Certain Chemical Substances, Compositions, and Methods

Abstract

Provided herein are inhibitors of IGF-1R, pharmaceutical compositions comprising said inhibitory compounds, and methods of using said IGF-1R inhibitory 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. 63 / 306,944, filed February 4, 2022, and U.S. Patent Application No. 63 / 419,988, filed October 27, 2022, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Dysregulation of IGF-1R has been associated with abnormal cell division, loss of apoptosis control, chromosomal instability, and increased incidence of cancer. Therefore, therapies targeting IGF-1R activity are desirable for use in treating cancer, autoimmune disorders, and other disorders characterized by aberrant IGF-1R pathway signaling. Summary of the Invention

[0003] Provided herein are inhibitors of IGF-1R, pharmaceutical compositions comprising said inhibitory compounds, and methods of using said inhibitory compounds for the treatment of disease.

[0004] One embodiment is a compound of formula (I)

[0005] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; L is a bond, or optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; R 2 is an optionally substituted carbocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl, and the optional substitutions of the optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl are cyano, halo, hydroxy, azido, amino, nitro, —COH, —S(O)—R 10 , -SR 10 , -S(O)2-R 10 , optionally substituted C1-C6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O-, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R 11 )2, -CO-R 10 , -CO2-R 10 , -CON(R 11 )2, -NR 11 CO-R 10 , -NR 11 CO2-R 10 , -SO2N(R 11 )2, -C(=NR 12 )-N(R 11 )2, -NR 11 CO-N(R 10 )2, or -NR 11 SO2-N(R 10 )2, X 3 is N or CR 3 and X 4 is N or CR 4 and X 5 is N or CR 5 and X 6 is N or CR 6 and X 8 is N or CR 8 and R 3 , R 4 , R 5 , R 6 , and R 8 are independently hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -COH, -S(O)-R 10 , -SR 10 , -S(O)2-R 10 , optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted heterocyclyl, -N(R 11 )2, -CO-R 10 , -CO2-R 10 , -CON(R 11 )2, -NR 11 CO-R 10 , -NR 11 CO2-R 10 , -SO2N(R 11 )2, -C(=NR 12 )-N(R 11 )2, -NR 11 CO-N(R 10 )2, and -NR 11 SO2-N(R 10 )2, R 10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 11are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 12 is H or optionally substituted C1-C6 alkyl, R 9 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted C4-C10 carbocyclylalkyl; R 9 and L, or R 9 and X may be taken together with any intervening atoms to form an optionally substituted heterocyclyl ring.

[0006] 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.

[0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a method wherein the disease or disorder is selected from cancer, an autoimmune disease, or thyroid eye disease.

[0008] 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

[0009] 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 relating to 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% to 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 specific embodiments, such as, for example, any composition of matter, composition of matter, method, or process described herein, "consist of" or "consist essentially of" the described feature.

[0010] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0011] "Amino" refers to the -NH2 radical.

[0012] "Cyano" refers to the -CN radical.

[0013] "Nitro" refers to the -NO2 radical.

[0014] "Oxa" refers to the -O- radical.

[0015] "Oxo" refers to the =O radical.

[0016] "Thioxo" refers to the =S radical.

[0017] "Imino" refers to the =NH radical.

[0018] "Oximo" refers to the =N-OH radical.

[0019] "Hydrazino" refers to the =N-NH2 radical.

[0020] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C 15 Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In 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 may include 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 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). In certain embodiments, the optionally substituted alkyl is haloalkyl. In other embodiments, the optionally substituted alkyl is fluoroalkyl. In other embodiments, the optionally substituted alkyl is a -CF3 group.

[0021] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0022] "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 certain embodiments, alkenyl contains from 2 to 8 carbon atoms. In other embodiments, 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 may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... 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).

[0023] "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 certain 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 specified in the specification, an alkynyl group may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... 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).

[0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms (e.g., methylene, ethylene, propylene, n-butylene, etc.), that connects the rest of the molecule to the radical group. 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 certain 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, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified in the specification, an alkylene chain may include any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O, -O- ... 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).

[0025] "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 certain 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 may include any 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).

[0026] "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 certain 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 may include any 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] "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 hydrogen and carbon atoms from 5 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel 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 otherwise specified in this specification, the term "aryl" or the prefix "ar" (as in "aralkyl") refers to an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -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, where 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 linear or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, R a , R b , or R c Each of the substituents in is unsubstituted.

[0028] "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.

[0029] "Aralkenyl" refers to a group of the formula -R d -refers to the aryl radical, R dis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "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.

[0031] "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.

[0032] "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 specified in this specification, the term "carbocyclyl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -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, where 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 bare each independently a direct bond or a linear or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, R a , R b , or R c Each of the substituents in is unsubstituted.

[0033] 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.

[0034] "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.

[0035] "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.

[0036] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0037] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, 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.

[0038] "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 in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including 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 otherwise stated in this specification, the term "heterocyclyl" includes any of the following: optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -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), wherein 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 linear or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, R a , R b , or R c Each of the substituents in is unsubstituted.

[0039] "N-heterocyclyl" or "N-linked 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.

[0040] "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 radical 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.

[0041] "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.

[0042] "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.

[0043] "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, 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 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]i midazo[1,2a]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-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 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-oxo Azepinyl, 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, pyridinyl Lido[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-d]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term "heteroaryl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -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 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 linear or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, R a , R b , or R c Each of the substituents in is unsubstituted.

[0044] "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.

[0045] "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.

[0046] "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.

[0047] "Heteroarylalkoxy" has 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.

[0048] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving 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.

[0049] 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:

[0050] [ka]

[0051] "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 certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on various factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium are:

[0052] [ka] Includes.

[0053] 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 14 The 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.

[0054] 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 with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0055] 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 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, 17F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All 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.

[0056] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 The compound is substituted with an atom of H. Methods for the synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0057] 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.

[0058] Deuterated starting materials are readily available and amenable to the synthetic methods described herein for the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical companies such as Aldrich Chemical Co.

[0059] 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:

[0060] [ka]

[0061] Deuterium transfer reagents, such as lithium aluminum deuteride (LiAlD4), are used to transfer deuterium to reaction substrates under reducing conditions. The use of LiAlD4 is illustrated, by way of example only, in the following reaction scheme:

[0062] [ka]

[0063] 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:

[0064] [ka]

[0065] 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 the synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0066] "Pharmaceutically acceptable salt" includes both acid and base addition salts. The pharmaceutically acceptable salt of any one of the IGF-1R inhibitor compounds described herein is intended to encompass 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.

[0067] "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.

[0068] "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 and 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.

[0069] "Pharmaceutically acceptable solvate" refers to a composition of a substance in a solvent addition form. In some embodiments, the solvate contains either a stoichiometric or non-stoichiometric solvent and is formed during the manufacturing process using a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or 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 exist in solvated or non-solvated forms.

[0070] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cows, horses, sheep, goats, pigs, and other domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0071] 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 an underlying disease, such that an improvement is observed in a patient despite the patient still suffering from the underlying disease. For a prophylactic benefit, the composition, in some embodiments, is administered to a patient at risk of contracting a particular disease or to a patient reporting one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0072] IGF-1R tyrosine kinase The type 1 insulin-like growth factor receptor (IGF-1R) is a two-transmembrane receptor tyrosine kinase (RTK) belonging to the insulin receptor family that plays an important role in differentiation, cell proliferation, and cell survival. Signaling through IGF-1R is the primary pathway involved in somatic cell proliferation in fetal mammals, whereas somatic cell proliferation in postnatal animals is achieved through the synergistic interaction of growth hormone (GH) and insulin-like growth factors (IGF1 and IGF2). IGF-1R expression is widespread among many different cell types. Granular cytoplasmic protein expression appears ubiquitous in human cells, and IGF-1R endocytosis and transport to specific subcellular locations during signaling define the nature of specific signaling responses that are essential during normal and pathological cellular processes. Dysregulation of IGF-1R signaling and function has been implicated in human disorders, including cancer and ongoing growth retardation. IGF1 signaling continues to have anabolic effects during adulthood, and this signaling pathway further influences the aging process. Specific developmental functions of IGF-1R have also been elucidated, such as the region-specific regulation of axon growth in medial forebrain regions including the hippocampus and cingulate cortex.

[0073] IGF-1R has been shown to play an important role in cell transformation events. It is highly overexpressed in a variety of malignant tissues, where it functions as an anti-apoptotic agent by enhancing cell survival. Elevated IGF-1R expression has been implicated in the role of transformation in cancers of the breast, ovary, prostate, colon, and lung tissue, as well as in rhabdomyosarcoma, melanoma, and glioma.

[0074] The IGF-1R gene is located on chromosome 15q26.3. It contains 21 exons and spans approximately 100 kb. The IGF-1R promoter region contains many potential SP1 and AP2 binding sites, as well as thyroid response elements, but does not contain TATA or CCAAT elements. It is expressed as multiple mRNA transcripts, the most abundant of which is 12 kb, followed by several shorter transcripts of 7 kb and 6.4 kb. In the 12 kb IGF-1R mRNA transcript, 1 kb is the 5'-UTR, 4 kb is the coding sequence, and 7 kb is the 3'-UTR. The protein product of this gene is the insulin-like growth factor 1 (IGF-1) receptor. An alternative human IGF-1R mRNA transcript can be expressed in which a three-base pair (CAG) deletion results in the substitution of Arg for Thr898Gly899, eight residues upstream from the start of the IGF-1R transmembrane domain. This CAG- isoform exhibits reduced internalization and enhanced signaling properties compared to the CAG+ isoform.

[0075] Transcriptional regulation of IGF-1R is controlled by complex interactions involving DNA-binding and non-DNA-binding transcription factors. Stimulatory nuclear proteins, including the zinc finger protein Sp1, EWS-WT1, E2F1, Klippel-like factor-6 (KLF6), and high-mobility group A1 (HMGA1), promote IGF-1R expression. Many tumor suppressors, including breast cancer gene 1 (BRCA1), p53, Wilms tumor protein 1 (WT1), and von Hippel-Lindau gene (VHL), also regulate the IGF-1R locus. Loss of tumor suppressor function can derepress IGF-1R expression, thereby increasing IGF signaling. This IGF-1R dysregulation is associated with abnormal cell division, loss of apoptotic regulation, chromosomal instability, and increased cancer incidence. The p53 gene, the most frequently mutated gene in human cancer, functions as a nuclear transcription factor that blocks cell cycle progression and induces apoptosis. While wild-type p53 serves to repress transcriptional activation of the IGF-1R promoter, mutant p53 can have a stimulatory effect on IGF-1R promoter activity. Because of the central role of insulin-like growth factor signaling in cell cycle progression and cellular transformation, derepression of the IGF-1R promoter constitutes an important paradigm for tumorigenesis.

