hz, 2 H) 2.85 (br t, J=12.33 Hz, 1 H) 3.11 (br t, J=12.33 Hz, 1 H) 3.39 - 3.49 (m, 2 H) 3.55 - 3.61 (m, 1 H) 3.68 (br d, J=12.91 Hz, 1 H) 3.75 (td, J=11.74, 7.04 Hz, 1 H) 4.12 (br s, 1 H) 4.58 - 4.64 (m, 3 H) 7.02 - 7.11 (m, 2 H) 7.13 (s, 1 H) 7.51 (d, J=8.22 Hz, 2 H) 7.76 (d, J=8.22 Hz, 2 H) 8.36 (d, J=1.76 Hz, 1 H) 8.70 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 556.5 [M+H]⁺

Example 422. 2-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using dimethylamine, the title compound was obtained as described for the example 419. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.15 (t, J=7.63 Hz, 3 H) 2.22 (s, 3 H) 2.58 (q, J=7.63 Hz, 2 H) 3.01 (s, 3 H) 3.11 (s, 3 H) 3.38 - 3.50 (m, 2 H) 3.52 - 3.66 (m, 1 H) 3.67 - 3.81 (m, 1 H) 4.12 (br s, 1 H) 4.57 - 4.68 (m, 3 H) 7.05 (s, 2 H) 7.13 (s, 1 H) 7.54 (d, J=8.80 Hz, 2 H) 7.75 (d, J=8.22 Hz, 2 H) 8.36 (d, J=1.76 Hz, 1 H) 8.68 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 502.4 [M+H]⁺

Example 423. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide

Scheme for the preparation of the Compound of Example 423:

Intermediate 31.

Using intermediate 29 and 4-formylphenylboronic acid, the title compound was obtained as described for the synthesis of intermediate 30. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.30 (t, J=7.63 Hz, 3 H), 1.42 (s, 9 H), 2.26 (br s, 3 H) 2.58 (q, J=7.63 Hz, 2 H) 3.37-3.84 (m, 4H) 4.17 (br s, 1 H) 4.64 (br s, 2 H) 4.77 (br s, 1 H) 6.59 (br s, 2 H) 7.05 - 7.20 (m, 3 H) 7.55 - 7.73 (m, 2 H) 7.86 (br d, J=5.28 Hz, 2 H) 8.04 (br s, 1 H) 8.46 (br s, 1 H) 9.86 (br s, 1 H); MS (ESI, m/z): 559.4 [M+H]⁺

Example 423. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide

To a mixture of intermediate 31 (40 mg, 0.07 mmol) in 0.4 ml of dichloroethane was added 4-methylpiperidine (0.017 ml, 0.14 mmol) followed by NaBH(OAc)₃ (30 mg, 0.21 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was dissolved with 0.5 ml of CH₂Cl₂ / TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 10 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 0.99 (d, J=6.46 Hz, 3 H) 1.16 (t, J=7.34 Hz, 3 H) 1.34 - 1.46 (m, 2 H) 1.91 (br d, J=14.09 Hz, 2 H) 2.25 (s, 3 H) 2.61 (q, J=7.63 Hz, 2 H) 2.93 - 3.07 (m, 2 H) 3.43 - 3.49 (m, 3 H) 3.57 (ddd, J=16.43, 12.91, 3.52 Hz, 2 H) 3.76 (dd, J=12.62, 6.75 Hz, 2 H) 4.27 - 4.39 (m, 3 H) 4.59 - 4.76 (m, 3 H) 7.05 - 7.14 (m, 2 H) 7.17 (s, 1 H) 7.60 (d, J=8.22 Hz, 2 H) 7.80 (d, J=8.22 Hz, 2 H) 8.39 (d, J=1.76 Hz, 1 H) 8.67 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 542.3 [M+H]⁺

Example 424. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide

Using morpholine, the title compound was obtained as described for the example 423. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 2.25 (s, 3 H) 2.61 (q, J=7.63 Hz, 2 H) 3.09 - 3.27 (m, 2 H) 3.31 - 3.40 (m, 2 H) 3.46 (d, J=12.33 Hz, 1 H) 3.52 - 3.67 (m, 2 H) 3.76 (br dd, J=12.91, 7.04 Hz, 1 H) 3.77 (br s, 2 H) 4.03 (br s, 2 H) 4.35 (br d, J=4.11 Hz, 1 H) 4.41 (s, 2 H) 4.63 - 4.71 (m, 2 H) 4.72 (br d, Hz, 1 H) 7.06 - 7.12 (m, 2 H) 7.17 (s, 1 H) 7.63 (d, J=8.22 Hz, 2 H) 7.82 (d, J=8.22 Hz, 2 H) 8.40 (d, J=2.35 Hz, 1 H) 8.66 - 8.70 (m, 1 H); MS (ESI, m/z): 530.3 [M+H]⁺

Example 425. 2-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide

Using 3,3-difluoropiperidine, the title compound was obtained as described for the example 423. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.16 (t, J=7.63 Hz, 3 H) 1.97 - 2.09 (m, 2 H) 2.15 (br s, 2 H) 2.25 (s, 3 H) 2.61 (q, J=7.63 Hz, 2 H) 3.22 - 3.28 (m, 2 H) 3.38 - 3.49 (m, 4 H) 3.50 - 3.66 (m, 2 H) 3.76 (dd, J=12.33, 7.04 Hz, 1 H) 4.35 (br d, J=4.70 Hz, 1 H) 4.40 (s, 2 H) 4.62 - 4.73 (m, 3 H) 7.07 - 7.12 (m, 2 H) 7.17 (s, 1 H) 7.61 (d, J=8.22 Hz, 2 H) 7.81 (d, J=8.22 Hz, 2 H) 8.40 (d, J=2.35 Hz, 1 H) 8.61 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 564.3 [M+H]⁺

Example 426. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Scheme for the preparation of the Compound of Example 426:

To compound 388 (40 mg, 0.09 mmol) in 0.4 ml of 1,2-dichloroethane was added formaldehyde (0.015 ml, 0.18 mmol) followed by NaBH(OAc)₃ (38 mg, 0.28 mmol). The mixture was stirred at room temperature for 1 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 30 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.12 - 1.17 (m, 3 H) 2.23 (s, 3 H) 2.55 - 2.65 (m, 2 H) 3.01 (s, 3 H) 3.43 - 3.54 (m, 1 H) 3.60 - 3.71 (m, 1 H) 3.73 - 3.84 (m, 1 H) 3.92 (s, 3 H) 4.08 - 4.23 (m, 1 H) 4.31 - 4.45 (m, 1 H) 4.62 - 4.70 (m, 2 H) 4.72 (br d, J=5.87 Hz, 1 H) 7.04 - 7.11 (m, 2 H) 7.15 (s, 1 H) 7.88 (s, 1 H) 8.05 (s, 1 H) 8.26 (d, J=2.35 Hz, 1 H) 8.66 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 449.3 [M+H]⁺

