RAF Kinase Inhibitors

Abstract

Provided herein are inhibitors of the receptor tyrosine kinase effector RAF, pharmaceutical compositions containing such compounds, and methods of using such compounds for the treatment of disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 62 / 925,596, filed October 24, 2019, and U.S. Patent Application No. 62 / 044,898, filed June 26, 2020, both of which are incorporated by reference in their entireties. [Background technology]

[0002] RAF kinase functions in the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway (also known as the MAPK / ERK pathway) by phosphorylating and activating MEK. MAPK alters the levels and activity of transcription factors, thereby altering the transcription of genes important for the cell cycle. Dysregulation of MAPK activity frequently occurs in tumors. Therefore, therapeutics targeting RAF kinase activity are desirable for the treatment of cancer and other diseases characterized by aberrant signaling in the MAPK / ERK pathway. Summary of the Invention

[0003] Provided herein are inhibitors of the receptor tyrosine kinase effector Raf (RAF), pharmaceutical compositions containing such compounds, and methods of using such compounds for the treatment of disease.

[0004] One embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0005] [ka] During the ceremony, Ring A is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl; W is NH, NR 7 , or O, X is N, CH, CF, or C-CN; Y is N, CF, or CH; R is H, optionally substituted C1-C8 alkyl, (optionally substituted C1-C8 alkylene)-OPO(OH)2, optionally substituted C3-C6 cycloalkyl, (optionally substituted C3-C6 cycloalkylene)-OPO(OH)2, optionally substituted C4-C8 cycloalkylalkyl, (optionally substituted C3-C6 cycloalkylalkylene)-OPO(OH)2, optionally substituted C3-C6 heterocyclyl, (optionally substituted C3-C6 heterocyclyl)-OPO(OH)2, optionally substituted C3-C6 heterocyclylalkyl, -(optionally substituted C3-C6 heterocyclylalkyl)-OPO(OH)2, or optionally substituted C1-C8 alkyl-CO-; R 2 is H, D, or F, R 4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R 6 is H, D, Cl, or F, R 7 is optionally substituted C1-C8 alkyl, or R is not H and R and R 7 are optionally joined to form an optionally substituted heterocyclyl ring; Z is (a)

[0006] [ka] wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R 11are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups taken together to form oxo), or (b)

[0007] [ka] wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R 11 are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 The groups together form an oxo.

[0008] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0009] One embodiment provides a method of treating a disease or disorder in a patient, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the above method, wherein the disease or disorder is cancer.

[0010] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges for physical properties, such as molecular weight, or chemical properties, such as formula, are used herein, all combinations and subcombinations of ranges and specific embodiments within the ranges are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is approximate within experimental variation (or within statistical experimental error), and thus the number or range of numbers may, in some cases, vary by 1%-15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other embodiments, such as, for example, any composition of matter, composition, method, or process described herein, "consist of" or "consist essentially of" the described features.

[0012] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0013] "Amino" refers to the -NH2 radical.

[0014] "Cyano" refers to the -CN radical.

[0015] "Nitro" refers to the -NO2 radical.

[0016] "Oxa" refers to the -O- radical.

[0017] "Oxo" refers to the =O radical.

[0018] "Thioxo" refers to the =S radical.

[0019] "Imino" refers to the =NH radical.

[0020] "Oximo" refers to the =N-OH radical.

[0021] "Hydrazino" refers to the =N-NH2 radical.

[0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In some embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13In some embodiments, an alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0024] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In some embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specified in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In some embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise stated in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O-R ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)ORa , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain (e.g., methylene, ethylene, propylene, n-butylene, etc.) that connects the rest of the molecule to a radical group, consists of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon atom in the alkylene chain or any two carbon atoms within the chain. In some embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene contains 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene contains 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene contains 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms, linking the radical group to the rest of the molecule. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise in the specification, an alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, linking a radical group to the rest of the molecule. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise in the specification, an alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 5-18 carbon atoms, where at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in the specification, the term "aryl" or the prefix "ar" (as in "aralkyl") is meant to include aryl radicals that are optionally substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(Ra )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0030] "Aralkyl" is a group of the formula -R c-refers to the aryl radical, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] "Aralkenyl" refers to a group of the formula -R d -refers to the aryl radical, R d is an alkenylene chain as defined above. The aryl group part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene group part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0032] "Aralkynyl" has the formula -R e -refers to the aryl radical, R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0033] "Aralkoxy" has the formula -OR c -refers to an aryl radical attached by an oxygen atom, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0034] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated in this specification, the term "carbocyclyl" is meant to include carbocyclyl radicals optionally substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -Rb -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0035] A "carbocyclylalkyl" is a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0036] "Carbocyclylalkynyl" refers to a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0037] "Carbocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a carbocyclyl, R c is an alkylene chain as defined below: The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0038] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0039] [ka]

[0040] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0041] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0042] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in this specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above optionally substituted by one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -Rb -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0043] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0044] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, and the point of attachment of the heterocyclyl to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-piperidinyl or 3-piperidinyl or 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl or 3-pyrrolidinyl, and the like.

[0045] "Heterocyclylalkyl" refers to a group of the formula -R c - refers to the heterocyclyl radical, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0046] "Heterocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a heterocyclyl, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0047] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imino Dazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloopta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, Pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] Pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]puridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated in this specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above, optionally substituted by one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O)t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0048] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0049] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0050] "Heteroarylalkyl" has the formula -R c - refers to the heteroaryl radical, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0051] "Heteroarylalkoxy" refers to a group of the formula -OR c - refers to a heteroaryl radical attached by an oxygen atom, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0052] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0053] "Tautomer" refers to a molecule in which a proton transfer from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein exist as tautomers in some embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0054] [ka]

[0055] In some embodiments, the compounds disclosed herein are available in various isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14The compound is enriched to a C content and used. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, thereby increasing the duration of action of pharmaceuticals.

[0056] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium; 13 C enriched or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0057] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It can be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125All isotopic substitutions with I are contemplated. In some embodiments, 18 Isotopic substitution with F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0058] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 The atom is replaced with a H. Methods for the synthesis of compounds containing deuterium are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0059] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)]2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0060] Deuterated starting materials are readily available and amenable to the synthetic methods described herein for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical companies such as Aldrich Chemical Co.

[0061] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be used to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated, by way of example only, in the following reaction scheme:

[0062] [ka]

[0063] A deuterium transfer reagent, such as lithium aluminum deuteride (LiAlD4), is used to transfer deuterium to the reaction substrate under the above reducing conditions. The use of LiAlD4 is illustrated, by way of example only, in the following reaction scheme:

[0064] [ka]

[0065] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and, by way of example only, to effect reductive displacement of aryl carbon-halogen bonds as illustrated in the following reaction scheme:

[0066] [ka]

[0067] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and are non-exchangeable. 1 In one embodiment, the level of deuterium incorporation is determined by a synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0068] " Pharmaceutically acceptable salt " includes both acid and base addition salt.The pharmaceutically acceptable salt of any one of the heterocyclic aromatic RAF inhibitor compounds described herein is intended to include any pharmaceutically suitable salt form.Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0069] "Pharmaceutically acceptable acid addition salts" refer to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared, in some embodiments, by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0070] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, made with metals or amines, such as alkali, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0071] A "pharmaceutically acceptable solvate" refers to a composition of a substance in a solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric solvents and are formed during the manufacturing process using pharmaceutically acceptable solvents such as water or ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in solvated or unsolvated forms. The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following mammalian classes: humans, non-human primates such as chimpanzees, and other apes and monkey species; livestock such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0072] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A "therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient even though the patient still suffers from the underlying disease. For a prophylactic effect, the composition, in some embodiments, is administered to a patient at risk of contracting the disease or reporting one or more physiological symptoms of the disease, even if a diagnosis of the specific disease has not been made.

[0073] RAF family of kinases RAF kinases are a family of serine / thoronine protein kinases that constitute the core components of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade (also known as the MAPK / ERK pathway), a pathway that mediates signals from cell surface receptors to the nucleus to control cell growth, differentiation, and survival. RAF proteins are related to retroviral oncogenes and, like the MAPK / ERK pathway, are structurally conserved from metazoans to mammals. Their dysregulation leads to uncontrolled cell proliferation, survival, and dedifferentiation. Consequently, RAF kinases are altered or inappropriately activated in the majority of cancers.

[0074] The MAPK / ERK signaling pathway is a network of intracellular proteins that transmits signals from receptors on the cell surface to DNA in the cell's nucleus. Signaling begins when a signaling molecule binds to a receptor on the cell surface and ends when the DNA in the nucleus expresses a protein that causes some internal change, such as cell division. This pathway involves many proteins that communicate with each other by adding phosphate groups to neighboring proteins, which act as "on" or "off" switches. Overall, this pathway can be divided into three steps: (i) activation of Ras, (ii) kinase-mediated signaling cascades, and (iii) regulation of translation and transcription. Briefly, extracellular mitogens or signaling molecules bind to membrane receptors, activating Ras (a small GTPase) by exchanging GDP for GTP. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinase phosphorylates and activates MEK (MEK1 and MEK2), which in turn phosphorylates and activates MAPK (also known as ERK). Activation of MAPKs regulates the activity of several transcription factors, which in turn alters the translation of mRNA into protein. MAPKs alter the levels and activity of transcription factors, thereby altering the transcription of genes important for the cell cycle.

[0075] There are three known mammalian RAF isoforms: C-RAF (also known as RAF-1 or c-RAF-1), B-RAF, and A-RAF. All RAF kinases share a common modular structure consisting of three conserved regions (CR1, CR2, and CR3) with distinct functions. 1 It contains (i) a Ras-binding domain (RBD) required for interaction with Ras and membrane phospholipids required for membrane recruitment, and (ii) a cysteine-rich domain (CRD) that is a secondary Ras-binding site and is required for interaction with the CR1 and kinase domains for autoinhibition of RAF. 2 contains a critical phosphorylation inhibitory site involved in the negative regulation of Ras binding and RAF activation. CR3 features a kinase domain containing an activation segment, the phosphorylation of which is essential for kinase activation.

[0076] Functionally, the RAF structure can be divided into a regulatory N-terminal region containing the RBD, which is important for activation, as well as inhibitory phosphorylation sites, and a catalytic C-terminal region containing the phosphorylation sites required for kinase activation. The regulatory domain suppresses the activity of the kinase domain, and its removal results in constitutive oncogenic activation. However, the activity of the isolated c-RAF kinase domain is subject to further regulation and can be stimulated by phorbol esters, v-Src, and phosphorylation.

[0077] A common and critical step in the activation of all three RAF kinase isoforms is membrane recruitment by Ras family proteins. RAF kinases are inactive and located in the cytoplasm when bound to 14-3-3 proteins. In the presence of active Ras, they translocate to the plasma membrane. This membrane translocation triggers further activation events, such as the binding of PP2A, which dephosphorylates the inhibitory pS259 site in RAF-1 (and possibly the corresponding sites in A-RAF and B-RAF), and colocalization with kinases involved in multiple activating phosphorylations. The sequences forming the binding interface are well conserved within the RAF and Ras families, indicating that some members of the Ras family possess the ability to bind RAF kinases. H-Ras, N-Ras, and K-Ras are the only Ras proteins that stimulate all three RAF isoforms and activate B-RAF. In contrast, A-RAF is also activated by R-Ras3, and C-RAF is weakly activated by R-Ras3, Rit, and TC21as. However, all RAF kinases share MEK1 / 2 kinase as a substrate. MEK1 / 2 activates ERK1 / 2, and this pathway controls many cellular functions, including cell proliferation, differentiation, migration, and apoptosis.

[0078] C-RAF C-RAF was the first to be identified and is a ubiquitously expressed isoform. In humans, C-RAF is encoded by the RAF1 gene. C-RAF also has known splice variants that are preferentially expressed in muscle and brain. C-RAF plays an important role in mediating the cellular effects of growth factor signals. In its inactive state, C-RAF exists in a closed conformation in which the N-terminal regulatory domain folds over and occludes the catalytic domain. This conformation is stabilized by 14-3-3 dimers that bind to phospho-S259 (pS259) on the N-terminus and pS621 on the C-terminus. Dephosphorylation of pS259 on the plasma membrane by specific phosphatases (PP2A, PP1) releases 14-3-3 from its N-terminal binding site in C-RAF, thereby unmasking the RBD and CRD domains of the CR1 region, allowing Ras binding and recruitment to the membrane.

[0079] B-RAF B-RAF is encoded by the BRAF gene, also known in humans as the proto-oncogene B-RAF and v-RAF murine sarcoma viral oncogene homolog B. Alternative splicing results in multiple B-RAF isoforms that are differentially expressed in various tissues. While A-RAF and C-RAF require both phosphorylation and dephosphorylation of specific residues for activation, B-RAF is activated immediately upon translocation to the plasma membrane. B-RAF exhibits higher basal kinase activity than A-RAF and C-RAF. B-RAF requires binding of Ras and 14-3-3 for activation and is inhibited or activated by PKA depending on the level of 14-3-3 expression, which must be high to allow activation. B-RAF activity is also regulated by splicing. B-RAF isoforms containing exon 8b are more phosphorylated at the inhibitory S365 site, which enhances their interaction with 14-3-3 and strengthens the inhibitory interaction between the N-terminal regulatory domain and the kinase domain, resulting in reduced kinase activity.

[0080] A-RAFThe serine / threonine-protein kinase A-RAF, or A-RAF, is an enzyme encoded by the human ARAF gene. A-RAF has two known splice isoforms, DA-RAF1 and D-RAF2, which lack the kinase domain and function as dominant inhibitory variants of Ras and ARF GTPases. DA-RAF1 is a positive regulator of myogenic differentiation by mediating inhibition of the ERK pathway, which is required for differentiation. A-RAF differs from other RAF kinases in several ways. A-RAF is the only RAF isoform that is regulated by steroid hormones. In addition, A-RAF protein contains amino acid substitutions in the negatively charged region (N-region) upstream of the kinase domain, which contribute to its low basal activity. Furthermore, A-RAF is only weakly activated by oncogenic H-Ras and Src and exhibits low kinase activity toward MEK (it has the lowest kinase activity toward MEK among the Raf kinase family). In addition to phosphorylating MEK, A-RAF also inhibits MST2, a tumor suppressor and proapoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A-RAF prevents apoptosis from occurring. However, this inhibition occurs only if the splice factor heterogeneous nuclear ribonucleoprotein H (hnRNP H) maintains expression of the full-length A-RAF protein. Tumor cells often overexpress hnRNP H, resulting in full-length A-RAF expression, inhibiting apoptosis and allowing cancer cells that should be destroyed to survive. A-RAF also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is involved in the Warburg effect in cancer cells. A-RAF upregulates PKM2 activity by promoting a conformational change in PKM2, which shifts it from a less active dimer to a more active tetramer. This allows more glucose carbons to be converted to pyruvate and lactate to generate cellular energy, implicating A-Raf in the regulation of energy metabolism and cellular transformation, both of which are critical for tumorigenesis.

[0081] RAF kinase inhibitors Aberrant activation of the MAPK / ERK pathway is frequently observed in various cancers and has become a target for cancer therapeutics. In particular, B-RAF has emerged as one of the most attractive molecular targets for cancer therapeutics, as somatic mutations in B-RAF are frequently found in human tumors. B-RAF mutations are found in approximately 20% of all cancer samples examined to date. B-RAF-V600E, a missense mutation within the kinase domain created by a glutamic acid to valine substitution at position 600, is the most common B-RAF mutation. C-RAF is mutated in less than 1% of various tumor types, with A-RAF mutation rates being even lower. B-RAF and C-RAF form homodimers and heterodimers as part of their activation mechanism, with A-RAF stabilizing the B-RAF:C-RAF complex to maintain signaling efficiency. Similarly, it is C-RAF, not B-RAF, that transmits signals from oncogenic RAS to MEK. Thus, each of the RAF isoforms serves as a therapeutic target in various contexts.

[0082] Sorafenib was the first RAF inhibitor to enter clinical trials. It is a broad-specificity drug that inhibits additional kinases, including the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3), the platelet-derived growth factor receptor family (PDGFR-b and KIT), and FLT3. Clinical trials showed no correlation between clinical response and B-RAF mutation status, indicating that it is a weak inhibitor of B-RAF. This led to the development of a new generation of B-RAF inhibitors, including, but not limited to, vemurafenib, SB-590885, and dabrafenib (GSK2118436). While early results from clinical trials targeting B-RAF-mutant melanoma were promising, as clinical trials began targeting other B-RAF-mutant cancers (e.g., thyroid and colorectal cancers), it has become clear that tumors of different cell types harboring B-RAF mutations respond differently to selective B-RAF inhibition. Furthermore, the existence of both primary and secondary resistance to RAF inhibition poses one of the greatest challenges for the advancement of RAF kinase inhibitor therapy. Resistance mechanisms fall into two broad categories. Intrinsic / primary resistance is observed in approximately 50% of patients. The remaining 50% of patients initially respond to RAF inhibitors (>30% tumor shrinkage) but subsequently develop progressive disease associated with acquired / secondary resistance to RAF inhibitors. These two categories are not mutually exclusive, as nearly all responders have residual disease and therefore may exhibit intrinsic resistance. The determinants of primary resistance to RAF inhibitors appear to vary by tumor type and may also involve alterations in RTK signaling. Possible mechanisms of secondary resistance to B-RAF inhibitors include, but are not limited to, reactivation of the ERK1 / 2 pathway, upregulation of RTK signaling, upregulation of receptor tyrosine kinases, RAS mutations, and upregulation of COT. Alternative splicing of B-RAF and B-RAF-V600E amplification are also involved in ∼30% and ∼20% of patients, respectively.Furthermore, RAF kinase inhibitors can cause paradoxical activation of the MAPK pathway, potentially leading to the development of malignancies caused by secondary RAS gene mutations.Therefore, the field is seeking new RAF kinase inhibitors that overcome the existing pitfalls and challenges posed by current inhibitors.

[0083] Heteroaromatic RAF inhibitors In one aspect, provided herein are heteroaromatic RAF inhibitor compounds.

[0084] One embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0085] [ka] During the ceremony, Ring A is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl; W is NH, NR 7 , or O, X is N, CH, CF, or C-CN; Y is N, CF, or CH; R is H, optionally substituted C1-C8 alkyl, (optionally substituted C1-C8 alkylene)-OPO(OH)2, optionally substituted C3-C6 cycloalkyl, (optionally substituted C3-C6 cycloalkylene)-OPO(OH)2, optionally substituted C4-C8 cycloalkylalkyl, (optionally substituted C3-C6 cycloalkylalkylene)-OPO(OH)2, optionally substituted C3-C6 heterocyclyl, (optionally substituted C3-C6 heterocyclyl)-OPO(OH)2, optionally substituted C3-C6 heterocyclylalkyl, -(optionally substituted C3-C6 heterocyclylalkyl)-OPO(OH)2, or optionally substituted C1-C8 alkyl-CO-; R 2 is H, D, or F, R 4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R 6 is H, D, Cl, or F, R 7 is optionally substituted C1-C8 alkyl, or R is not H and R and R 7 are optionally joined to form an optionally substituted heterocyclyl ring; Z is (a)

[0086] [ka] wherein m is 0, 1, 2, or 3, p is 0, 1, 2, 3, or 4, and R 11 are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups taken together to form oxo), or (b)

[0087] [ka] wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R 11are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 The groups together form an oxo.

[0088] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5- or 6-membered optionally substituted heteroaryl.

[0089] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted pyridine or optionally substituted pyrazole.Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted 4-pyridinyl or optionally substituted 3-pyrazole.

[0090] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5- or 6-membered optionally substituted heterocyclyl.

[0091] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted dihydropyran, optionally substituted tetrahydropyran, optionally substituted dihydrofuran, or optionally substituted tetrahydrofuran. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted dihydro-2H-pyran-4-yl, optionally substituted tetrahydropyran-4-yl, optionally substituted 2,5-dihydrofuran-3-yl, optionally substituted tetrahydrofuran-3-yl, 3-oxabicyclo[3.1.0]hexan-1-yl, or 3-oxabicyclo[4.1.0]heptan-6-yl.

[0092] Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is an optionally substituted morpholine.

[0093] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (II):

[0094] [ka] During the ceremony, W is NH, NR 7 , or O, X is N, CH, CF, or C-CN; Y is N, CF, or CH; R is H, optionally substituted C1-C8 alkyl, (optionally substituted C1-C8 alkylene)-OPO(OH)2, optionally substituted C3-C6 cycloalkyl, (optionally substituted C3-C6 cycloalkylene)-OPO(OH)2, optionally substituted C4-C8 cycloalkylalkyl, (optionally substituted C3-C6 cycloalkylalkylene)-OPO(OH)2, optionally substituted C3-C6 heterocyclyl, (optionally substituted C3-C6 heterocyclyl)-OPO(OH)2, optionally substituted C3-C6 heterocyclylalkyl, -(optionally substituted C3-C6 heterocyclylalkyl)-OPO(OH)2, or optionally substituted C1-C8 alkyl-CO-; R 1 is optionally substituted C1-C3 alkyl, and q is 0, 1, or 2; R 2 is H, D, or F, R 4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R 6 is H, D, Cl, or F, R 7 is optionally substituted C1-C8 alkyl, or R is not H and R and R 7 are optionally joined to form an optionally substituted heterocyclyl ring; R c is H or D, Z is (a)

[0095] [ka] wherein m is 0, 1, 2, or 3, p is 0, 1, 2, 3, or 4, and R 11are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups taken together to form oxo), or (b)

[0096] [ka] wherein n is 1, 2, or 3, m is 1, 2, or 3, p is 0, 1, 2, 3, or 4, and R 11 are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 The groups together form an oxo.

[0097] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (III):

[0098] [ka] During the ceremony, W is NH or O; X is N, CH, or C-CN; Y is N or CH; R is optionally substituted C1-C8 alkyl, -(optionally substituted C1-C8 alkylene)-OPO(OH), optionally substituted C3-C6 cycloalkyl, -(optionally substituted C3-C6 cycloalkylene)-OPO(OH), optionally substituted C4-C6 cycloalkylalkyl, -(optionally substituted C3-C6 cycloalkylalkylene)-OPO(OH), optionally substituted C3-C6 heterocyclyl, -(optionally substituted C3-C6 heterocyclyl)-OPO(OH), optionally substituted C3-C6 heterocyclylalkyl, -(optionally substituted C3-C6 heterocyclylalkyl)-OPO(OH), R 1 is optionally substituted C1-C3 alkyl, and q is 0, 1, or 2; R 2 is H, D, or F, R 4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R 6 is H, D, Cl, or F, R c is H or D, Z is

[0099] [ka] wherein m is 0, 1, 2, or 3, p is 0, 1, 2, 3, or 4, and R 11are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 The groups together form an oxo.

[0100] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH.

[0101] Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NR 7 Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is an optionally substituted C1 alkyl.

[0102] Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NR 7 and R is not H, but R and R 7are linked to form an optionally substituted heterocyclyl ring. Another embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl ring is a 1-aztidinyl ring, a 1-pyrrolidinyl ring, or a 1-piperidinyl ring. Another embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl ring is substituted with at least one substituent selected from -OH, halogen, optionally substituted C-C alkyl, or optionally substituted C-C alkoxy.

[0103] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C-C alkyl, optionally substituted C-C cycloalkyl, optionally substituted C-C cycloalkylalkyl, optionally substituted C-C heterocyclyl, or optionally substituted C-C heterocyclylalkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C-C alkyl, optionally substituted C-C cycloalkyl, optionally substituted C-C cycloalkylalkyl, optionally substituted C-C heterocyclyl, or optionally substituted C-C heterocyclylalkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C8 alkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C4 alkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C3 alkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C2 alkyl. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C1-C6 alkyl, wherein the alkyl is substituted with at least one hydroxyl.

[0104] Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is H.

[0105] Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C8 alkyl-CO-.

[0106] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C6 cycloalkyl.

[0107] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C4-C6 cycloalkylalkyl.

[0108] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted C3-C6 heterocyclyl.

[0109] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C6 heterocyclylalkyl.

[0110] Another embodiment provides compounds of Formula (II)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C alkyl. Another embodiment provides a compound of Formula (II)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. Another embodiment provides a compound of Formula (II)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

[0111] Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

[0112] [ka] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0113] Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C6 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C4 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C3 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C2 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C4 fluoroalkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is an optionally substituted C3-C6 cycloalkyl.

[0114] Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein: Z is

[0115] [ka] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0116] Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C6 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C4 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11is optionally substituted C1-C3 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C2 alkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C4 fluoroalkyl. Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 Another embodiment provides compounds of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is an optionally substituted C3-C6 cycloalkyl.

[0117] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH and ring A is an optionally substituted morpholine.

[0118] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0119] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is an optionally substituted morpholine and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0120] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0121] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C4 alkyl, W is NH, and ring A is optionally substituted morpholine.

[0122] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C4 alkyl, W is NH, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0123] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, where R is optionally substituted C-C alkyl, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine. Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, where R is optionally substituted C-C alkyl, W is NH, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0124] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, W is NH, and ring A is an optionally substituted morpholine.

[0125] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, W is NH, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0126] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0127] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, W is NH, ring A is an optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0128] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, R is optionally substituted C-C alkyl, W is NH, and ring A is optionally substituted morpholine.