[0076] After translation, IGF-1R is a 1,367-amino acid receptor precursor containing a 30-residue signal peptide that is removed during translocation of the nascent polypeptide chain. Cleavage of the precursor generates the α and β subunits. Two α subunits and two β subunits constitute the IGF-1 receptor. Both α and β subunits are synthesized from a single mRNA precursor. The precursor is then glycosylated, proteolytically cleaved, and cross-linked by cysteine ​​bonds to form functional transmembrane αβ chains. After transport to the plasma membrane, the two α chains are located extracellularly, while the β subunit spans the membrane and mediates intracellular signal transduction upon ligand stimulation. The ectodomain of IGF-1R contains an arrangement of two homologous domains (L1 and L2) separated by a furin-like cysteine-rich region. Each L domain (L1 spans residues 1–150, L2 spans residues 300–460) consists of five and a half leucine-rich repeats, making them members of the leucine-rich repeat superfamily. The C-terminal half of their ectodomains consists of three fibronectin type 3 repeats and an insert domain containing an α-β cleavage site. IGF-1R has a single transmembrane sequence (residues 906–929). The cytoplasmic portion of IGF-1R consists of a tyrosine kinase catalytic domain adjacent to the juxtamembrane and C-tail regions, which are binding sites for various signaling molecules. The cytoplasmic domain (residues 930–1337), which contains the tyrosine kinase domain, spans 408 amino acid residues.

[0077] A key feature that distinguishes IGF-1R and its related family members from most other receptor tyrosine kinase families is that they exist on the cell surface as constitutive disulfide-bonded dimers and require domain rearrangement rather than receptor oligomerization for cell signaling. Recent studies of signal transduction suggest that ligand-induced conformational changes in the extracellular domain, followed by closure and dimerization of the transmembrane domain, lead to trans-autophosphorylation and kinase activity in the intracellular segment of IGF-1R. Ligand binding brings the distalmost fibronectin type 3 repeats into close proximity with each other, triggering a conformational change that subsequently leads to dimerization of the transmembrane segments within the lipid bilayer. In its basal state, one of three tyrosines in the activation loop (A-loop), Tyr1162, binds to the active site but cannot phosphorylate MgATP in cis because part of the A-loop interferes with the ATP-binding site and the catalytic Asp1150 is not properly positioned to coordinate MgATP. Upon activation, autophosphorylation of Tyr1162, Tyr1158, and Tyr1163 occurs in trans by the kinase domain of the second monomer. Thus, in the basal state, Tyr1162 competes with the adjacent beta strand for binding to the active site but is not phosphorylated in cis due to steric constraints that prevent simultaneous binding of Tyr1162 and MgATP. Autophosphorylation of the three tyrosines in the A-loop results in a dramatic change in configuration, thereby activating the kinase domain.

[0078] Three ligands have been identified that mediate signaling through the IGF-1R. These are insulin-like growth factor (IGF1), insulin-like growth factor 2 (IGF2), and insulin. IGF-1R binds to its endogenous ligands with the following order of affinity: highest affinity to IGF1, lower affinity to IGF2, and weaker affinity to insulin. The biological activity of IGF1 and IGF2 is regulated by a family of six IGF-binding proteins. These binding proteins control IGF transport and bioavailability and compete with IGFs for binding to the IGF-1R. Two ligand-binding sites exist in the extracellular portion of each αβ dimer of the IGF-1R. The IGF-1R extracellular domain is autoinhibitory, and ligand binding releases this autoinhibition, bringing the TM domains together to allow autophosphorylation and subsequent activation of the kinase domain. IGF2 is the primary growth factor required for early development, while IGF1 is required to achieve maximal proliferation. After birth, IGF1 is primarily secreted by the liver in response to stimulation from GH, but can also be expressed by other cell types. IGF1 is known to regulate normal physiological functions, inhibit apoptosis, and promote cancer progression by stimulating cell proliferation. Unlike most growth factors, whose biological activity is primarily regulated by release from secretory granules, serum concentrations of both IGF1 and IGF2 in the circulation and tissues far exceed those required for maximal cell stimulation. Over 99% of circulating IGFs bind to IGFBPs, mostly forming a 150 kDa complex with IGFBP-3 and the acid-labile subunit (ALS). This complex extends the serum half-life of IGF1 from approximately 10 minutes to 15 hours and helps tightly regulate IGF bioavailability at the cellular level. Because IGF binding affinity for IGFBPs is greater than that for the IGF-1R, IGFBPs competitively inhibit IGF / IGF-1R binding and signaling. Local proteases can cleave IGFBPs into fragments with lower binding affinity, thereby releasing IGFs for IGF-1R binding.

[0079] In leukemia and malignant solid tumors, the IGF pathway is disrupted in many ways during cellular transformation and tumor metastasis. Genetic risk factors, including those affecting the expression of IGF-1R, IGF1, IGF2, and IGFBPs, contribute to the risk of developing tumors. As mentioned previously, IGF-1R expression is tightly regulated and is often derepressed due to the loss of activity of various tumor suppressor pathways. Another type of indirect involvement of the IGF pathway in cancer progression involves the interaction between the IGF pathway and other hormones. Estrogen in breast cancer and androgen in prostate cancer have been shown to enhance IGF-1R signaling. IGF signaling also directly contributes to cancer progression in that activated pathways include both enhanced cell survival and proliferation, as well as cell cycle arrest and the ability to escape apoptotic mechanisms that normally function to disable such abnormal cells.

[0080] IGF-1R activation and intracellular signaling pathways The life cycle of human cells is tightly regulated by intracellular and extracellular signals that together control cell proliferation, senescence, and apoptosis. When the sum of growth-stimulatory and inhibitory signals favors proliferation, cells enter mitosis. For example, circulating IGF1 and IGF2 bind to IGF-1R, triggering a signaling cascade that leads to increased proliferation and enhanced survival of IGF-responsive cells. Such signaling is central to the process of carcinogenesis, involving downstream effector mechanisms that mediate the effects of signal initiation.

[0081] Ligand binding to IGF-1R activates the receptor kinase, leading to receptor autophosphorylation and tyrosine phosphorylation of several substrates, including insulin receptor substrates (IRS1 / 2), Src homology and collagen (Shc) adaptor proteins, and 14-3-3 proteins. Phosphorylation of IRS1 and IRS2 proteins leads to activation of two major signaling pathways: the PI3K-AKT / PKB pathway and the Ras-MAPK pathway.

[0082] While activation of the MAPK pathway leads to increased cell proliferation, activation of the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to the activation of several downstream substrates, including the proteins AKT / PKB. AKT phosphorylation can enhance protein synthesis via mTOR activation and induce the anti-apoptotic effects of IGF-1R via the phosphorylation and inactivation of BAD (a pro-apoptotic member of the BCL2 family). In an alternative pathway for activation of the PI3K pathway, a distinct regulatory subunit of PI3K (PIK3R3) associates with the IGR1R and insulin receptor (INSR) in a kinase-dependent manner via its SH2 domain, providing a means by which these two receptors can regulate the PI3K pathway.

[0083] In parallel with PI3K-driven signaling, recruitment of Grb2 / SOS by phosphorylated IRS1 or phosphorylated Shc family members leads to recruitment of Ras and activation of the Ras-MAPK pathway. The Ras / MAPK pathway has many documented roles in mediating mitogenic, differentiation, and migration signals. The mitogenic activity of IGF-1R is mediated through Ras and the PI3K-AKT pathway, resulting in upregulation of cyclin D1 and its binding partner CDK4. This leads to phosphorylation of retinoblastoma protein, release of E2F transcription factors, and expression of downstream target genes such as cyclin E (a key regulator of S-phase initiation). Other pathways, including cell proliferation, are also regulated by IGF-1R activation. IGF-1R pathway activation also upregulates the cell cycle inhibitor p27. kip1 , p57 kip2 , and has been shown to downregulate PTEN.

[0084] In addition to these two major signaling pathways (PI3K-AKT / PKB and Ras-MAPK), IGF-1R signals through the Janus kinase / signal transducer and activator of transcription pathway (JAK / STAT). Phosphorylation of JAK proteins can lead to the phosphorylation and subsequent activation of signal transducer and activator of transcription (STAT) proteins. The JAK / STAT pathway activates gene transcription and may be involved in transforming activity. Specific activation of STAT3 has been demonstrated to be regularly involved in the transforming activity of IGF-1R. JNK kinases have also been shown to be activated by IGF-1R.

[0085] Further integration of signaling pathways is evidenced by the multiple ways in which the IGF-1R and epidermal growth factor receptor (EGFR) pathways interact. IGF-1R and EGFR can directly associate with each other and heterodimerize. IGF-1R and EGFR can further mediate the availability of ligands to each other. Indirect interactions between the IGF-1R and EGFR pathways involve the use of shared G protein-coupled receptors or other downstream signaling molecules.

[0086] Internalization of cell surface receptor tyrosine kinases was previously thought to terminate their signaling. However, it is now generally accepted that internalized receptors, including IGF-1R, can signal from endosomes and intracellular membrane compartments. In addition, they can further regulate gene transcription by translocating to the nucleus. Although the details of the mechanisms determining the subcellular localization of IGF-1R or its compartmentalization with other signaling proteins are still unclear, it has been suggested that intracellular IGF-1R trafficking is regulated in a cell-type-specific manner and that cell-specific signals can influence the recruitment and activation of effector proteins. Thus, cell-specific IGF-1R trafficking, compartmentalization, and intracellular location may define how cells respond to extracellular stimuli.

[0087] IGF-1R inhibitors Forced overexpression of IGF-1R leads to malignant transformation of cultured cells, and elevated levels of IGF-1R are observed in various human tumor types. Downregulation of IGF-1R levels can reverse the transformed phenotype of tumor cells and sensitize them to apoptosis in vivo.

[0088] Several kinase inhibitors and blocking monoclonal antibodies that inhibit ligand binding and signal transduction have been developed and tested. Examples of human monoclonal antibodies that bind to IGF-1R include cizutumumab, ganitumab, teprotumumab, figitumumab, dalotuzumab, and R1507. Several clinical trials involving subjects with metastatic pancreatic cancer demonstrated little effect of ganitumab in improving survival. Teprotumumab, sold under the trade name Tepezza, is another human monoclonal antibody that binds to IGF-1R. Tepezza is approved for the treatment of thyroid eye disease (TED), an autoimmune disorder characterized by proptosis. Tepezza has been shown to reduce inflammation, thereby preventing muscle and fat tissue remodeling and, thereby, preventing tissue expansion behind the eye. While Tepezza has been shown to be effective in treating TED, phase 1 trials of teprotumumab in the treatment of malignant tumors have demonstrated little efficacy. The fact that these monoclonal antibody inhibitors of IGF-1R have been largely unsuccessful in clinical trials may potentially be related to how IGF-1R internalization, subcellular location, and signaling are controlled in normal and cancer cells.