Example 427. 2-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using benzaldehyde, the title compound was obtained as described for the example 426. MS (ESI, m/z): 525.7 [M+H]⁺

Example 428. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 3-phenylpropanal, the title compound was obtained as described for the example 426.¹H NMR (600 MHz, CD₃OD) δ ppm 1.14 (t, J=7.63 Hz, 3 H) 1.97 - 2.13 (m, 2 H) 2.22 (s, 3 H) 2.58 (q, J=7.63 Hz, 2 H) 2.70 (t, J=7.63 Hz, 2 H) 3.27 (t, J=7.63 Hz, 2 H) 3.43 - 3.54 (m, 1 H) 3.60 - 3.71 (m, 1 H) 3.73 - 3.84 (m, 1 H) 3.92 (s, 3 H) 4.08 - 4.23 (m, 1 H) 4.36 (br s, 1 H) 4.6 -4.72(m, 3 H) 7.01 - 7.10 (m, 2 H) 7.12 - 7.15 (m, 1 H) 7.15 - 7.30 (m, 5 H) 7.87 (s, 1 H) 8.04 (s, 1 H) 8.25 (d, J=1.76 Hz, 1 H) 8.64 (br s, 1 H); MS (ESI, m/z): 553.3 [M+H]⁺

Example 429. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using phenylacetaldehyde, the title compound was obtained as described for the example 426. MS (ESI, m/z): 539.3[M+H]⁺

Example 430. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using isobutyraldehyde, the title compound was obtained as described for the example 426. ¹H NMR (600 MHz, CD₃OD) δ ppm 1.04 (br d, J=3.52 Hz, 6 H) 1.14 (t, J=7.63 Hz, 3 H) 2.10 (dt, J=13.65, 6.97 Hz, 1 H) 2.22 (s, 3 H) 2.58 (q, J=7.63 Hz, 2 H) 3.14 (br d, J=6.46 Hz, 2 H) 3.32 - 3.42 (m, 1 H) 3.52 (br s, 1 H) 3.70 - 3.83 (m, 1 H) 3.93 (s, 3 H) 3.99 - 4.17 (m, 1 H) 4.41 (br d, J=16.43 Hz, 1 H) 4.59 - 4.75 (m, 3 H) 7.02 - 7.12 (m, 2 H) 7.15 (br s, 1 H) 7.87 (br s, 1 H) 8.05 (br d, J=11.15 Hz, 1 H) 8.28 (d, J=1.76 Hz, 1 H) 8.59 (br s, 1 H); MS (ESI, m/z): 491.3 [M+H]⁺

Example 431. 2-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)-oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using butyraldehyde, the title compound was obtained as described for the example 426. MS (ESI, m/z): 491.4 [M+H]⁺

Example 432. 2-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)-oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using acetaldehyde, the title compound was obtained as described for the example 426. MS (ESI, m/z): 463.3 [M+H]⁺

Example 433. 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide

From compound 359, the title compound was obtained as described for the example 426. MS (ESI, m/z): 532.3 [M+H]⁺

Example 434 and Example 435.

Scheme for the preparation of the Compounds of Example 434 and 435:

Intermediate 32.

To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine (0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol) followed by tert-butyl (3S,4S)-3-amino-4-((4-bromobenzyl)oxy)pyrrolidine-1-carboxylate (657 mg, 1.76 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 700 mg of off-white solid. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.43 (br s, 9 H) 3.42 (br d, J=10.56 Hz, 1 H) 3.51 - 3.65 (m, 2 H) 3.80 (dd, J=12.03, 5.58 Hz, 1 H) 3.89 (s, 3 H) 4.03 - 4.20 (m, 1 H) 4.54 - 4.77 (m, 3 H) 6.29 (br s, 2 H) 7.25 (br d, J=8.22 Hz, 2 H) 7.46 (br d, J=8.22 Hz, 2 H) 7.53 (br s, 1 H) 7.57 - 7.67 (m, 2 H) 8.29 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 571.2 [M+H]⁺

Example 434. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide

To a mixture of intermediate 32 (40 mg, 0.07 mmol) and 4-((4-methylpiperazin-1-yl)-methylphenylboronic acid pinacol ester (27 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/ water (3/1) was added K₂CO₃ (29 mg, 0.21 mmol) followed by Pd(PPh₃)₄ (4 mg, 0.003 mmol) Pd(PPh₃)₄. The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. The crude residue was dissolved with 0.5 ml of CH₂Cl₂ / TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 2.88 (s, 3 H) 2.91 - 3.13 (m, 4 H) 3.31 - 3.46 (m, 4 H) 3.52 - 3.65 (m, 3 H) 3.80 (dd, J=12.91, 7.04 Hz, 1 H) 3.87 - 3.96 (m, 5 H) 4.39 - 4.45 (m, 1 H) 4.71 - 4.83 (m, 3 H) 7.46 (br d, J=8.22 Hz, 2 H) 7.49 (br d, J=8.22 Hz, 2 H) 7.62 (dd, J=8.22, 2.35 Hz, 4 H) 7.87 (s, 1 H) 8.04 (s, 1 H) 8.25 (d, J=1.76 Hz, 1 H) 8.65 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 581.4 [M+H]⁺

Example 435. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methy1-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide

To a mixture of compound 434 (52 mg, 0.09 mmol) in 0.4 ml of 1,2-dichloroethane was added formaldehyde (0.015 ml, 0.18 mmol) followed by NaBH(OAc)₃ (38 mg, 0.28 mmol). The mixture was stirred at room temperature for 1 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 35 mg of the title compound. ¹H NMR (600 MHz, CD₃OD) δ ppm 2.94 (s, 3 H) 3.04 (s, 3 H) 3.36 - 3.47 (m, 6 H) 3.48 - 3.58 (m, 6 H) 3.91 (s, 3 H) 4.27 (s, 2 H) 4.44 (br s, 1 H) 4.72 - 4.83 (m, 3 H) 7.49 (d, J=8.22 Hz, 2 H) 7.53 (d, J=8.22 Hz, 2 H) 7.61 (d, J=8.22 Hz, 2 H) 7.66 (d, J=8.22 Hz, 2 H) 7.86 (s, 1 H) 8.03 (s, 1 H) 8.22 (d, J=1.76 Hz, 1 H) 8.67 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 595.3 [M+H]⁺