[0129] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, R is optionally substituted C1-C4 alkyl, W is NH, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0130] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, R is optionally substituted C-C alkyl, Ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0131] Another embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, R is optionally substituted C-C alkyl, W is NH, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0132] One embodiment provides a compound having the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof:

[0133] [ka] During the ceremony, Ring A is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl; W is NH or NR 7 and X is N, CH, CF, or C-CN; Y is N, CF, or CH; R is -SO2- (optionally substituted C1-C8 alkyl), -SO2- (optionally substituted C3-C6 cycloalkyl), -SO2- (optionally substituted C4-C8 cycloalkylalkyl), -SO2- (optionally substituted C3-C6 heterocyclyl), -SO2- (optionally substituted C3-C6 heterocyclylalkyl), -SO2-N(R 8 )R 9 -optionally substituted C1-C8 alkyl, -CO2-optionally substituted C1-C8 alkyl, or -CO-N(R 8 )R 9 - optionally substituted C1-C8 alkyl; R 2 is H, D, or F, R 4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R 6is H, D, Cl, or F, R 7 is optionally substituted C1-C8 alkyl; or R and R 7 is optionally joined to form a heterocyclyl ring; R 8 and R 9 are each independently selected from H or optionally substituted C1-C8 alkyl; Z is (a)

[0134] [ka] wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R 11 are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups taken together to form oxo), or (b)

[0135] [ka] wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R 11are each independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 The groups together form an oxo.

[0136] Another embodiment provides a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5- or 6-membered optionally substituted heteroaryl.

[0137] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted pyridine or optionally substituted pyrazole.Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted 4-pyridinyl or optionally substituted 3-pyrazole.

[0138] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5- or 6-membered optionally substituted heterocyclyl.

[0139] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted dihydropyran, optionally substituted tetrahydropyran, optionally substituted dihydrofuran, or optionally substituted tetrahydrofuran. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted dihydro-2H-pyran-4-yl, optionally substituted tetrahydropyran-4-yl, optionally substituted 2,5-dihydrofuran-3-yl, optionally substituted tetrahydrofuran-3-yl, 3-oxabicyclo[3.1.0]hexan-1-yl, or 3-oxabicyclo[4.1.0]heptan-6-yl.

[0140] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted morpholine. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH.

[0141] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NR 7 Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is optionally substituted C1-C8 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R 7 are optionally joined to form an optionally substituted heterocyclyl ring.

[0142] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —SO 2 —(optionally substituted C 1 -C 8 alkyl).

[0143] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —SO 2 —(optionally substituted C 3 -C 6 cycloalkyl).

[0144] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —SO 2 —(optionally substituted C 4 -C 8 cycloalkylalkyl).

[0145] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —SO 2 —(optionally substituted C 3 -C 6 heterocyclyl).

[0146] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —SO 2 —(optionally substituted C 3 -C 6 heterocyclylalkyl).

[0147] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —SO—N(R 8 )R 9 -optionally substituted C1-C8 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 and R 9 are each independently selected from H or optionally substituted C1-C8 alkyl.

[0148] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CO2- optionally substituted C1-C8 alkyl.

[0149] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —CO—N(R 8 )R 9-optionally substituted C1-C8 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 and R 9 are each independently selected from H or optionally substituted C1-C8 alkyl.

[0150] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

[0151] [ka] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0152] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

[0153] [ka] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0154] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C4 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C3 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C2 alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C4 fluoroalkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is an optionally substituted C3-C6 cycloalkyl.

[0155] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH and ring A is an optionally substituted morpholine.

[0156] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0157] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is optionally substituted morpholine and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0158] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0159] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, W is NH, and ring A is an optionally substituted morpholine.

[0160] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, W is NH, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0161] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, ring A is optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0162] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH, Y is CH, W is NH, ring A is an optionally substituted morpholine, and Z is 3-(2,2,2-trifluoroethyl)pyrrolidine.

[0163] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N and Y is CH.

[0164] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N and Y is N.

[0165] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH and Y is CH.

[0166] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH and Y is N.

[0167] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CF and Y is CH.

[0168] Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH and Y is CF.

[0169] Another embodiment provides compounds of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H.

[0170] Another embodiment provides compounds of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1-C3 alkyl.

[0171] Another embodiment provides compounds of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1 alkyl.

[0172] Another embodiment provides compounds of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is CH3.

[0173] Another embodiment provides compounds of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is H.

[0174] In some embodiments, heteroaromatic RAF kinase inhibitor compounds as described herein have the structures provided in Table 1.

[0175] [Table 1-1]

[0176] [Table 1-2]

[0177] [Table 1-3]

[0178] Table 1-4

[0179] Table 1-5

[0180] Table 1-6

[0181] Table 1-7

[0182] Table 1-8

[0183] Table 1-9

[0184] Table 1-10

[0185] Table 1-11

[0186] Table 1-12

[0187] Table 1-13

[0188] Table 1-14

[0189] Table 1-15

[0190] Table 1-16

[0191] Table 1-17

[0192] Table 1-18

[0193] Table 1-19

[0194] Table 1-20

[0195] Table 1-21

[0196] Table 1-22

[0197] Table 1-23

[0198] Table 1-24

[0199] Table 1-25

[0200] Table 1-26

[0201] Table 1-27

[0202] Table 1-28

[0203] Table 1-29

[0204] Table 1-30

[0205] Table 1-31

[0206] Table 1-32

[0207] Table 1-33

[0208] Table 1-34

[0209] Table 1-35

[0210] Table 1-36

[0211] Table 1-37

[0212] Table 1-38

[0213] Table 1-39

[0214] Table 1-40

[0215] Table 1-41

[0216] Table 1-42

[0217] Table 1-43

[0218] Table 1-44

[0219] [Table 1-45]

[0220] [Table 1-46]

[0221] [Table 1-47]

[0222] [Table 1-48]

[0223] [Table 1-49]

[0224] Preparation of compounds The compounds used in the reactions described herein are made by organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; includes Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0225] Suitable reference books and articles detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif., 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RCMarch, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0226] Certain similar reactants are optionally identified by indexes of known chemicals prepared by the American Chemical Society's Chemical Abstract Service, available at most public and university libraries and via online data services (for more information, contact the American Chemical Society in Washington, D.C.). Known chemicals not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. For information on the preparation and selection of pharmaceutical salts of the compounds described herein, see P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0227] Pharmaceutical Composition In certain embodiments, the heteroaromatic RAF kinase inhibitor compounds described herein are administered as pure chemicals. In other embodiments, the heteroaromatic RAF kinase inhibitor compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0228] Provided herein are pharmaceutical compositions comprising at least one heteroaromatic RAF kinase inhibitor compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (i.e., subject or patient).

[0229] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof.

[0230] One embodiment provides a method for preparing a pharmaceutical composition, the method comprising the step of mixing a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0231] In certain embodiments, heteroaromatic RAF kinase inhibitor compounds as described by Formulas (I)-(IV) are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0232] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0233] In some embodiments, the heteroaromatic RAF kinase inhibitor compound described by Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some examples, the injection formulation is an aqueous formulation. In some examples, the injection formulation is a non-aqueous formulation. In some examples, the injection formulation is an oil-based formulation, such as sesame oil.

[0234] The dosage of the compositions comprising at least one heteroaromatic RAF kinase inhibitor compound as described herein will vary depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include health status, age, and other factors.

[0235] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dosage and treatment regimen provides the composition in an amount sufficient to bring about a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome), such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body type, weight, or blood volume.

[0236] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0237] Treatment method One embodiment provides a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0238] One embodiment provides a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

[0239] One embodiment provides the use of a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0240] In some embodiments, described herein are methods of treating cancer in a patient, comprising administering to the patient a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof. Also described herein are methods of treating cancer in a patient, in some embodiments, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0241] Methods are provided herein wherein the pharmaceutical composition is administered orally.Methods are provided herein wherein the pharmaceutical composition is administered by injection.

[0242] Other embodiments and uses will be apparent to those skilled in the art in view of the present disclosure. The following examples are provided only as illustrative of various embodiments and are not to be construed as limiting the invention in any way. [Example]

[0243] I. Chemical synthesis In some embodiments, heteroaromatic RAF kinase inhibitor compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the present invention, the following abbreviations shall be understood to have the following meanings, unless otherwise specified: ℃ Celsius δ HChemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DMF Dimethylformamide DMSO dimethyl sulfoxide EA Ethyl acetate ESI electrospray ionization Et Ethyl g grams h time HPLC High Performance Liquid Chromatography Hz Hertz J coupling constant (measured by NMR spectroscopy) LCMS Liquid Chromatography Mass Spectrometry μ Micro m multiplet (spectrum), meter, millimeter M mole M + Parent molecular ion Me methyl MHz Megahertz min mol mole, molecule (mol wt) mL milliliter MS mass spectrometry nm nanometer NMR nuclear magnetic resonance pH: Hydrogen ion potential; a measure of the acidity or basicity of an aqueous solution PE Petroleum Ether RT room temperature s singlet (spectrum) t triplet (spectrum) T temperature TFA trifluoroacetic acid THF tetrahydrofuran

[0244] Example 1: (3S)—N-(3-[6-[(3,3-difluorocyclopentyl)amino]-2-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0245] [ka]

[0246] Synthesis scheme

[0247] [ka]

[0248] Preparation 1A: (3S)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0249] [ka]

[0250] To a stirred solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (11.0 g, 47.186 mmol, 1.00 equiv.) in THF (1000 mL) was added DIEA (30.5 g, 235.930 mmol, 5.00 equiv.) and triphosgene (5.6 g, 18.874 mmol, 0.40 equiv.) at ambient temperature under a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at ambient temperature. To this was added a solution of (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (8.95 g, 47.186 mmol, 1.00 equiv.) in THF (100 mL). The resulting mixture was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (5%-45%) to give (3S)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (16.3 g, 84%) as a white solid. MS ESI calculated for C 20 H 28 BF3N2O3[M+H] + , 413.21, found 413.25. 1 H NMR(300MHz,chloroform-d) δ 7.75(dd,J=8.4, 2.7Hz,1H),7.44(d,J=2.7Hz,1H),7.14(d,J=8.4Hz,1H),6.14(s,1H),3.86-3.74(m,1H),3.69-3.56(m,1H),3.43(td,J=9.6, 6.6Hz,1H),3.11(t,J=9.6Hz,1H),2.58(dd,J=16.5, 8.4Hz,1H),2.50(s,3H),2.37-2.18(m,3H),1.82-1.75(m,1H),1.36(s,12H). 19 F NMR (282 MHz, chloroform-d) δ -64.95.

[0251] Preparation 1B: N-(3,3-dimethylcyclopentyl)-6-methyl-2-(morpholin-4-yl)pyrimidin-4-amine

[0252] [ka]

[0253] To a stirred solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (140 mg, 0.598 mmol) and 3,3-difluorocyclopentan-1-amine hydrochloride (104 mg, 0.658 mmol) in DMSO (1 mL) was added dropwise DIEA (386 mg, 2.990 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / (EA / EtOH=3:1) (3:1) to give N-(3,3-dimethylcyclopentyl)-6-methyl-2-(morpholin-4-yl)pyrimidin-4-amine (160 mg, 92%) as an off-white solid. MS ESI calculated for C 13 H 17 ClF2N4O [M+H] + , 319.11, found 319.15. 1 H NMR(400MHz,DMSO-d6) δ 7.55(s,1H),5.81(s,1H),4.36(s,1H),3.61(s,8H),3.42(s,2H),2.62-2.55(m,1H),2.28-1.92(m,2H),1.73-1.63(m,1H). 19 F NMR(376MHz,DMSO-d6) δ-87.90(2F).

[0254] Example 1: (3S)—N-(3-[6-[(3,3-difluorocyclopentyl)amino]-2-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0255] [ka]

[0256] To a stirred solution of 6-chloro-N-(3,3-difluorocyclopentyl)-2-(morpholin-4-yl)pyrimidin-4-amine (140 mg, 0.439 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (181 mg, 0.439 mmol), and KPO (186 mg, 0.878 mmol) in dioxane:HO = 2:1 (2 mL), Pd(DtBPF)Cl (29 mg, 0.044 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / (EA / EtOH=3:1) (2:1) to give 150 mg of crude product. The residue was purified by reverse flash chromatography at 210 / 254 nm under the following conditions: Column: XBridge C18 OBD Preparative Column, 100A, 10 μm, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 40% B to 80% B in 5.8 min; to give (3S)-N-(3-[6-[(3,3-difluorocyclopentyl)amino]-2-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (130 mg, 52%) as an off-white solid. MS ESI calculated for C 27 H 33F5N6O2[M+H] + , 569.26, found 569.25. 1 H NMR(400MHz,DMSO-d6) δ 8.13(s,1H),7.52(m,1H),7.42-7.41(m,1H),7.30-7.28(m,1H),7.09- 7.06(m,1H),5.86(s,1H),4.40(s,1H),3.69-3.64(m,9H),3.55-3.50( m,1H),3.31-3.28(m,1H),3.05-3.00(m,1H),2.59-2.51(m,1H),2.49- 2.40(m,3H),2.26-2.13(m,5H),2.13-2.03(m,3H),1.75-1.66(m,2H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F),-87.70-87.80(2F).

[0257] Examples 2 and 3: (3S)—N-[3-(6-[[(1R)-3,3-difluorocyclopentyl]amino]-2-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-(6-[[(1S)-3,3-difluorocyclopentyl]amino]-2-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0258] [ka]

[0259] (3S)-N-(3-[6-[(3,3-difluorocyclopentyl)amino]-2-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (130 mg) was purified using the following conditions: column: CHIRALPAK AD-H (2.0 cm - 25 cm); mobile phase A: hexachloroisothiazolinone (8 mmol / L); Purification by chiral preparative HPLC (mobile phase B: NH3.MeOH, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 20B to 20B in 18 min; 220 / 254 nm) gave (3S)-N-[3-(6-[[(1R)-3,3-difluorocyclopentyl]amino]-2-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (41 mg, 32%) as an off-white solid. MS ESI calculated for C 27 H 33 F5N6O2[M+H] + , 569.26, found 569.25. 1 H NMR(400MHz,DMSO-d6) δ 8.14(s,1H),7.52(m,1H),7.43-7.41(m,1H),7.30(s,1H),7.09-7.07(m,1H),5.86(s,1H),4.40(s,1H),3.69-3.64(m,9H),3.55-3.50(m, 1H),3.31-3.28(m,1H),3.05-3.00(m,1H),2.61-2.55(m,1H),2.46-2 .38(m,3H),2.26-2.13(m,5H),2.13-1.91(m,3H),1.78-1.61(m,2H). 19 F NMR(376MHz,DMSO-d6) δ-63.33(3F),-87.67(2F).

[0260] Similarly, (3S)-N-[3-(6-[[(1S)-3,3-difluorocyclopentyl]amino]-2-(morpholin-4-yl)pyrimidin-4-yl)4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (44 mg, 34%) was obtained as an off-white solid. MS ESI calculated for C 27 H 33 F5N6O2[M+H] + , 569.26, found 569.25. 1 H NMR(400MHz,DMSO-d6) δ 8.14(s,1H),7.52(m,1H),7.43-7.40(m,1H),7.30(s,1H),7.09-7.06(m,1H),5.86(s,1H),4.40(s,1H),3.69-3.64(m,9H),3.55-3.50(m, 1H),3.31-3.28(m,1H),3.05-3.00(m,1H),2.61-2.55(m,1H),2.46-2 .38(m,3H),2.26-2.13(m,5H),2.13-1.91(m,3H),1.78-1.61(m,2H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F),-87.68(2F).

[0261] Examples 4 and 5: (3S)—N-[3-(2-[[(1S,3S)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-(2-[[(1R,3R)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0262] [ka]

[0263] Preparation 4A: 4-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]morpholine

[0264] [ka]

[0265] To a stirred solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (2.20 g, 11.28 mmol) in THF (29 mL) was added dropwise DIPEA (1.60 g, 12.41 mmol) and morpholine (1.08 g, 12.40 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The precipitated solid was collected by filtration to give 4-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]morpholine (2.7 g, 97%) as a pale yellow solid. MS ESI calculated for CH 12 ClN3OS [M+H] + , 246.04;found 245.95. 1 H NMR(400MHz,DMSO-d6) δ 6.68(s,1H),3.68-3.64(m,8H),2.45(s,3H).

[0266] Preparation 4B: 4-(6-chloro-2-methanesulfonylpyrimidin-4yl)morpholine

[0267] [ka]

[0268] To a stirred solution of 4-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]morpholine (12.33 g, 50.18 mmol) and m-CPBA (23.43 g, 115.41 mmol, 85%) in DCM (172.6 mL) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding aqueous NaHCO3 (200 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with aqueous NaHCO3 (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give 4-(6-chloro-2-methanesulfonylpyrimidin-4-yl)morpholine (13.3 g, 95%) as a white solid. MS ESI calculated for CH 12 ClN3O3S [M+H] + , 278.03; found 277.95. 1 H NMR (300 MHz, chloroform-d) δ 6.62 (s, 1H), 3.82-3.75 (m, 8H), 3.36-3.31 (m, 3H).

[0269] Preparation 4C: trans-3-[[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino]-cyclopentan-1-ol

[0270] [ka]

[0271] A mixture of 4-(6-chloro-2-methanesulfonylpyrimidin-4-yl)morpholine (1.00 g, 3.60 mmol), (trans)-3-aminocyclopentan-1-ol hydrochloride (0.55 g, 4.00 mmol), and DIEA (1.40 g, 10.80 mmol) in DMSO (10 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / (EtOAc:EtOH=3:1) (1:1) to give trans-3-[[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino]cyclopentan-1-ol (0.38 g, 33%) as an off-white solid. MS ESI calculated for C 13 H 19 ClN4O2[M+H] + , 299.77, found 299.10. 1 H NMR(300MHz,DMSO-d6) δ 6.07(s,1H),4.29(m,1H),4.18(m,1H),3.64(m,4H),3.54(m,4H),3.40(m,2H),2.05(m,1H),1.86(m,2H),1.64-1.58(m,1H),1.41(m,2H).

[0272] Preparation 4D: (3S)-N-[3-(2-[[trans-3-hydroxycyclopentyl]amino)-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0273] [ka]

[0274] A mixture of trans-3-[[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino]cyclopentan-1-ol (200 mg, 0.669 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (276 mg, 0.669 mmol), Pd(DtBPF)Cl (44 mg, 0.067 mmol), and KPO (284 mg, 1.339 mmol) in 1,4-dioxane (3.6 mL) and HO (0.9 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE / ((EtOAc:EtOH=3:1):NH4OH=20:1) (1:1). The crude product was purified by reverse flash chromatography at 210 / 254 nm under the following conditions: Column: XBridge C18 OBD Prep Column, 100A, 10 μm, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 35B to 70B in 5.8 min; to give (3S)-N-[3-(2-[[(trans)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (180 mg, 29%) as an off-white solid. MS ESI calculated for C 27 H 35 F3N6O3[M+H] + , 549.27; found 549.30.

[0275] Example 4: (3S)—N-[3-(2-[[(1S,3S)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0276] Examples 4 and 5: (3S)—N-[3-(2-[[(1R,3R)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0277] [ka]

[0278] (3S)-N-[3-(2-[[(trans)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (180 mg) was resolved by chiral HPLC using the following conditions: Column: Reg-AD, 30 x 250 mm, 5 μm; Mobile phase A: Hexa (8 mmol / L NH3.MeOH), Mobile phase B: IPA; Flow rate: 45 mL / min; Gradient: 20B to 20B in 25 min; 220 / 254 nm) to give 75 mg (44%) of an off-white solid. MS ESI calculated for C 27 H 35 F3N6O3[M+H] + , 549.61; found 549.30. 1 H NMR (300 MHz, DMSO-d6) δ 8.11(s,1H),7.46-7.43(m,2H),7.09-7.06(m,1H),6.52-6.50(m,1H),5. 99(s,1H),4.41-4.36(m,2H),4.18-4.17(m,1H),3.70-3.43(m,10H),3.35 -3.28(m,1H),3.05-2.99(m,1H),2.50-2.32(m,3H),2.25-2.16(m,3H),2. 08-1.91(m,2H),1.90-1.75(m,2H),1.74-1.65(m,2H),1.64-1.30(m,2H). 19F NMR (282 MHz, DMSO-d6) δ -63.39-63.45 (3F) and (3S)-N-[3-(2-[[(1R,3R)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (77 mg, 45%) was obtained as an off-white solid. MS ESI calculated for C 27 H 35 F3N6O3[M+H] + , 549.61; found 549.30. 1 H NMR (300 MHz, DMSO-d6) δ 8.11(s,1H),7.46-7.43(m,2H),7.09-7.06(m,1H),6.52(m,1H),5.99(s, 1H),4.41-4.32(m,2H),4.17(m,1H),3.69-3.64(m,5H),3.55-3.50(m,5H) ,3.35-3.26(m,1H),3.05-2.99(m,1H),2.51-2.40(m,3H),2.25(s,3H),2. 07-1.99(m,2H),1.93-1.85(m,2H),1.70-1.55(m,2H),1.54-1.25(m,2H). 19 F NMR(376MHz,DMSO-d6) δ-63.35(3F).

[0279] Example 6: (3S)—N-[3-(2-[[(3-hydroxyoxetan-3-yl)methyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0280] [ka]

[0281] Preparation 6A: 3-([[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]methyl)oxetan-3-ol

[0282] [ka]

[0283] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (500 mg, 1.623 mmol), 3-(aminomethyl)oxetan-3-ol (251 mg, 2.434 mmol), and K2CO3 (449 mg, 3.246 mmol) in NMP (15 mL) was stirred overnight at 150 °C under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20 / 1) to give the crude product. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 50% gradient in 30 min; detector, UV 254 nm to give 3-([[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]methyl)oxetan-3-ol (148 mg, 23%) as a light brown solid. MS ESI calculated for C 13 H 18 IN3O3[M+H] + , 392.04, found 392.00. 1 H NMR(400MHz,DMSO-d6) δ 6.56-6.53(m,1H),6.33(m,1H),6.23(m,1H),5.90(s,1H),4.41-4.36(m,4H),3.66-3.63(m,4H),3.54-3.53(m,2H),3.36-3.34(m,4H).

[0284] Example 6: (3S)—N-[3-(2-[[(3-hydroxyoxetan-3-yl)methyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0285] [ka]

[0286] To a stirred solution of 3-([[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]methyl)oxetan-3-ol (140 mg, 0.358 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (162 mg, 0.394 mmol), and NaCO (114 mg, 1.074 mmol) in dioxane:HO = 4:1 (2.00 mL) was added Pd(dppf)Cl.CHCl (29 mg, 0.036 mmol) under a nitrogen atmosphere at 25 °C. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / (EA / EtOH=3:1) (2:1) to give 150 mg of crude product. The residue was purified under the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 * 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 20 mL / min; gradient: 45B to 60B in 4.5 min; purification by reverse flash chromatography at 254 / 210 nm gave (S)-N-[3-(2-[[(3-hydroxyoxetan-3-yl)methyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (100 mg, 51%) as an off-white solid. MS ESI calculated for C 27 H 34 F3N5O4[M+H] + , 550.26, found 550.25. 1H NMR (300 MHz, DMSO-d6) δ 8.11(s,1H),7.44-7.35(m,2H),7.11-7.09(m,1H),6.45-6.42(m,1H),6.05( s,1H),5.86-5.81(m,2H),4.46-4.39(m,4H),3.69-3.64(m,5H),3.61-3.59( m,2H),3.55-3.50(m,1H),3.39-3.34(m,4H),3.30-3.27(m,1H),3.05-3.00( m,1H),2.48-2.36(m,3H),2.16(s,3H),2.10-2.07(m,1H),1.71-1.61(m,1H). 19 F NMR(376MHz,DMSO-d6) δ-63.38(3F).

[0287] Example 7: (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0288] [ka]

[0289] Preparation 7A: 4-chloro-N-(3,3-difluorocyclopentyl)-6-(morpholin-4-yl)pyrimidin-2-amine

[0290] [ka]

[0291] To a stirred solution of 4-(6-chloro-2-methanesulfonylpyrimidin-4-yl)morpholine (200 mg, 0.720 mmol) and 3,3-difluorocyclopentan-1-amine hydrochloride (125 mg, 0.79 mmol) in DMSO (4 mL) was added dropwise DIEA (279 mg, 2.16 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give 4-chloro-N-(3,3-difluorocyclopentyl)-6-(morpholin-4-yl)pyrimidin-2-amine (84 mg, 37%) as a white solid. MS ESI calculated for C 13 H 17 ClF2N4O [M+H] + , 319.11; found 319.15. 1 H NMR(300MHz,DMSO-d6) δ 5.93(s,1H),5.16(s,1H),4.47-4.42(m,1H),3.79-3.76(m,4H),3.60- 3.57(m,4H),2.70-2.53(m,1H),2.32-1.82(m,4H),1.79-1.73(m,1H).