[0089] Given the failure of clinical trials of antibodies targeting IGF-1R as cancer therapeutics, renewed attention is being directed toward potential small molecule inhibitors of IGF-1R. One such small molecule inhibitor is the dual IGF-1R / INSR kinase inhibitor OSI-906. OSI-906 potently and selectively inhibits the autophosphorylation of both human IGF-1R and IR, exhibiting in vitro antiproliferative effects in various tumor cell lines and, when administered orally once daily, demonstrating potent in vivo antitumor efficacy in IGF-1R-driven xenograft models. Unfortunately, a phase 3 trial testing the efficacy of OSI-906 (linsitinib) in treating adrenocortical carcinoma concluded that linsitinib did not increase overall survival. Effective therapeutic targeting of IGF-1R to improve cancer survival currently represents a significant unmet need.

[0090] IGF-1R kinase inhibitor compounds In one aspect, provided herein are IGF-1R inhibitor compounds.

[0091] One embodiment is a compound of formula (I)

[0092] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; L is a bond, or optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; R2 is an optionally substituted carbocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl, and the optional substitutions of the optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl are cyano, halo, hydroxy, azido, amino, nitro, —COH, —S(O)—R 10 , -SR 10 , -S(O)2-R 10 , optionally substituted C1-C6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O-, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R 11 )2, -CO-R 10 , -CO2-R 10 , -CON(R 11 )2, -NR 11 CO-R 10 , -NR 11 CO2-R 10 , -SO2N(R 11 )2, -C(=NR 12 )-N(R 11 )2, -NR 11 CO-N(R 10 )2, or -NR 11 SO2-N(R 10 )2, X 3 is N or CR 3 and X 4 is N or CR 4 and X 5 is N or CR 5 and X 6 is N or CR 6 and X8 is N or CR 8 and R 3 , R 4 , R 5 , R 6 , and R 8 are independently hydrogen, cyano, halo, hydroxy, azido, amino, nitro, -COH, -S(O)-R 10 , -SR 10 , -S(O)2-R 10 , optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted heterocyclyl, -N(R 11 )2, -CO-R 10 , -CO2-R 10 , -CON(R 11 )2, -NR 11 CO-R 10 , -NR 11 CO2-R 10 , -SO2N(R 11 )2, -C(=NR 12 )-N(R 11 )2, -NR 11 CO-N(R 10 )2, and -NR 11 SO2-N(R 10 )2, R 10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 11 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 12 is H or optionally substituted C1-C6 alkyl, R 9 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted C4-C10 carbocyclylalkyl; R 9 and L, or R 9 and X may be taken together with any intervening atoms to form an optionally substituted heterocyclyl ring.

[0093] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is N, and X 4 is CR 4 is.

[0094] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is CR 3 and X 4 is N.

[0095] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is CR 3 and X 4 is CR 4 is.

[0096] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is a bond. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted C3-C7 cycloalkyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted C4 cycloalkyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted heterocyclyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted piperidine or pyrrolidine. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted piperidin-4-yl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted C1-C8 alkyl.

[0097] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted cycloalkyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted C3-C7 cycloalkyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted heterocyclyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted C1-C8 alkyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted C4-C10 cycloalkylalkyl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted heterocyclylalkyl.

[0098] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is H.

[0099] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is H. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1-C4 alkoxy.

[0100] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 8 is N.

[0101] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 8 is CR 8 Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is H. Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is halogen. Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is F.

[0102] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is H.

[0103] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted aryl.

[0104] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is optionally substituted phenyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is phenyl substituted with at least one halogen. Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is 2-fluorophenyl.

[0105] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted heteroaryl. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted pyridine.

[0106] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 6 is N.

[0107] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 6 is CR 6 Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is H.

[0108] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 5 is N.

[0109] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 5 is CR 5 Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is H.

[0110] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 5 is CR 5 and X 6 is CR 6 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 5 is CH, and X 6 is CH.

[0111] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 5 is CR 5 and X 6 is CR 6 and X 8 is CR 8 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 5 is CH and X 6 is CH and X 8 is CF.

[0112] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is CR 3 and X 4 is CR 4 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is CH, and X 4 is CR 4 and R 4 is optionally substituted C1-C4 alkoxy. Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is CH, and X 4 is C-OCH3.

[0113] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is CR 3 and X 4 is CR 4 and X 5 is CR 5 and X 6 is CR 6 and X 8 is CR 8 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is CH and X 4 is C-OCH3, and X 5 is CH and X 6 is CH and X 8 is CF.

[0114] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is phenyl substituted with at least one halogen, and X 3 is CR 3 and X 4 is CR 4 and X 5 is CR 5 and X 6 is CR 6 and X 8 is CR 8 Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is phenyl substituted with at least one halogen, and X 3 is CH and X 4 is C-OCH3, and X 5 is CH and X 6 is CH and X 8 Another embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is 2-fluorophenyl.

[0115] Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -LX is

[0116] [ka] is.

[0117] One embodiment provides an IGF-1R inhibitor compound having the structure shown in Table 1A, or a pharmaceutically acceptable salt or solvate thereof.

[0118] [Table 1-1]

[0119] [Table 1-2]

[0120] [Table 1-3]

[0121] [Table 1-4]

[0122] [Table 1-5]

[0123] [Table 1-6]

[0124] [Table 1-7]

[0125] [Table 1-8]

[0126] [Table 1-9]

[0127] Another embodiment provides an IGF-1R inhibitor compound as provided in Table 1B, or a pharmaceutically acceptable salt or solvate thereof.

[0128] [Table 2-1]

[0129] [Table 2-2]

[0130] Preparation of compounds The compounds used in the synthetic chemical reactions described herein are made according to 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" refers to 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, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0131] Suitable references 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.G. 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, RC“Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN:0-471-19031-4; March, 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-X8 (8 volumes); "Organic Reactions" (1942-2000) John Wiley & Sons (over 55 volumes), and "Chemistry of Functional Groups" John Wiley & Sons (73 volumes).

[0132] Certain similar reactants are optionally identified by indexes of known chemical products 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.). Chemicals that are known but 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.

[0133] Pharmaceutical Composition In certain embodiments, the IGF-1R inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the IGF-1R inhibitory 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), which is selected based on the selected route of administration and standard pharmaceutical practice, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0134] Provided herein are pharmaceutical compositions comprising at least one IGF-1R 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).

[0135] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0136] One embodiment provides a method of preparing a pharmaceutical composition, comprising the step of mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0137] In certain embodiments, the IGF-1R inhibitory compounds as described by Formula (I) are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more steps of the synthetic process.

[0138] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof.

[0139] One embodiment provides a method of preparing a pharmaceutical composition, the method comprising mixing a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0140] In certain embodiments, an IGF-1R inhibitory compound as described by Table 1A or Table 1B is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more steps of the synthetic process.

[0141] 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))).

[0142] In some embodiments, the IGF-1R inhibitor compound described by Formula (I) or Table 1A or Table 1B, or its pharmaceutically acceptable salt or solvate, is formulated for injection administration.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.

[0143] The dosage of the compositions comprising at least one IGF-1R inhibitory compound as described herein varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include health status, age, and other factors.

[0144] The pharmaceutical composition is administered in a manner appropriate to 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 specific form of the active ingredient, and the method of administration. In general, an appropriate dose 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 reduced severity of symptoms. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose varies depending on the patient's body type, weight, or blood volume.

[0145] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0146] Treatment method One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0147] One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0148] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treating cancer or a neoplastic disease.

[0149] One embodiment provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0150] In some embodiments, methods of treating cancer in a patient in need thereof are provided, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating cancer in a patient in need thereof are provided, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0151] One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of an autoimmune disease.

[0152] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treating an autoimmune disease.

[0153] One embodiment provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

[0154] In some embodiments, methods are provided for treating an autoimmune disease in a patient in need thereof, the methods comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating an autoimmune disease in a patient in need thereof, the methods comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0155] One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method for the treatment of thyroid eye disease.

[0156] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method for the treatment of thyroid eye disease.

[0157] One embodiment provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of thyroid eye disease.

[0158] In some embodiments, methods of treating thyroid eye disease in a patient in need thereof are provided, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating thyroid eye disease in a patient in need thereof are provided, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0159] One embodiment provides a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0160] One embodiment provides a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

[0161] One embodiment provides a pharmaceutical composition comprising a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treating cancer or a neoplastic disease.

[0162] One embodiment provides the use of a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0163] In some embodiments, methods of treating cancer in a patient in need thereof are provided, comprising administering to the patient a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating cancer in a patient are provided, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0164] One embodiment provides a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating an autoimmune disease.

[0165] One embodiment provides a pharmaceutical composition comprising a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treating an autoimmune disease.

[0166] One embodiment provides the use of a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

[0167] In some embodiments, methods are provided for treating an autoimmune disease in a patient in need thereof, the methods comprising administering to the patient a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating an autoimmune disease in a patient in need thereof, the methods comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0168] One embodiment provides a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, for use in a method for the treatment of thyroid eye disease.

[0169] One embodiment provides a pharmaceutical composition comprising a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method for the treatment of thyroid eye disease.

[0170] One embodiment provides the use of a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of thyroid eye disease.

[0171] In some embodiments, provided are methods of treating thyroid eye disease in a patient in need thereof, comprising administering to the patient a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided are methods of treating thyroid eye disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0172] Provided herein are methods wherein the pharmaceutical composition is administered orally. Provided herein are methods wherein the pharmaceutical composition is administered by injection.

[0173] One embodiment provides a method of inhibiting the IGF-1R enzyme, the method comprising contacting the IGF-1R enzyme with a compound of Formula (I) or Table 1A or Table 1B. Another embodiment provides a method of inhibiting the IGF-1R enzyme, wherein the IGF-1R enzyme is contacted in an in vivo setting. Another embodiment provides a method of inhibiting the IGF-1R enzyme, wherein the IGF-1R enzyme is contacted in an in vitro setting.