Example 436. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)-pyrrolidin-3-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434. MS (ESI, m/z): 649.3 [M+H]⁺

Example 437. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide

From compound 436, the title compound was obtained as described for the example 435. MS (ESI, m/z): 663.3 [M+H]⁺

Example 438. 2-amino-S-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide

Using (4-acetylphenyl)boronic acid, the title compound was obtained as described for the example 434. MS (ESI+) m/z 595.3 [M+H]⁺

Example 439. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-meth-yl-4-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamide

From compound 438, the title compound was obtained as described for the example 435. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (d, J=7.04 Hz, 3 H) 2.90 (s, 3 H) 3.05 (s, 3 H) 3.08 - 3.17 (m, 2 H) 3.46 (br s, 4 H) 3.93 (s, 3 H) 4.16 (br d, J=6.65 Hz, 2 H) 4.49 (s, 1 H) 4.75 - 4.87 (m, 3 H) 7.51 (dd, J=8.22, 4.70 Hz, 4 H) 7.57 - 7.70 (m, 4 H) 7.88 (s, 1 H) 8.05 (s, 1 H) 8.26 (d, J=1.96 Hz, 1 H) 8.68 (d, J=1.96 Hz, 1 H); MS (ESI+) m/z 609.4 [M+H]⁺

Example 440. 2-amino-N-((3S,4S)-4-((4'-(2-(4-(2-hydroxvethvl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.77 (s, 6 H) 3.50 - 3.68 (m, 6 H) 3.80 (s, 1 H) 3.83 - 3.89 (m, 2 H) 3.92 (s, 3 H) 4.42 (br d, J=4.30 Hz, 1 H) 4.73 - 4.88 (m, 3 H) 7.52 (d, J=8.22 Hz, 2 H) 7.65 (d, J=8.22 Hz, 2 H) 7.67 - 7.84 (m, 3 H) 7.86 - 7.92 (m, 1 H) 8.06 (s, 1 H) 8.26 (d, J=2.35 Hz, 1 H) 8.70 (d, J=2.35 Hz, 1 H); MS (ESI, m/z): 639.4 [M+H]⁺

Example 441. 2-amino-N-((3S,4S)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1'-biphenyl]-4-)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

From compound 440, the title compound was obtained as described for the example 435. MS (ESI, m/z): 653.4 [M+H]⁺

Example 442. 2-amino-N-((3S,4S)-4-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434. MS (ESI, m/z): 625.4 [M+H]⁺

Example 443. 2-amino-N-((3S,4S)-4-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

From compound 442, the title compound was obtained as described for the example 435. MS (ESI, m/z): 639.4 [M+H]⁺

Example 444. 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434. MS (ESI, m/z): 679.3 [M+H]⁺

Example 445. 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using 1-(4-bromo-2-(trifluoromethyl)benzyl)piperazine, the title compound was obtained as described for the example 435. MS (ESI, m/z): 693.3 [M+H]⁺

Example 446. 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamide

Using (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434. MS (ESI, m/z): 611.3 [M+H]⁺

Example 447. 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

From compound 446, the title compound was obtained as described for the example 435. MS (ESI, m/z): 625.4 [M+H]⁺

Example 448. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-nicotinamide

Scheme for the preparation of the Compound of Example 448:

Intermediate 33.

Using intermediate 2 and (3S,4R)-4-((4-bromobenzyl)oxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the intermediate 4. ¹H NMR (600 MHz, CD₃OD) δ ppm 3.81 (td, J=10.27, 2.35 Hz, 2 H) 3.91 (s, 3 H) 4.05 (dd, J=9.98, 5.28 Hz, 1 H) 4.11 (dd, J=9.39, 5.87 Hz, 1 H) 4.13 - 4.16 (m, 1 H) 4.55 (dd, J=3.81, 2.05 Hz, 1 H) 4.60 (s, 2 H) 4.63 (d, J=12.33 Hz, 1 H) 4.74 (d, J=12.33 Hz, 1 H) 7.30 (m, J=8.22 Hz, 2 H) 7.45 - 7.49 (m, 2 H) 7.78 (s, 1 H) 7.90 (s, 1 H) 8.07 (d, J=2.35 Hz, 1 H) 8.26 (d, J=1.76 Hz, 1 H); MS (ESI, m/z): 472.1 [M+H]⁺

Example 448. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-nicotinamide

Using intermediate 33, the title compound was obtained as described for the example 172. ¹H NMR (600 MHz, CD₃OD) δ ppm 2.87 (s, 3 H) 3.80 - 3.89 (m, 4 H) 3.92 (s, 3 H) 4.04 - 4.15 (m, 2 H) 4.19 - 4.25 (m, 1 H) 4.57 - 4.63 (m, 1 H) 4.71 (d, J=11.74 Hz, 1 H) 4.82 (d, J=11.74 Hz, 1 H) 7.40 - 7.51 (m, 4 H) 7.57 - 7.63 (m, 4 H) 7.88 (s, 1 H) 8.02 (s, 1 H) 8.23 (s, 1 H) 8.62 (s, 1 H); MS (ESI, m/z): 582.3 [M+H]⁺

Example 449. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester pinacol ester, the title compound was obtained as described for the example 448. ¹H NMR (400 MHz, CD₃OD) δ ppm 2.91 (s, 3 H) 3.80 - 3.91 (m, 3 H) 3.94 (s, 2 H) 4.12 (td, J=9.59, 5.48 Hz, 2 H) 4.23 (br s, 1 H) 4.62 (br s, 1 H) 4.74 (d, J=12.13 Hz, 1 H) 7.52 (d, J=8.61 Hz, 2 H) 7.65 (d, J=8.22 Hz, 2 H) 7.88 (d, J=13.30 Hz, 4 H) 8.03 (s, 1 H) 8.25 (d, J=1.96 Hz, 1 H) 8.63 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 650.3 [M+H]⁺

Example 450. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl)-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

Using (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 448. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62 (s, 6 H) 2.89 (s, 3 H) 3.04 (br s, 2 H) 3.34 - 3.47 (m, 4 H) 3.82 - 3.91 (m, 2 H) 3.93 (s, 3 H) 4.12 (td, J=10.56, 5.48 Hz, 2 H) 4.22 (br s, 1 H) 4.61 (br s, 1 H) 4.66 - 4.77 (m, 1 H) 4.81 - 4.88 (m, 1 H) 7.47 (d, J=7.83 Hz, 2 H) 7.58 - 7.70 (m, 6 H) 7.89 (s, 1 H) 8.03 (s, 1 H) 8.24 (d, J=1.96 Hz, 1 H) 8.65 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 610.2 [M+H]⁺