[0292] Example 7: (3S)—N-(3-[2-[(3,3-difluorocyclopentyl)amino]-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0293] [ka]

[0294] To a stirred solution of 4-chloro-N-(3,3-difluorocyclopentyl)-6-(morpholin-4-yl)pyrimidin-2-amine (160 mg, 0.502 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (248 mg, 0.602 mmol), KPO (213 mg, 1.004 mmol) in dioxane (3.2 mL), HO (0.8 mL) was added Pd(DtBPF)Cl (33 mg, 0.050 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane / (EtOAc:EtOH=3:1) (1:1) to give the crude material. The crude product (150 mg) was purified by preparative HPLC using the following conditions: Column: XSelect CSH Preparative C18 OBD Column, 19 × 250 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 30B to 40B in 6.5 min; 254 / 210 nm to give (3S)-N-(3-[2-[(3,3-difluorocyclopentyl)amino]-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (85 mg, 30%) as a white solid. MS ESI calculated for C 27 H 33 F5N6O2[M+H] + , 569.26, found 569.20. 1 H NMR(400MHz,DMSO-d6) δ 8.14(s,1H),7.47-7.45(m,2H),7.11-7.09(m,2H),6.07(s,1H),4.37-4.35(m,1H),3.67-3.51(m,1 0H),3.05-3.00(m,1H),2.44-2.42(m,6H),2.34-2.21(m,3H),2.09-2.08(m,4H),1.79-1.63(m,2H). 19F NMR(376MHz,DMSO-d6) δ-63.37(3F),-87.50(2F).

[0295] Examples 8 and 9: (3S)—N-[3-(2-[[(1R)-3,3-difluorocyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-(2-[[(1S)-3,3-difluorocyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0296] [ka]

[0297] (3S)-N-(3-[2-[(3,3-difluorocyclopentyl)amino]-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (80 mg) was resolved by preparative chiral HPLC (Column: CHIRALPAK ADH, 2 x 25 cm, 5 μm; Mobile Phase A: Hexa (8 mmol / L NH3.MeOH)-HPLC (Mobile Phase B): IPA-HPLC; Flow Rate: 20 mL / min; Gradient: 20B to 20B in 35 min; 220 / 254 nm) to give 33 mg (41%) as a white solid. MS ESI calculated for C 27 H 33 F5N6O2[M+H] + , 569.26, found 569.25. 1H NMR(400MHz,DMSO-d6) δ 8.13(s,1H),7.47-7.44(m,2H),7.10-7.08(m,2H),6.06(s,1H),4.36-4.34(m,1H),3.69- 3.51(m,11H),3.05-3.00(m,1H),2.47-2.27(m,7H),2.11-2.08(m,5H),1.75-1.66(m,2H). 19 F NMR (376 MHz, DMSO-d) δ -63.37 (3F), -87.50 (2F) and 33 mg (41%) of a white solid were obtained. MS ESI calculated for C 27 H 33 F5N6O2[M+H] + , 569.26, found 569.25. 1 H NMR(400MHz,DMSO-d6) δ 8.13(s,1H),7.47-7.44(m,2H),7.10-7.08(m,1H),6.93-6.82(m,1H),6.06(s,1H),4.39-4.27(m,1 H),3.66-3.55(m,11H),3.05-3.00(m,1H),2.47-2.27(m,7H),2.19-2.03(m,5H),1.79-1.66(m,2H). 19 F NMR(376MHz,DMSO-d6) δ-63.37(3F),-87.51(2F).

[0298] Example 10: (3S)—N-[3-(2-[[(cis-3-hydroxycyclopentyl]amino)-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0299] [ka]

[0300] Synthesis scheme

[0301] [ka]

[0302] Preparation 10A: cis-3-[[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino]-cyclopentan-1-ol

[0303] [ka]

[0304] To a stirred solution of 4-(6-chloro-2-methanesulfonylpyrimidin-4-yl)morpholine (500 mg, 1.800 mmol) and cis-3-aminocyclopentan-1-ol hydrochloride (273 mg, 1.980 mmol) in DMSO (9 mL) was added dropwise DIEA (698 mg, 5.401 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOEt (4×30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / (EtOAc:EtOH=3:1) (1:1) to give (cis)-3-[[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino]cyclopentan-1-ol (221 mg, 42%) as a white solid. MS ESI calculated for C 13 H 19 ClN4O2[M+H] + , 299.12; found 299.15 1 H NMR(300MHz,chloroform-d) δ 5.88-5.87(m,1H),5.57(m,1H),5.34-5.32(m,1H).4.43-4.35(m,2H),3. 78-3.75(m,4H),3.60-3.56(m,4H),2.23-2.07(m,2H),1.94-1.80(m,4H).

[0305] Example 10: (3S)—N-[3-(2-[[(cis-3-hydroxycyclopentyl]amino)-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0306] [ka]

[0307] To a stirred mixture of (cis)-3-[[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino]cyclopentan-1-ol (270 mg, 0.904 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (447 mg, 1.084 mmol), KPO (384 mg, 1.807 mmol) in dioxane (5.4 mL), HO (1.35 mL), Pd(DtBPF)Cl (59 mg, 0.090 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane / (EtOAc:EtOH=3:1) (1:1) to give a crude product. The crude product (277 mg) was purified by preparative HPLC under the following conditions: (Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 28B to 40B in 4.3 min; 254 / 210 nm) to give (3S)-N-[3-(2-[[(cis)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (165 mg, 33%) as a white solid. MS ESI calculated for C 27 H 35F3N6O3[M+H] + , 549.27; found 549.30. 1 H NMR(300MHz,DMSO-d6) δ 8.12(s,1H),7.44-7.42(m,2H),7.08-7.06(m,1H),6.41-6.39(m,1H),6.00(s,1H),4.60-5.59(m,1H),4.17-4.08(m,2H),3.69- 3.42(m,10H),3.05-2.99(m,1H),2.46-2.39(m,3H),2.24-2.15(m,3H),2.10-2.07(m,3H),1.88-1.85(m,1H),1.82-1.77(m,5H). 19 F NMR(282MHz,DMSO-d6) δ-63.35(3F).

[0308] Examples 11 and 12: (3S)—N-[3-(2-[[(1S,3R)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-(2-[[(1R,3S)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0309] [ka]

[0310] (3S)-N-[3-(2-[[(cis)-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (160 mg) was resolved by preparative chiral HPLC using the following conditions: column: CHIRALPAK ADH, 2 x 25 cm, 5 μm; mobile phase A: hexa(8 mmol / L NH3.MeOH) HPLC, mobile phase B: IPA HPLC; flow rate: 20 mL / min; gradient: 30B to 30B in 15 min; 220 / 254 nm) to give 66 mg (41%) of a white solid. MS ESI calculated for C 27 H 35 F3N6O3[M+H] + , 549.27; found 549.30. 1 H NMR(400MHz,DMSO-d6) δ 8.15-8.13(m,1H),7.49-7.46(m,2H),7.11-7.08(m,1H),6.52-6.33(m,1H),6.01(s,1H),4.63-4.61(m,1H),4.23-4.02(m,2H),3.7 9-3.52(m,11H),3.13-3.02(m,1H),2.46-2.44(m,3H),2.39-2.12(m,3H),2.17-2.05(m,2H),1.93-1.86(m,1H),1.73-1.46(m,5H). 19 F NMR (376 MHz, DMSO-d) δ -63.37 (3F) and 67 mg (42%) of a white solid were obtained. MS ESI calculated for C 27 H 35 F3N6O3[M+H] + , 549.27; found 549.30. 1H NMR(400MHz,DMSO-d6) δ 8.15-8.13(m,1H),7.57-7.40(m,2H),7.11-7.08(m,1H),6.52-6.43(m,1H),6.10-5.96(m,1H),4.63-5.61(m,1H),4.17-4.10(m,2H), 3.82-3.41(m,11H),3.10-3.02(m,1H),2.46-2.39(m,3H),2.24-2.19(m,3H),2.17-2.07(m,2H),1.88-1.68(m,1H),1.65-1.46(m,5H). 19 F NMR(376MHz,DMSO-d6) δ-63.34-63.37(3F).

[0311] Example 13: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0312] [ka]

[0313] Preparation 13A: (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol

[0314] [ka]

[0315] To a stirred solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (400 mg, 1.298 mmol) and K2CO3 (359 mg, 2.597 mmol) in NMP (4 mL) was added (R)-1-amino-2-propanol (146 mg, 1.947 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 150 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (200 mg, 42%) as an off-white solid. MS ESI calculated for C 12 H 18 IN3O2[M+H] + , 364.04, found 363.90. 1 H NMR(400MHz,DMSO-d6) δ 6.37(m,1H),6.25(m,1H),6.19(m,1H),4.64-4.63(m,1H),3.77-3.71(m,1H) ,3.66-3.63(m,4H),3.34-3.33(m,4H),3.17-3.06(m,2H),1.06-1.04(m,3H).

[0316] Example 13: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0317] [ka]

[0318] To a stirred solution of (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (50 mg, 0.138 mmol), (3S)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (60 mg, 0.145 mmol), and NaCO (44 mg, 0.413 mmol) in dioxane (0.8 mL) and HO (0.2 mL) was added Pd(dppf)Cl.CHCl (11 mg, 0.014 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) to give 50 mg of crude product. The residue was purified by reverse flash chromatography using the following conditions: Column: XBridge Prep Amide OBD Column, 19 x 150 mm, 5 um, 13 nm; Mobile Phase A: Water (10 mmol / L NHHCO), Mobile Phase B: CHCN; Flow Rate: 20 mL / min; Gradient: 40B to 70B in 4.3 min; 210 / 254 nm. This gave (3S)-N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (38 mg, 53%) as an off-white solid. MS ESI calculated for C 26 H 34 F3N5O3[M+H] + .522.26, found 522.15. 1H NMR(400MHz,DMSO-d6) δ 8.11(s,1H),7.43-7.40(m,1H),7.34-7.33(m,1H),7.10-7.08(m,1H),6.22-6.19(m,1H ),5.78-5.76(m,2H),4.70-4.69(m,1H),3.83-3.77(m,1H),3.69-3.55(m,5H),3.53-3.5 0(m,1H),3.38-3.36(m,4H),3.31-3.27(m,1H),3.22-3.13(m,2H),3.04-3.00(m,1H),2 .48-2.38(m,3H),2.16(s,3H),2.11-2.07(m,1H),1.68-1.63(m,1H),1.09-1.07(m,3H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F).

[0319] Example 14: (3S)—N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0320] [ka]

[0321] Preparation 14A: (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol

[0322] [ka]

[0323] To a stirred solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (269 mg, 1.947 mmol) in NMP (3 mL) was added (R)-(-)-2-amino-1-propanol (110 mg, 1.461 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 150 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (85 mg, 24%) as an off-white solid. MS ESI calculated for C 12 H 18 IN3O2[M+H] + , 364.04, found 364.10. 1 H NMR(400MHz,DMSO-d6) δ 6.23(s,1H),6.18-6.13(m,2H),4.63-4.60(m,1H),3.86-3.80(m,1H),3.66-3.63( m,4H),3.45-3.41(m,1H),3.38-3.34(m,4H),3.28-3.22(m,1H),1.09-1.07(m,3H).

[0324] Example 14: (3S)—N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0325] [ka]

[0326] To a stirred solution of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (50 mg, 0.138 mmol), (3S)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (57 mg, 0.138 mmol), and NaCO (44 mg, 0.413 mmol) in dioxane (0.8 mL) and HO (0.2 mL) was added Pd(dppf)Cl.CHCl (11 mg, 0.014 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA / EtOH (8 / 3 / 1) to give 50 mg of crude product. The residue was purified under the following conditions: Column: XBridge Shield RP18 OBD column, 30 * Purification by reverse flash chromatography at 210 / 254 nm yielded (3S)-N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (31 mg, 43%) as an off-white solid. MS ESI calculated for C 26 H 34 F3N5O3[M+H] + .522.26, found 522.10. 1H NMR(400MHz,DMSO-d6) δ 8.11(s,1H),7.42-7.40(m,1H),7.34(m,1H),7.10-7.08(m,1H),5.98-5.96(m,1 H),5.75(m,2H),4.66-4.64(m,1H),3.91-3.87(m,1H),3.69-3.65(m,5H),3.52- 3.47(m,2H),3.38-3.36(m,4H),3.32-3.26(m,2H),3.04-3.00(m,1H),2.48-2.3 8(m,3H),2.16(s,3H),2.10-2.07(m,1H),1.71-1.61(m,1H),1.13-1.12(m,3H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F).

[0327] Example 15: (3S)—N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0328] [ka]

[0329] Preparation 15A: 1-[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]azetidin-3-ol

[0330] [ka]

[0331] A mixture of 4-(6-chloro-2-methanesulfonylpyrimidin-4-yl)morpholine (200 mg, 0.720 mmol), azetidin-3-ol hydrochloride (87 mg, 0.792 mmol), and 2,6-dimethylpyridine (232 mg, 2.160 mmol) in DMSO (2 mL) was stirred at 60° C. for 16 hours under a nitrogen atmosphere. The reaction was quenched by the addition of room temperature water (20 mL). The resulting mixture was extracted with EtOAc (5×20 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) to give 1-[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]azetidin-3-ol (110 mg, 48%) as an off-white solid. MS ESI calculated for C 11 H 15 ClN4O2[M+H] + , 271.09, found 271.05. 1 H NMR(400MHz,DMSO-d6) δ 6.15(s,1H),5.64(d,J=6.4Hz,1H),4.51-4.44(m,1H),4.15-4.11(m,2H),3.70-3.66(m,2H),3.61-3.59(m,4H),3.52-3.50(m,4H).

[0332] Example 15: (3S)—N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0333] [ka]

[0334] A mixture of 1-[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]azetidinol (50 mg, 0.185 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (76 mg, 0.185 mmol), Pd(DtBPF)Cl (12 mg, 0.018 mmol), and KPO (78 mg, 0.369 mmol) in 1,4-dioxane (0.9 mL) and HO (0.2 mL) was stirred at 80° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) and the crude product (50 mg) was purified by preparative HPLC under the following conditions: (Column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 40B to 75B in 4.3 min; 210 / 254 nm) to give (3S)-N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (38 mg, 39%) as an off-white solid. MS ESI calculated for C 25 H 31 F3N6O3[M+H] + , 521.24, found 521.25. 1H NMR(400MHz,DMSO-d6) δ 8.15(s,1H),7.48-7.45(m,2H),7.10-7.08(m,1H),6.10(s,1H),5.60-5.58(m,1H),4.52-4.50(m,1H),4.18-4.14(m,2H),3.83(m,2H),3. 74-3.64(m,5H),3.56-3.51(m,5H),3.31-3.30(m,1H),3.05-3.00(m, 1H),2.51-2.41(m,3H),2.24(s,3H),2.08(m,1H),1.75-1.55(m,1H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F).

[0335] Example 16: (3S)—N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0336] [ka]

[0337] Preparation 16A: 1-[4-iodo-6-(morpholin-4-yl)pyrimidin-2-yl]azetidin-3-ol

[0338] [ka]

[0339] To a stirred solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (269 mg, 1.947 mmol) in NMP (3 mL) was added azetidin-3-ol hydrochloride (160 mg, 1.461 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 150 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give 1-[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]azetidin-3-ol (90 mg, 26%) as an off-white solid. MS ESI calculated for C 12 H 16 IN3O2[M+H] + , 361.03, found 361.90. 1 H NMR(400MHz,DMSO-d6) δ 6.37(m,1H),6.06-6.05(m,1H),5.61-5.59(m,1H),4.53-4.43(m,1H),4.09-4.03(m,2H),3.65-3.58(m,6H),3.37-3.35(m,4H).

[0340] Example 16: (3S)—N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0341] [ka]

[0342] To a stirred solution of 1-[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]azetidin-3-ol (50 mg, 0.138 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (60 mg, 0.145 mmol), and NaCO (44 mg, 0.415 mmol) in dioxane (0.8 mL) and HO (0.2 mL) was added Pd(dppf)Cl.CHCl (11 mg, 0.014 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA / EtOH (8 / 3 / 1) to give 50 mg of crude product. The residue was purified under the following conditions: Column: XBridge Prep C18 OBD column, 30 * Purification by reverse flash chromatography at 210 / 254 nm yielded (3S)-N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (33 mg, 46%) as an off-white solid. MS ESI calculated for C 26 H 32 F3N5O3[M+H] + .519.25, found 520.15. 1H NMR(400MHz,DMSO-d6) δ 8.12(s,1H),7.45-7.42(m,1H),7.34-7.33(m,1H),7.12-7.10(m,1H),5.93(s,1 H),5.61-5.57(m,2H),4.56-4.52(m,1H),4.12-4.08(m,2H),3.69-3.61(m,7H), 3.59-3.50(m,1H),3.41-3.39(m,4H),3.31-3.27(m,1H),3.04-3.00(m,1H),2.4 7-2.38(m,2H),2.16(s,3H),2.10-2.08(m,1H),1.71-1.63(m,1H),1.24(m,1H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F).

[0343] Example 17: (3R)—N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide

[0344] [ka]

[0345] Preparation 17A: (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide

[0346] [ka]

[0347] To a stirred solution of (3R)-3-(trifluoromethoxy)pyrrolidine hydrochloride (150 mg, 0.64 mmol) and DIEA (415.80 mg, 3.22 mmol) in THF (5 mL) was added triphosgene (76 mg, 0.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To this was added (3R)-3-(trifluoromethoxy)pyrrolidine hydrochloride (136 mg, 0.708 mmol). The solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA / PE (0-60%) to give (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (250 mg, 94%) as an off-white solid. MS ESI calculated for C 19 H 26 BF3N2O4[M+H] + , 415.19, found 415.25. 1 H NMR (400 MHz, chloroform-d) δ 7.73-7.71 (m, 1H), 7.46-7.45 (m, 1H), 7.16-7.14 (m, 1H), 6.14 (s, 1H), 4.95-4.92 (m, 1H), 3.80-3.71 (m, 2H), 3.64-3.61 (m, 2H), 2.51 (s, 3H), 2.37-2.20 (m, 2H), 1.37 (s, 12H). 19 F NMR (376 MHz, chloroform-d) δ -58.70 (3F).

[0348] Example 17: (3R)—N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide

[0349] [ka]

[0350] To a stirred solution of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (109 mg, 0.300 mmol) in dioxane (2 mL) and HO (0.2 mL), (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (149 mg, 0.360 mmol), NaCO (191 mg, 0.900 mmol), and Pd(dppf)ClCHCl (25 mg, 0.030 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE (0-82%) to give the crude product as a brown solid. The crude product (201 mg) was purified under the following conditions: Column: Atlantis Prep T3 OBD column, 19 * 250 mm 10 μl; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 25B to 50B in 6 min; Purification by preparative HPLC at 210 / 254 nm gave (3R)-N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (83 mg, 53%) as an off-white solid. MS ESI calculated for C 25 H 33 F3N5O4[M+H] + , 524.25, 526.25, found 524.10.526.10. 1H NMR(300MHz,DMSO-d6) δ 8.24(s,1H),7.47-7.34(m,2H),7.12(d,J=8.4Hz,1H),5.98(d,J=7.7Hz,1H),5.77(s,2H),5.16(s,1H),4. 65(s,1H),3.90(t,J=6.5Hz,1H),3.82-3.59(m,7H),3.55-3.37(m,6H),2.18(s,6H),1.14(d,J=6.6Hz,3H).

[0351] Example 18: N-[3-2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide

[0352] [ka]

[0353] Preparation 18A: N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide

[0354] [ka]

[0355] To a stirred mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (68 mg, 0.292 mmol, 1.00 equiv.) in THF (4 mL) was added DIEA (188 mg, 1.458 mmol) and triphosgene (35 mg, 0.117 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours. To this was added 3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole hydrochloride (60 mg, 0.321 mmol) in THF (3 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with MeOH (10 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane / (EtOAc:EtOH=3:1) (1:1) to give N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (100 mg, 84%) as a light brown oil. MS ESI calculated for C 20 H 26 BF3N2O3[M+H] + , 411.20, found 411.20. 1 H NMR(300MHz,DMSO-d6) δ 8.22(s,1H),7.69(d,J=2.4Hz,1H),7.64(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H ),5.95(s,1H),4.21(s,4H),3.32(q,J=11.7Hz,2H),2.40(s,3H),1.31(s,12H).

[0356] Example 18: N-[3-2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide

[0357] [ka]

[0358] To a solution of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (132 mg, 0.36 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (149 mg, 0.363 mmol) in 1,4-dioxane (2 mL) and HO (0.2 mL) was added Pd(dppf)Cl·CHCl (30 mg, 0.030 mmol) and KPO (231 mg, 1.090 mmol). After stirring at 80 °C under a nitrogen atmosphere for 1 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE (0-50%) to give the crude product. The crude product was purified by preparative HPLC using the following conditions: Column: Spherical C18, 19 x 150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 30% B to 60% B in 4.3 min; Detector: UV 210 and 254 nm to give N-[3-2-[[(2R)-1-hydroxypropan-2-yl]amino]6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (82 mg, 44%) as a light pink solid. MS ESI calculated for C 26 H 34 F3N5O3[M+H] + ,520.25, found 520.10. 1H NMR(400MHz,DMSO-d6) δ 8.19(s,1H),7.43(dd,J=8.2, 2.3Hz,1H),7.35(d,J=2.3Hz,1H),7.11(d,J=8.3Hz,1H),6.00-5.91(m,2H),5.76(d,J=1.6Hz,2H),4.64(t,J=5.5Hz,1H),4.18(s,4H)3.89(p ,J=6.5Hz,1H),3.72-3.64(m,4H),3.50(dt,J=10.0,5.0Hz,1H),3.37(t,J=4.9Hz,4H),3.32-3.25(m,2H),2.17(s,3H),1.13(d,J=6.5Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-63.28(3F).

[0359] Example 19: (3S)—N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0360] [ka]

[0361] Preparation 19A: 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]ethanol

[0362] [ka]

[0363] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (2.00 g, 6.492 mmol) and K2CO3 (1.79 g, 12.983 mmol) in NMP (20 mL) was added ethanolamine (595 mg, 9.737 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]ethanol (2 g, 88%) as a yellow oil. MS ESI calculated for C 15 H 20 BrN3O2[M+H] + 350.03 found 350.00. 1 H NMR(300MHz,DMSO-d6) δ 6.23(m,2H),4.64(m,1H),3.66(t,J=4.6Hz,4H),2.72(d,J=1.2Hz,8H).

[0364] Example 19: (3S)—N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0365] [ka]

[0366] To a stirred mixture of 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]ethanol (150 mg, 0.430 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (142 mg, 0.344 mmol) in dioxane (4 mL) and HO (1 mL), NaCO (137 mg, 1.289 mmol) and Pd(dppf)ClCHCl (35 mg, 0.043 mmol) were added portionwise at 60 °C under a nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give (3S)-N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (95 mg, 43%) as a light green solid. MS ESI calculated for C 15 H 20 BrN3O2[M+H] + 508.25 found 508.00. 1 H NMR(400MHz,DMSO-d6) δ 8.11(s,1H),7.49-7.27(m,2H),7.09(d,J=8.4Hz,1H),6.21(s,1H),5.76(s,2H),4.66(t,J=5.5Hz,1H),3.68(s,3H),3 .53(d,J=7.4Hz,3H),3.38(s,9H),3.02(t,J=9.4Hz,1H),2.44(s,3H),2.12(d,J=29.5Hz,4H),1.66(t,J=10.6Hz,1H).

[0367] Example 20: N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide

[0368] [ka]

[0369] To a stirred mixture of 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]ethanol (150 mg, 0.430 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (141 mg, 0.344 mmol) in dioxane (4 mL) and HO (1 mL), NaCO (137 mg, 1.289 mmol) and Pd(dppf)ClCHCl (35 mg, 0.043 mmol) were added portionwise at 60 °C under a nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (97 mg, 44%) as a light green solid. MS ESI calculated for C 25 H 30 F3N5O3[M+H] + 506.23 found 506.00. 1H NMR(400MHz,DMSO-d6) δ 8.20(s,1H),7.49-7.30(m,2H),7.11(d,J=8.4Hz,1H),6.23(s,1H),5.94(s,1H),5.77(s,2H) ),4.66(s,1H),4.20(s,4H),3.68(s,4H),3.54(s,2H),3.36(d,J=18.2Hz,8H),2.17(s,3H).

[0370] Example 21: (3S)—N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0371] [ka]

[0372] Preparation 21A: 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]ethanol

[0373] [ka]

[0374] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (500 mg, 1.623 mmol) and K2CO3 (449 mg, 3.246 mmol) in NMP (5 mL) was added methylethanolamine (183 mg, 2.434 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]ethanol (480 mg, 81%) as a yellow oil. MS ESI calculated for C 12 H 18 IN3O2[M+H] + , 363.95, found 363.95. 1 H NMR (300 MHz, chloroform-d) δ 6.34-6.26 (m, 2H), 3.80 (m, 6H), 3.70 (dd, J = 5.5, 4.4 Hz, 2H), 3.47-3.36 (m, 4H), 3.02 (s, 3H).