[0174] Other embodiments and uses will be apparent to those skilled in the art in light 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]

[0175] I. Chemical synthesis In some embodiments, the IGF-1R 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 δH chemical shift in parts per million (ppm) downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DMF Dimethylformamide DMSO dimethyl sulfoxide EA Ethyl acetate ESI electrospray ionization Et Ethyl g grams h time(s) 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 minutes (s) mol mole, molecule (mol weight) 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 doublet (spectrum) T temperature TFA trifluoroacetic acid THF tetrahydrofuran

[0176] Example 1: Preparation of 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0177] [ka]

[0178] To a solution of 7-bromoquinoline (20 g, 96.6 mmol, 1.0 equiv.), DPPP (8.0 g, 19.3 mmol, 0.2 equiv.), and Pd(OAc)2 (2.1 g, 9.7 mmol, 0.1 equiv.) in DMSO / MeOH (300 mL / 300 mL) was added TEA (40 mL, 289.8 mmol, 3.0 equiv.). The mixture was stirred at 120 °C under CO2 (5 atm) for 15 h and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl quinoline-7-carboxylate (16.4 g, 91.1%) as a yellow solid. LRMS (M+H) + )m / z 188.1, calculatedfound 188.0.

[0179] [ka]

[0180] To a stirred solution of methyl quinoline-7-carboxylate (16.4 g, 87.7 mmol, 1.0 equiv) in DCM (300 mL) was added m-CPBA (22.7 g, 131.6 mmol, 1.5 equiv) at 25 °C. The mixture was stirred for 2 h at 25 °C, then poured onto ice, adjusted to pH 13 by adding saturated aqueous Na2CO3, and extracted with DCM (500 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 7-(methoxycarbonyl)quinoline 1-oxide (17.5 g, 98.3%) as a yellow oil. LRMS (M+H)+ )m / z 204.1, calculatedfound 204.1.

[0181] [ka]

[0182] To a solution of 7-(methoxycarbonyl)quinoline 1-oxide (17.5 g, 86.2 mmol, 1.0 equiv.) in DCM (500 mL) was added POBr (32.1 g, 112.1 mmol, 1.3 equiv.) and DMF (3.3 mL, 43.1 mmol, 0.5 equiv.) at -78 °C. The mixture was stirred for 2 h at 25 °C, then poured onto ice, adjusted to pH 13 by adding saturated aqueous NaCO solution, and extracted with DCM (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl 2-bromoquinoline-7-carboxylate (17.2 g, 75.4%) as a yellow solid. LRMS (M+H) + )m / z 266.0, calculatedfound 266.0. 1 H NMR (DMSO-d6,400MHz) δ 8.50(s,1H),8.45(d,1H),8.12-8.21(m,2H),8.86(d,1H),3.95(s,3H).

[0183] [ka]

[0184] To a solution of methyl 2-bromoquinoline-7-carboxylate (17.2 g, 64.7 mmol, 1.0 equiv.) in dioxane (300 mL) were added phenylboronic acid (15.8 g, 129.3 mmol, 2.00 equiv.) and Pd(PPh3)4 (7.5 g, 6.4 mmol, 0.1 equiv.). The mixture was stirred at 120 °C for 1 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl 2-phenylquinoline-7-carboxylate (8.8 g, 50.2%) as a white solid. LRMS (M+H + )m / z 264.1, calculatedfound 264.1.

[0185] [ka]

[0186] To a solution of methyl 2-phenylquinoline-7-carboxylate (8.8 g, 33.5 mmol, 1.0 equiv.) in MeOH (100 mL) and HO (30 mL) was added NaOH (2.0 g, 50.2 mmol, 1.5 equiv.). The mixture was stirred for 15 hours at 80° C., then concentrated in vacuo and diluted with water (60 mL). The pH was adjusted to 2 by adding 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 2-phenylquinoline-7-carboxylic acid (7.8 g, 93.9%) as a white solid. LRMS (M+H + )m / z 250.1, calculatedfound 250.0.

[0187] [ka]

[0188] To a solution of 2-phenylquinoline-7-carboxylic acid (2.1 g, 8.4 mmol, 1.0 equiv) in DCM (100 mL) was added (COCl) (3.6 mL, 42.1 mmol, 5.0 equiv) and DMF (5 drops) at -78 °C. The mixture was stirred at room temperature for 7 h and then concentrated in vacuo to give 2-phenylquinoline-7-carbonyl chloride as a yellow solid (2.6 g, ca. 100.0%). LRMS (M+H + )m / z 264.1, calculatedfound 264.1 in MeOH.

[0189] [ka]

[0190] To a solution of 2-phenylquinoline-7-carbonyl chloride (1.0 g, 3.7 mmol, 1.0 equiv.) in THF (100 mL) was added malononitrile (247.1 mg, 3.70 mmol, 1.0 equiv.) and DIEA (1.8 mL, 11.20 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-(hydroxy(2-phenylquinolin-7-yl)methylene)malononitrile as a yellow oil (600 mg, 67.5%). LRMS (M+H + )m / z 298.1, calculatedfound 298.0.

[0191] [ka]

[0192] To a solution of 2-(hydroxy(2-phenylquinolin-7-yl)methylene)malononitrile (500 mg, 1.70 mmol, 1.0 equiv.) in THF (30 mL) was added MeSO (0.3 mL, 3.4 mmol, 2.0 equiv.) and DIEA (0.6 mL, 3.4 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile as a yellow oil (450 mg, 94.2%). LRMS (M+H + )m / z 312.1, calculatedfound 312.1.

[0193] [ka]

[0194] To a solution of 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (450 mg, 1.80 mmol, 1.0 equiv.) in EtOH (30 mL) was added hydrazine hydrate (0.9 mL, 18.00 mmol, 10.0 equiv.). The mixture was stirred at 90° C. for 2 hours, then concentrated in vacuo and diluted with water (20 mL). The resulting mixture was stirred for 5 minutes and filtered. The solid was dried to give 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a white solid (456 mg, 100.0%). LRMS (M+H) + )m / z 312.1, calculatedfound 312.1.

[0195] [ka]

[0196] A solution of 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (150 mg, 0.48 mmol, 1.0 equiv) in H3PO4 (10 mL) was stirred for 1 h at 120 °C. The reaction mixture was diluted with water (20 mL). Na2CO3 was added to adjust the pH to 12-13. The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (132 mg, 88.0%). LRMS (M+H + )m / z 330.1, calculatedfound 330.1.

[0197] [ka]

[0198] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (60 mg, 0.18 mmol, 1.0 equiv) in DMSO (20 mL) was added 3-bromocyclobutan-1-one (1.7 mg, 0.72 mmol, 4.0 equiv) and KCO (75 mg, 0.54 mmol, 3.0 equiv). The mixture was stirred at 100° C. for 2 hours, then diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×2) and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (1.0 mg, 1.6%). LRMS(M+H + )m / z 398.2, calculatedfound 398.0. 1H NMR(400MHz,DMSO) δ 8.61(s,1H),8.40(d,1H),8.29(d,2H),8.04-8.10(m,2H),7.86(d,1H),7. 49-7.58(m,3H),4.26-4.28(m,1H),2.60-2.67(m,2H),2.32-2.34(m,2H).

[0199] Example 2: Preparation of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide

[0200] [ka]

[0201] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (260 mg, 0.8 mmol, 1.0 equiv.) in DMF (20 mL) was added tert-butyl 4-bromopiperidine-1-carboxylate (1.3 g, 4.8 mmol, 6.0 equiv.) and CsCO (770.5 mg, 2.4 mmol, 3.0 equiv.). The mixture was stirred at 80° C. for 24 hours, then diluted with water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give tert-butyl 4-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow oil (240 mg, 94.2%). LRMS (M+H + )m / z 513.3, calculatedfound 513.3.

[0202] [ka]

[0203] To a solution of tert-butyl 4-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (220 mg, 0.5 mmol, 1.0 equiv) in DCM (5 mL) was added 1 M HCl / EA (5 mL). The mixture was stirred at room temperature for 3 h and then concentrated. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (2.1 mg, 1.2%) as a white solid. LRMS (M+H + )m / z 413.2, calculatedfound 413.2, 1 H NMR(400MHz,DMSO) δ 8.49(d,1H),8.28-8.48(m,4H),8.16-8.19(m,2H),8.04(d,1H),7.76(dd,1H),7.51-7. 59(m,4H),6.33(s,2H),4.31-4.35(m,1H),3.23(d,2H),2.78(t,2H),1.92-2.21(m,4H).

[0204] Example 3: Preparation of 4-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxamide

[0205] [ka]

[0206] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (37 mg, 0.09 mmol, 1.0 equiv) in DCM (5 mL) was added TEA (0.1 mL, 0.72 mmol, 8.0 equiv) and isocyanatotrimethylsilane (20.7 mg, 0.18 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h and then partitioned between saturated NaHCO (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 4-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxamide (9.6 mg, 23.4%) as a white solid. LRMS (M+H + )m / z 456.2, calculatedfound 456.1. 1 H NMR(DMSO-d6,400MHz) δ 8.56(d,1H),8.28-8.30(m,2H),8.23(s,1H),8.19(d,1H),8.06(d,1H),7.80(dd,1H),7.53 -7.61(m,3H),4.34-4.39(m,1H),4.07-4.11(m,2H),2.77-2.85(m,2H),1.83-1.89(m,4H).

[0207] Example 4: Preparation of methyl 4-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0208] [ka]

[0209] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (70 mg, 0.2 mmol, 1.0 equiv.) and NaHCO (44.7 mg, 0.5 mmol, 3.0 equiv.) in MeCN (6.0 mL) and HO (2.0 mL), methyl carbonochloridate (18.9 mg, 0.2 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 5 hours, then quenched with HO (20.0 mL) and extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give methyl 4-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a white solid (17.0 mg, 21.3%). LRMS (M+H + )m / z 471.2, calculatedfound 471.1. 1 H NMR(DMSO-d6,400MHz) δ 8.48(d,1H),8.29-8.31(m,2H),8.17(d,2H),8.03(d,1H),7.76(d,1H),7.51-7.59(m,3H),6.35( s,2H),4.38-4.22(m,1H),4.11-4.13(m,2H),3.65(s,3H),2.94-2.95(m,2H),1.86-1.91(m,4H).

[0210] Example 5: Preparation of 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0211] [ka]

[0212] MeMgBr (3 M, 85.2 mL, 255.7 mmol, 1.5 equiv) was added dropwise to a solution of 3-(benzyloxy)cyclobutanone (30 g, 170.5 mmol, 1.0 equiv) in THF (300 mL) at −78° C. The mixture was stirred at −78° C. for 1 h and then quenched with aqueous NH4Cl (500 mL). The aqueous layer was extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 3-(benzyloxy)-1-methylcyclobutan-1-ol (30.3 g, 92.6%) as a yellow oil. 1 H NMR (DMSO-d6,400MHz) δ 7.27-7.36(m,5H),4.97(s,1H),4.34(s,2H),3.64-3.68(m,1H),2.22-2.28(m,2H),1.91-1.96(m,2H),1.15(s,3H).