Example 451. 2-amino-N-((3S,4R)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 448. MS (ESI, m/z): 612.3 [M+H]⁺

Example 452. 2-amino-N-((3S,4R)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-boronic acid pinacol ester, the title compound was obtained as described for the example 448.¹H NMR (400 MHz, CD3OD) δ ppm 2.62 (br s, 4 H) 3.25 - 3.29 (m, 2 H) 3.34 - 3.40 (m, 2 H) 3.82 - 3.84 (m, 2 H) 3.85 - 3.91 (m, 2 H) 3.94 (s, 2 H) 4.06 - 4.17 (m, 2 H) 4.23 (br s, 1 H) 4.62 (br s, 1 H) 4.74 (m, 1 H) 7.52 (m, J=8.22 Hz, 2 H) 7.65 (m, J=8.22 Hz, 2 H) 7.86 (s, 2 H) 7.89 (s, 2 H) 8.03 (s, 1 H) 8.25 (d, J=1.96 Hz, 1 H) 8.63 (d, J=1.96 Hz, 1 H); MS (ESI, m/z): 680.3 [M+H]⁺

Example 453. 2-amino-N-((3S,4R)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

Using (4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 448. MS (ESI, m/z): 640.2 [M+H]⁺

Example 454. 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

Using trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-amine, the title compound was obtained as described for the example 448. ¹H NMR (400 MHz, CD₃OD) δ ppm 2.88(s, 3 H) 3.76 - 3.89 (m, 4 H) 4.09 (ddd, J=16.92, 9.88, 5.28 Hz, 2 H) 4.20 (br d, J=4.70 Hz, 1 H) 4.57 (br s, 1 H) 4.70 (br d, J=11.74 Hz, 1 H) 6.98 (dd, J=7.43, 6.26 Hz, 1 H) 7.46 (d, J=8.22 Hz, 4 H) 7.56 - 7.67 (m, 4 H) 7.99 - 8.06 (m, 1 H) 8.40 (dd, J=7.43, 1.56 Hz, 1 H); MS (ESI, m/z): 582.3 [M+H]⁺

Example 455. 2-amino-N-(trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

Using 2-aminonicotinic acid and trans-4-((4-bromobenzyl)oxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 448. ¹H NMR (400 MHz, CD₃OD) δ ppm 2.88(s, 3 H) 3.76 - 3.89 (m, 4 H) 4.09 (ddd, J=16.92, 9.88, 5.28 Hz, 2 H) 4.20 (br d, J=4.70 Hz, 1 H) 4.57 (br s, 1 H) 4.70 (br d, J=11.74 Hz, 1 H) 6.98 (dd, J=7.43, 6.26 Hz, 1 H) 7.46 (d, J=8.22 Hz, 4 H) 7.56 - 7.67 (m, 4 H) 7.99 - 8.06 (m, 1 H) 8.40 (dd, J=7.43, 1.56 Hz, 1 H); MS (ESI, m/z): 502.3 [M+H]⁺

Example 456. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamide

Scheme for the preparation of the Compound of Example 456:

Intermediate 34.

To a suspension of methyl 2-amino-6-chloronicotinate (100 mg, 0.54 mmol) in 3 ml of MeOH was added 2N NaOH (1 ml, 2 mmol) and the mixture was heated at 65 °C for 1 hr, cooled to room temperature, neutralized (1 ml of 2N HCl), and the resulting precipitate was filtered, washed with MeOH, and dried to give 80 mg of off-white solid. ¹H NMR (400 MHz, DMSO-d₆ ) δ ppm 6.61 (d, J=7.83 Hz, 1 H) 7.53 (br s, 2 H) 8.01 (d, J=8.22 Hz, 1 H); MS (ESI, m/z): 173.2 [M+H]⁺

Intermediate 35.

To a mixture of intermediate 34 (50 mg, 0.29 mmol) and triethylamine (0.061 ml , 0.43 mmol) in 2 ml of DMF was added HATU (132 mg, 0.35 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine(55 mg, 0.29 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 80 mg of the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.39 - 1.52 (m, 1 H) 1.68 - 1.81 (m, 2 H) 1.83 - 1.89 (m, 1 H) 1.89 - 2.02 (m, 1 H) 2.27 (td, J=13.69, 7.83 Hz, 1 H) 3.80 - 3.87 (m, 1 H) 4.27 - 4.37 (m, 1 H) 4.58 - 4.67 (m, 2 H) 5.79 (br d, J=6.26 Hz, 1 H) 6.51 (br s, 2H) 6.56 (d, J=7.83 Hz, 1 H) 7.25 - 7.37 (m, 5 H) 7.39 (d, J=7.83 Hz, 1 H); MS (ESI, m/z): 345.3 [M+H]⁺

Example 456. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamide

To a mixture of intermediate 35 (186 mg, 1 mmol) and 4-((4-methylpiperazine-1-yl)methyl)aniline (240 mg, 1.2 mmol) in 5 ml of 1,4-dioxane was added 480 mg of K₂CO₃ followed by Pd₂(dba)₃ (30 mg, 0.3 mmol). The reaction mixture was heated at 100 °C for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated under vacuum. The crude product was purified by silicagel column chromatography to give 170 mg of off-white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.57 (br dd, J=13.30, 7.04 Hz, 1 H) 1.66 - 1.87 (m, 3 H) 1.97 (dt, J=13.01, 6.60 Hz, 1 H) 2.13 (br dd, J=13.11, 6.85 Hz, 1 H) 2.95 (s, 3 H) 3.44 - 3.62 (m, 4 H) 3.87 - 3.97 (m, 1 H) 4.17 (s, 2 H) 4.31 - 4.39 (m, 1 H) 4.60 (s, 2 H) 6.25 (d, J=9.00 Hz, 1 H) 7.21 - 7.35 (m, 4 H) 7.43 (d, J=8.22 Hz, 2 H) 7.58 (d, J= 8.61 Hz, 2 H) 8.08 (d, J=9.00 Hz, 1 H); MS (ESI, m/z): 515.3 [M+H]⁺

Example 457. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(phenylamino)-nicotinamide

Using aniline, the title compound was obtained as described for the example 456. MS (ESI, m/z): 403.2 [M+H]⁺

Example 458. 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)nicotinamide

Using 4-(4-methylpiperazin-1-yl)aniline, the title compound was obtained as described for the example 456. MS (ESI, m/z): 501.3 [M+H]⁺