[0375] Example 21: (3S)—N-[3-[2-(3-hydroxyazetidin-1-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0376] [ka]

[0377] To a stirred solution of 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]ethanol (200 mg, 0.551 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (227 mg, 0.551 mmol) in 1,4-dioxane (2 mL) and HO (0.5 mL), NaCO (175 mg, 1.652 mmol) and Pd(dppf)ClCHCl (40 mg, 0.055 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) to give (3S)—N-(3-[2-[(2-hydroxyethyl)(methyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (172 mg, 60%) as a light brown solid. MS ESI calculated for C 26 H 34 F3N5O3[M+H] + , 522.15, found 522.15. 1H NMR(400MHz,DMSO-d6) δ 8.12(s,1H),7.44(dd,J=8.3, 2.3Hz,1H),7.34(d,J=2.3Hz,1H),7.11(d,J=8.4Hz,1H),5.84(d,J=13.6Hz,2H),4.68-4.59(m,1H),3.69(d,J=5.2Hz,5H),3.61-3 .48(m,5H),3.40(t,J=4.7Hz,4H),3.03(s,4H),2.44(t,J=10.4Hz,3H),2.17(s,3H),2.09(s,1H),2.01(s,1H),1.73-1.60(m,1H). 19 F NMR(376MHz,DMSO-d6) δ-63.36(3F).

[0378] Example 22: (3R)—N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide

[0379] [ka]

[0380] To a stirred mixture of 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]ethanol (150 mg, 0.430 mmol) and (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (142 mg, 0.344 mmol) in dioxane (4 mL) and HO (1 mL), NaCO (137 mg, 1.289 mmol) and Pd(dppf)ClCHCl (35 mg, 0.043 mmol) were added portionwise at 60 °C under a nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (3R)-N-(3-[2-[(2-hydroxyethyl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (74.3 mg, 34%) as a light green solid. MS ESI calculated for C 24 H 30 F3N5O4[M+H] + , 510.22 found 510.00. 1 H NMR(400MHz,DMSO-d6) δ 8.24(s,1H),7.53-7.24(m,2H),7.11(d,J=8.3Hz,1H),6.22(t,J=5.9Hz,1H),5.7 7(s,2H),5.15(s,1H),4.66(t,J=5.5Hz,1H),3.78-3.62(m,5H),3.56(dd,J=14.2, 8.1Hz,3H),3.46(d,J=8.9Hz,1H),3.38(s,3H),3.34(s,3H),3.31(d,J=5.9Hz,1H),2.20-2.00(m,5H).

[0381] Example 23: (3R)—N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide

[0382] [ka]

[0383] To a stirred solution of (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (132 mg, 0.363 mmol), (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (151 mg, 0.363 mmol), and Na2CO3 (116 mg, 1.090 mmol) in dioxane (0.8 mL) and water (0.2 mL) was added Pd(dppf)Cl.CHCl2 (30 mg, 0.036 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) to give 125 mg of crude product. The residue was purified by reverse flash chromatography at 210 / 254 nm under the following conditions: Column: XBridge Prep C18 OBD column, 19 x 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 40B to 75B in 4.3 min; This gave (3R)-N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (102 mg, 54%) as a light green solid. MS ESI calculated for C 25 H 32 F3N5O4[M+H] + , 524.24, found 524.15. 1H NMR(400MHz,DMSO-d6) δ 8.22(s,1H),7.42-7.33(m,2H),7.12-7.09(m,1H),6.20-6.15(m,1H),5.83-5.76(m,2H),5.14(s,1H),4.69-4.67(m,1 H),3.83-3.76(m,1H),3.67-3.55(m,7H),3.48-3.37(m,5H),3.20-3.14(m,2H),2.24-2.16(m,5H),1.09-1.07(m,3H). 19 F NMR(376MHz,DMSO-d6) δ-56.69(3F).

[0384] Example 24: N-[3-2-[[(2R)-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide

[0385] [ka]

[0386] A mixture of (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (133 mg, 0.366 mmol), N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (150 mg, 0.370 mmol), Pd(dppf)Cl.CHCl (30 mg, 0.040 mmol), and KPO (233 mg, 1.100 mmol) in dioxane (3 mL) and HO (0.3 mL) was stirred at 80 °C for 2 h under a N atmosphere. The mixture was cooled. The resulting mixture was added with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50-100%) to give the crude product. The crude material was purified by preparative HPLC under the following conditions: Column: X-Bridge Prep C18 OBD column, 19 x 150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20B to 55B in 4.3 min; 210 / 254 nm to give N-[3-2-[[(2R)-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-1-carboxamide (97 mg, 51%) as a white solid. MS ESI calculated for C 19 H 25 BrN4O3[M+H] + , 437.11, found 437.00. 1H NMR(400MHz,CDCL3) δ 7.37(dd,J=8.2, 2.4Hz,1H),7.24(d,J=2.4Hz,1H),7.18(d,J=8.2Hz,1H),6.13(s,1H),5.88-5.82(m,3H),4.70(brs,1H),4.32-4.30(m,4H),4.0 6-3.98(m,1H),3.84-3.81(m,4H),3.54-3.43(m,5H),3.31-3.28(m,1H),3.05-2.98(m,2H),2.24(s,3H),1.25(d,J=6.3Hz,3H).

[0387] Example 25: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl](methyl)amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0388] [ka]

[0389] Preparation 25A: (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]propan-2-ol

[0390] [ka]

[0391] To a stirred solution of (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (500 mg, 1.377 mmol) and K2CO3 (571 mg, 4.130 mmol) in acetone (10 mL) was added methyl iodide (234 mg, 1.652 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 48 h. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]propan-2-ol (150 mg, 29%) as an off-white solid. MS ESI calculated for C 13 H 20 IN3O2[M+H] + , 378.06, found 378.10. 1 H NMR(400MHz,CDCL3) δ 6.33-6.30(m,2H),4.16-4.09(m,1H),3.81-3.79(m,4H),1.66-1.61(m,1H),3.48-3.42(m,5H),3.04(s,3H),1.23-1.22(m,3H).

[0392] Example 25: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl](methyl)amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0393] [ka]

[0394] To a stirred solution of (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]propan-2-ol (200 mg, 0.530 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (219 mg, 0.530 mmol), and NaCO (169 mg, 1.591 mmol) in dioxane (1.6 mL) and HO (0.4 mL) was added Pd(dppf)Cl.CHCl (43 mg, 0.053 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) to give 70 mg of crude product. The residue was purified by reverse flash chromatography at 210 / 254 nm under the following conditions: Column: XBridge Prep C18 OBD column, 19 x 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: CHCN; Flow rate: 20 mL / min; Gradient: 40B to 70B in 4.3 min; This gave (3S)-N-[3-(2-[[(2R)-2-hydroxypropyl](methyl)amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (144 mg, 51%) as a light green solid. MS ESI calculated for C 27 H 36 F3N5O3[M+H] + , 536.28, found 536.20. 1H NMR (400 MHz, DMSO-d6) δ 8.11(s,1H),7.44-7.40(m,1H),7.33-7.32(m,1H),7.11-7.08(m,1H),5.8 4-5.79(m,2H),4.66-4.65(m,1H),3.92-3.86(m,1H),3.69-3.63(m,5H),3. 55-3.44(m,2H),3.40-3.37(m,4H),3.29-3.26(m,2H),3.02-2.98(m,4H),2 .46-2.39(m,3H),2.15-2.06(m,4H),1.71-1.61(m,1H),1.06-1.04(m,3H). 19 F NMR(376MHz,DMSO-d6) δ-63.35(3F).

[0395] Example 26: (3S)—N-[3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0396] [ka]

[0397] Preparation 26A: (2R)-1-[(6-chloro-4-iodopyridin-2-yl)amino]propan-2-ol

[0398] [ka]

[0399] To a stirred solution of 2,6-dichloro-4-iodopyridine (1 g, 3.651 mmol) and K2CO3 (1 g, 7.302 mmol) in NMP (20 mL) was added (R)-1-amino-2-propanol (274 mg, 3.651 mmol) at room temperature. A portion of the resulting mixture was stirred at 100 °C for 16 h. The reaction was quenched by the addition of water (70 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give (2R)-1-[(6-chloro-4-iodopyridin-2-yl)amino]propan-2-ol (410 mg, 36%) as a yellow oil. MS ESI calculated for C8H 10 ClIN2O [M+H] + , 312.54, found 312.95. 1 H NMR(300MHz,chloroform-d) δ 6.96(d,J=1.0Hz,1H),6.74(d,J=1.1Hz,1H),5.31(s,1H),3.46(dd,J=13.7, 3.1Hz,2H),3.19(dd,J=13.7, 7.7 Hz,1H),1.26(d,J=6.2Hz,3H).

[0400] Preparation 26B: (3S)-N-[3-(2-chloro-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0401] [ka]

[0402] To a stirred mixture of (2R)-1-[(6-chloro-4-iodopyridin-2-yl)amino]propan-2-ol (380 mg, 1.216 mmol) and (3S)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrod-ine-1-carboxamide (501 mg, 1.216 mmol) and KPO (774 mg, 3.648 mmol) in dioxane (4 mL), HO (0.4 mL), Pd(dppf)ClCHCl (99 mg, 0.122 mmol) was added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 70 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc in PE, to give (3S)-N-[3-(2-chloro-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (510 mg, 89%) as a yellow solid. MS ESI calculated for C 22 H 26 ClF3N4O2[M+H] + , 471.17, found 471.20. 1 H NMR(300MHz,DMSO-d6) δ 8.19(s,1H),7.49(s,1H),7.41(s,1H),7.15(s,1H),7.00(s,1H),6.44 (d,J=1.1Hz,2H),4.75(s,1H),4.05-3.98(m,1H),3.69-3.60(m,1H),3. 55-3.51(m,1H),3.33-3.29(m,2H),3.21-3.18(m,2H),2.19(s,1H),2. 16-2.05(m,2H),2.01(d,J=1.1Hz,1H),1.67-1.61(m,2H),1.07(s,3H).

[0403] Example 26: (3S)—N-[3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0404] [ka]

[0405] To a stirred mixture of (3S)—N-[3-(2-chloro-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (430 mg, 0.913 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (384 mg, 1.826 mmol), CsCO (893 mg, 2.739 mmol) in dioxane (5 mL), HO (0.5 mL), Pd(dppf)ClCHCl (75 mg, 0.091 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0% to 90% EtOAc in PE, to give (3S)-N-[3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (310 mg, 65%) as a yellow solid. MS ESI calculated for C 27 H 33 F3N4O3[M+H] + , 519.25, found 519.15. 1H NMR(300MHz,DMSO-d6) δ 8.17(s,1H),7.47-7.45(m,2H),7.40(s,1H),7.16-7.13(m,1H),6.73( s,1H),6.53(s,1H),6.36(s,1H),4.84-4.83(m,1H),4.27(s,2H),3.81 (s,3H),3.71-3.69(m,2H),3.57-3.31(m,4H),3.07-3.01(m,1H),2.52 -2.42(m,4H),2.18-2.10(m,4H),1.70-1.64(m,1H),1.12-1.10(m,3H).

[0406] Example 27: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(oxan-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0407] [ka]

[0408] To a solution of (3S)—N-[3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-2-hydroxypropyl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (150 mg, 0.289 mmol) in MeOH (2 mL) and CH3COOH (0.1 mL) was added Pd / C (92 mg, 0.868 mmol) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 hours using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following conditions: (Column: XBridge Prep C18 OBD Column, 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 20B to 50B in 4.3 min; 210 / 254 nm) to give (3S)-N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(oxan-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (115 mg, 76%) as a white solid. MS ESI calculated for C 27 H 35 F3N4O3[M+H] + , 521.27, found 521.15. 1 H NMR(300MHz,DMSO-d6) δ 8.14(s,1H),7.41(s,2H),7.36-7.35(m,1H),7.13-7.10(m,1H),6.29- 6.27(m,2H),4.84(s,1H),3.95(s,2H),3.91(s,1H),3.41(s,1H),3.37 -3.33(m,3H),3.27-3.25(m,2H),3.10-2.98(m,1H),2.78(s,1H),2.50 -2.42(m,4H),2.15-2.10(m,4H),1.75-1.71(m,5H),1.09-1.07(m,3H).

[0409] Example 28: N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide

[0410] [ka]

[0411] Preparation 28A: N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide

[0412] [ka]

[0413] To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (435 mg, 1.867 mmol) and triphosgene (246 mg, 0.830 mmol) in THF (40 mL) was added DIEA (1.81 mL, 13.977 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. To this was added 3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride (180 mg, 1.037 mmol), and the mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide (500 mg, 61%) as a yellow oil. MS ESI calculated for C 19 H 24 F3N2O3[M+H] + , 397.25, found 397.25. 1H NMR(400MHz,CDCl3-d) δ 7.71(dd,J=8.3, 2.5Hz,1H),7.48(d,J=2.6Hz,1H),7.15(d,J=8.3Hz,1H),6.45-6.40(m,1H),6.16(s,1H),4.44(s,4H),2.50(s,3H),1.36(s,12H). 19 F NMR(376MHz,CDCl3-d) δ-65.69(3F).

[0414] Example 28: N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide

[0415] [ka]

[0416] To a stirred solution of (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (160 mg, 0.441 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide (174 mg, 0.441 mmol) in 1,4-dioxane (2 mL) and HO (0.5 mL) was added Pd(dppf)Cl.CHCl (36 mg, 0.044 mmol) and NaCO (140 mg, 1.322 mmol). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 2) to give N-[3-(2-[[(2R)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide (116 mg, 44%) as a light green solid. MS ESI calculated for C 25 H 30 F3N5O3[M+H] + , 506.05, found 506.05. 1 H NMR(300MHz,DMSO-d6) δ 8.31(s,1H),7.45(dd,J=8.2, 2.3Hz,1H),7.37(d,J=2.3Hz,1H),7.14(d,J=8.3Hz,1H),6.75(d,J=2.6Hz,1H),6.23(s,1H),5.79(d,J=6.5Hz,2H),4.70(s,1H) ,4.41(s,4H),3.81(s,1H),3.70(t,J=4.8Hz,4H),3.39(t,J=4.8Hz,4H),3.23-3.09(m,2H),2.19(s,3H),1.10(d,J=6.2Hz,3H).19 F NMR(282MHz,DMSO-d6) δ-63.98(3F).

[0417] Example 29: N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide

[0418] [ka]

[0419] To a stirred solution of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (150 mg, 0.413 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide (164 mg, 0.413 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added NaCO (131 mg, 1.239 mmol) and Pd(dppf)Cl.CHCl (34 mg, 0.041 mmol). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 2) to give N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide (116 mg, 56%) as a pale yellow solid. MS ESI calculated for C 25 H30 F3N5O3[M+H] + , 506.10, found 506.10. 1 H NMR(400MHz,DMSO-d6) δ 8.29(s,1H),7.45-7.40(m,1H),7.36(d,J=2.3Hz,1H),7.13(d,J=8.4Hz,1H),6.76-672(m,1H),5.99( s,1H),5.76(s,2H),4.65(s,1H),4.39(s,4H),3.93-3.85(m,1H),3.71-3.64(m,4H),3.49(dd,J=10.3, 4.9Hz,1H),3.37(t,J=4.8Hz,4H),3.34-3.33(m,1H),2.17(s,3H),1.13(d,J=6.5Hz,3H). 19 F NMR(376MHz,DMSO-d6) δ-63.99(3F).

[0420] Example 30: (3S)—N-[3-(2-[[(2S)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0421] [ka]

[0422] Preparation 30A: (2S)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol

[0423] [ka]

[0424] To a stirred solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (269 mg, 1.947 mmol) in NMP (3 mL) was added (2S)-2-aminopropan-1-ol (110 mg, 1.461 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 150 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (2S)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (198 mg, 55%) as an off-white solid. MS ESI calculated for C 12 H 18 IN3O2[M+H] + , 364.04, found 364.10. 1 H NMR(400MHz,CDCL3) δ 6.29-6.25(m,2H),4.32-4.28(m,1H),4.02(s,1H),3.81-3.72(m,5H),3.58-3.54(m,1H),3.45-3.43(m,4H),1.23-1.22(m,3H).

[0425] Example 30: (3S)—N-[3-(2-[[(2S)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0426] [ka]

[0427] A mixture of (2S)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (200 mg, 0.551 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (227 mg, 0.551 mmol), NaCO (175 mg, 1.652 mmol), 1,4-dioxane (1.6 mL), HO (0.4 mL), and Pd(dppf)Cl.CHCl (45 mg, 0.055 mmol) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (8 / 3 / 1) and then purified by reverse flash chromatography at 254 / 210 nm under the following conditions: Column: SunFire Prep C18 OBD column 19 x 150 mm, 5 µm, 10 nm; Mobile phase A: water (0.05% TFA) and Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 25B to 65B in 5.3 min; This gave (3S)-N-[3-(2-[[(2S)-1-hydroxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (111 mg, 37%) as an off-white solid. MS ESI calculated for C 26 H 34 F3N5O3[M+H] + , 522.26, found 522.30. 1H NMR (400 MHz, DMSO-d6) δ 8.11(s,1H),7.42-7.40(m,1H),7.34-7.33(m,1H),7.10-7.08(m,1H),5.98 -5.96(m,1H),5.75(m,2H),4.65(s,1H),3.90-3.87(m,1H),3.69-3.65(m,5 H),3.55-3.48(m,2H),3.38-3.34(m,5H),3.04-2.99(m,1H),2.48-2.41(m, 3H),2.16(s,3H),2.10-2.07(m,1H),1.70-1.60(m,1H),1.13-1.12(m,3H). 19 F NMR(376MHz,DMSO-d6) δ-63.37(3F).

[0428] Example 31: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl](methyl)amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0429] [ka]

[0430] Preparation 31A: (2R)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl](methyl)amino]propan-2-ol

[0431] [ka]

[0432] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), K2CO3 (269 mg, 1.947 mmol), NMP (3 mL), and (2S)-1-aminopropan-2-ol (110 mg, 1.461 mmol) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (2S)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (222 mg, 63%) as an off-white solid. MS ESI calculated for C 12 H 18 IN3O2[M+H] + , 364.04, found 364.10. 1 H NMR (400 MHz, chloroform-d) δ 6.29-6.25 (m, 2H), 4.65 (s, 1H), 4.05-3.97 (m, 1H), 3.81-3.78 (m, 4H), 3.47-3.41 (m, 5H), 3.25-3.18 (m, 1H), 1.25-1.23 (m, 3H).

[0433] Example 31: (3S)—N-[3-(2-[[(2R)-2-hydroxypropyl](methyl)amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0434] [ka]

[0435] A mixture of (2S)-1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-2-ol (200 mg, 0.551 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (227 mg, 0.551 mmol), NaCO (175 mg, 1.652 mmol), dioxane:HO = 4:1 (2 mL), and Pd(dppf)Cl.CHCl (45 mg, 0.055 mmol) was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) and then purified by reverse flash chromatography using the following conditions: Column: SunFire Prep C18 OBD column, 19 x 150 mm, 5 µm x 10 nm; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 25B to 65B in 5.3 min; 254 / 210 nm. This gave (3S)-N-[3-(2-[[(2S)-2-hydroxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (145 mg, 49%) as an off-white solid. MS ESI calculated for C 26 H 34 F3N5O3[M+H] + , 522.26, found 522.25. 1H NMR(400MHz,DMSO-d6) δ 8.11(s,1H),7.43-7.40(m,1H),7.34-7.33(m,1H),7.10-7.08(m,1H),6.22-6.19 (m,1H),5.78-5.76(m,2H),4.70(s,1H),3.82-3.77(m,1H),3.69-3.65(m,5H),3. 55-3.50(m,1H),3.38-3.36(m,4H),3.23-3.11(m,2H),3.04-2.99(m,1H),2.48-2 .36(m,3H),2.16(s,3H),2.11-2.07(m,1H),1.70-1.60(m,1H),1.09-1.07(m,3H). 19 F NMR(376MHz,DMSO-d6) δ-63.37(3F).

[0436] Example 32: (3S)—N-[3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0437] [ka]

[0438] Preparation 32A: (2R)-2-[(6-chloro-4-iodopyridin-2-yl)amino]propan-1-ol

[0439] [ka]

[0440] To a stirred solution of 2,6-dichloro-4-iodopyridine (1 g, 3.651 mmol) and K2CO3 (1 g, 7.302 mmol) in NMP (20 mL) was added (R)-(-)-2-amino-1-propanol (274 mg, 3.651 mmol) at room temperature. A portion of the resulting mixture was stirred at 100 °C for 16 h. The reaction was quenched by the addition of water (70 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give (2R)-2-[(6-chloro-4-iodopyridin-2-yl)amino]propan-1-ol (240 mg, 21%) as a yellow oil. MS ESI calculated for C8H 10 C lI NO[M+H] + ,312.95,found 312.95. 1 H NMR(300 MHz,chloroform-d) δ 6.97(d,J=1.0 Hz,1H),6.77(d,J=1.1 Hz,1H),4.90(s,1H),3.76(dd,J=13.7,3.1 Hz,2H),3.61(dd,J=13.7,7.7 Hz,1H),1.28(d,J=6.2 Hz,3H).

[0441] Preparation 32B: (3S)-N-[3-(2-chloro-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0442] [ka]

[0443] To a stirred mixture of (2R)-2-[(6-chloro-4-iodopyridin-2-yl)amino]propan-1-ol (230 mg, 0.736 mmol) and (3S)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (303 mg, 0.736 mmol), KPO (469 mg, 2.208 mmol) in dioxane (3 mL), HO (0.3 mL), Pd(dppf)ClCHCl (60 mg, 0.074 mmol) was added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 90% EtOAc in PE to give (3S)-N-[3-(2-chloro-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (310 mg, 89%) as a yellow solid. MS ESI calculated for C 22 H 26 ClF3N4O2[M+H] + ,471.17,found 471.05. 1 H NMR (300 MHz, DMSO-d6) δ 8.17(s,1H),7.48-7.45(m,1H),7.40-7.34(m,1H),7.15-7.12(m,1H),6.87- 6.81(m,1H),6.41(s,1H),7.41(s,1H),6.36(s,1H),4.04-4.02(m,1H),3.90( s,1H),3.67(s,1H),3.52(s,2H),3.36-3.25(m,2H),3.03(s,1H),2.51-2.34( m,3H),2.17(s,3H),2.13-2.05(m,1H),1.73-1.59(m,1H),1.26-1.10(m,4H).

[0444] Example 32: (3S)—N-[3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0445] [ka]

[0446] To a stirred mixture of (3S)—N-[3-(2-chloro-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (310 mg, 0.658 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (277 mg, 1.317 mmol), CsCO (643 mg, 1.975 mmol) in dioxane (4 mL), HO (0.4 mL) was added Pd(dppf)ClCHCl (54 mg, 0.066 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 90% EtOAc in PE to give (3S)-N-3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (130 mg, 38%) as a yellow solid. MS ESI calculated for C 27 H 33 F3N4O3[M+H] +,519.25,found 519.15. 1 H NMR (300 MHz, DMSO-d6) δ 8.15(s,1H),7.45-7.39(m,2H),7.14-7.12(m,1H),6.71(s,1H),6.50(s,1H ),6.31(s,2H),4.85-4.83(m,1H),4.25-4.24(m,2H),4.07(s,1H),3.81(s, 2H),3.67-3.66(m,1H),3.52-3.50(m,2H),3.33-3.29(m,2H),3.02(s,1H), 2.51-2.43(m,5H),2.41-2.17(m,4H),1.75-1.70(m,1H),1.16-1.14(m,3H).

[0447] Example 33: (3S)—N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(oxan-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0448] [ka]

[0449] To a solution of (3S)-N-3-[2-(3,6-dihydro-2H-pyran-4-yl)-6-[[(2R)-1-hydroxypropan-2-yl]amino]pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (130 mg, 0.251 mmol) in MeOH (2 mL) and CH3COOH (0.1 mL) was added Pd / C (80 mg, 0.752 mmol) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature using a hydrogen balloon for 2 hours. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD Column, 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 20B to 50B in 4.3 min; 210 / 254 nm) to give (3S)-N-[3-(2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-(oxan-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (63 mg, 48%) as a white solid. MS ESI calculated for C 27 H 35 F3N4O3[M+H] + ,521.27,found 521.15. 1 H NMR(300 MHz,DMSO-d6) δ 8.13(s,1H),7.43-7.41(m,2H),7.36(s,1H),6.26-6.19(m,3H),4.77(s,1H),3.95-3.91(m,3H),3.63(s,1H),3.55-3. 25(m,5H),3.04-2.98(m,1H),2.76(s,1H),2.50-2.39(m,4H),2.27-2.06(m,4H),1.78-1.61(m,5H),1.23-1.13(m,3H).

[0450] Example 34: (S)—N-(3-(2-(((1S,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0451] [ka]

[0452] Preparation 34A: (1S,3S)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclobutan-1-ol

[0453] [ka]

[0454] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), (1S,3S)-3-amino-1-methylcyclobutan-1-ol hydrochloride (134 mg, 0.974 mmol), and K2CO3 (269 mg, 1.947 mmol) in NMP (3 mL) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched with room temperature water (2 × 8 mL). The resulting mixture was extracted with EtOAc (2 × 8 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) to give (1S,3S)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclobutan-1-ol (270 mg, 64%) as an off-white solid. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.06,found 390.05. 1H NMR(300 MHz,CDCL3) δ 6.32(s,1H),6.11(s,1H),4.48(m,1H),3.81-3.78(m,4H),3.73-3.66(m,1H),3.46-3.42(m,4 H),2.65-2.58(m,1H),2.01-1.95(m,2H),1.45(s,3H),1.31-1.26(m,1H),0.91-0.86(m,1H).