[0213] [ka]

[0214] A mixture of 3-benzyloxy-1-methyl-cyclobutanol (30.3 g, 157.8 mmol, 1.0 equiv) and Pd / C (10 wt%, 10 g) in MeOH (500 mL) was stirred under hydrogen (1 atm) at room temperature for 16 h, then filtered and concentrated in vacuo to give 1-methylcyclobutane-1,3-diol (16 g, ca. 100%) as a yellow oil. 1 H NMR (DMSO-d6,400MHz) δ 4.87(d,1H),4.81(s,1H),3.69-3.71(m,1H),2.16-2.22(m,2H),1.84-1.89(m,2H),1.13(s,3H).

[0215] [ka]

[0216] A mixture of 1-methylcyclobutane-1,3-diol (16 g, 156.9 mmol, 1.0 equiv) and IBX (87.8 g, 313.7 mmol, 2.0 equiv) in MeCN (200 mL) was stirred at 80° C. for 15 h, then filtered and concentrated in vacuo to give 3-(benzyloxy)cyclobutanone (10 g, 64.1%) as a yellow oil. 1 H NMR(DMSO-d6,400MHz) δ 5.49(s,1H),2.98(s,4H),1.48(s,3H).

[0217] [ka]

[0218] To a stirred solution of 3-hydroxy-3-methylcyclobutan-1-one (10 g, 100.0 mmol, 1.0 equiv) in MeOH (200 mL) at room temperature, BocNHNH (15.8 g, 120.0 mmol, 1.2 equiv) and AcOH (0.5 mL, 8.3 mmol, 0.1 equiv) were added. The reaction mixture was stirred at room temperature for 3 hours, after which NaBHCN (12.6 g, 200.0 mol, 2.0 equiv) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then stirred at 80 °C for 18 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give tert-butyl 2-((1s,3s)-3-hydroxy-3-methylcyclobutyl)hydrazine-1-carboxylate (4.8 g, 22.2%) and tert-butyl 2-((1r,3r)-3-hydroxy-3-methylcyclobutyl)hydrazine-1-carboxylate (3.6 g, 16.6%) as colorless oils. tert-Butyl 2-((1s,3s)-3-hydroxy-3-methylcyclobutyl)hydrazine-1-carboxylate: 1H NMR(DMSO-d6,400MHz) δ 8.15(s,1H),4.78(s,1H),4.32-4.34(m,1H),2.95-3.01(m,1H),1.94-1.99(m,2H),1.79-1.84(m,2H),1.38(s,9H),1.15(s,3H).LRMS(M+H + ) m / z calculated 217.1, found 217.1. tert-Butyl 2-((1r,3r)-3-hydroxy-3-methylcyclobutyl)hydrazine-1-carboxylate: 1 H NMR(DMSO-d6,400MHz) δ 8.17(s,1H),4.67(s,1H),4.35-4.37(m,1H),3.44-3.46(m,1H),1.93-1.99(m,2H),1.67-1.76(m,2H),1.38(s,9H),1.25(s,3H).LRMS(M+H + )m / z 217.1, calculatedfound 217.1.

[0219] [ka]

[0220] To a stirred solution of tert-butyl 2-((1s,3s)-3-hydroxy-3-methylcyclobutyl)hydrazine-1-carboxylate (1.5 g, 6.9 mmol, 1.0 equiv) in DCM (10 mL) was added HCl in dioxane (4 N, 10 mL). The reaction was stirred for 30 minutes at 30° C., after which the mixture was concentrated in vacuo to give (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (1.2 g, ca. 100%) as a white solid. LRMS (M+H + )m / z 117.1, calculatedfound 117.1.

[0221] [ka]

[0222] To a solution of 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (2.1 g, 6.9 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (1.2 g, 10.3 mmol, 1.5 equiv.) in EtOH (50 mL), TEA (7.6 mL, 55.2 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was stirred at 90 °C for 2 h, after which the mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (1.7 g, 62.9%) as a yellow solid. LRMS (M+H) + )m / z calculated 395.2,found 396.3.

[0223] [ka]

[0224] To a stirred solution of 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (1.7 g, 4.3 mmol, 1.0 equiv) and KCO (1.8 g, 12.9 mmol, 3.0 equiv) in DMSO (30 mL) at room temperature was added HO (30%, 9.8 g, 86.1 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred for 1 h at 60 °C. Water (80 mL) was added, and the mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (1050.2 mg, 61.8%) as a white solid. LRMS (M+H + )m / z 414.2, calculatedfound 414.1. 1H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.30(d,2H),8.21(s,1H),8.18(d,1H),8.05(d,1H),7.78(dd,1H),7.49-7.59(m,3H),6 .31(brs,2H),5.19(brs,1H),4.42-4.51(m,1H),2.59-2.65(m,2H),2.36-2.42(m,2H),1.35(s,3H).

[0225] Example 6: Preparation of 5-amino-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0226] [ka]

[0227] To a solution of 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (268.1 mg, 0.86 mmol, 1.0 equiv.) and 3-hydrazinyl-1-methylcyclobutan-1-ol (150 mg, 1.3 mmol, 1.5 equiv.) in EtOH (50 mL) was added TEA (1.0 mL, 6.9 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography, eluting with MeCN (10% to 70%) in HO to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (55 mg, 16.2%) and 5-amino-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (60 mg, 17.6%) as yellow solids. These were confirmed by NOESY. 1H NMR(DMSO-d6,400MHz) δ 8.54(s,1H),8.48(d,1H),8.28-8.31(m,2H),8.17(d,1H),8.09(s,2H),7.49-7.59(m,3H),6.80(s ,2H),5.28(s,1H),4.45-4.50(m,1H),2.60-2.66(m,2H),2.39-2.44(m,2H),1.34(s,3H).LRMS(M+H + ) m / z calculated 396.2, found 396.3. 5-amino-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile 1 H NMR(DMSO-d6,400MHz) δ 8.53(s,1H),8.48(d,1H),8.28-8.31(m,2H),8.17(d,1H),8.09(s,2H),7.50-7.60(m,3H),6.77(s ,2H),5.03(s,1H),4.94-4.99(m,1H),2.54-2.58(m,2H),2.43-2.49(m,2H),1.41(s,3H).LRMS(M+H + )m / z calculated found 396.3.

[0228] [ka]

[0229] To a stirred solution of 5-amino-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (60 mg, 0.15 mmol, 1.0 equiv) and KCO (62.9 mg, 0.46 mmol, 3.0 equiv) in DMSO (30 mL) at room temperature was added HO (30%, 344.3 mg, 3.0 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred for 2 h at 60 °C. Water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (5.7 mg, 9.5%) as a white solid. LRMS (M+H + )m / z 414.2, calculatedfound 414.1. 1 H NMR(DMSO-d6,400MHz) δ 8.49(d,1H),8.29-8.32(m,2H),8.16-8.20(m,2H),8.05(d,1H),7.78(dd,1H),7.49-7.59( m,3H),6.28(s,2H),4.93-4.97(m,1H),2.54-2.56(m,2H),2.39-2.45(m,2H),1.36(s,3H).

[0230] Example 7: Preparation of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide

[0231] [ka]

[0232] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (20 mg, 0.05 mmol, 1.0 equiv.) in MeOH (10 mL) was added HCHO (37%, 0.24 mL, 0.05 mmol, 1.0 equiv.), AcOH (1 drop), and NaBH3CN (9.5 mg, 0.15 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 18 h and then diluted with water (10 mL). The pH was adjusted to 10-11 by adding Na2CO3. The mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-(1-methylpiperidin-4-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (1.9 mg, 9.2%) as a white solid. LCMS (M+H + )m / z 427.2, calculatedfound 427.3, 1 H NMR(400MHz,CD3OD) δ 8.40(d,1H),8.01(d,1H),8.05(d,2H),8.01(d,2H) 7.75(d,1H),7.40-7.45(m,3H),4.58(s,3H),3.18-3.22(m,2H),2.47(s,3H),2.31-2.35(m,2H),2.04(d,2H).

[0233] Example 8: Preparation of 5-amino-1-(1-(2-hydroxyethyl)piperidin-4-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0234] [ka]

[0235] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (20 mg, 0.049 mmol, 1.0 equiv.) in MeCN (8 mL) was added 2-bromoethan-1-ol (8 mg, 0.064 mmol, 1.3 equiv.) and CsCO (32 mg, 0.098 mmol, 2 equiv.). The mixture was stirred at 80° C. for 15 hours, then diluted with water (50 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-(1-(2-hydroxyethyl)piperidin-4-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (2.7 mg, 12.2%). LRMS (M+H + )m / z 457.2, calculatedfound 457.1. 1 H NMR(DMSO-d6,400MHz) δ 8.48(d,1H),8.28-8.30(m,2H),8.15-8.18(m,2H),8.03(d,1H),7.57-7.78(dd,1H),7.49-7.59(m,3H),6.30(s,2 H),4.39(s,1H),4.13-4.18(m,1H),3.51(s,2H),3.00(d,2H),2.44(t,2H),1.99-2.17(m,4H),1.80-1.83(m,2H).

[0236] Example 9 Preparation of 5-amino-1-((1s,3s)-3-hydroxycyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide and 5-amino-1-((1r,3r)-3-hydroxycyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0237] [ka]

[0238] To a solution of 3-(benzyloxy)cyclobutan-1-one (2.0 g, 11.40 mmol, 1.0 equiv.) in hexane (100 mL) was added NH2-NH2Boc (1.5 g, 11.40 mmol, 1.0 equiv.). The mixture was stirred at 80 °C for 3 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give tert-butyl 2-(3-(benzyloxy)cyclobutylidene)hydrazine-1-carboxylate as a yellow oil (2.4 g, 90.2%). LRMS (M+H + )m / z 291.2, calculatedfound 291.1

[0239] [ka]

[0240] To a solution of tert-butyl 2-(3-(benzyloxy)cyclobutylidene)hydrazine-1-carboxylate (2.0 g, 6.9 mmol, 1.0 equiv.) in THF (100 mL) was added BH (1 M, 22 mL, 22.00 mmol, 3.0 equiv.) under ice bath. The mixture was stirred at room temperature for 15 h, then quenched with saturated aqueous NH Cl and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL) and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give tert-butyl 2-((1s,3s)-3-(benzyloxy)cyclobutyl)hydrazine-1-carboxylate (2.1 g, ca. 100%) as a colorless oil. LRMS (M+H + )m / z 293.2, calculatedfound 293.1.