Biochemical Assay

For the SAR (structure-activity relationship) and compound screening, LanthaScreen™ TR-FRET (Time-Resolved fluorescence energy transfer) assay was employed using the phospho-tyrosine specific Terbium (Tb)-labelded antibody with a fluorescein labeled poly-GT (glutamate-tyrosine) as a substrate. Upon excitation at 340 nm by UV, the energy from Tb donor of the antibody is transferred to the fluorescein of the phosphorylated poly GT substrate, and fluorescein emits light at 520 nm. The ratio between the intensity of primary emission at 495 nm and that of secondary emission at 520 nm was used to quantify the level of kinase activity. The recombinant proteins of human c-MER and AXL catalytic domains, Fluorescein-labeled poly-GT substrate, Tb-labeled anti-phosphorylated tyrosine antibodies, the kinase assay buffer, and 0.5M EDTA solution were purchased (Life technologies, USA). The TR-FRET assays were carried out in the white low volume 384-well plate (Corning, USA). To measure the compound mediated inhibition of kinase activity, the recombinant kinases were pre-incubated with test compounds for 20 minutes prior to the addition of 200 nM fluorescein labeled poly-GT substrates and 10 uM ATP, and then the reaction was carried out for 1 hour at room temperature. 10 mM EDTA was added to terminate the enzyme reaction, and the level of phosphorylation of poly-GT substrate was determined following 30 min incubation with 2 nM Tb-labeled antibody. The fluorescence intensity was measured with Envision™ plate reader (PerkinElmer, USA).

In Cell MER Kinase Assay Using BaF3 Cellular System

CD8-MerTK is a chimeric fusion protein consisting of the extracellular and transmembrane domains of the human CD8α (amino acids 1 to 209) at its N-terminus and the kinase domain and intracellular parts of MerTK (amino acids 521-994) at its C-terminus. To establish an in cell kinase assay for MerTK kinase, the IL-3 dependent Ba/F3 cells of murine lymphoid origin was transfected with CD8-MerTK. The resulting Ba/F3-CDM line was then validated that Ba/F3-CDM cell proliferation is completely dependent on the activity of MerTK kinase activity when growing in the absence of IL-3. For a routine cellular assay, Ba/F3-CDM cells were seeded at 2,000 cells per well in 384-well cell culture plate containing DMEM/10% FBS culture media and incubated for 24 hours before addition of compounds pre-diluted in culture media. Following compound treatment, cells were further incubated for 48 hours and the proliferation was measured. To discriminate a Ba/F3 growth inhibition by a specific inhibition of MerTK kinase following compound treatment vs growth inhibition due to a non-specific unintended cytotoxicity of compounds, we routinely carried out control sets of Ba/F3 cells in parallel that grown in IL3-supplemented growth media. In the presence of IL-3, the proliferation of Ba/F3 is no longer dependent on the MerTK activity. Cell growth and proliferation was measured with Celltiter-Glo™ system (Promega, USA) according to the manufacturer's instruction. The half-maximal growth inhibitory concentration (GI₅₀) value was calculated with Prism6.0 software (GraphPad, USA).

TABLE 1. Biochemical IC50 and cell growth inhibitory GI50 values.

Compound No.	Mer TK inhibition (IC50)	Cell growth inhibition (GI50)
1	+++	+
2	++
3	++
4	+
5	+
6	+++
7	+++
8	+++
9	+++
10	++
11	+++
12	++
13	+++
14	+++
15	+	+
16	+++
17	+++
18	+++
19	+++
20	+++
21	++++	+
22	+++
23	++	+
24	+++
25	+++
26	++
27	++
28	++
29	++
30	+
31	+
32	+
33	++
34	++
35	+
36	+
37	++
38	++
39	++
40	++
41	+++
42	+
43	++
44	++	+
45	++
46	++
47	++
48	++
49	++
50	+
51	+
52	++
53	+
54	++
55	+
56	+
57	+
58	+
59	+
60	++
61	++
62	+
63	+++	+
64	++
65	+++	++
66	+
67	++
68	+++	+
69	+
70	+
71	+
72	+
73	+
74	+
75	+
76	+
77	++
78	+++	+
79	+
80	++
81	+++	+
82	++
83	+
84	++
85	++
86	++++	+++
87	++
88	++
89	++
90	+
91	+
92	+
93	++	+
94	+
95	+
96	+
97	+
98	+
99	+
100	+
101	++
102	+
103	+
104	+
105	+
106	+
107	+
108	+
109	+
110	+
111	+
112	+
113	+
114	+
115	+
116	+
117	+
118	+
119	+
120	+
121	+
122	+
123	+
124	+
125	+
126	+
127	+
128	+
129	+
130	+++	+
131	+
132	++
133	+
134	+++
135	+++	+
136	++++	+++
137	++++	++++
138	++++	+
139	+
140	+++
141	+++
142	++++	+++
143	+
144	++++	++
145	++++	+
146	++++	++++
147	++++	+++
148	++++	+
149	+++	+
150	+++	+
151	+++
152	+++
153	++++	++
154	++	+
155	+++	+
156	++++	++++
157	++++	+++
158	++	+
159	++++	+++
160	+++	+++
161	++++	++++
162	+++
163	++
164	+	+
165	+
166	+
167	++++
168	++	+
169	+
170	+
171	+
172	++++	++++
173	+++	+
174	++++	+++
175	+++	+
176	+++	+
177	++++	+++
178	++	+
179	++++	+++
180	++++	+
181	++++	++++
182	++++	++++
183	++++	++++
184	++++	++++
185	++++	+++
186	++++	++++
187	++++	++++
188	++++	++++
189	++++	+++
190	++++	++++
191	++++	+++
192	++++	++++
193	++++	++++
194	++++	++++
195	++++	++++
196	++++	+++
197	++++	++++
198	++++	++++
199	++++	++++
200	++++	+++
201	+++	+++
202	++++	+++
203	++++	+++
204	++++
205	++++	++++
206	++++	+++
207	++++
208	++++	++++
209	++++	++++
210	++++	++++
211	++++	++++
212	++++	+
213	++++	+++
214	++++	++++
215	++++	++++
216	++++	++++
217	++++	++++
218	++++	++++
219	++++	++++
220	++++	++++
221	++++	++++
222	++++	++++
223	++++	+++
224	++++	+++
225	++++	+++
226	++++	++++
227	++++	++++
228	++++	+++
229	++++	++++
230	++++	++++
231	++++
232	++++	++
233	++++	+++
234	++
235	++++	++
236	++++	++++
237	++++	++++
238	++++	++++
239	++++	++++
240	++++	++++
241	++++	++
242	++++	++++
243	++	+
244	+
245	++++	++
246	++++	+++
247	++++	+++
248	+++	+
249	++++	+
250	++++	+++
251	++++	+
252	+++	+
253	+++	+
254	+++	+
255	+++	++
256	+++
257	+++	+
258	+++
259	++
260	+++
261	++
262	+
263	+
264	+
265	++
266	++
267	+
268	++
269	++
270	+++
271	+++
272	+++
273	+++	+
274	+++
275	+++	++
276	+++
277	+++
278	+++
279	+++
280	+++
281	+++
282	+++
283	+++
284	+++
285	+++
286	+++
287	++	+
288	++
289	+++
290	+++
291	+++
292	+++
293	+++	+
294	++
295	++
296	++
297	+++	+
298	++
299	+++
300	+++
301	+++
302	+++	+
303	+++
304	+++
305	++
306	+++
307	+++
308	++
309	++
310	++
311	+++
312	+++
313	+++	+
314	+++
315	+++
316	+++
317	++
318	++++	++
319	+++
320	+++
321	+++	+
322	+++
323	+++
324	+++
325	++++	+
326	+++
327	++++	+
328	++++	++
329	++++
330	++++
331	+++	+
332	+++
333	+++	+
334	++
335	++
336	++
337	++++	++
338	+++	+
339	+++
340	+++	+
341	+++
342	++++
343	+++
344	+++
345	+++
346	+++	+
347	++++	+
348	++++	+
349	+++	+
350	+++
351	+++
352	+++	+
353	+++
354	++
355	+++	+
356	+++	+
357	+++	+
358	+++	+
359	+++	+
360	++++	+
361	+++	+
362	+
363	++++	+++
364	++++	++++
365	+++	+
366	++++	++++
367	++++	++++
368	++++	++++
369	++++	++++
370	++++	++++
371	++++	++++
372	++++	++++
373	++++	+++
374	++++	+++
375	++++	++++
376	++++	++++
377	++++	++++
378	++++	++++
379	++++	++++
380	++++	++++
381	++++	++++
382	++++
383	++++	++++
384	++++	++++
385	++++	+++
386	++++	++++
387	++++	++++
388	++++	+++
389	++++	+++
390	++++	+++
391	++++	+
392	+++	+
393	++	+
394	++++	++
395	++++	++
396	++++	+
397	+++	+
398	+++	++
399	++++	++
400	++++	++
401	++++	+
402	++	+
403	++	++
404	++	+
405	++++	+++
406	+++	+
407	+++	++
408	+++	+
409	+++	+
410	+++	+
411	++++	+++
412	++++	+
413	++++	++
414	+++	+
415	++++	+
416	++++	+++
417	+++	++
418	+++	++
419	++++	+
420	+++	+
421	+++	+
422	+++	+
423	+++	++
424	+++	+
425	+++	++
426	++++	++
427	+++	+
428	+++	+
429	++	+
430	+++	+
431	+++	+
432	+++
433	++++	+++
434	++++	++
435	++++	+++
436	++++	++
437	++++	++++
438	++++	++
439	++++	+++
440	++++	+
441	++++	+++
442	++++	+
443	++++	++++
444	++++	+
445	++++	++++
446	++++	+
447	++++	++++
448	++++	++++
449	++++	++++
450	++++	++++
451	++++	++++
452	++++	++++
453	++++	+++
454	++++
455	+++
456	+
457	+
458	+