[0455] Example 34: (S)—N-(3-(2-(((1S,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0456] [ka]

[0457] A mixture of (1S,3S)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclobutan-1-ol (142 mg, 0.364 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (150 mg, 0.364 mmol), Pd(dppf)Cl.CHCl (30 mg, 0.036 mmol), and NaCO (116 mg, 1.092 mmol) in dioxane (1.2 mL) and HO (0.3 mL) was stirred at 60° C. for 16 hours under a nitrogen atmosphere. The reaction was quenched by the addition of room temperature water (3 mL). The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1), and the crude product was purified by reverse flash chromatography at 210 / 254 nm under the following conditions: Column: SunFire Prep C18 OBD Column, 19 × 150 mm, 5 μm, 10 nm; Mobile Phase A: water (0.1% FA), Mobile Phase B: CHCN; Flow Rate: 20 mL / min; Gradient: 35B to 70B in 4.3 min; This resulted in (S)-N-(3-(2-(((1S,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (117 mg, 58%) as an off-white solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.28,found 548.20. 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.11(m,1H),7.42-7.40(m,1H),7.33(s,1H),7.10-7.07(m,1H),6.4 4-6.32(m,1H),5.77-5.69(m,2H),4.90-4.87(m,1H),3.89-3.60(m,6H),3. 55-3.49(m,1H),3.37-3.29(m,5H),3.07-2.99(m,1H),2.51-2.34(m,5H),2 .20-1.94(m,4H),1.90-1.81(m,2H),1.80-1.50(m,1H),1.45-1.05(m,3H). 19 F NMR(282 MHz,DMSO-d6) δ -63.35(3F).

[0458] Example 35: (S)—N-(3-(2-(((1R,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0459] [ka]

[0460] Preparation 35A: (1R,3R)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclobutan-1-ol

[0461] [ka]

[0462] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), (trans)-3-amino-1-methylcyclobutan-1-ol hydrochloride (201 mg, 1.461 mmol), and K2CO3 (269 mg, 1.947 mmol) in NMP (3 mL) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched by the addition of room temperature water (30 mL). The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) to give (1R,3R)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclobutan-1-ol (370 mg, 88%) as an off-white solid. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.06,found 390.05. 1 H NMR (300 MHz, chloroform-d) δ 6.33-6.32 (m, 1H), 6.11-6.10 (s, 1H), 4.47-4.45 (m, 1H), 4.23-4.11 (m, 1H), 3.80-3.77 (m, 4H), 3.45-3.42 (m, 4H), 2.60-2.53 (m, 1H), 2.00-1.93 (m, 2H), 1.46 (s, 3H), 1.31-1.26 (m, 1H), 0.91-0.88 (m, 1H).

[0463] Example 35: (S)—N-(3-(2-(((1R,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0464] [ka]

[0465] A mixture of (1R,3R)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclobutan-1-ol (142 mg, 0.364 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (150 mg, 0.364 mmol), Pd(dppf)Cl.CHCl (30 mg, 0.036 mmol), and NaCO (116 mg, 1.092 mmol) in dioxane (1.2 mL) and HO (0.3 mL) was stirred under a hydrogen atmosphere at 60° C. for 16 hours. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH = (4 / 3 / 1), and the crude product was purified under the following conditions: Column: SunFire Prep C 18 OBD Column, 19 x 150 mm, 5 µm, 10 nm; Mobile phase A: water (0.1% FA), Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 35B to 70B in 4.3 min; Purification by reverse flash chromatography at 210 / 254 nm resulted in (S)-N-(3-(2-(((1R,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (114 mg, 56%) as an off-white solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.28,found 548.15. 1H NMR(300 MHz,DMSO-d6) δ 8.13-8.11(m,1H),7.43-7.40(m,1H),7.33(s,1H),7.10-7.08(m,1H),6.42(m,1) H),5.77(s,1H),5.64(s,1H),4.83-4.23(m,1H),4.45-4.05(m,1H),3.80-3.67( m,5H),3.57-3.55(m,1H),3.52-3.38(m,5H),3.10-2.99(m,1H),2.46-2.32(m,5 H),2.29-2.08(m,4H),1.94-1.84(m,2H),1.72-1.62(m,1H),1.27-1.06(m,3H). 19 F NMR(282 MHz,DMSO-d6) δ -63.35-63.42(3F).

[0466] Example 36: (S)—N-(3-(2-(((1S,4R)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0467] [ka]

[0468] Preparation 36A: (1S,4S)-4-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclohexan-1-ol

[0469] [ka]

[0470] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (407 mg, 2.921 mmol) in NMP (3 mL) was added (cis)-4-amino-1-methylcyclohexan-1-ol (189 mg, 1.461 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 h. The mixture was cooled to room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, 30% to 70% gradient in 20 min; detector, UV 254 nm to give (1S,4S)-4-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclohexan-1-ol (290 mg, 71%) as a light brown solid. MS ESI calculated for C 16 H 24 IN3O2418.09,found 417.95. 1 H NMR (300 MHz, chloroform-d) δ 6.26 (s, 1H), 6.16 (s, 1H), 4.24 (d, J = 8.0 Hz, 1H), 3.84-3.75 (m, 4H), 3.45-3.42 (m, 5H), 2.00-1.40 (m, 8H), 1.29 (s, 3H), 1.13 (s, 1H).

[0471] Example 36: (S)—N-(3-(2-(((1S,4R)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0472] [ka]

[0473] To a stirred mixture of (1S,4S)-4-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclohexan-1-ol (150 mg, 0.359 mmol) and (3S)—N-[4-methyl-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (143 mg, 0.359 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added NaCO (114 mg, 1.078 mmol) and Pd(dppf)Cl.DCM (29 mg, 0.036 mmol) under a nitrogen atmosphere at 70 °C. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give (S)—N-(3-(2-(((1S,4R)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (98 mg, 47%) as a light green solid. MS ESI calculated for C 30 H 40 F3N5O3,576.31 found 576.20. 1H NMR(300 MHz,DMSO-d6) δ 8.12(s,1H),7.41(dd,J=8.2,2.3 Hz,1H),7.33(d,J=2.3 Hz,1H),7.09(d,J=8.4 Hz,1H),6.07(d,J=7.4 Hz,1H),5.73(s,2H),4.02(s,1H),3.68(dd,J=5.9,3.7 Hz,5H),3.52(td,J=9.4,8.3,5.3 Hz,2H),3.37(s,3H),3.02(t,J=9.4 Hz,1H),2.44(dd,J=12.6,8.1 Hz,3H),2.16(s,3H),2.09(d,J=11.9 Hz,1H),1.69(t,J=7.9 Hz,3H),1.56(p,J=9.9,8.8 Hz,5H),1.43-1.28(m,3H),1.24(s,1H),1.12(s,3H).

[0474] Example 37: (S)—N-(3-(2-(((1R,4S)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0475] [ka]

[0476] Preparation 37A: (1R,4R)-4-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclohexan-1-ol

[0477] [ka]

[0478] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (404 mg, 2.921 mmol) in NMP (3 mL) was added (1R,4R)-4-amino-1-methylcyclohexan-1-ol (189 mg, 1.461 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 h. The mixture was cooled to room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, 30% to 70% gradient in 20 min; detector, UV 254 nm to give (1R,4R)-4-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclohexan-1-ol (320 mg, 79%) as a light brown solid. MS ESI calculated for C 16 H 24 IN3O2[M+H] + 418.09 found 418.00. 1 H NMR (300 MHz, chloroform-d) δ 6.28 (s, 1H), 6.18 (s, 1H), 4.27 (s, 1H), 3.84-3.75 (m, 4H), 3.63-3.39 (m, 5H), 2.02-1.36 (m, 8H), 1.31 (s, 3H), 1.27 (s, 1H).

[0479] Example 37: (S)—N-(3-(2-(((1R,4S)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0480] [ka]

[0481] A mixture of (1R,4R)-4-((4-iodo-6-morpholinopyridin-2-yl)amino)-1-methylcyclohexan-1-ol (220 mg, 0.527 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (217 mg, 0.527 mmol), 1,4-dioxane (5.3 mL), HO (1.3 mL), NaCO (168 mg, 1.582 mmol), and Pd(dppf)Cl.DCM (43 mg, 0.053 mmol) was stirred at 70° C. under a nitrogen atmosphere for 2 hours. The reaction was quenched by the addition of room temperature water (20 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (S)—N-(3-(2-(((1R,4S)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (153 mg, 50%) as a light green solid. MS ESI calculated for C 30 H 40 F3N5O3[M+H] + 576.31,found 576.15. 1H NMR(300 MHz,DMSO-d6) δ 8.12(s,1H),7.41(dd,J=8.3,2.3 Hz,1H),7.34(d,J=2.3 Hz,1H),7.09(d,J=8.4 Hz,1H),6.08(d,J=7.3 Hz,1H),5.74(d,J=4.4 Hz,2H),4.20(s,1H),3.67(q,J=8.3,6.4 Hz,6H),3.57-3.50(m,1H),3.44 -3.27(m,5H),3.02(t,J=9.4 Hz,1H),2.47(d,J=19.5 Hz,3H),2.18-2.16(m,4H),1.93-1.81(m,2H),1.75-1.53(m,3H),1.41(h,J=10.4 Hz,4H),1.14(s,3H).

[0482] Example 38: (3S)—N-[3-[2-(3-hydroxy-3-methylazetidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0483] [ka]

[0484] Preparation 38A: 1-[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]-3-methylazetidin-3-ol

[0485] [ka]

[0486] To a stirred solution / mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and 3-methylazetidin-3-ol (127 mg, 1.461 mmol) in NMP (3 mL) was added KCO (404 mg, 3.00 equiv.) at room temperature. The resulting mixture was stirred at 150 °C for 16 h. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 30 min; detector, UV 254 nm, to give 1-[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]-3-methylazetidin-3-ol (270 mg, 74%) as an off-white solid. MS ESI calculated for C 13 H 18 IN3O2, [M+H] + ,376.21,found 376.00. 1 H NMR(300 MHz,chloroform-d) δ 6.32(s,1H),6.10(s,1H),3.89(q,J=8.6 Hz,4H),3.83-3.75(m,4H),3.50-3.41(m,4H),1.60(s,3H)

[0487] Example 38: (3S)—N-[3-[2-(3-hydroxy-3-methylazetidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0488] [ka]

[0489] A mixture of 1-[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]-3-methylazetidin-3-ol (150 mg, 0.400 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (181 mg, 0.440 mmol), 1,4-dioxane (1.6 mL), HO (0.4 mL), KPO (255 mg, 1.199 mmol), and Pd(dppf)Cl.DCM (43 mg, 0.053 mmol) was stirred under a N atmosphere at room temperature. The resulting mixture was stirred at 80 °C for 1 hour under a N atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (3S)-N-[3-[2-(3-hydroxy-3-methylazetidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (79 mg, 37%) as an off-white solid. MS ESI calculated for C 27 H 34 F3N5O3[M+H] + ,534.26,found 534.15. 1 H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.43(dd,J=8.3,2.3 Hz,1H),7.33(d,J=2.4 Hz,1H),7.10(d,J=8.4 Hz,1H),5.93(d,J=1.0 Hz,1H),5.61(d,J=0.9 Hz,1H),5.49(s,1H),3.80-3.62(m,9H),3.52(ddd,J=10.4,8.3,2.3 Hz,1H),3.40(t,J=4.9 Hz,4H),3.32(d,J=2.5 Hz,1H),3.02(t,J=9.5 Hz,1H),2.45(d,J=11.3 Hz,1H),2.41(s,2H),2.15(s,3H),2.12-2.00(m,1H),1.65(p,J=9.9 Hz,1H),1.43(s,3H). 19F NMR(376 MHz,DMSO-d6) δ -63.12.

[0490] Example 39: (3S)—N-[3-[2-(isopropylamino)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0491] [ka]

[0492] Preparation 39A: 4-iodo-N-isopropyl-6-(morpholin-4-yl)pyridin-2-amine

[0493] [ka]

[0494] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), isopropylamine (86 mg, 1.461 mmol), NMP (3 mL), and K2CO3 (404 mg, 2.921 mmol) was stirred at 150 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-50%) to give 4-iodo-N-isopropyl-6-(morpholin-4-yl)pyridin-2-amine (210 mg, 62%) as a white solid. MS ESI calculated for C 12 H 18 IN3O[M+H] + ,348.05,found 348.10. 1 H NMR (300 MHz, chloroform-d) δ 6.27 (s, 1H), 6.16 (s, 1H), 4.17 (d, J = 7.7 Hz, 1H), 3.92-3.74 (m, 5H), 3.48-3.39 (m, 4H), 1.22 (d, J = 6.4 Hz, 6H).

[0495] Example 39: (3S)—N-[3-[2-(isopropylamino)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0496] [ka]

[0497] A mixture of 4-iodo-N-isopropyl-6-(morpholin-4-yl)pyridin-2-amine (150 mg, 0.432 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (196 mg, 0.475 mmol), 1,4-dioxane (2 mL), HO (0.5 mL), KPO (275 mg, 1.296 mmol), and Pd(dppf)Cl.DCM (43 mg, 0.053 mmol) was stirred under a N atmosphere at 80° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (3S)-N-[3-[2-(isopropylamino)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (86 mg, 40%) as an off-white solid. MS ESI calculated for C 26 H 34 F3N5O2[M+H] + ,506.27,found 506.15. 1H NMR(400 MHz,DMSO-d6) δ 8.13(d,J=17.1 Hz,1H),7.41(dd,J=8.3,2.3 Hz,1H),7.33(d,J=2.4 Hz,1H),7.09(d,J=8.4 Hz,1H),6.05(d,J=7.5 Hz,1H),5.72(dd,J=8.5,1.0Hz,2H),3.96(h,J=6.6 Hz,1H),3.71-3.62(m,5H),3.57-3.47(m,1H),3.36-3.30(m,5H),3.02(t,J=9.4 Hz,1H),2.50-2.42(m,1H),2.41-2.39(m,2H),2.16(s,3H),2.08(s,1H),1.67(q,J=10.5,10.1 Hz,1H),1.15(d,J=6.5 Hz,6H).

[0498] Example 40: (3S)—N-[3-[2-(tert-butylamino)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0499] [ka]

[0500] Preparation 40A: N-tert-butyl-4-iodo-6-(morpholin-4-yl)pyridin-2-amine

[0501] [ka]

[0502] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), 3-methylazetidin-3-ol (127 mg, 1.461 mmol), NMP (3 mL), and K2CO3 (404 mg, 2.921 mmol) was stirred at 150 °C for 16 h. The reaction was monitored by LCMS. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give N-tert-butyl-4-iodo-6-(morpholin-4-yl)pyridin-2-amine (120 mg, 34%) as a white solid. MS ESI calculated for C 13 H 20 IN3O[M+H] + ,362.07,found 362.05. 1 H NMR(400 MHz,DMSO-d6) δ 6.28(d,J=1.0 Hz,1H),6.19-6.11(m,2H),3.66(t,J=4.9 Hz,4H),3.44-3.29(m,4H),1.34(s,9H).

[0503] Example 40: (3S)—N-[3-[2-(tert-butylamino)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0504] [ka]

[0505] To a stirred mixture of N-tert-butyl-4-iodo-6-(morpholin-4-yl)pyridin-2-amine (100 mg, 0.277 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (126 mg, 0.305 mmol) in dioxane (1 mL), HO (0.2 mL), KPO (176 mg, 0.831 mmol) and Pd(dppf)Cl.CHCl (23 mg, 0.028 mmol) were added in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 80 °C under a N atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1). The residue was purified by reverse flash chromatography using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 150 mm, 5 µm, 13 nm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 30B to 70B in 4.2 min; 254 / 210 nm. Fractions containing the desired product were combined and concentrated to give (3S)-N-[3-[2-(tert-butylamino)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (86 mg, 60%). MS ESI calculated for C 27 H 36 F3N5O2[M+H] + ,520.28,found 520.15. 1H NMR(400 MHz,DMSO-d6) δ 8.10(s,1H),7.40(dd,J=8.2,2.3 Hz,1H),7.34(d,J=2.3 Hz,1H),7.09(d,J=8.3 Hz,1H),5.98(s,1H),5.81(s,1H),5.73(s,1H),3.69(q,J=8.0,6.3Hz,5H),3.57-3.48(m,1H),3.37(s,1H),3.32(s,1H),3.02(t,J=9.4 Hz,1H),2.45(d,J=11.3 Hz,1H),2.41(s,2H),2.16(s,3H),2.12-2.05(m,1H),1.70-1.61(m,1H),1.40(s,9H). 19 F NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0506] Example 41: (3S)—N-(3-[2-[(1-hydroxy-2-methylpropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0507] [ka]

[0508] Preparation 41A: 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]-2-methylpropan-1-ol

[0509] [ka]

[0510] To a stirred solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and 2-amino-2-methyl-1-propanol (130 mg, 1.461 mmol) in NMP (3 mL) was added KCO (404 mg, 2.922 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-50%) to give 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]-2-methylpropan-1-ol (160 mg, 44%) as a light blue solid. MS ESI calculated for C 13 H 20 IN3O2[M+H] + ,378.06,found 378.10. 1 H NMR(400 MHz,DMSO-d6) δ 6.67(s,1H),6.49(s,1H),3.87(s,2H),3.67(t,J=4.7 Hz,4H),3.42(t,J=4.8 Hz,4H),1.57(s,2H),1.05(s,6H).

[0511] Example 41: (3S)—N-(3-[2-[(1-hydroxy-2-methylpropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0512] [ka]

[0513] To a stirred mixture of 2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]-2-methylpropan-1-ol (100 mg, 0.265 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (120 mg, 0.292 mmol) in dioxane (2 mL), HO (0.5 mL), KPO (169 mg, 0.795 mmol) and Pd(dppf)Cl.CHCl (22 mg, 0.027 mmol) were added at room temperature under a N atmosphere. The resulting mixture was stirred at 80 °C under a N atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA. The residue was purified by reverse flash chromatography at 254 / 210 nm under the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 150 mm, 5 μm, 13 nm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 40B to 75B in 4.3 min. Fractions containing the desired product were combined and concentrated to give (3S)-N-(3-[2-[(1-hydroxy-2-methylpropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (31 mg, 22%) as a light blue solid. MS ESI calculated for C 27 H 36 F3N5O2[M+H] + ,536.28,found 536.15. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.40(dd,J=8.2,2.4 Hz,1H),7.35(d,J=2.3 Hz,1H),7.09(d,J=8.3 Hz,1H),5.82(d,J=14.0 Hz,2H),5.75(s,1H),4.90(t,J=5.7 Hz,1H),3.73-3.62(m,5H),3.58-3.48(m,3H),3.32(dd,J=16.9,10.3 Hz,3H),3.02(t,J=9.4 Hz,1H),2.51-2.34(m,2H),2.17(s,3H),2.08(t,J=5.8 Hz,1H),1.67(q,J=10.0 Hz,1H),1.32(s,6H).19F-NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0514] Example 42: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-(oxetan-3-ylamino)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0515] [ka]

[0516] Preparation 42A: 6-Fluoro-4-iodo-N-(oxetan-3-yl)pyridin-2-amine

[0517] [ka]

[0518] To a stirred mixture of 2,6-difluoro-4-iodopyridine (300 mg, 1.245 mmol), oxetan-3-amine hydrochloride (150 mg, 1.369 mmol), DIEA (354 mg, 2.739 mmol) in DMSO (4 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 3 hours. It was used directly in the next step without further workup. MS ESI calculated for C H F I O [M + H] + ,294.97,found 295.05.

[0519] Preparation 42B: 4-iodo-6-(morpholin-4-yl)-N-(oxetan-3-yl)pyridin-2-amine

[0520] [ka]

[0521] A mixture of 6-fluoro-4-iodo-N-(oxetan-3-yl)pyridin-2-amine (300 mg, 1.020 mmol), morpholine (444 mg, 5.101 mmol), and DIEA (145 mg, 1.122 mmol) in DMSO (4.5 mL) was stirred under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) to give 4-iodo-6-(morpholin-4-yl)-N-(oxetan-3-yl)pyridin-2-amine (395 mg, 90%) as an off-white solid. MS ESI calculated for C 12 H 16 IN3O2[M+H] + ,362.03,found 362.00. 1H NMR (400 MHz, chloroform-d) δ 6.35-6.34 (m, 1H), 6.15 (s, 1H), 4.99-4.95 (m, 2H), 4.57-4.55 (m, 2H), 3.81-3.87 (m, 4H), 3.86-3.43 (m, 5H).

[0522] Example 42: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-(oxetan-3-ylamino)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0523] [ka]

[0524] A mixture of 4-iodo-6-(morpholin-4-yl)-N-(oxetan-3-yl)pyridin-2-amine (200 mg, 0.554 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (228 mg, 0.554 mmol), NaCO (176 mg, 1.661 mmol), dioxane (1.6 mL), HO (0.4 mL), and Pd(dppf)Cl.CHCl (45 mg, 0.055 mmol) was stirred at 60° C. for 16 hours. The resulting mixture was diluted with HO (20 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×15 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1), followed by preparative HPLC under the following conditions (Column: SunFire Prep C18 OBD Column, 19 x 150 mm, 5 µm, 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 20B to 50B in 4.3 min; 210 / 254 nm) to give (3S)-N-[4-methyl-3-[2-(morpholin-4-yl)-6-(oxetan-3-ylamino)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (160 mg, 55%) as a white solid. MS ESI calculated for C 26 H 32 F3N5O3[M+H] + ,520.25,found 520.15. 1H NMR(400 MHz,DMSO-d6) δ 8.13(s,1H),7.54-7.34(m,2H),7.11-7.01(m,2H),5.83-5.74(m,2H),4.87-4.77(m,3H),4.48-4.32(m,2H),3. 76-3.60(m,6H),3.54-3.21(m,5H),3.04-2.99(m,1H),2.45-2.41(m,3H),2.34-2.07(m,4H),1.68-1.63(m,1H). 19 F NMR(376 MHz,DMSO-d6) δ -63.36(3F).

[0525] Example 43: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-oxolan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0526] [ka]

[0527] Preparation 43A: 4-Iodo-6-(morpholin-4-yl)-N-[(3R)-oxolan-3-yl]pyridin-2-amine

[0528] [ka]

[0529] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (404 mg, 2.921 mmol) in NMP (3 mL) was added (3R)-oxolan-3-amine (127 mg, 1.461 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 h. The mixture was cooled to room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, gradient 30% to 70% in 20 min; detector, UV 254 nm to give 4-iodo-6-(morpholin-4-yl)-N-[(3R)-oxolan-3-yl]pyridin-2-amine (230 mg, 63%) as a brown solid. MS ESI calculated for C 13 H 18 IN3O2[M+H] + 376.04 found 375.90. 1 H NMR(300 MHz,chloroform-d) δ 6.32(d,J=1.0 Hz,1H),6.20(d,J=1.0 Hz,1H),4.47-4.28(m,2H),4.04-3.91(m,2H),3.91-3.81(m,1H),3.85-3.75(m,4H),3.68(dd,J=9.2,3.3 Hz,1H),3.56-3.40(m,4H),2.38-2.20(m,1H),1.92-1.79(m,1H).

[0530] Example 43: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-oxolan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0531] [ka]

[0532] To a stirred mixture of 4-iodo-6-(morpholin-4-yl)-N-[(3R)-oxolan-3-yl]pyridin-2-amine (130 mg, 0.346 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (142.84 mg, 0.346 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added NaCO (110 mg, 1.039 mmol) and Pd(dppf)Cl.CHCl (29 mg, 0.035 mmol) under a nitrogen atmosphere at 70° C. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 4 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give (3S)-N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-oxolan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (55 mg, 30%) as a light green solid. MS ESI calculated for C 27 H 34 F3N5O4[M+H] + 534.26 found 534.10. 1H NMR(300 MHz,DMSO-d6) δ 8.12(s,1H),7.49-7.30(m,2H),7.10(d,J=8.3 Hz,1H),6.53(s,1H),5.79(d,J=6.6 Hz,2H),4.33(s,1H),3.92(dd,J=8.7,6.0 Hz,1H),3.84(dd,J=8.3,7.0 Hz,1H),3.77-3.64(m,6H),3.59-3.46(m,2H),3.39(d,J=4.8 Hz,4H),3.29(dd,J=10.1,6.7 Hz,1H),3.02(t,J=9.3 Hz,1H),2.44(dd,J=12.8,7.7 Hz,3H),2.36-1.94(m,5H),1.89-1.74(m,1H),1.67(q,J=9.8 Hz,1H).