[0241] [ka]

[0242] To a stirred solution of tert-butyl 2-((1s,3s)-3-(benzyloxy)cyclobutyl)hydrazine-1-carboxylate (2.4 g, 10.30 mmol, 1.0 equiv) in DCM (80 mL) was added 4N HCl / dioxane (50 mL). The reaction was stirred for 30 minutes at 30° C. and then concentrated in vacuo to give ((1s,3s)-3-(benzyloxy)cyclobutyl)hydrazine (2.1 g, approx. 100.0%). LRMS (M+H + )m / z 193.1, calculatedfound 193.0.

[0243] [ka]

[0244] To a solution of ((1s,3s)-3-(benzyloxy)cyclobutyl)hydrazine (500 mg, 2.60 mmol, 1.0 equiv) in EtOH (30 mL) was added 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (1.2 g, 3.9 mmol, 1.5 equiv) and TEA (5.4 mL, 39.1 mmol, 15.0 equiv). The mixture was stirred at 90° C. for 2 hours, then concentrated, diluted with water (20 mL), and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-1-((1s,3s)-3-(benzyloxy)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (450 mg, 36.8%) as a yellow solid. LRMS (M+H + )m / z 472.2, calculatedfound 472.2.

[0245] [ka]

[0246] A solution of 5-amino-1-((1s,3s)-3-(benzyloxy)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (450 mg, 0.95 mmol, 1.0 equiv) in H2SO4 (10 mL) was stirred at room temperature for 5 h and then poured onto ice. Na2CO3 was added to adjust the pH to 12-13. The aqueous layer was concentrated in vacuo, and the resulting residue was triturated with DCM / MeOH (1 / 1, 300 mL) and filtered. The organic layer was concentrated in vacuo, and the resulting residue was purified by preparative HPLC to give 5-amino-1-((1s,3s)-3-hydroxycyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (250 mg, 65.8%). LRMS (M+H + )m / z 400.2, calculatedfound 400.3. 1 H NMR(400MHz,DMSO-d6) δ 8.49(d,1H),8.40-8.33(m,2H),8.22(d,1H),8.17(d,1H),8.05(d,1H),7.83( dd,1H),7.49-7.59(m,3H),6.26(s,2H),4.33-4.49(m,2H),2.57-2.76(m,4H).

[0247] Example 10: Preparation of 1-(1-acetylpiperidin-4-yl)-5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0248] [ka]

[0249] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (25 mg, 0.06 mmol, 1.0 equiv.) in MeCN / HO (1 / 1, 5 mL) was added NaHCO (15 mg, 0.18 mmol, 3.0 equiv.) and (CHCO)O (0.1 mL, 0.09 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo, diluted with water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 1-(1-acetylpiperidin-4-yl)-5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (22 mg, 78.5%) as a white solid. LRMS (M+H + )m / z 455.2, calculatedfound 455.1. 1 H NMR(400MHz,DMSO-d6) δ 8.48(d,1H),8.29(d,2H),8.15-8.19(m,2H),8.03(d,1H),7.76(d,1H),7.51-7.59(m,3H),6.35(s,2H),4. 42-4.54(m,2H),3.95-3.99(m,1H),3.17-3.33(m,1H),2.50-2.71(m,1H),1.98(s,3H),1.75-1.96(m,4H).

[0250] Example 11: Preparation of ethyl (1s,3s)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate

[0251] [ka]

[0252] To a solution of ethyl 3-oxocyclobutane-1-carboxylate (20.0 g, 140.8 mmol, 1.0 equiv.) in hexane (200 mL) was added tert-butyl hydrazine carboxylate (22.3 g, 169.0 mmol, 1.2 equiv.) at room temperature. The mixture was stirred at 80° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give tert-butyl 2-(3-(ethoxycarbonyl)cyclobutylidene)hydrazine-1-carboxylate (32 g, 88.9%) as a white solid. LRMS (M+H) + )m / z 257.1, calculatedfound 257.0.

[0253] [ka]

[0254] To a stirred solution of tert-butyl 2-(3-(ethoxycarbonyl)cyclobutylidene)hydrazine-1-carboxylate (27 g, 105.5 mmol, 1.0 equiv) and NaBHCN (13.3 g, 210.9 mmol, 2.0 equiv) in MeOH (100 mL) / THF (200 mL) was added AcOH (3 mL, 50 mmol, 0.5 equiv) at room temperature. The reaction mixture was stirred for 18 hours at 70° C., then cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=40:1, v / v) to give tert-butyl 2-(3-(ethoxycarbonyl)cyclobutyl)hydrazine-1-carboxylate (27.3 g, approximately 100%) as a white solid. LRMS (M+H + )m / z 259.2, calculatedfound 259.1

[0255] [ka]

[0256] To a stirred solution of tert-butyl 2-(3-(ethoxycarbonyl)cyclobutyl)hydrazine-1-carboxylate (27.3 g, 105.8 mmol, 1.0 equiv) in DCM (80 mL) was added HCl in dioxane (4 N, 30 mL). The reaction was stirred for 30 minutes at 30° C. and then concentrated in vacuo to give ethyl 3-hydrazinylcyclobutane-1-carboxylate as a white solid (23.1 g, ca. 100%). LRMS (M+H + )m / z 159.1, calculatedfound 159.0.

[0257] [ka]

[0258] To a solution of 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (2 g, 6.4 mmol, 1.0 equiv.) and ethyl 3-hydrazinylcyclobutane-1-carboxylate (1.5 g, 9.6 mmol, 1.5 equiv.) in EtOH (30 mL) was added TEA (7.1 mL, 51.4 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE / EA=2 / 1, v / v) to give ethyl (1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (900 mg, 32.1%) and ethyl (1r,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (830 mg, 29.6%) as a white solid. Ethyl (1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate: 1H NMR(DMSO-d6,400MHz) δ 8.53(s,1H),8.49(d,1H),8.30(d,2H),8.18(d,1H),8.05-8.10(m,2H),7.50-7.59(m,3H),6.85(s,2H),4.7 7-4.81(m,1H),4.13(q,2H),2.95-2.99(m,1H),2.73-2.80(m,2H),2.64-2.69(m,2H),1.22(t,3H).LRMS(M+H + ) m / z calculated 438.2, found 438.1. Ethyl (1r,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate: 1 H NMR(DMSO-d6,400MHz) δ 8.56(s,1H),8.49(d,1H),8.30(d,2H),8.18(d,1H),8.07-8.13(m,2H),7.51-7.60(m,3H),6.85(s,2H),5.0 2-5.06(m,1H),4.15(q,2H),3.23-3.28(m,1H),2.84-2.91(m,2H),2.61-2.68(m,2H),1.25(t,3H).LRMS(M+H + )m / z 438.2, calculatedfound 438.1.

[0259] [ka]

[0260] A solution of ethyl (1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (25 mg, 0.057 mmol, 1.0 equiv) in concentrated H2SO4 (3 mL) was stirred for 15 h at 25 °C, adjusted to pH 8 with saturated sodium carbonate solution, and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give ethyl (1s,3s)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate as a white solid (8.5 mg, 32.6%). LRMS (M+H + )m / z 456.2, calculatedfound 456.1. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.29-8.31(m,2H),8.17-8.20(m,2H),8.06(d,1H),7.75-7.78(dd,1H),7.50-7.59(m,3H),6.31(s, 2H),4.76-4.80(m,1H),4.06-4.12(m,2H),2.94-2.98(m,1H),2.70-2.77(m,2H),2.58-2.65(m,2H),1.23(s,3H).

[0261] Example 12: Preparation of 5-amino-1-((1s,3s)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0262] [ka]

[0263] To a stirred solution of ethyl (1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (2.0 g, 4.6 mmol, 1.0 equiv.) in anhydrous THF (20 mL) was added DIBAL-H in hexane (1 N, 9.2 mL, 9.2 mmol, 2.0 equiv.) under an ice bath. The reaction was stirred at 0° C. for 2 h, then quenched with saturated aqueous NH4Cl (20.0 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give 5-amino-1-((1s,3s)-3-(hydroxymethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow oil (600 mg, 33.3%). LRMS (M+H + )m / z 396.2, calculatedfound 396.1.

[0264] [ka]

[0265] To a stirred solution of 5-amino-1-((1s,3s)-3-(hydroxymethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (600 mg, 1.5 mmol, 1.0 equiv) and DMAP (366.6 mg, 3.0 mmol, 2.0 equiv) in DCM (30 mL) was added TsCl (438.6 mg, 2.3 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at 35° C. for 1 h, then quenched with HO (20.0 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give ((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate as a pale yellow solid (800 mg, 95.9%). LRMS (M+H + )m / z 550.2, calculatedfound 550.3.

[0266] [ka]

[0267] A solution of ((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (800 mg, 1.5 mmol, 1.0 equiv) and morpholine (652.5 mg, 7.5 mmol, 5.0 equiv) in DMA (10.0 mL) was stirred at 100° C. for 4 h, then quenched with HO (100.0 mL) and extracted with DCM / MeOH (10 / 1, 50 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-1-((1s,3s)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow oil (600 mg, 88.6%). LRMS (M+H + )m / z 465.2, calculatedfound 465.1.

[0268] [ka]

[0269] A mixture of 5-amino-1-((1s,3s)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (400 mg, 0.9 mmol, 1.0 equiv) in HSO (1 mL) was stirred at room temperature for 12 h, then quenched with HO (20.0 mL), and the mixture was adjusted to pH 8.0 by adding saturated aqueous NaCO, followed by extraction with DCM:MeOH (10:1, 50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography, eluting with MeCN (10% to 70%) in HO to give 5-amino-1-((1s,3s)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (301.5 mg, 72.5%). LRMS (M+H) + )m / z 483.2, calculatedfound 483.1. 1 H NMR(MeOD-d4,400MHz) δ 9.22(d,1H),8.72(s,1H),8.17-8.44(m,5H),7.77-7.81(m,3H),4.03-4.07(m 2H),3.83-4.03(m,3H),3.41-3.50(m,5H),3.18-3.30(m,3H),2.70-2.82(m,2H),2.62(s,1H).

[0270] Example 13: Preparation of 5-amino-1-((1r,3r)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0271] [ka]

[0272] To a solution of ethyl (1r,3r)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (530 mg, 1.2 mmol, 1.0 equiv) in DCM (15 mL) was added DIBAL-H (1 M, 1.5 mL, 1.5 mmol, 1.2 equiv) dropwise over 10 min under N at −78° C. The reaction mixture was stirred for 30 min at −70° C., then quenched with water (5 mL) at 0° C. and filtered. The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-amino-1-((1r,3r)-3-formylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (471 mg, ca. 100%) as a white solid. LRMS (M+H + )m / z 394.2, calculatedfound 394.1.