TABLE 1. Biochemical IC50 and cell growth inhibitory GI50 values.

++++: IC50<10, +++: 10≤IC50<100, ++: 100≤IC50<1000, +: IC50≥1000 nM ++++: GI50<100, +++: 100≤GI50<500, ++: 500≤GI50<1000, +: GI50≥1000 nM

As can be seen in Table 1 above, the heterocyclic compounds of the present invention showed the activity of Mer, which compounds are useful for the prevention and/or the treatment of cancer.

Claims

A heterocyclic compound represented by the following Formula Ib, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof: wherein
X is CH, or N;

W is CH₂, NR¹¹, or O;

V¹ and V² each independently is CR¹³R^13', NR¹³, or O;

at least one of V₁ and V₂ is CR¹³R^13';

X¹ to X⁵ are the same as or different from each other, and are each independently CR¹⁴ or N;

at least one of X¹ to X⁵ is CR¹⁴;

R³ is H, halogen, CN, C_1-3 alkyl, cycloalkenyl, C_2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C_1-2 alkylaryl, C_1-2 alkylheteroaryl, or C_1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C_1-2 alkylaryl, C_1-2 alkylheteroaryl, or C_1-2 alkylheterocyclyl may optionally be substituted with one or more R⁹;

R⁸ is H, C_1-6 alkyl, C_1-4 fluoroalkyl, C_1-4 hydroxyalkyl, C_1-3 alkylaryl, or C(=O)R¹⁰ which C_1-6 alkyl or C_1-3 alkylaryl may optionally be substituted with one or more R⁹;

R⁹ is halogen, hydroxyl, -CN, -NO₂, -COOH, -(C=O)H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_1-4 hydroxyalkyl, C_1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -NR¹⁵R¹⁶, -L-NR¹⁵R¹⁶, -L-COOR¹⁷, -L-alkyl, -L-C_3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_1-4 hydroxyalkyl, C_1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C_3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may be substituted with halogen, hydroxyl, -CN, -NR¹⁵R¹⁶, C_1-6 alkyl, C_3-10 cycloalkyl, C_1-4 hydroxyalkyl, C_2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or -(CH₂)₁-C(=O)-NR¹⁵R¹⁶;

R¹⁰ is C_1-3 alkyl or C_1-3 alkylaryl;

R¹¹ is H, C_1-6 alkyl, C_1-4 fluoroalkyl, C_1-4 hydroxyalkyl, C_1-3 alkylaryl or C(=O)R¹⁰ which C_1-6 alkyl or C_1-3 alkylaryl may optionally be substituted with one or more R⁹;

R¹³ and R^13' each independently is H, C_1-3 alkyl, C_2-3 hydroxyalkyl;

each R¹⁴ is independently selected from H, halogen, hydroxyl, -CN, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -NR¹⁵R¹⁶, - L-alkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C_1-6 alkyl, aryl, heteroaryl, heterocyclyl may optionally be substituted with one or more R⁹; or adjacent groups among a plurality of R¹⁴s are bonded to each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR¹¹ O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C_1-4 alkyl or C_1-4 alkoxy;

R¹⁵ and R¹⁶ each independently is H, C_1-6 alkyl, C_3-10 cycloalkyl or SO₂R¹⁷;

R¹⁷ is H, C_1-3alkyl or C_1-3 alkylaryl;

L is C_1-3 alkyl, C_1-3 alkylO, C_2-6 alkynyl, C_3-10 cycloalkyl, -(CH₂)₁-C(=O)-(CH₂)_m-, C(=O)O, -(CH₂)₁-C(=O)NH-(CH₂)_m-, -(CH₂)₁-NHC(=O)-(CH₂)_m-, -(CH₂)₁-NH-(CH₂)_m-, NR⁸, -NH-C(=O)-CR¹⁵R¹⁶-NH-C(=O)-, NHC(=O), O, O(C=O) S, S, S(=O), or SO₂; and

1 and m each independently is an integer of 0 to 2.

The heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein the heterocyclic compound represented by formula Ib is represented by any one of the following compounds. Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 2 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 3 2-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 4 2-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 5 2-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 6 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 7 2-amino-N-((1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 8 2-amino-N-((1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 9 2-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 10 2-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 11 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 12 2-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 13 2-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 14 2-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 15 2-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 16 2-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 17 2-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 18 2-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 19 2-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 20 2-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 21 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 22 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamide Example 23 2-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 24 2-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 25 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 26 2-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 27 2-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 28 2-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 29 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide Example 30 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamide Example 31 2-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 32 2-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 33 2-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 34 2-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 35 2-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 36 2-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 37 2-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 38 2-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 39 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamide Example 40 2-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 41 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamide Example 42 methyl 3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate Example 43 2-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 44 2-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 45 2-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 46 2-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamid Example 47 2-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 48 2-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 49 2-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 50 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamide Example 51 2-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 52 2-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 53 2-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 54 2-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 57 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)oxy)cyclopentyl)nicotinamide Example 61 N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 62 N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 63 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamide Example 64 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamide Example 65 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 66 N-(trans-2-([1,1'-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 67 N-((1S,2S)-2-([1,1'-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 68 N-((1S,2S)-2-([1,1'-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 76 2-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 77 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamide Example 78 2-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 80 2-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 81 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamide Example 82 2-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 83 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide Example 84 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamide Example 86 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)methyl)cyclopentyl)nicotinamide Example 88 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamide Example 89 2-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 93 2-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 94 2-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 129 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 130 3-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 132 3-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 133 3-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 134 2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 135 2-amino-N-((1S,2S)-2-((4'-amino-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 136 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(methylamino)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 137 2-amino-N-((1S,2S)-2-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 138 2-amino-N-((1S,2S)-2-((4'-((dimethylamino)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 139 2-amino-N-((1S,2S)-2-((3'-amino-2'-methyl-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 140 2-amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 141 2-amino-N-((1S,2S)-2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 142 2-amino-N-((1S,2S)-2-((4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 143 2-amino-N-((1S,2S)-2-((3'-(ammomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 144 2-amino-N-((1S,2S)-2-((4'-(aminomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 145 2-amino-N-((1S,2S)-2-((4'-(2-aminoethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 146 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(4-methylpiperazin-1-yl)-[ 1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 147 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 148 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 149 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-(piperazin-1-yl)-[ 1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 150 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 151 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 152 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 153 2-amino-N-((1S,2S)-2-((4'-ethyl-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 154 2-amino-N-((1S,2S)-2-((4'-(cyanomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 155 2-amino-N-((1S,2S)-2-((4'-carbamoyl-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 156 2-amino-N-((1S,2S)-2-((3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 157 2-amino-N-((1S,2S)-2-((3-fluoro-4'-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 158 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 159 2-amino-N-((1S,2S)-2-((2-chloro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 160 2-amino-N-((1S,2S)-2-((3-fluoro-4'-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 161 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 162 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 163 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 164 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 165 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 166 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamide Example 167 2-amino-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 168 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 169 2-amino-N-((1S,2S)-2-((3'-hydroxy-[1,1'-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 170 2-amino-N-((1S,2S)-2-((3'-amino-[1,1'-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 171 2-amino-N-((1S,2S)-2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 172 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 174 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 175 2-amino-N-((1S,2S)-2-((4'-((3,3-difluoropiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 176 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 177 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(piperazin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 178 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-phenylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 179 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 180 2-amino-N-((1S,2S)-2-((4'-((4-hydroxypiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 181 2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 182 2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 183 2-amino-N-((1S,2S)-2-((4'-((4-ethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 184 2-amino-N-((1S,2S)-2-((4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 185 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(((R)-3-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 186 2-amino-N-((1S,2S)-2-((4'-(((R)-3,4-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 187 2-amino-N-((1S,2S)-2-((4'-(((R)-2,4-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 188 2-amino-N-((1S,2S)-2-((4'-((3-ethyl-4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 189 2-amino-N-((1S,2S)-2-((4'-((cis-3,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 190 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 191 2-amino-N-((1S,2S)-2-((4'-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 192 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 193 2-amino-N-((1S,2S)-2-((4'-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 194 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)pyrazine-2-carboxamide Example 195 2-amino-N-((1S,2S)-2-((3'-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 196 2-amino-N-((1S,2S)-2-((3',5'-difluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 197 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 198 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3'-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 199 2-amino-N-((1S,2S)-2-((3'-hydroxy-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 200 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-nitro-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 201 2-amino-N-((1S,2S)-2-((3'-methoxy-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 202 2-amino-N-((1S,2S)-2-((2'-chloro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 203 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 204 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 205 2-amino-N-((1S,2S)-2-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 206 2-amino-N-((1S,2S)-2-((2'-chloro-4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 207 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 208 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 209 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 210 2-amino-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 211 2-amino-N-((1S,2S)-2-((4'-(1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 212 2-amino-N-((1S,2S)-2-((3',5'-difluoro-4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 213 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((R)-1-(piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 214 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 215 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 216 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 217 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 218 2-amino-N-((1S,2S)-2-((4'-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 219 2-amino-N-((1S,2S)-2-((4'-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 220 2-amino-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 221 2-amino-N-((1S,2S)-2-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 222 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 223 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 224 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 225 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 226 6-ammo-6'-fluoro-N-((1S,2S)-2-((4'-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 227 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 228 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 229 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine] -5-carboxamide Example 230 6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)- [3,3'-bipyridine]-5-carboxamide Example 231 2-amino-5-chloro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 232 2-amino-5-fluoro-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 233 2-amino-5-cyano-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl] -4-yl)methoxy)cyclopentyl)nicotinamide Example 235 2-amino-N-((1S,2S)-2-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 236 6-amino-5'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 237 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 238 6-amino-2'-fluoro-N-((1S,2S)-2-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 239 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-yl)methyl)-[ 1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 240 2-amino-N-((1S,2S)-2-((4'-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 242 2-amino-N-((1S,2S)-2-((4'-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 243 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide Example 244 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 245 2-amino-N-((1S,2S)-2-((4'-(2-(dimethylamino)ethoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 246 2-amino-N-((1S,2S)-2-((4'-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 247 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4'-((1-methylpiperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 253 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 254 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 255 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 256 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 257 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 258 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 259 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 260 2-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 261 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 262 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 263 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 264 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)nicotinamide Example 265 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)nicotinamide Example 266 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)phenyl)nicotinamide Example 267 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)nicotinamide Example 268 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 269 6-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6'-(hydroxymethyl)-[3,3'-bipyridine]-5-carboxamide Example 270 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 271 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 272 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 273 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 274 2-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 275 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example 276 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 277 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 278 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide Example 279 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamide Example 280 2-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 281 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 282 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamide Example 283 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 284 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 285 2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 286 2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 287 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamide Example 288 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide Example 289 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 290 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide Example 291 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 292 2-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 293 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide Example 294 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2'-methoxy-[3,3'-bipyridine]-5-carboxamide Example 295 2-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 296 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxyphenyl)nicotinamide Example 297 2-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 298 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methylsulfonamido)phenyl)nicotinamide Example 299 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxymethyl)phenyl)nicotinamide Example 300 2-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 301 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxypropyl)phenyl)nicotinamide Example 302 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide Example 303 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 304 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamide Example 305 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acid Example 306 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)-2-methylbenzoic acid Example 307 2-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 308 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid Example 309 3-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid Example 310 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 311 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 312 2-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 313 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 314 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formylphenyl)nicotinamide Example 315 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid Example 316 3-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)phenyl)propanoic acid Example 317 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxyphenyl)nicotinamide Example 318 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 319 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamide Example 320 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 321 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6'-(hydroxymethyl)-[3,3'-bipyridine]-5-carboxamide Example 322 2-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid Example 323 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamide Example 324 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamide Example 325 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example 326 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamide Example 327 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 328 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 329 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamide Example 330 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 331 2-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 332 2-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 333 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamide Example 334 2-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 335 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)nicotinamide Example 336 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamide Example 337 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 338 2-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 339 2-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 340 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 341 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 342 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 343 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 344 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 345 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide Example 346 2-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 347 2-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 348 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 349 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 350 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 351 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamide Example 352 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamide Example 353 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 354 amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamide Example 355 2-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 356 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 357 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 358 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 359 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example 360 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example 361 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 363 2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 364 2-amino-5-(3,4-difluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 365 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide Example 366 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 367 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide Example 368 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 369 2-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 370 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide Example 371 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide Example 372 2-amino-5-(4-hydroxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 373 2-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 374 2-amino-5-methyl-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 375 6-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 376 2-amino-5-(4-methoxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 377 6-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4'-bipyridine]-5-carboxamide Example 378 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide Example 379 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 380 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 381 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamide Example 382 2-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 383 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 384 6-amino-2',6'-difluoro-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4'-bipyridine]-5-carboxamide Example 385 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide Example 386 6-amino-6'-fluoro-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3'-bipyridine]-5-carboxamide Example 387 2-amino-N-((1S,2S)-2-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)nicotinamide Example 388 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 389 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamide Example 390 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 391 2-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 392 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamide Example 393 4-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoic acid Example 394 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamide Example 395 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4'-bipyridine]-5-carboxamide Example 396 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3'-bipyridine]-5-carboxamide Example 397 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamide Example 398 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamide Example 399 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamide Example 400 2-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 401 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamide Example 402 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamide Example 403 5-([1,1'-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 404 2-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 405 2-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 406 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamide Example 407 2-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 408 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamide Example 409 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide Example 410 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamide Example 411 2-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 412 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 413 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 414 2-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 415 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 416 2-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 417 2-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 418 2-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 419 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 420 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide Example 421 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonyl)phenyl)nicotinamide Example 422 2-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 423 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide Example 424 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 425 2-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 426 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 427 2-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 428 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 429 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 430 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 431 2-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 432 2-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 433 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 434 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[ 1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 435 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-((4-methylpiperazin-1-yl)methyl)-[ 1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 436 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamid Example 437 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 438 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 439 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 440 2-amino-N-((3S,4S)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 441 2-amino-N-((3S,4S)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 442 2-amino-N-((3S,4S)-4-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 443 2-amino-N-((3S,4S)-4-((4'-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 444 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 445 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 446 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 447 2-amino-N-((3S,4S)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 448 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 449 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-((4-methylpiperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 450 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4'-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 451 2-amino-N-((3S,4R)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 452 2-amino-N-((3S,4R)-4-((4'-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 453 2-amino-N-((3S,4R)-4-((4'-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 454 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 455 2-amino-N-(trans-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide

A pharmaceutical composition comprising the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof according to claims 1 or 2 together with a pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 3, wherein the composition comprises, as active ingredient, the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof for use in prevention or treatment of a disease which is influenced by inhibition of Mer kinase, wherein the disease which is influenced by inhibition of Mer kinase is cancer or an immune-related disease.
The pharmaceutical composition for use of claim 4, wherein the cancer is selected from the group consisting of: glioma, gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, small cell lung carcinoma, cervical carcinoma, colon cancer, rectal cancer, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, colorectal cancer, endometrium cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladder carcinoma, angiosarcoma, endotheliosarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenosarcoma, cystadenosarcoma, bronchogenic carcinoma, medullary carcinoma, mastocytoma, mesotheliorma, synovioma, melanoma, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodentroglioma, acoustic neuroma, hemangioblastoma, meningioma, pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma, embryonal carcinoma, squamous cell carcinoma, base cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcorna, chondrosarcoma, osteogenic sarcoma, leukemia and metastatic lesions secondary to these primary tumors.
The pharmaceutical composition for use of claim 4, wherein the immune-related disease is selected from the group consisting of infection and sepsis.
A heterocyclic compound, stereoisomer thereof or enantiomer thereof or a pharmaceutically acceptable salt thereof according to claims 1 or 2 for use in a method of treating or preventing an immune-related disease or cancer.
A heterocyclic compound according to claim 1 having a structure: or a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceuticallyl acceptable salt thereof according to claim 8 together with pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 9, wherein the composition comprises, as active ingredient, the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof in an amount effective for prevention or treatment of a disease that is influenced by inhibition of Mer kinase, wherein the disease that is influenced by inhibition of Mer kinase is cancer or an immune-related disease.
A heterocyclic compound according to claim 1 having a structure: or a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof according to claim 11 together with pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 12, wherein the composition comprises, as active ingredient, the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof in an amount effective for prevention or treatment of a disease that is influenced by inhibition of Mer kinase, wherein the disease that is influenced by inhibition of Mer kinase is cancer or an immune-related disease.