[0533] Example 44: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-oxolan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (FT002912 PH-FNT-KIN-04-1601-0)

[0534] [ka]

[0535] Preparation 44A: 4-Iodo-6-(morpholin-4-yl)-N-[(3S)-oxolan-3-yl]pyridin-2-amine

[0536] [ka]

[0537] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (404 mg, 2.921 mmol) in NMP (3 mL) was added (3S)-oxolan-3-amine (127 mg, 1.461 mmol) at room temperature. The resulting mixture was stirred at 150 °C for 16 hours. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give 4-iodo-6-(morpholin-4-yl)-N-[(3S)-oxolan-3-yl]pyridin-2-amine (304 mg, 83%) as a light green solid. MS ESI calculated for C 13 H 18 IN3O2376.04,found 375.95. 1 H NMR(400 MHz,chloroform-d) δ 6.32(d,J=1.1 Hz,1H),6.20(d,J=1.0 Hz,1H),4.42(s,1H),3.98(dd,J=9.0,5.7 Hz,2H),3.86(td,J=8.4,5.6 Hz,1H),3.80(t,J=4.9 Hz,4H),3.69(dd,J=9.1,3.2 Hz,1H),3.45(s,4H),2.36-2.22(m,1H),1.60(s,1H),1.28(s,1H).

[0538] Example 44: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-oxolan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0539] [ka]

[0540] To a stirred mixture of 4-iodo-6-(morpholin-4-yl)-N-[(3S)-oxolan-3-yl]pyridin-2-amine (150 mg, 0.400 mmol) and (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)cyclopentane-1-carboxamide (132 mg, 0.321 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added NaCO (127 mg, 1.199 mmol) and Pd(dppf)Cl.CHCl (33 mg, 0.040 mmol) under a nitrogen atmosphere at 150 °C. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm, 5 um, 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CH3CN; Flow Rate: 20 mL / min; Gradient: 35B to 70B in 5.3 min; 254 / 210 nm to give (3S)-N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-oxolan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (61 mg, 29%) as a light green solid. MS ESI calculated for 534.26, found for 534.15. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.51-7.25(m,2H),7.10(d,J=8.3 Hz,1H),6.51(d,J=5.8 Hz,1H),5.88-5.64(m,2H),4.33(s,1H),3.92(dd,J=8.7,6.0 Hz,1H),3.82(q,J=7.5 Hz,1H),3.68(t,J=4.9 Hz,6H),3.51(dd,J=8.7,3.9 Hz,3H),3.39(d,J=5.4 Hz,5H),3.02(t,J=9.4 Hz,1H),2.44(t,J=10.9 Hz,2H),2.16(s,4H),2.12-2.04(m,1H),1.80(dq,J=12.3,6.0 Hz,1H),1.67(q,J=10.0 Hz,1H).

[0541] Example 45: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-oxan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0542] [ka]

[0543] Preparation 45A: 4-iodo-6-(morpholin-4-yl)-N-[(3R)-oxan-3-yl]pyridin-2-amine

[0544] [ka]

[0545] A stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), K2CO3 (673 mg, 4.869 mmol), (3R)-oxan-3-amine hydrochloride (670 mg, 4.869 mmol) in NMP (3 mL) at room temperature under a nitrogen atmosphere was added. The resulting mixture was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc / EtOH (4 / 3 / 1) to give 4-iodo-6-(morpholin-4-yl)-N-[(3R)-oxan-3-yl]pyridin-2-amine (322 mg, 85%) as a white solid. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.06,found 389.95.

[0546] Example 45: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-oxan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0547] [ka]

[0548] To a stirred mixture of 4-iodo-6-(morpholin-4-yl)-N-[(3R)-oxan-3-yl]pyridin-2-amine (150 mg, 0.385 mmol) and (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)cyclopentane-1-carboxamide (127 mg, 0.308 mmol) in 1,4-dioxane (4 mL) and HO (1 mL), NaCO (122 mg, 1.156 mmol) and Pd(dppf)Cl.CHCl (31 mg, 0.039 mmol) were added under a nitrogen atmosphere and stirred at 150 °C for 2 h. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give (3S)-N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-oxan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (25 mg, 12%) as a light green solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,547.28 found 548.15. 1 H NMR(400 MHz,DMSO-d6) δ 8.13(s,1H),7.49-7.29(m,2H),7.10(d,J=8.3 Hz,1H),6.20(brs,1H),5.81(s,2H),3.92(s,1H),3.81(s,1H),3.73-3.62(m,6H),3.52(ddd,J=10.3,8.3,2.3 Hz,1H),3.36-3.30(m,8H),2.48-2.32(m,3H),2.16(s,3H),2.11-2.06(m,1H),1.92-1.90(m,1H),1.76-1.59(m,4H).

[0549] Example 46: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-(oxan-4-ylamino)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0550] [ka]

[0551] Preparation 46A: 4-iodo-6-(morpholin-4-yl)-N-(oxan-4-yl)pyridin-2-amine

[0552] [ka]

[0553] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and oxan-4-amine (541.70 mg, 5.355 mmol) in NMP (3 mL) was added KCO (269.15 mg, 1.947 mmol) at 60 °C under a nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 4-iodo-6-(morpholin-4-yl)-N-(oxan-4-yl)pyridin-2-amine (150 mg, 40%) as a light green solid. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.06,found 389.95 1H NMR(400 MHz,DMSO-d6) δ 6.38(d,J=7.3 Hz,1H),6.23(d,J=1.0 Hz,1H),6.20(d,J=1.0 Hz,1H),3.84(dt,J=11.7,3.7 Hz,2H),3.68-3.61(m,4H),3.44-3.30(m,4H),1.84(d,J=12.2 Hz,2H),1.49-1.30(m,2H),1.24(s,1H),0.89(dd,J=29.8,6.5 Hz,2H).

[0554] Example 46: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-(oxan-4-ylamino)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0555] [ka]

[0556] To a stirred mixture of 4-iodo-6-(morpholin-4-yl)-N-(oxan-4-yl)pyridin-2-amine (150 mg, 0.385 mmol) and (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)cyclopentane-1-carboxamide (127 mg, 0.308 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added NaCO (122 mg, 1.156 mmol) and Pd(dppf)Cl.CHCl (31 mg, 0.039 mmol) under a nitrogen atmosphere at 150 °C. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19 x 150 mm, 5 um, 10 nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CHCN; Flow Rate: 20 mL / min; Gradient: 30B to 75B in 5.5 min; 254 / 210 nm to give (3S)-N-[4-methyl-3-[2-(morpholin-4-yl)-6-(oxan-4-ylamino)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (89 mg, 42%) as a light green solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.28,found 548.15. 1H NMR(400 MHz,DMSO-d6) δ 8.13(d,J=14.5 Hz,1H),7.41(dd,J=8.3,2.4 Hz,1H),7.34(d,J=2.3 Hz,1H),7.09(d,J=8.4 Hz,1H),6.21(d,J=7.4 Hz,1H),5.76(s,2H),3.95-3.76(m,4H),3.76-3.59(m,6H),3.52(t,J=8.8 Hz,1H),3.45-3.39(m,5H),3.02(t,J=9.5 Hz,1H),2.44(t,J=11.0 Hz,3H),2.16(s,3H),2.08(s,1H),1.90(d,J=13.2 Hz,2H),1.66(p,J=10.1 Hz,1H),1.52-1.32(m,2H).

[0557] Example 47: (S)—N-(3-(2-(((1S,3R)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0558] [ka]

[0559] Preparation 47A: (1S,3S)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)cyclobutan-1-ol

[0560] [ka]

[0561] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), (cis)-3-aminocyclobutan-1-ol hydrochloride (181 mg, 1.461 mmol), and K2CO3 (404 mg, 2.921 mmol) in NMP (5 mL) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (80%) to give (1S,3S)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)cyclobutan-1-ol (300 mg, 80%) as an off-white solid. MS ESI calculated for C 13 H 18 IN3O2[M+H] + ,376.04,found 375.95. 1 H NMR (400 MHz, chloroform-d) δ 6.31 (s, 1H), 6.12 (s, 1H), 4.45-4.44 (m, 1H), 4.17-4.10 (m, 1H), 3.80-3.78 (m, 4H), 3.68-3.62 (m, 1H), 3.46-3.43 (m, 4H), 2.92-2.85 (m, 1H), 1.83-1.81 (m, 4H).

[0562] Example 47: (S)—N-(3-(2-(((1S,3R)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0563] [ka]

[0564] A mixture of (1S,3S)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)cyclobutan-1-ol (200 mg, 0.533 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (242 mg, 0.586 mmol), Pd(dppf)Cl.CHCl (43 mg, 0.053 mmol), NaCO (169 mg, 1.599 mmol), 1,4-dioxane (6 mL), and water (1.5 mL) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / EtOH (3 / 1) in PE (65%), followed by trituration with DCM / hexane (1 / 5) to give (S)-N-(3-(2-(((1S,3R)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (214 mg, 74%) as a pale yellow solid. MS ESI calculated for C 27 H 34 F3N5O3[M+H] + ,534.26,found 534.20. 1 H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.42-7.40(m,1H),7.40(s,1H),7.33-7.32(m,1H),7.10-7.08(m,1H),5.76(s,1H),5.68(s,1H),5.00(s,1H),3.86-3.84(m, 1H),3.69-3.65(m,6H),3.52-3.50(m,1H),3.38-3.29(m,5H),3.04-2 .99(m,1H),2.63-2.41(m,5H),2.15-2.07(m,4H),1.74-1.66(m,3H). 19 F NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0565] Example 48: (S)—N-(3-(2-(((1R,3S)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0566] [ka]

[0567] Preparation 48A: (1R,3R)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)cyclobutan-1-ol

[0568] [ka]

[0569] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), (1R,3R)-3-aminocyclobutan-1-ol hydrochloride (181 mg, 1.461 mmol), and K2CO3 (404 mg, 2.921 mmol) in NMP (5 mL) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (80%) to give (1R,3R)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)cyclobutan-1-ol (270 mg, 74%) as a pale yellow solid. MS ESI calculated for C 13 H 18 IN3O2[M+H] + ,376.04,found 375.90. 1H NMR(400 MHz,DMSO-d6) δ 6.63-6.60(m,1H),6.22(s,1H),6.11(s,1H),4.96(s,1H),4.29-4.13(m,2H),3.65-3.63(m,4H),3.41-3.33(m,4H),2.16-2.06(m,4H).

[0570] Example 48: (S)—N-(3-(2-(((1R,3S)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0571] [ka]

[0572] A mixture of (1R,3R)-3-((4-iodo-6-morpholinopyridin-2-yl)amino)cyclobutan-1-ol (200 mg, 0.533 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (242 mg, 0.586 mmol), Pd(dppf)Cl.CHCl (43 mg, 0.053 mmol), NaCO (169 mg, 1.599 mmol), 1,4-dioxane (6 mL), and water (1.5 mL) was added. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / EtOH (3 / 1) in PE (65%), followed by trituration with DCM / hexane (1 / 5) to give (S)-N-(3-(2-(((1R,3S)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (190 mg, 65) as a brown-yellow solid. MS ESI calculated for C 27 H34 F3N5O3[M+H] + ,534.26,found 534.30. 1 H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.42-7.41(m,1H),7.40(s,1H),7.33-7.32(m,1H),7.10-7.08(m,1H),5.78(s,1H),5.63(s,1H),4.97-4.95(m,1H),4. 31-4.18(m,2H),3.69-3.50(m,6H),3.39-3.29(m,5H),3.04-2.99(m,1H),2.50-2.41(m,3H),2.16-2.08(m,8H),1.68-1.66(m,1H). 19 F NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0573] Example 49: (3S)—N-[3-(2-[[(2R)-1-hydroxybutan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0574] [ka]

[0575] Preparation 49A: (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butan-1-ol

[0576] [ka]

[0577] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), K2CO3 (269 mg, 1.947 mmol), NMP (3 mL), and (2R)-2-aminobutan-1-ol (130 mg, 1.461 mmol) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched by adding water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butan-1-ol (90 mg, 24%) as an off-white solid. MS ESI calculated for C 13 H 20 IN3O2[M+H] + ,378.06,found 377.90. 1 H NMR(300 MHz,CDCL3) δ 6.29-6.26(m,2H),4.23(s,1H),3.81-3.76(m,6H),3.62-3.55(m,1H),3.45-3.4 2(m,4H),3.14(s,1H),1.77-1.63(m,1H),1.57-1.43(m,1H),1.03-0.96(m,3H).

[0578] Example 49: (3S)—N-[3-(2-[[(2R)-1-hydroxybutan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0579] [ka]

[0580] A mixture of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butan-1-ol (90 mg, 0.239 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (98 mg, 0.239 mmol), NaCO (76 mg, 0.716 mmol), dioxane:HO = 4:1 (1 mL), and Pd(dppf)Cl.CHCl (19 mg, 0.024 mmol) was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) to give 70 mg of crude product. The residue was purified by reverse flash chromatography using the following conditions: Column: SunFire Prep C18 OBD Column, 19 × 150 mm, 5 μm, 10 nm; Mobile Phase A: water (0.1% FA), Mobile Phase B: CHCN; Flow rate: 20 mL / min; Gradient: 25B to 65B in 5.1 min; 254 / 210 nm. This resulted in (3S)-N-[3-(2-[[(2R)-1-hydroxybutan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (59 mg, 46%) as an off-white solid. MS ESI calculated for C 27 H 36 F3N5O3[M+H] + .536.28,found 536.15. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.42-7.40(m,1H),7.34-7.33(m,1H),7.10-7.08(m,1H),5.95-5.93 (m,1H),5.78-5.73(m,2H),4.59(s,1H),3.75-3.64(m,6H),3.55-3.48(m,2H),3. 38-3.36(m,4H),3.31-3.27(m,2H),3.04-2.99(m,1H),2.48-2.38(m,3H),2.16(s ,3H),2.12-2.07(m,1H),1.70-1.60(m,2H),1.48-1.37(m,1H),0.91-0.88(m,3H). 19 F NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0581] Example 50: (3S)—N-[3-(2-[[(2R)-1-methoxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0582] [ka]

[0583] Preparation 50A: 4-Iodo-N-[(2R)-1-methoxypropan-2-yl]-6-(morpholin-4-yl)pyridin-2-amine

[0584] [ka]

[0585] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (269 mg, 1.947 mmol), NMP (3 mL), and (2R)-1-methoxypropan-2-amine (434 mg, 4.869 mmol) was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched by adding water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give 4-iodo-N-[(2R)-1-methoxypropan-2-yl]-6-(morpholin-4-yl)pyridin-2-amine (150 mg, 41%) as an off-white solid. MS ESI calculated for C 13 H 20 IN3O2[M+H] + ,378.06,found 377.95. 1 H NMR(400 MHz,CDCL3) δ 6.27(m,1H),6.20(s,1H),4.45-4.43(m,1H),4.00-3.97(m,1H),3.84-3.78(m,4H),3.53-3.27(m,8H),1.28-1.23(m,3H).

[0586] Example 50: (3S)—N-[3-(2-[[(2R)-1-methoxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0587] [ka]

[0588] A mixture of 4-iodo-N-[(2R)-1-methoxypropan-2-yl]-6-(morpholin-4-yl)pyridin-2-amine (150 mg, 0.398 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (172 mg, 0.418 mmol), NaCO (126 mg, 1.193 mmol), and dioxane:HO = 4:1 (2 mL) was added to Pd(dppf)Cl.CHCl (32 mg, 0.040 mmol) and stirred at 60 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) to give 70 mg of crude product. The residue was purified under the following conditions: Column: Welch Xtimate C18, 21.2 * 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: CH3CN; flow rate 20 mL / min; gradient: 20B to 60B in 5.5 min; purified by reverse flash chromatography at 254 / 210 nm. This resulted in (3S)-N-[3-(2-[[(2R)-1-methoxypropan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (41 mg, 19%) as an off-white solid. MS ESI calculated for C 27 H 36 F3N5O3[M+H] + .536.28,found 536.20. 1H NMR(400 MHz,DMSO-d6) δ 8.13(s,1H),7.44-7.36(m,2H),7.12-7.09(m,1H),6.12-6.09(m,1H), 5.77(s,2H),4.14-4.10(m,1H),3.77-3.69(m,6H),3.57-3.36(m,5H), 3.29(s,4H),3.27-3.22(m,1H),3.07-3.00(m,1H),32.48-2.41(m,3H) ,2.17(s,3H),2.08-2.03(m,1H),1.71-1.64(m,1H),1.16-1.14(m,3H). 19 F NMR(376 MHz,DMSO-d6) δ -63.36(3F).

[0589] Example 51: (3S)—N-[3-(2-[[(2S)-2-methoxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0590] [ka]

[0591] Preparation 51A: 4-iodo-N-[(2S)-2-methoxypropyl]-6-(morpholin-4-yl)pyridin-2-amine

[0592] [ka]

[0593] A mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and (2S)-2-methoxypropan-1-amine (87 mg, 0.974 mmol), NMP (3 mL), and K2CO3 (269 mg, 1.947 mmol) was stirred at 60 °C for 16 hours under a nitrogen atmosphere. The reaction was quenched by the addition of room temperature water (15 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 8 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give 4-iodo-N-[(2S)-2-methoxypropyl]-6-(morpholin-4-yl)pyridin-2-amine (120 mg, crude) as a light green solid, which was used in the next step without further purification. MS ESI calculated for C 13 H 20 IN3O2378.06,found 378.00.

[0594] Example 51: (3S)—N-[3-(2-[[(2S)-2-methoxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0595] [ka]

[0596] A mixture of 4-iodo-N-[(2S)-2-methoxypropyl]-6-(morpholin-4-yl)pyridin-2-amine (112 mg, 0.297 mmol), (3R)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)cyclopentane-1-carboxamide (98 mg, 0.238 mmol), 1,4-dioxane (4 mL), HO (1 mL), NaCO (94 mg, 0.891 mmol), and Pd(dppf)Cl.CHCl (24 mg, 0.030 mmol) was stirred at 70 °C under a nitrogen atmosphere. The reaction was quenched by the addition of room temperature water (10 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 8 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (3S)-N-[3-(2-[[(2S)-2-methoxypropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (22 mg, %) as a light green solid. MS ESI calculated for C 27 H 36 F3N5O3536.28,found 536.00. 1 H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.42(dd,J=8.3,2.3 Hz,1H),7.33(d,J=2.4 Hz,1H),7.09(d,J=8.4 Hz,1H),6.29(t,J=5.9 Hz,1H),5.78(d,J=15.3 Hz,2H),3.71-3.62(m,5H),3.57-3.45(m,2H),3.38(t,J=4.9 Hz,4H),3.32(s,6H),3.02(t,J=9.4 Hz,1H),2.50(s,3H),2.16(s,3H),2.12-2.05(m,1H),1.64(q,J=10.2 Hz,1H),1.10(d,J=6.2 Hz,3H).

[0597] Example 52: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-oxan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0598] [ka]

[0599] Preparation 52A: 4-Iodo-6-(morpholin-4-yl)-N-[(3S)-oxan-3-yl]pyridin-2-amine

[0600] [ka]

[0601] A stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol), K2CO3 (673 mg, 4.869 mmol), (3S)-oxan-3-amine hydrochloride (670 mg, 4.869 mmol) in NMP (3 mL) at room temperature under a nitrogen atmosphere was added. The resulting mixture was stirred at 150 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc / EtOH (4 / 3 / 1) to give 4-iodo-6-(morpholin-4-yl)-N-[(3S)-oxan-3-yl]pyridin-2-amine (260 mg, 69%) as a white solid. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.06,found 389.95. 1H NMR (300 MHz, chloroform-d) δ 6.33-6.32 (m, 1H), 6.11-6.10 (s, 1H), 4.47-4.45 (m, 1H), 4.23-4.11 (m, 1H), 3.80-3.77 (m, 4H), 3.45-3.42 (m, 4H), 2.60-2.53 (m, 1H), 2.00-1.93 (m, 2H), 1.46 (s, 3H), 1.31-1.26 (m, 1H), 0.91-0.88 (m, 1H).

[0602] Example 52: (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-oxan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0603] [ka]

[0604] A mixture of 4-iodo-6-(morpholin-4-yl)-N-[(3S)-oxan-3-yl]pyridin-2-amine (200 mg, 0.514 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (212 mg, 0.514 mmol), dioxane (2 mL), HO (0.5 mL), Pd(dppf)Cl.CHCl (42 mg, 0.051 mmol), and NaCO (163 mg, 1.541 mmol) was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0%-80%) followed by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD Column, 19-150 mm, 5 um, 10 nm; Mobile Phase A: water (0.1% FA), Mobile Phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 25B to 65B in 5.3 min; 254 / 210 nm to give (3S)-N-[4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-oxan-3-ylamino]pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (120 mg, 43%) as an off-white solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.28,found 548.10. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.41(dd,J=8.3,2.3 Hz,1H),7.34(d,J=2.4 Hz,1H),7.09(d,J=8.3 Hz,1H),6.19(s,1H),5.78(d,J=4.9 Hz,2H),3.94(dd,J=10.8,4.0 Hz,1H),3.82(dt,J=13.4,6.3 Hz,1H),3.77-3.62(m,6H),3.52(ddd,J=10.5,8.3,2.3 Hz,1H),3.41-3.25(m,6H),3.05(dt,J=24.7,9.5 Hz,2H),2.51-2.34(m,3H),2.16(s,3H),2.08(dd,J=9.6,3.5 Hz,1H),1.99-1.90(m,1H),1.75-1.50(m,4H).

[0605] Example 53: (3S)—N-(4-methyl-3-[2-[(3-methyloxolan-3-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0606] [ka]

[0607] Preparation 53A: 4-Iodo-N-(3-methyloxolan-3-yl)-6-(morpholin-4-yl)pyridin-2-amine

[0608] [ka]

[0609] A mixture of 2,6-difluoro-4-iodopyridine (300 mg, 1.245 mmol), 3-methyloxolan-3-amine (138 mg, 1.369 mmol), DMSO (3 mL), and DIEA (0.48 mL, 3.691 mmol) was stirred at 110° C. for 4 hours. Morpholine (361 mg, 4.150 mmol) was added to the above mixture at room temperature. The resulting mixture was stirred at 110° C. for 16 hours. The mixture was cooled to room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give 4-iodo-N-(3-methyloxolan-3-yl)-6-(morpholin-4-yl)pyridin-2-amine (230 mg, 47%) as a yellow solid. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.05,found 390.05. 1 H NMR (300 MHz, chloroform-d) δ 6.28 (d, J = 1.0 Hz, 1H), 6.20 (d, J = 1.0 Hz, 1H), 4.39 (s, 1H), 4.00-3.91 (m, 3H), 3.82-3.76 (m, 5H), 3.51-3.37 (m, 4H), 2.41-2.31 (m, 1H), 2.03-1.93 (m, 1H), 1.57 (s, 3H).

[0610] Example 53: (3S)—N-(4-methyl-3-[2-[(3-methyloxolan-3-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0611] [ka]

[0612] A mixture of 4-iodo-N-(3-methyloxolan-3-yl)-6-(morpholin-4-yl)pyridin-2-amine (230 mg, 0.591 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (244 mg, 0.591 mmol), 1,4-dioxane (3 mL), HO (0.6 mL), NaCO (188 mg, 1.773 mmol), and Pd(dppf)Cl.CHCl (48 mg, 0.059 mmol) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give (3S)—N-(4-methyl-3-[2-[(3-methyloxolan-3-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (200 mg, 62%) as a pale pink solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.15,found 548.15. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.40(dd,J=8.3,2.3 Hz,1H),7.35(d,J=2.3 Hz,1H),7.09(d,J=8.4 Hz,1H),6.45(s,1H),5.80(dd,J=10.3,1.0 Hz,2H),3.95(d,J=8.5 Hz,1H),3.86-3.74(m,2H),3.73-3.67(m,6H),3.57-3.44(m,1H),3.39-3.22(m,5H),3.02(t,J=9.4 Hz,1H),2.49-2.36(m,3H),2.33-2.22(m,1H),2.16(s,3H),2.08(d,J=11.2 Hz,1H),1.95-1.86(m,1H),1.70-1.61(m,1H),1.50(s,3H). 19 F NMR(376 MHz,DMSO-d6) δ -63.61(3F).

[0613] Example 54: (3S)—N-[3-(2-[[1-(hydroxymethyl)cyclobutyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0614] [ka]

[0615] Preparation 54A: [1-[(6-fluoro-4-iodopyridin-2-yl)amino]cyclobutyl]methanol

[0616] [ka]

[0617] To a mixture of 2,6-difluoro-4-iodopyridine (550 mg, 2.282 mmol), (1-aminocyclobutyl)methanol hydrochloride (345 mg, 2.511 mmol), and DMSO (6 mL) was added DIEA (944 mg, 7.304 mmol) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 70° C. under a nitrogen atmosphere for 3 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated brine (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give [1-[(6-fluoro-4-iodopyridin-2-yl)amino]cyclobutyl]methanol (320 mg, 43%) as an off-white solid. MS ESI calculated for C 10 H 12 FIN2O[M+H] + ,323.00,found 322.85. 1 H NMR (300 MHz, chloroform-d) δ 6.60-6.55 (m, 2H), 3.86 (s, 2H), 2.35-2.25 (m, 2H), 2.17-2.07 (m, 2H), 2.06-1.83 (m, 2H).

[0618] Preparation 54B: (1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]cyclobutyl)methanol

[0619] [ka]

[0620] To a stirred solution of [1-[(6-fluoro-4-iodopyridin-2-yl)amino]cyclobutyl]methanol (210 mg, 0.652 mmol) and morpholine (125 mg, 1.434 mmol) in DMSO (2.1 mL) was added DIEA (185 mg, 1.434 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 110° C. under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated brine (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2 / 1) to give (1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]cyclobutyl)methanol (195 mg, 77%) as a pale yellow oil. MS ESI calculated for C 14 H 20 IN3O2[M+H] + .390.06,found 389.95. 1 H NMR(300 MHz,DMSO-d6) δ 6.45(s,1H),6.24-6.18(m,2H),4.71(s,1H),3.66-3.63(m,6H),3.32-3.29(m,4H),2.13-2.08(m,4H),1.84-1.66(m,2H).