[0273] [ka]

[0274] To a solution of 5-amino-1-((1r,3r)-3-formylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.51 mmol, 1.0 equiv) in MeOH (20 mL) was added NaBH(OAc) (161.8 mg, 0.76 mmol, 1.5 equiv), AcOH (15.3 mg, 0.25 mmol, 0.5 equiv), and morpholine (66.4 mg, 0.76 mmol, 1.5 equiv), and the mixture was stirred for 3 h at 20 °C, after which it was quenched with water and MeOH was removed in vacuo. The resulting residue was diluted with HO (20 mL), extracted with EtOAc (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-1-((1r,3r)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (150 mg, 63.5%) as a white solid.

[0275] [ka]

[0276] 5-Amino-1-((1r,3r)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (150 mg, 0.32 mmol, 1.0 equiv) was added to 98% sulfuric acid (3 mL) at room temperature. The mixture was stirred for 1 hour and then slowly poured onto ice. The mixture was adjusted to pH 7 with saturated aqueous NaHCO3 and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford 5-amino-1-((1r,3r)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (60.2 mg, 38.7%) as a white solid. LRMS(M+H +)m / z 483.2, calculatedfound 483.1. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.29-8.32(m,2H),8.22(s,1H),8.18(d,1H),8.06(d,1H),7.80(dd,1H),7.52-7.60(m,3H),6.28 (s,2H),4.96-5.00(m,1H),3.58(t,4H),2.63-2.68(m,2H),2.50-2.52(m,3H),2.36-2.39(m,4H),2.16(t,2H).

[0277] Example 14: Preparation of 5-amino-1-((1r,3r)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0278] [ka]

[0279] To a solution of 5-amino-1-((1r,3r)-3-formylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (70 mg, 0.18 mmol, 1.0 equiv) in DCM (20 mL) was added NaBH(OAc) (56.6 mg, 0.27 mmol, 1.5 equiv), AcOH (5.3 mg, 0.09 mmol, 0.5 equiv), and azetidine (15.2 mg, 0.27 mmol, 1.5 equiv). The mixture was stirred for 3 h at 20 °C, then quenched with water and concentrated in vacuo. The resulting residue was diluted with HO (20 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 5-amino-1-((1r,3r)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (20 mg, 63.5%) as a yellow solid. LRMS (M+H + )m / z 435.2, calculatedfound 435.1.

[0280] [ka]

[0281] 5-Amino-1-((1r,3r)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (20 mg, 0.32 mmol, 1.0 equiv) was added to 98% sulfuric acid (3 mL), and the mixture was stirred at room temperature for 3 hours. Then, it was slowly poured onto ice and saturated NaHCO3 (aq) was added to adjust the pH to 7. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-((1r,3r)-3-(morpholinomethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (60.2 mg, 38.7%) as a white solid. LRMS(M+H + )m / z 453.2, calculatedfound 453.1. 1 H NMR(CD3OD,400MHz) δ 8.46(d,1H),8.32(s,1H),8.16(d,2H),8.06(dd,2H),7.76-7.80(m,1H),7.50-7,58 (m,3H),4.86-4.90(m,1H),3.31-3.35(m,5H),2.70-2.80(m,4H),2.11-2.28(m,4H).

[0282] Example 15: Preparation of 5-amino-3-(2-phenylquinolin-7-yl)-1-((1s,3s)-3-(piperazin-1-ylmethyl)cyclobutyl)-1H-pyrazole-4-carboxamide

[0283] [ka]

[0284] A solution of ((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (40 mg, 0.07 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (651.0 mg, 3.5 mmol, 5.0 equiv.) in DMA (5.0 mL) was stirred at 100° C. for 4 h, then quenched with HO (50.0 mL) and extracted with DCM:MeOH (10:1, 20 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give tert-butyl 4-(((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)piperazine-1-carboxylate as a pale yellow oil (20 mg, 48.8%). LRMS (M+H + )m / z 564.3, calculatedfound 564.4.

[0285] [ka]

[0286] A mixture of tert-butyl 4-(((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)piperazine-1-carboxylate (20 mg, 0.04 mmol, 1.0 equiv) in concentrated H2SO4 (1.0 mL) was stirred at room temperature for 12 h and then quenched with HO (20.0 mL). Then, saturated aqueous Na2CO3 solution was added to adjust the pH to 8.0. The mixture was extracted with DCM / MeOH (10 / 1, 50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-phenylquinolin-7-yl)-1-((1s,3s)-3-(piperazin-1-ylmethyl)cyclobutyl)-1H-pyrazole-4-carboxamide as a white solid (1.9 mg, 11.2%). LRMS (M+H + )m / z 482.3, calculatedfound 482.2. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.31(d,2H),8.17-8.19(m,2H),8.06(d,1H),7.77(d,1H),7.52-7.59(m,3H),6.26(s, 2H),4.66-4-70(m,1H),2.67-2.72(m,4H),2.39-2.50(m,3H),2.19-2.31(m,5H),2.18-2.19(m,3H).

[0287] Example 16: Preparation of 5-amino-3-(2-phenylquinolin-7-yl)-1-((1r,3r)-3-(piperazin-1-ylmethyl)cyclobutyl)-1H-pyrazole-4-carboxamide

[0288] [ka]

[0289] To a solution of 5-amino-1-((1r,3r)-3-formylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (140 mg, 0.36 mmol, 1.0 equiv) in DCM (20 mL) was added NaBH(OAc) (113.2 mg, 0.53 mmol, 1.5 equiv), AcOH (10.7 mg, 0.18 mmol, 0.5 equiv), and tert-butyl piperazine-1-carboxylate (99.4 mg, 0.53 mmol, 1.5 equiv). The mixture was stirred for 3 h at 20 °C, then quenched with water and concentrated in vacuo. The resulting residue was diluted with HO (20 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO, PE / EA=1 / 1, v / v) to give tert-butyl 4-(((1r,3r)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)piperazine-1-carboxylate (30 mg, 15.0%) as a yellow solid. LRMS (M+H + )m / z 564.3, calculatedfound 564.2.

[0290] [ka]

[0291] Tert-butyl 4-(((1r,3r)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl)piperazine-1-carboxylate (30 mg, 0.053 mmol, 1.0 equiv) was added to concentrated H2SO4 (3 mL) at room temperature, and the mixture was stirred for 3 h, then slowly poured onto ice and adjusted to pH 7 by addition of saturated NaHCO3 (aq). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-phenylquinolin-7-yl)-1-((1r,3r)-3-(piperazin-1-ylmethyl)cyclobutyl)-1H-pyrazole-4-carboxamide (6.3 mg, 24.6%) as a white solid. LRMS (M+H + )m / z 482.3, calculatedfound 482.2. 1 H NMR(CD3OD,400MHz) δ 8.79(d,1H),8.46(s,1H),8.21(d,2H),8.14-8.17(m,2H),8.00(d,1H),7.64-7.66(m,3H), 4.86-4.95(m,1H),3.47(brs,4H),3.24-3.31(m,4H),2.86-2.91(m,3H),2.44-2.47(m,2H).

[0292] Example 17: Preparation of (1s,3s)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid

[0293] [ka]

[0294] To a solution of ethyl (1s,3s)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (70 mg, 0.15 mmol, 1.0 equiv) in MeOH / HO (9 mL / 3 mL) was added LiOH (10.8 mg, 0.45 mmol, 3.0 equiv). The mixture was stirred at 50 °C for 1 hour and then concentrated in vacuo. The mixture was adjusted to pH 5 with 37% HCl, and the solid was filtered and further purified by preparative HPLC to give (1s,3s)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid as a white solid (24.0 mg, 36.5%). LCMS (M+H + )m / z 428.2, calculatedfound 428.1. 1 H NMR(DMSO-d6,400MHz) δ 8.49(d,1H),8.29-8.31(m,2H),8.16-8.19(m,2H),8.05(d,1H),7.76-7.78(dd,1H),7. 51-7.58(m,3H),6.37(s,2H),4.71-4.75(m,1H),2.69-2.78(m,3H),2.54-2.57(m,2H).

[0295] Example 18: Preparation of 5-amino-1-((1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0296] [ka]

[0297] A solution of ((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (140 mg, 0.27 mmol, 1.0 equiv.) and azetidine (145 mg, 2.7 mmol, 10.0 equiv.) in DMA (5.0 mL) was stirred at 100° C. for 4 h, then quenched with HO (20.0 mL) and extracted with DCM / MeOH (10 / 1, 20 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-1-((1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a yellow solid (50 mg, 45.2%). LRMS (M+H + )m / z 435.2, calculatedfound 435.1.

[0298] [ka]

[0299] A mixture of 5-amino-1-((1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (20 mg, 0.04 mmol, 1.0 equiv) in HSO (2.0 mL) was stirred at room temperature for 12 h, then quenched with HO (20.0 mL) and saturated aqueous NaCO was added to adjust pH = 8.0. The mixture was extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography, eluting with 10% to 80% MeCN in HO, to give 5-amino-1-((1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (1.1 mg, 5.2%). LRMS (M+H) + )m / z 453.2, calculatedfound 453.2. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.29-8.31(m,2H),8.17-8.20(m,2H),8.07(d,1H),7.77(d,1H),7.52-7.59(m,3H),6.27( s,2H),4.67-4.71(m,1H),2.67-2.68(m,1H),2.33-2.38(m,6H),2.21-2.25(m,3H),1.98-2.08(m,3H).

[0300] Example 19: Preparation of 5-amino-1-((1s,3s)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0301] [ka]

[0302] A solution of ((1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (130 mg, 0.24 mmol, 1.0 equiv) and 1-methylpiperazine (118.4 mg, 1.2 mmol, 5.0 equiv) in DMA (5.0 mL) was stirred at 100° C. for 4 h, then quenched with HO (50.0 mL) and extracted with DCM / MeOH (10 / 1, 20 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-1-((1s,3s)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow oil (90 mg, 79.6%). LRMS (M+H + )m / z 478.3, calculatedfound 478.4.

[0303] [ka]

[0304] A mixture of 5-amino-1-((1s,3s)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (40 mg, 0.08 mmol, 1.0 equiv) in concentrated HSO (1.0 mL) was stirred at room temperature for 12 h, then quenched with HO (20.0 mL) and the mixture was adjusted to pH 8.0 by the addition of saturated aqueous NaCO solution. The mixture was extracted with DCM:MeOH (10:1, 50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-((1s,3s)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (21.7 mg, 52.3%). LRMS (M+H + )m / z 496.3, calculatedfound 496.3. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.30-8.32(m,2H),8.17-8.19(m,2H),8.06(d,1H),7.77(d,1H),7.52-7.59(m,3H),6. 26(s,2H),4.69-4.71(m,1H),2.49-2.51(m,3H),2.36-2.42(m,7H),2.13-2.35(m,5H),2.14(s,3H).