[0621] Example 54: (3S)—N-[3-(2-[[1-(hydroxymethyl)cyclobutyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0622] [ka]

[0623] A mixture of (1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]cyclobutyl)methanol (190 mg, 0.488 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (201 mg, 0.488 mmol), NaCO (155.21 mg, 1.464 mmol), dioxane:HO = 4:1 (2 mL), and Pd(dppf)Cl.CHCl (40 mg, 0.049 mmol) was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA / EtOH (8 / 3 / 1) to give 200 mg of crude product, followed by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, CHCN in water (10 mmol / L NHHCO), gradient 10% to 80% in 30 min; detector, UV 254 nm. This afforded (3S)-N-[3-(2-[[1-(hydroxymethyl)cyclobutyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (160 mg, 60%) as an off-white solid. MS ESI calculated for C 28 H 36 F3N5O3[M+H] + .548.28,found 548.15. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.41-7.35(m,2H),7.11-7.08(m,1H),6.29(s,1H),5.75(s,2H),4.86-4.82(m,1H),3.69-3.67(m,8 H),3.56-3.50(m,1H),3.32(s,3H),3.05-2.99(m,1H),2.47-2.40(m,3H),2.16-2.13(m,9H),1.83-1.59(m,3H). 19 F NMR(376 MHz,DMSO-d6) δ -63.36(3F).

[0624] Example 55: (3S)—N-[3-(2-[[3-(hydroxymethyl)oxetan-3-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0625] [ka]

[0626] Preparation 55A: [3-[(6-fluoro-4-iodopyridin-2-yl)amino]oxetan-3-yl]methanol

[0627] [ka]

[0628] To a stirred mixture of 2,6-difluoro-4-iodopyridine (1.00 g, 4.150 mmol) and (3-aminooxetan-3-yl)methanol (0.51 g, 4.980 mmol) in DMSO (8 mL) was added DIEA (1.34 g, 10.374 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with EtOAc (100 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (3-((6-fluoro-4-iodopyridin-2-yl)amino)oxetan-3-yl)methanol (1 g, crude) as a pale yellow oil. The crude product was used in the next step without further purification. MS ESI calculated for CH 10 FIN2O2[M+H] + ,324.98,found 324.95.

[0629] Preparation 55B: (3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]oxetan-3-yl)methanol

[0630] [ka]

[0631] To a stirred mixture of [3-[(6-fluoro-4-iodopyridin-2-yl)amino]oxetan-3-yl]methanol (600 mg, 1.851 mmol, 1.00 equiv.) and morpholine (177 mg, 2.036 mmol) in DMSO (4 mL), DIEA (526 mg, 4.073 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give (3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]oxetan-3-yl)methanol (300 mg, 41.42%) as a white solid. MS ESI calculated for C 13 H 18 IN3O3[M+H] + ,392.04,found 392.04. 1 H NMR(400 MHz,chloroform-d) δ 7.28(s,1H),6.34(d,J=1.0 Hz,1H),6.28(s,1H),4.73(d,J=6.4 Hz,1H),4.63(d,J=6.5 Hz,2H),4.14(s,1H),3.81-3.77(m,2H),3.37(s,2H),3.13(s,1H),1.59(s,2H),1.34-1.23(m,2H),0.93-0.81(m,2H).

[0632] Example 55: (3S)—N-[3-(2-[[3-(hydroxymethyl)oxetan-3-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0633] [ka]

[0634] A mixture of (3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]oxetan-3-yl)methanol (250 mg, 0.639 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (263 mg, 0.639 mmol), HO (0.75 mL), and 1,4-dioxane (3 mL), Pd(dppf)Cl.CHCl (52 mg, 0.064 mmol), and NaCO (203 mg, 1.917 mmol) was stirred at 60° C. under a nitrogen atmosphere for 2 hours. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc followed by reverse-phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 40 g; Mobile phase A: water (5 mM NH4HCO3); Mobile phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 5% to 5% B in 10 min, 5% to 40% B in 35 min, gradient from 40% B to 98% B in 10 min; Detection: 220 nm to give (3S)-N-[3-(2-[[3-(hydroxymethyl)oxetan-3-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (186 mg, 53%) as a light blue solid. MS ESI calculated for C 27 H 34 F3N5O4[M+H] + ,550.26,found 550.3. 1H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.43-7.33(m,2H),7.10(d,J=8.3 Hz,1H),6.81(s,1H),5.87-5.73(m,2H),5.03(t,J=5.7 Hz,1H),4.56(q,J=6.1 Hz,4H),3.81(d,J=5.8 Hz,2H),3.66(dd,J=5.9,3.9 Hz,5H),3.52(ddd,J=10.4,8.4,2.3 Hz,1H),3.32(s,5H),3.02(t,J=9.4 Hz,1H),2.44(t,J=10.8 Hz,3H),2.16(s,3H),2.09(q,J=5.3,4.7 Hz,1H),1.65(p,J=10.0 Hz,1H).

[0635] Example 56: (3S)—N-(4-methyl-3-[2-[(3-methyloxetan-3-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0636] [ka]

[0637] Preparation 56A: 6-Fluoro-4-iodo-N-(3-methyloxetan-3-yl)pyridin-2-amine

[0638] [ka]

[0639] A solution of 2,6-difluoro-4-iodopyridine (500 mg, 2.075 mmol), 3-methyloxetan-3-amine (181 mg, 2.075 mmol), and DIEA (295 mg, 2.282 mmol) in DMSO (5 mL) was stirred at 70 °C under a nitrogen atmosphere for 16 h. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (50%) to give 6-fluoro-4-iodo-N-(3-methyloxetan-3-yl)pyridin-2-amine (450 mg, 70%) as an off-white solid. MS ESI calculated for CH 10 FIN2O[M+H] + ,309.09,found 308.85. 1 H NMR(400 MHz,DMSO-d6) δ 7.62(s,1H),6.74-6.73(m,1H),6.59-6.58(m,1H),4.59-4.58(m,2H),4.39-4.38(m,2H),1.58(s,3H). 19 F NMR(376 MHz,DMSO-d6) δ -69.76(1F).

[0640] Preparation 56B: 4-Iodo-N-(3-methyloxetan-3-yl)-6-(morpholin-4-yl)pyridin-2-amine

[0641] [ka]

[0642] A solution of 6-fluoro-4-iodo-N-(3-methyloxetan-3-yl)pyridin-2-amine (400 mg, 1.298 mmol), morpholine (124 mg, 1.428 mmol), and DIEA (335 mg, 2.597 mmol) in DMSO (4 mL) was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (50%) to give 4-iodo-N-(3-methyloxetan-3-yl)-6-(morpholin-4-yl)pyridin-2-amine (270 mg, 55%) as a pale yellow solid. MS ESI calculated for C 13 H 18 IN3O2[M+H] + ,376.21,found 375.90. 1 H NMR(400 MHz,DMSO-d6) δ 6.90(s,1H),6.25(s,1H),6.20(s,1H),4.63-4.60(m,2H),4.36-4.34(m,2H),3.65-3.62(m,4H),3.31-3.28(m,4H),1.59(s,3H).

[0643] Example 56: (3S)—N-(4-methyl-3-[2-[(3-methyloxetan-3-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0644] [ka]

[0645] A mixture of 4-iodo-N-(3-methyloxetan-3-yl)-6-(morpholin-4-yl)pyridin-2-amine (200 mg, 0.533 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (242 mg, 0.586 mmol), Pd(dppf)Cl.CHCl (43 mg, 0.053 mmol), NaCO (169 mg, 1.599 mmol), 1,4-dioxane (6 mL), and HO (1.5 mL) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / EtOH (3 / 1) in PE (58%) followed by preparative HPLC using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 150 mm, 5 µm, 13 nm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 20 mL / min; Gradient: 40B to 65B in 5.5 min; 254 / 210 nm to give (3S)-N-(4-methyl-3-[2-[(3-methyloxetan-3-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (97 mg, 33%) as an off-white solid. MS ESI calculated for C 27 H 34 F3N5O3[M+H] + ,534.26,found 534.25. 1H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.42-7.35(m,2H),7.11-7.09(m,1H),6.77(s,1H),5.81(s,1H),5.73(s,1H),4.70-4.69(m,2H),4.40-4.38(m,2H),3.68-3. 64(m,5H),3.52-3.50(m,1H),3.35-3.29(m,5H),3.04-2.99(m,1H),2 .52-2.41(m,3H),2.16(s,3H),2.06-2.04(m,1H),1.75-1.60(m,4H). 19 F NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0646] Example 57: (3S)—N-(4-methyl-3-[2-[(4-methyloxan-4-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0647] [ka]

[0648] Preparation 57A: 4-iodo-N-(4-methyloxan-4-yl)-6-(morpholin-4-yl)pyridin-2-amine

[0649] [ka]

[0650] A solution of 2,6-difluoro-4-iodopyridine (200 mg, 0.830 mmol), 4-methyloxan-4-amine (105 mg, 0.913 mmol), DMSO (2 mL), and DIEA (0.32 mL, 2.461 mmol) was stirred at 110° C. for 4 hours. To this was added morpholine (361 mg, 4.150 mmol). The resulting mixture was stirred at 110° C. for 16 hours. The mixture was cooled to room temperature and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give 4-iodo-N-(4-methyloxan-4-yl)-6-(morpholin-4-yl)pyridin-2-amine (220 mg, 66%) as a yellow solid. MS ESI calculated for C 15 H 22 IN3O2[M+H] + ,404.10,found 404.10. 1 H NMR(300 MHz,CDCl3-d) δ 6.23(dd,J=10.0,1.0 Hz,2H),4.05(s,1H),3.86-3.67(m,11H),3.43-3.35(m,5H),2.10(t,J=12.3 Hz,3H).

[0651] Example 57: (3S)—N-(4-methyl-3-[2-[(4-methyloxan-4-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0652] [ka]

[0653] A mixture of 4-iodo-N-(4-methyloxan-4-yl)-6-(morpholin-4-yl)pyridin-2-amine (220 mg, 0.546 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (225 mg, 0.546 mmol), 1,4-dioxane (2 mL), HO (0.4 mL), NaCO (173 mg, 1.637 mmol), and Pd(dppf)Cl.CHCl (44 mg, 0.055 mmol) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 2) to give (3S)—N-(4-methyl-3-[2-[(4-methyloxan-4-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (158 mg, 52%) as a pale yellow solid. MS ESI calculated for C 29 H 38 F3N5O3[M+H] + ,562.15,found 562.15. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.42(dd,J=8.3,2.4 Hz,1H),7.35(d,J=2.3 Hz,1H),7.09(d,J=8.4 Hz,1H),5.97(s,1H),5.91(d,J=0.9 Hz,1H),5.75(d,J=1.0 Hz,1H),3.72-3.54(m,9H),3.52-3.49(m,1H),3.36-3.32(m,5H),3.02(t,J=9.5 Hz,1H),2.47-2.35(m,3H),2.21(s,1H),2.17(s,4H),2.09(dd,J=12.4,6.2 Hz,1H),1.73-1.53(m,3H),1.46(s,3H). 19 F NMR(376 MHz,DMSO-d6) δ -63.36(3F).

[0654] Example 58: (3S)—N-[3-(2-[[1-(hydroxymethyl)cyclopropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0655] [ka]

[0656] Preparation 58A: [1-[(6-fluoro-4-iodopyridin-2-yl)amino]cyclopropyl]methanol

[0657] [ka]

[0658] A mixture of 2,6-difluoro-4-iodopyridine (500 mg, 2.075 mmol), (1-aminocyclopropyl)methanol hydrochloride (282 mg, 2.282 mmol), and NaHCO (523 mg, 6.225 mmol) in DMSO (5 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 h. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (58%) to give [1-[(6-fluoro-4-iodopyridin-2-yl)amino]cyclopropyl]methanol (575 mg, 90%) as a pale yellow oil. MS ESI calculated for CH 10 FIN2O[M+H] + ,309.09,found 308.90. 1 H NMR(400 MHz,DMSO-d6) δ 7.42(s,1H),6.84(s,1H),6.59(s,1H),4.77(brs,1H),3.48-3.42(m,2H),0.80-0.74(m,2H),0.61-0.55(m,2H). 19 F NMR(376 MHz,DMSO-d6) δ -70.00(1F).

[0659] Preparation 58B: (1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]cyclopropyl)methanol

[0660] [ka]

[0661] A solution of [1-[(6-fluoro-4-iodopyridin-2-yl)amino]cyclopropyl]methanol (575 mg, 1.866 mmol), morpholine (179 mg, 2.053 mmol), and DIEA (482 mg, 3.733 mmol) in DMSO (6 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, quenched with water (60 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (76%) to give (1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]cyclopropyl)methanol (315 mg, 45%) as a pale yellow solid. MS ESI calculated for C 13 H 18 IN3O2[M+H] + ,376.21,found 375.90. 1 H NMR(400 MHz,DMSO-d6) δ 6.60(s,1H),6.29-6.27(m,2H),4.68(brs,1H),3.64-3.62(m,4H),3.50 -3.41(m,2H),3.33-3.30(m,4H),0.75-0.72(m,2H),0.57-0.55(m,2H).

[0662] Example 58: (3S)—N-[3-(2-[[1-(hydroxymethyl)cyclopropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0663] [ka]

[0664] A mixture of (1-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]cyclopropyl)methanol (200 mg, 0.533 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (242 mg, 0.586 mmol), Pd(dppf)Cl.CHCl (43 mg, 0.053 mmol), NaCO (169 mg, 1.599 mmol), 1,4-dioxane (6 mL), and water (1.5 mL) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / EtOH (3 / 1) in PE (60%) followed by preparative HPLC using the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 150 mm, 5 µm, 13 nm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 20 mL / min; Gradient: 45B to 65B in 5.5 min; 254 / 210 nm to give (3S)-N-[3-(2-[[1-(hydroxymethyl)cyclopropyl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (151 mg, 51%) as an off-white solid. MS ESI calculated for C 27 H 34 F3N5O3[M+H] + ,534.59,found 534.25. 1H NMR(400 MHz,DMSO-d6) δ 8.12(s,1H),7.43-7.33(m,2H),7.11-7.09(m,1H),6.43(s,1H),5.85-5 .83(m,2H),4.75-4.74(m,1H),3.68-3.66(m,5H),3.52-3.49(m,3H),3. 38-3.30(m,5H),3.03-3.02(m,1H),2.52-2.44(m,3H),2.16(s,3H),2.0 8-2.06(m,1H),1.78-1.65(m,1H),0.76-0.75(m,2H),0.63-0.62(m,2H). 19 F NMR(376 MHz,DMSO-d6) δ -63.36(3F).

[0665] Examples 59 and 60: (S)—N-(3-(2-(((1R,3S)-3-hydroxy-1-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3R)-3-hydroxy-1-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0666] [ka]

[0667] Preparation 59A: tert-butyl (3-hydroxy-1-methylcyclobutyl)carbamate

[0668] [ka]

[0669] To a solution of tert-butyl N-(1-methyl-3-oxocyclobutyl)carbamate (2.00 g, 10.04 mmol) in THF (20 mL) was added dropwise NaBH (0.76 g, 20.07 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NH Cl (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 4.72 (s, 1H), 4.17-4.10 (m, 2H), 1.99-1.86 (m, 2H), 1.30 (d, J = 20.8 Hz, 9H).

[0670] Preparation 59B: 3-amino-3-methylcyclobutan-1-ol hydrochloride

[0671] [ka]

[0672] To a solution of tert-butyl (3-hydroxy-1-methylcyclobutyl)carbamate (1.50 g, 7.46 mmol) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (2 mL, 65.82 mmol, 4 M) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6) δ 8.37(s,2H),4.43-4.35(m,1H),4.04(p,J=7.1 Hz,1H),2.26(ddt,J=9.3,7.1,2.3 Hz,2H),2.17-2.08(m,2H),1.33(s,3H).

[0673] Preparation 59C: 3-((6-fluoropyridin-2-yl)amino)-3-methylcyclobutan-1-ol

[0674] [ka]

[0675] To a solution of 3-amino-3-methylcyclobutan-1-ol hydrochloride (1.3 g, 9.489 mmol) in DMSO (13 mL) were added 2,6-difluoro-4-iodopyridine (1.37 g, 5.67 mmol) and DIEA (6.10 g, 47.23 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 hours. The reaction was quenched by the addition of water (130 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give 3-((6-fluoropyridin-2-yl)amino)-3-methylcyclobutan-1-ol (800 mg, 26%) as a pale yellow oil. MS ESI calculated for C 10 H 13 FN2O[M+H] + ,323.00,found 323.05. 1 H NMR (400 MHz, chloroform-d) δ 6.55-6.45 (m, 2H), 4.63 (d, J = 53.3 Hz, 1H), 4.23 (p, J = 6.9 Hz, 1H), 4.13-4.03 (m, 1H), 2.51-2.43 (m, 2H), 2.37-2.25 (m, 2H), 1.34-1.22 (m, 3H).

[0676] Preparation 59D: 3-((4-iodo-6-morpholinopyridin-2-yl)amino)-3-methylcyclobutan-1-ol

[0677] [ka]

[0678] To a solution of 3-((6-fluoro-4-iodopyridin-2-yl)amino)-3-methylcyclobutan-1-ol (980 mg, 3.043 mmol) in DMSO (10 mL) was added DIEA (786 mg, 6.085 mmol) at room temperature. The resulting mixture was stirred at 110° C. for 16 h. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 3-((4-iodo-6-morpholinopyridin-2-yl)amino)-3-methylcyclobutan-1-ol (200 mg, 17%) as a pale yellow oil. MS ESI calculated for C 14 H 20 IN3O2[M+H] + ,390.06,found 389.95. 1 H NMR(400 MHz,DMSO-d6) δ 6.17(d,J=1.1 Hz,1H),6.14(d,J=1.0 Hz,1H),4.03(q,J=7.1 Hz,3H),3.90(t,J=7.3 Hz,1H),3.64(dd,J=5.8,3.9 Hz,4H),2.39(ddd,J=12.0,6.0,2.6 Hz,2H),2.23- 2.20(m,2H),1.21(s,3H).

[0679] Examples 59 and 60: (S)—N-(3-(2-(((1R,3S)-3-hydroxy-1-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3R)-3-hydroxy-1-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0680] [ka]

[0681] A mixture of 3-((4-iodo-6-morpholinopyridin-2-yl)amino)-3-methylcyclobutan-1-ol (200 mg, 0.514 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (212 mg, 0.514 mmol), Pd(dppf)Cl.CHCl (42 mg, 0.051 mmol), and NaCO (163 mg, 1.541 mmol) in dioxane (2 mL) and HO (0.2 mL) was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 2). The resulting mixture was purified under the following conditions: Column: CHIRALPAK IE, 2 * 25 cm, 5 μm; Mobile phase A: Hex (0.5% of 2 M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 18 mL / min; A:B = 70:30; Resolution by chiral HPLC at 220 / 254 nm yielded 14.7 mg (9%) as a light blue solid (MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.28,found 548.25. 1H NMR(400 MHz, DMSO-d6) δ 8.10(s,1H),7.48-7.32(m,2H),7.09(d,J=8.3 Hz,1H),6.24(s,1H),5.73(d,J=28.8 Hz,2H),4.91(d,J=5.8 Hz,1H),4.16(h,J=6.7 Hz,1H),3.75-3.60(m,5H),3.53(ddd,J=10.4,8.2,2.3 Hz,1H),3.36(d,J=9.6 Hz,4H),3.32-3.25(m,1H),3.02(t,J=9.4 Hz,1H),2.63(ddd,J=10.0,7.3,2.6 Hz,2H),2.43(dd,J=15.0,7.1 Hz,3H),2.17(s,4H),1.89-1.77(m,2H),1.77-1.59(m,1H),1.49(s,3H). 19 F NMR (376 MHz, DMSO-d6) δ -63.36), および, aqua solid として50.5mg (30%) (MS ESI calculated for C 28 H 36 F3N5O3[M+H] + ,548.28,found 548.25. 1 H NMR(300 MHz, DMSO-d6) δ 8.11(s,1H),7.49-7.30(m,2H),7.09(d,J=8.3 Hz,1H),6.42(s,1H),5.72(d,J=19.3 Hz,2H),4.93(d,J=6.2 Hz,1H),4.03(h,J=7.1 Hz,1H),3.80-3.62(m,5H),3.53(ddd,J=10.5,8.3,2.4 Hz,1H),3.39(s,1H),3.37- 3.21(m,3H),3.03(t,J=9.3 Hz,1H),2.50-2.34(m,5H),2.17(s,3H),2.05(t,J=10.2 Hz,3H),1.85 -1.55(m,1H),1.42(s,3H))をgetた. 19 F NMR (282 MHz, DMSO-d6) δ -63.36,-63.43.

[0682] Example 61: (3S)—N-[3-(2-[[(2R,3R)-3-hydroxybutan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0683] [ka]

[0684] Preparation 61A: (2R,3R)-3-[(6-fluoro-4-iodopyridin-2-yl)amino]butan-2-ol

[0685] [ka]

[0686] A solution of 2,6-difluoro-4-iodopyridine (300 mg, 1.245 mmol), DMSO (3 mL), (2R,3R)-3-aminobutan-2-ol (133 mg, 1.494 mmol), and DIEA (804 mg, 6.225 mmol) was stirred at 70 °C for 2 h. The resulting mixture was quenched with HO (100 mL) and extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with brine (4 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give (2R,3R)-3-[(6-fluoro-4-iodopyridin-2-yl)amino]butan-2-ol (172 mg, 44%) as a pale yellow oil. MS ESI calculated for CH 12 FIN2O[M+H] + ,311.11,found 310.90. 1 H NMR (400 MHz, chloroform-d) δ 6.65 (s, 1H), 6.52 (m, 1H), 4.78 (s, 1H), 3.80 (m, 2H), 2.19 (s, 1H), 1.32–1.19 (m, 6H).

[0687] Preparation 61B: (2R,3R)-3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butan-2-ol

[0688] [ka]

[0689] A mixture of (2R,3R)-3-[(6-fluoro-4-iodopyridin-2-yl)amino]butan-2-ol (110 mg, 0.355 mmol), DMSO (2 mL), morpholine (102 mg, 1.171 mmol), and DIEA (55 mg, 0.426 mmol) was stirred at 70 °C for 16 hours. The resulting mixture was quenched with HO (100 mL) and extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with brine (4 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 39% EtOAc in PE to give (2R,3R)-3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butan-2-ol (110 mg, 67%) as a thick yellow oil. MS ESI calculated for C 13 H 20 IN3O2[M+H] + ,379.06,found 379.00.C 13 H 20 IN3O2: 1 H NMR (400 MHz, chloroform-d) δ 7.28 (s, 1H), 6.28 (s, 1H), 6.24 (s, 1H), 4.44-4.20 (m, 1H), 3.79 (s, 4H), 3.72 (m, 1H), 3.43 (s, 4H), 2.07 (s, 1H), 1.29-1.20 (m, 6H).

[0690] Example 61: (3S)—N-[3-(2-[[(2R,3R)-3-hydroxybutan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0691] [ka]

[0692] A mixture of (2R,3R)-3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butan-2-ol (110 mg, 0.292 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (120 mg, 0.292 mmol), 1,4-dioxane (2 mL), HO (0.5 mL), NaCO (93 mg, 0.875 mmol), and Pd(dppf)Cl.CHCl (24 mg, 0.029 mmol) was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc followed by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN in water, 5% to 95% gradient in 10 min; detector, UV 254 nm) to give (3S)-N-[3-(2-[[(2R,3R)-3-hydroxybutan-2-yl]amino]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (59 mg, 38%) as a white solid. MS ESI calculated for C 27 H 36 F3N5O3[M+H] + ,536.61,found 536.15. 1H NMR(300 MHz,DMSO-d6) δ 8.11(s,1H),7.41(m,1H),7.33(s,1H),7.09(s,1H),5.86(s,1H),5.79(s,1H),5.73(s,1H),4.59(s,1H),3.87(s,1H),3.78-3.62(m,6H), 3.57-3.47(m,1H),3.37(sz,4H),3.31-3.25(m,1H),3.02(m,1H),2.50(s,3H),2.16(s,3H),2.12-1.97(m,1H),1.66(m,1H),1.06(m,6H). 19 F NMR(376 MHz,DMSO-d6) δ -63.4(3F).

[0693] Example 62: (3S)—N-(3-[2-[(1-cyanopropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0694] [ka]

[0695] Preparation 62A: 3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butanenitrile

[0696] [ka]

[0697] A solution of 2,6-difluoro-4-iodopyridine (300 mg, 1.245 mmol), DMSO (4 mL), 3-aminobutanenitrile hydrochloride (165 mg, 1.369 mmol), and DIEA (354 mg, 2.739 mmol) was stirred at 70° C. for 3 hours. Morpholine (357 mg, 4.097 mmol) was added to the stirred mixture. The resulting mixture was stirred at 100° C. for 16 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc / EtOH (4 / 3 / 1) to give 3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butanenitrile (351 mg, 75%) as an off-white solid. MS ESI calculated for C 13 H 17 IN4O[M+H] + ,373.04,found 372.90. 1 H NMR (300 MHz, chloroform-d) δ 6.45-6.40 (m, 1H), 6.23-6.22 (m, 1H), 4.25-4.22 (m, 1H), 3.84-3.78 (m, 5H), 3.54-3.37 (m, 4H), 2.84-2.64 (m, 2H), 1.47-1.42 (m, 3H).

[0698] Example 62: (3S)—N-(3-[2-[(1-cyanopropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0699] [ka]

[0700] A mixture of 3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]butanenitrile (150 mg, 0.403 mmol), (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (166 mg, 0.403 mmol), NaCO (128 mg, 1.209 mmol), dioxane (4 mL), HO (1 mL), and Pd(dppf)Cl.CHCl (33 mg, 0.040 mmol) was stirred at 60° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2 × 40 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc / EtOH (4 / 3 / 1) followed by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient from 5% to 95% in 10 min; detector, UV 254 nm to give (3S)-N-(3-[2-[(1-cyanopropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (149 mg, 69%) as a white solid. MS ESI calculated for C 27 H 33 F3N6O2[M+H] + ,531.26,found 531.15. 1H NMR(300 MHz,DMSO-d6) δ 8.01(s,1H),7.43-7.33(m,2H),7.11-7.08(m,1H),6.53-6.51(m,1H) ,5.82-5.81(m,2H),4.16-4.15(m,1H),3.68-3.49(m,5H),3.52-3.49( m,1H),3.39-3.33(m,4H),3.04-3.02(m,1H),2.98-2.72(m,2H),2.50- 2.42(m,3H),2.18-2.01(m,5H),2.71-2.59(m,1H),1.29-1.22(m,3H). 19 F NMR(282 MHz,DMSO-d6) δ -63.36(3F).

[0701] Examples 63 and 64: (S)—N-(3-(2-(((1R,4S)-4-hydroxy-1-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,4R)-4-hydroxy-1-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0702] [ka]

[0703] Preparation 63A: tert-butyl N-(4-hydroxy-1-methylcyclohexyl)carbamate

[0704] [ka]

[0705] To a solution of tert-butyl N-(1-methyl-4-oxocyclohexyl)carbamate (700 mg, 3.080 mmol) in MeOH (10 mL) was added NaBH (174 mg, 4.619 mmol) portionwise at room temperature. The mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl N-(4-hydroxy-1-methylcyclohexyl)carbamate (600 mg, 85%) as a colorless oil. MS ESI calculated for C 12 H 23 NO3[M+H] + ,230.17 found N / A. 1 H NMR (400 MHz, chloroform-d) δ 3.65 (td, J = 10.1, 4.8 Hz, 1H), 1.47 (s, 3H), 1.46-1.40 (m, 8H), 1.44 (s, 9H).

[0706] Preparation 63B: 4-amino-4-methylcyclohexan-1-ol hydrochloride

[0707] [ka]

[0708] To a solution of tert-butyl N-(4-hydroxy-1-methylcyclohexyl)carbamate (600 mg, 2.616 mmol) in EtOAc (5 mL) was added HCl (gas) in EtOAc (10 mL) at room temperature. The mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. This gave 4-amino-4-methylcyclohexan-1-ol hydrochloride (400 mg, 92%) as a white solid. The crude product was used directly in the next step without further purification. MS ESI calculated for CH 15 NO[M+H] +,130.12 found N / A. 1 H NMR (400 MHz, methanol-d₄) δ 3.84 (td, J = 6.1, 3.1 Hz, 1H), 1.93–1.66 (m, 8H), 1.37 (s, 3H).

[0709] Preparation 63C: 4-[(6-fluoro-4-iodopyridin-2-yl)amino]-4-methylcyclohexan-1-ol

[0710] [ka]

[0711] To a solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (744 mg, 2.415 mmol) and 4-amino-4-methylcyclohexan-1-ol hydrochloride (500 mg, 3.018 mmol) in DMSO (10 mL) was added DIEA (1.95 g, 15.091 mmol) at room temperature. The mixture was stirred at 100° C. for 3 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. MS ESI calculated for C 12 H 16 FIN2O[M+H] + ,351.03,found 350.95. 1 H NMR (400 MHz, chloroform-d) δ 6.67-6.61 (m, 1H), 6.51 (dd, J = 2.9, 1.0 Hz, 1H), 3.69 (td, J = 9.3, 4.2 Hz, 1H), 2.33-2.25 (m, 2H), 1.94-1.78 (m, 3H), 1.49 (d, J = 20.6 Hz, 3H), 1.44 (s, 3H).

[0712] Preparation 63D: 4-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]-4-methylcyclohexan-1-ol

[0713] [ka]

[0714] To a solution of 4-[(6-fluoro-4-iodopyridin-2-yl)amino]-4-methylcyclohexan-1-ol (130 mg, 0.371 mmol) and morpholine (48 mg, 0.557 mmol) in DMSO (5 mL) was added DIEA (96 mg, 0.742 mmol) at room temperature. The mixture was stirred at 110° C. for 16 hours. The resulting solution was purified under the following conditions (column: XBridge Shield RP18 OBD Column, 30 * Purification by preparative HPLC (150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 35B to 75B in 25 min) gave 4-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]-4-methylcyclohexan-1-ol (80 mg, 52%) as a pale yellow solid. MS ESI calculated for C 16 H 24 IN3O2[M+H] + ,418.09,found 418.00. 1 H NMR(400 MHz,chloroform-d) δ 6.60-6.44(m,1H),6.32(dd,J=9.8,1.2 Hz,1H),3.85(q,J=3.9,2.7 Hz,5H),3.54(dd,J=5.7,3.8 Hz,4H),2.18(d,J=13.6 Hz,1H),1.99-1.76(m,3H),1.70-1.44(m,2H),1.42(s,3H),1.32-1.30(m,2H).

[0715] Examples 63 and 64: (S)—N-(3-(2-(((1S,4R)-4-hydroxy-1-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,4S)-4-hydroxy-1-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0716] [ka]

[0717] To a solution of 4-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]-4-methylcyclohexan-1-ol (130 mg, 0.312 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (128 mg, 0.312 mmol) in 1,4-dioxane (10 mL) and HO (1 mL), Pd(dppf)Cl.CHCl (25 mg, 0.031 mmol) and KCO (129 mg, 0.935 mmol) were added at room temperature. The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The crude product was purified under the following conditions (column: XBridge Shield RP18 OBD Column, 30 * The racemic compound (40 mg) was purified by preparative HPLC using a 150 mm column, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 35B to 75B in 25 min to give the racemic compound (40 mg) as a white solid. The mixture (40 mg) was purified using the following conditions: Column: CHIRALPAK IH, 2.0 *Separation was performed by chiral HPLC using a 25 cm column, 5 μm column; mobile phase A: MeOH (0.1% DEA), mobile phase B: CO2; flow rate: 50 mL / min; gradient: 50% B. The first peak yielded 8 mg (4%) as a white solid. MS ESI calculated for C 30 H 40 F3N5O3[M+H] + ,576.31,found 576.15. 1 H NMR (400 MHz, methanol-d4) δ 7.27(dt,J=4.1,2.4 Hz,2H),7.14(d,J=8.9 Hz,1H),5.87(d,J=16.9 Hz,2H),3.84-3.75(m,6H),3.63(ddd,J=10.5,8.4,2.3 Hz,1H),3.44(h,J=6.5 Hz,5H),3.18 * 3.09(m,1H),2.55(s,1H),2.47-2.32(m,2H),2.23(s,4H),2.05(t,J=9.4 Hz,2H),1.97-1.67(m,5H),1.54(q,J=8.4,7.1 Hz,2H),1.49(s,3H). 19 F NMR (376 MHz, chloroform-d) δ -66.49 (3F). Second peak yielded 33 mg (18%) as a white solid. MS ESI calculated for C 30 H 40 F3N5O3[M+H] + ,576.31,found 576.15. 1 H NMR (400 MHz, methanol-d4) δ 7.31-7.25(m,2H),7.15(d,J=9.0 Hz,1H),5.93(s,1H),5.84(s,1H),3.84-3.75(m,5H),3.68-3.53(m,2H),3.49 -3.38(m,5H),3.13(t,J=9.7 Hz,1H),2.65-2.30(m,5H),2.24(s,4H),1.97-1.67(m,3H),1.68-1.53(m,2H),1.46(s,3H),1.44-1.29(m,2H). 19 F NMR (376 MHz, chloroform-d) δ −66.48 (3F).

[0718] Example 65: (3S)—N-(3-[2-[(1,3-dihydroxypropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0719] [ka]

[0720] Preparation 65A: 2-((4-iodo-6-morpholinopyridin-2-yl)amino)propane-1,3-diol

[0721] [ka]

[0722] To a stirred mixture of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300 mg, 0.974 mmol) and K2CO3 (404 mg, 2.921 mmol) in NMP (4 mL) was added 2-aminopropane-1,3-diol (443 mg, 4.869 mmol) at room temperature. The reaction mixture was stirred at 150 °C for 16 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 55% CH3CN in water (with 0.5% NH4HCO3). Fractions containing the desired product were collected and concentrated under reduced pressure to give 2-((4-iodo-6-morpholinopyridin-2-yl)amino)propane-1,3-diol (110 mg, 25%) as a pink solid. MS ESI calculated for C 12 H 18 IN3O3[M+H] + ,380.04 found 380.05. 1H NMR(400 MHz,DMSO-d6) δ 6.29(d,J=1.0 Hz,1H),6.19(d,J=1.0 Hz,1H),4.55(t,J=5.5 Hz,2H),3.64(t,J=4.9 Hz,4H),3.52-3.40(m,4H),3.34(d,J=4.9 Hz,4H),1.06(t,J=7.0 Hz,1H).

[0723] Example 65: (3S)—N-(3-[2-[(1,3-dihydroxypropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0724] [ka]

[0725] To a stirred mixture of 2-((4-iodo-6-morpholinopyridin-2-yl)amino)propane-1,3-diol (80 mg, 0.211 mmol), KCO (87 mg, 0.633 mmol), and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (104 mg, 0.253 mmol) in dioxane (2 mL) and HO (0.5 mL), Pd(dppf)Cl.CHCl (17 mg, 0.021 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C under a N atmosphere for 2 hours. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 50% PE in EA. Fractions containing the desired product were collected and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography eluting with 50% CHCN in water (with 10 mmol / mL NHHCO). Fractions containing the desired product were collected and concentrated under reduced pressure to give (3S)—N-(3-[2-[(1,3-dihydroxypropan-2-yl)amino]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (105 mg, 98%) as an off-white solid. MS ESI calculated for C 26 H 34 F3N5O4[M+H] + ,538.26 found 538.35. 1H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.41(dd,J=8.3,2.3 Hz,1H),7.34(d,J=2.3 Hz,1H),7.09(d,J=8.4 Hz,1H),5.86(d,J=7.6 Hz,1H),5.81(d,J=0.9 Hz,1H),5.76(d,J=1.1 Hz,1H),4.58(t,J=5.5 Hz,2H),3.82(d,J=6.7 Hz,1H),3.67(q,J=8.3,6.4 Hz,5H),3.58-3.45(m,5H),3.37(d,J=9.6 Hz,4H),3.30(d,J=10.0 Hz,1H),3.02(t,J=9.4 Hz,1H),2.44(t,J=10.7 Hz,3H),2.16(s,3H),2.08(d,J=3.7 Hz,1H),1.66(p,J=9.9 Hz,1H).

[0726] Example 66: (3S)—N-[3-[2-amino-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0727] [ka]

[0728] Preparation 66A: 4-iodo-6-(morpholin-4-yl)pyridin-2-amine

[0729] [ka]

[0730] A solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (2.00 g, 6.492 mmol) and NHOH (140 mL) in n-BuOH (20 mL) was stirred at 120 °C for 16 h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give 4-iodo-6-(morpholin-4-yl)pyridin-2-amine (0.70 g, 35%) as a pale yellow oil. MS ESI calculated for CH 12 IN3O[M+H] + ,306.00,found 305.95. 1 H NMR(300 MHz,chloroform-d) δ 6.32(dd,J=15.3,1.0 Hz,2H),4.21(s,2H),3.82-3.73(m,4H),3.48-3.39(m,4H).

[0731] Example 66: (3S)—N-[3-[2-amino-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0732] [ka]

[0733] To a stirred solution of 4-iodo-6-(morpholin-4-yl)pyridin-2-amine (100 mg, 0.328 mmol) and (3S)—N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (135 mg, 0.328 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL), NaCO (104 mg, 0.983 mmol) and Pd(dppf)Cl.CHCl (27 mg, 0.033 mmol) were added at room temperature. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give (3S)—N-[3-[2-amino-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (73 mg, 48%) as a pale yellow solid. MS ESI calculated for C 23 H 28 F3N5O2[M+H] + ,464.22,found 464.10. 1 H NMR(400 MHz,DMSO-d6) δ 8.11(s,1H),7.42(dd,J=8.3,2.4 Hz,1H),7.34(d,J=2.4 Hz,1H),7.09(d,J=8.4 Hz,1H),5.77(dd,J=17.6,1.0 Hz,2H),5.64(s,2H),3.71-3.63(m,5H),3.55-3.49(m,1H),3.41-3.35(m,3H),3.32-3.26(m,2H),3.02(t,J=9.4 Hz,1H),2.51-2.36(m,3H),2.16(s,3H),2.08(d,J=10.6 Hz,1H),1.67(q,J=10.4,10.0 Hz,1H).19 F NMR(376 MHz,DMSO-d6) δ -63.37(3F).

[0734] Example 67: (3S)—N-[4-methyl-3-[2-(methylamino)-6-(morpholin-4-yl)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0735] [ka] ...

Claims

1. A compound having the structure of formula (II), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 1】 During the ceremony, W is NH or NR ７ and X is N, C—H, C—F, or C—CN; Y is N, C-F, or C-H; R is H, optionally substituted C １ -C ８ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ４ -C ８ Cycloalkylalkyl, optionally substituted C ３ -C ６ Heterocyclyl, optionally substituted C ３ -C ６ heterocyclylalkyl or optionally substituted C １ -C ８ alkyl-CO-, R １ is optionally substituted C １ -C ３ alkyl and q is 0; R ２ is H, D, or F; R ４ is halogen, optionally substituted C １ -C ３ Alkyl, -CD ３ or optionally substituted C １ -C ３ is an alkoxy; R ６ is H, D, Cl, or F; R ７ is optionally substituted C １ -C ８ alkyl, or R is not H, and R and R ７ is optionally joined to form an optionally substituted heterocyclyl ring; R ｃ is H or D, Z is, (a) 【Chemistry 2】 wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R １１ each independently represents amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C ２ -C ６ Alkynyl, optionally substituted -S-alkyl, optionally substituted -SO ２ Alkyl, optionally substituted C ３ -C ６ cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R １１ the groups taken together form oxo), or (b) 【Chemistry 3】 wherein n is 1, 2, or 3; m is 1, 2, or 3; p is 0, 1, 2, 3, or 4; and R １１ each independently represents amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C ２ -C ６ Alkynyl, optionally substituted -S-alkyl, optionally substituted -SO ２ Alkyl, optionally substituted C ３ -C ６ cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R １１ The groups together form an oxo. or a pharma- ceutically acceptable salt or solvate thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein W is NH.

3. The R is an optionally substituted C １ -C ６ 3. The compound of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

4. The R is an optionally substituted C １ -C ３ 4. The compound of claim 3, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

5. The R is an optionally substituted C １ -C ２ 4. The compound of claim 3, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

6. The R is an optionally substituted C １ -C ６ 4. The compound of claim 3, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group; and R is an alkyl group substituted with at least one hydroxyl.

7. The Z is 【Chemistry 4】 2. The compound of claim 1, wherein:

8. 2. The compound of claim 1, wherein m is 1, or a pharma- ceutically acceptable salt or solvate thereof.

9. 2. The compound of claim 1, wherein p is 1, or a pharma- ceutically acceptable salt or solvate thereof.

10. The R １１ is optionally substituted C １ -C ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

11. The R １１ Ha-CH ２ CF ３ 2. The compound of claim 1, wherein:

12. The R ４ is CH ３ 2. The compound of claim 1, wherein:

13. The R ２ is H, and said R ６ is H, or a pharma- ceutically acceptable salt or solvate thereof.

14. 10. A pharmaceutical composition comprising a compound of formula (II) as defined in claim 1, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

15. (3S)—N-(3-(6-((3,3-difluorocyclopentyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((R)-3,3-difluorocyclopentyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((S)-3,3-difluorocyclopentyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3S)-3-hydroxycyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,3R)-3-hydroxycyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((3-hydroxyoxetan-3-yl)methyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-(2-((3,3-difluorocyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-3,3-difluorocyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-3,3-difluorocyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-(2-[[(cis-3-hydroxycyclopentyl]amino]-6-(morpholin-4-yl)pyrimidin-4-yl)-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3R)-3-hydroxycyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,3S)-3-hydroxycyclopentyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(3-hydroxyazetidin-1-yl)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(3-hydroxyazetidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (R)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide, (R)—N-(3-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, (S)—N-(3-(2-((2-hydroxyethyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, N-(3-(2-((2-hydroxyethyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, (S)—N-(3-(2-((2-hydroxyethyl)(methyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (R)—N-(3-(2-((2-hydroxyethyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide, (R)-N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide, (R)—N-(3-(2-((2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, (S)—N-(3-(2-(((R)-2-hydroxypropyl)(methyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(((R)-2-hydroxypropyl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (R)—N-(3-(2-((2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, (R)—N-(3-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, (S)—N-(3-(2-(((S)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(((R)-1-hydroxypropan-2-yl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,4R)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,4S)-4-hydroxy-4-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(3-hydroxy-3-methylazetidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(isopropylamino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(tert-butylamino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-(oxetan-3-ylamino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-(((R)-tetrahydrofuran-3-yl)amino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-(((S)-tetrahydrofuran-3-yl)amino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-(((R)-tetrahydro-2H-pyran-3-yl)amino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3R)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,3S)-3-hydroxycyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-1-hydroxybutan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-1-methoxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-2-methoxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(4-methyl-3-(2-((3-methyltetrahydrofuran-3-yl)amino)-6-morpholinopyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1-(hydroxymethyl)cyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((3-(hydroxymethyl)oxetan-3-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-((3-methyloxetan-3-yl)amino)-6-morpholinopyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-6-morpholinopyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1-(hydroxymethyl)cyclopropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1R,3S)-3-hydroxy-1-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,3R)-3-hydroxy-1-methylcyclobutyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((2R,3R)-3-hydroxybutan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-(2-((1-cyanopropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((1S,4R)-4-hydroxy-1-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, and (S)—N-(3-(2-(((1R,4S)-4-hydroxy-1-methylcyclohexyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1,3-dihydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-amino-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-(methylamino)-6-morpholinopyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-(3-oxomorpholino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-acetamido-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(3-fluoro-2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(3-fluoro-6-(((R)-1-hydroxypropan-2-yl)amino)-2-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-morpholino-6-(((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(2-hydroxy-2-methylpropanamido)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(2-fluoro-5-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (R)—N-(2-fluoro-5-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, (S)—N-(3-(2-(2,5-dihydrofuran-3-yl)-6-(((R)-1-hydroxypropan-2-yl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-(tetrahydrofuran-3-yl)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-1-hydroxypropan-2-yl)amino)-6-(1H-pyrazol-4-yl)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((R)-1-hydroxypropan-2-yl)amino)-[2,4′-bipyridin]-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2′-amino-6-(((R)-1-hydroxypropan-2-yl)amino)-[2,4′-bipyridin]-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2′-cyano-6-(((R)-1-hydroxypropan-2-yl)amino)-[2,4′-bipyridin]-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1R,6S)-3-oxabicyclo[4.1.0]heptan-6-yl)-6-(((R)-1-hydroxypropan-2-yl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1S,6R)-3-oxabicyclo[4.1.0]heptan-6-yl)-6-(((R)-1-hydroxypropan-2-yl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-2,3-dihydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-2,3-dihydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1S,5R)-3-oxabicyclo[3.1.0]hexan-1-yl)-6-(((R)-1-hydroxypropan-2-yl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((1R,5S)-3-oxabicyclo[3.1.0]hexan-1-yl)-6-(((R)-1-hydroxypropan-2-yl)amino)pyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((R)-2-hydroxypropyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (R)-N-(3-(6-(((R)-2-hydroxypropyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((S)-2-hydroxypropyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-((2-hydroxyethyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((S)-1-hydroxypropan-2-yl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-((2-hydroxy-2-methylpropyl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((2-hydroxyethyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((2-hydroxy-2-methylpropyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(6-(((R)-1-hydroxypropan-2-yl)amino)-2-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-1-hydroxypropan-2-yl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (R)—N-(3-(2-((S)-3-hydroxypyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-3-hydroxypyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-(((S)-2-hydroxypropyl)amino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(3R)-3-aminopyrrolidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(3S)-3-aminopyrrolidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(3R)-3-aminopiperidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(3S)-3-aminopiperidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-(2-oxopyrrolidin-1-yl)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(3R)-3-hydroxypyrrolidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[4-methyl-3-[2-(3-methyl-2-oxoimidazolidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[4-methyl-3-[2-(N-methylacetamido)-6-(morpholin-4-yl)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-[2-methanesulfonamido-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-[2-(3-hydroxy-2-oxopyrrolidin-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[4-methyl-3-[2-(morpholin-4-yl)-6-(2-oxo-1,3-oxazolidin-3-yl)pyridin-4-yl]phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(5R)-5-hydroxy-2-oxopiperidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(4-methyl-3-(2-morpholino-6-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-[2-cyclopropanesulfonamido-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-3-amino-2-oxopyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-4-amino-2-oxopyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-3-amino-3-methylpiperidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-[2-[(4R)-4-hydroxy-2-oxopyrrolidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-[3-[2-(1,1-dioxo-1lambda 6,2-thiazolidin-2-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((R)-4-amino-2-oxopyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((R)-3,3-difluoro-4-hydroxypyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-3,3-difluoro-4-hydroxypyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-(2-((1R)-1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-(2-((1S)-1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((R)-4-amino-2-oxopyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((R)-4-amino-3,3-difluoropyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(3-(2-((S)-4-amino-3,3-difluoropyrrolidin-1-yl)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-{2-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-(3-{2-[(3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-(((R)-1-(methylamino)-1-oxopropan-2-yl)amino)-6-morpholinopyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (S)—N-(4-methyl-3-(2-(((S)-1-(methylamino)-1-oxopropan-2-yl)amino)-6-morpholinopyridin-4-yl)phenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-{3-[2-ethanesulfonamido-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, (3S)—N-{4-methyl-3-[2-(morpholin-4-yl)-6-(propane-2-sulfonamido)pyridin-4-yl]phenyl}-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, and (3S)-N-{4-methyl-3-[2-(1-methylcyclopropanesulfonamido)-6-(morpholin-4-yl)pyridin-4-yl]phenyl}-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide or a pharma- ceutically acceptable salt or solvate thereof.

16. 16. The compound of claim 15, wherein the compound is (S)-N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

17. 16. The compound of claim 15, wherein the compound is (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

18. 16. The compound of claim 15, wherein the compound is (R)-N-(3-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

19. 16. The compound of claim 15, wherein the compound is (R)-N-(3-(2-((2-hydroxyethyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

20. 16. The compound of claim 15, wherein the compound is (R)-N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

21. 16. The compound of claim 15, wherein the compound is (R)-N-(3-(2-((2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

22. 16. The compound of claim 15, wherein the compound is (R)-N-(3-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

23. 16. The compound of claim 15, wherein the compound is (S)-N-(3-(2-(((S)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

24. 16. The compound of claim 15, wherein the compound is (S)-N-(3-(2-(((R)-2,3-dihydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide or (S)-N-(3-(2-(((S)-2,3-dihydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof.

25. 16. A pharmaceutical composition comprising a compound of claim 15, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

26. 26. The pharmaceutical composition of claim 25, wherein the compound is (S)-N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

27. 26. The pharmaceutical composition of claim 25, wherein the compound is (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

28. 26. The pharmaceutical composition of claim 25, wherein the compound is (R)-N-(3-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide.

29. 26. The pharmaceutical composition of claim 25, wherein the compound is (R)-N-(3-(2-((2-hydroxyethyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide.

30. 26. The pharmaceutical composition of claim 25, wherein the compound is (R)-N-(3-(2-(((R)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide.

31. 26. The pharmaceutical composition of claim 25, wherein the compound is (R)-N-(3-(2-((2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide.

32. 26. The pharmaceutical composition of claim 25, wherein the compound is (R)-N-(3-(2-((1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide.

33. 26. The pharmaceutical composition of claim 25, wherein the compound is (S)-N-(3-(2-(((S)-2-hydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

34. 26. The pharmaceutical composition of claim 25, wherein the compound is (S)-N-(3-(2-(((R)-2,3-dihydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide or (S)-N-(3-(2-(((S)-2,3-dihydroxypropyl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

35. 25. Use of a compound according to any one of claims 1 to 13 or 15 to 24, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer.

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