[0305] Example 20: Preparation of ethyl (1r,3r)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate

[0306] [ka]

[0307] To a solution of ethyl 1-methyl-3-oxocyclobutane-1-carboxylate (5.0 g, 32.1 mmol, 1.0 equiv.) in hexane (80 mL) was added tert-butyl hydrazine carboxylate (5.1 g, 38.4 mmol, 1.2 equiv.) at room temperature. The mixture was stirred at 80° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give tert-butyl 2-(3-(ethoxycarbonyl)-3-methylcyclobutylidene)hydrazine-1-carboxylate (5 g, 58.1%) as a white solid. LRMS (M+H) + )m / z 271.2, calculatedfound 271.1.

[0308] [ka]

[0309] To a stirred solution of tert-butyl 2-(3-(ethoxycarbonyl)-3-methylcyclobutylidene)hydrazine-1-carboxylate (5 g, 18.4 mmol, 1.0 equiv) and NaBHCN (2.3 g, 36.7 mmol, 2.0 equiv) in MeOH (50 mL) / THF (50 mL) was added AcOH (0.6 mL, 9.2 mmol, 0.5 equiv) at room temperature. The reaction mixture was stirred for 16 hours at 70° C., then cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=40:1, v / v) to give tert-butyl 2-(3-(ethoxycarbonyl)-3-methylcyclobutyl)hydrazine-1-carboxylate (4.9 g, approximately 100%) as a white solid. LRMS (M+H + )m / z 273.2, calculatedfound 273.1

[0310] [ka]

[0311] To a stirred solution of tert-butyl 2-(3-(ethoxycarbonyl)-3-methylcyclobutyl)hydrazine-1-carboxylate (4.9 g, 18.0 mmol, 1.0 equiv) in DCM (30 mL) was added 4N HCl / dioxane (30 mL). The reaction was stirred for 30 minutes at 30° C. and then concentrated in vacuo to give ethyl 3-hydrazinyl-1-methylcyclobutane-1-carboxylate (4 g, approx. 100%) as a white solid. LRMS (M+H + )m / z 173.1, calculatedfound 173.0.

[0312] [ka]

[0313] To a solution of 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (3.0 g, 9.7 mmol, 1.0 equiv.) and ethyl 3-hydrazinyl-1-methylcyclobutane-1-carboxylate (2.5 g, 14.5 mmol, 1.5 equiv.) in EtOH (30 mL) was added TEA (10.7 mL, 77.5 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give ethyl (1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate (45 mg, 1.1%) and ethyl (1r,3r)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate (600 mg, 13.9%) as a white solid. Ethyl (1s,3s)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate:1 H NMR(DMSO-d6,400MHz) δ 8.54(s,1H),8.50(d,1H),8.30-8.32(m,2H),8.19(d,1H),8.05-8.12(m,2H),7.51-7.61(m,3H),6.88(s,2H) ),4.99-5.04(m,1H),4.16(q,2H),2.93-2.98(m,2H),2.31-2.37(m,2H),1.48(s,3H),1.26(t,3H).LRMS(M+H + ) m / z calculated 452.2, found 452.1. Ethyl (1r,3r)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate: 1 H NMR(DMSO-d6,400MHz) δ 8.56(s,1H),8.50(d,1H),8.29-8.32(m,2H),8.19(d,1H),8.11-8.12(m,2H),7.53-7.61(m,3H),6.85(s,2H) ),4.88-4.93(m,1H),4.18(q,2H),2.86-2.93(m,2H),2.55-2.61(m,2H),1.50(s,3H),1.26(t,3H).LRMS(M+H + )m / z 452.2, calculatedfound 452.1.

[0314] [ka]

[0315] Ethyl (1r,3r)-3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate (100 mg, 0.22 mmol, 1.0 equiv) was added to concentrated HSO (5 mL) at room temperature, and the mixture was stirred for 2 hours. It was then slowly poured onto ice, adjusted to pH 7 by adding saturated NaHCO solution, and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give ethyl (1r,3r)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate (23.8 mg, 23.1%) as a white solid. LRMS(M+H + )m / z 470.2, calculatedfound 470.2. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.30(d,2H),8.22(s,1H),8.18(d,1H),8.06(d,1H),7.79(dd,1H),7.51-7.59(m,3H),6.31 (s,2H),4.85-4.90(m,1H),4.17(q,2H),2.83-2.89(m,2H),2.52-2.58(m,2H),1.44(s,3H),1.26(t,3H).

[0316] Example 21: Preparation of 5-amino-1-((1r,3r)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0317] [ka]

[0318] To a solution of 5-amino-1-((1r,3r)-3-formylcyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (160 mg, 0.41 mmol, 1.0 equiv.) and 1-methylpiperazine (48.8 mg, 0.49 mmol, 1.2 equiv.) in DCE (35 mL) was added NaBH(OAc) (172 mg, 0.81 mmol, 2.0 equiv.). The mixture was stirred for 3 h at 25 °C and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=20 / 1, v / v) to give 5-amino-1-((1r,3r)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a yellow solid (110 mg, 56.6%). LRMS (M+H + )m / z 474.3, calculatedfound 474.2.

[0319] [ka]

[0320] A solution of 5-amino-1-((1r,3r)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (110 mg, 0.23 mmol, 1.0 equiv) in concentrated H2SO4 (3 mL) was stirred for 15 h at 25 °C, after which saturated aqueous sodium carbonate solution was added to adjust pH = 8. The mixture was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-((1r,3r)-3-((4-methylpiperazin-1-yl)methyl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (26.4 mg, 23.2%). LRMS (M+H + )m / z 496.3, calculatedfound 496.3.1 H NMR(DMSO-d6,400MHz) δ 8.49(d,1H),8.29-8.31,(m,2H),8.16-8.21,(m,2H),8.05(d,1H),7.79(dd,1H),7.49-7.59(m,3H),6.26 (s,2H),4.94-4.98(m,1H),2.63-2.65(m,2H),2.48-2.49,(m,4H),2.24-2.37(m,7H),2.11-2.15(m,5H).

[0321] Example 22: Preparation of (1r,3r)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylic acid

[0322] [ka]

[0323] A solution of ethyl (1r,3r)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylate (22 mg, 0.046 mmol, 1.0 equiv.) and LiOH (1.5 mg, 0.07 mmol, 1.5 equiv.) in MeOH / HO (20 mL / 5 mL) was stirred for 5 hours at 30° C., then the pH was adjusted to 5 with 37% HCl and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give (1r,3r)-3-(5-amino-4-carbamoyl-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)-1-methylcyclobutane-1-carboxylic acid (14.4 mg, 70.0%) as a yellow solid. LRMS (M+H + )m / z 442.2, calculatedfound 442.1. 1H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.30(d,2H),8.21(s,1H),8.17(d,1H),8.06(d,1H),7.79(dd,1H),7.49-7.60 (m,3H),6.28(s,2H),4.82-4.87(m,1H),2.74-2.80(m,2H),2.27-2.32(m,2H),1.30(s,3H).

[0324] Example 23: Preparation of 5-amino-1-(3-morpholinocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0325] [ka]

[0326] To a stirred mixture of 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (400 mg, 1.3 mmol, 1.0 equiv.) and K2CO3 (107.6 mg, 0.8 mmol, 0.6 equiv.) in DMF (5.0 mL), 3-bromocyclobutan-1-one (211.6 mg, 1.4 mmol, 1.1 equiv.) was added under ice bath. The mixture was stirred at room temperature for 4 hours, then quenched with HO (20.0 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow oil (200 mg, 41.1%). LRMS (M+H + )m / z 380.1, calculatedfound 380.1.

[0327] [ka]

[0328] To a stirred solution of 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.5 mmol, 1.0 equiv.), AcOH (45.0 mg, 0.8 mmol, 1.5 equiv.), and morpholine (130.5 mg, 1.5 mmol, 3.0 equiv.) in DCM (5 mL) was added NaBHCN (64 mg, 1.0 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 4 h, then quenched with HO (20.0 mL), and the mixture was extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-1-(3-morpholinocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow solid (100 mg, 42.2%). + )m / z 451.2, calculatedfound 451.2.

[0329] [ka]

[0330] A mixture of 5-amino-1-(3-morpholinocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (100 mg, 0.2 mmol, 1.0 equiv.) in concentrated HSO (1.0 mL) was stirred at room temperature for 12 hours, then quenched with HO (20.0 mL), and the mixture was adjusted to pH 8.0 by the addition of saturated aqueous NaCO. The mixture was extracted with DCM / MeOH (10 / 1, 20 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-(3-morpholinocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (61.4 mg, 59.0%). LRMS (M+H +)m / z 469.2, calculatedfound 469.1. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.30-8.31(m,2H),8.17-8.19(m,2H),8.06(d,1H),7.77(m,1H),7.52-7.60(m,3 H),6.30-6.32(s,2H),4.55-4.59(m,1H),3.58(d,4H),2.50-2.51(m,3H),2.30-2.39(m,6H).

[0331] Example 24: Preparation of 5-amino-1-isopropyl-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0332] [ka]

[0333] To a stirred solution of 2-(methoxy(2-phenylquinolin-7-yl)methylene)malononitrile (550 mg, 1.8 mmol, 1.0 equiv.) and TEA (545.4 mg, 5.4 mmol, 3.0 equiv.) in EtOH (10.0 mL) was added isopropylhydrazine hydrochloride (396 mg, 3.6 mmol, 2.0 equiv.). The mixture was stirred under reflux for 2 h, then quenched with HO (20.0 mL) and extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layers were concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-1-isopropyl-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow solid (450.0 mg, 72.1%). LRMS (M+H + )m / z 354.2, calculatedfound 354.2.

[0334] [ka]

[0335] A mixture of 5-amino-1-isopropyl-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.57 mmol, 1.0 equiv.) in HSO (1 mL) was stirred at room temperature for 12 hours, then quenched with HO (20.0 mL). The mixture was adjusted to pH 8.0 by the addition of saturated aqueous NaCO, and then extracted with DCM / MeOH (10 / 1, 30 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-isopropyl-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (94.4 mg, 45.0%). LRMS (M+H + )m / z 372.2, calculatedfound 372.1. 1 H NMR(DMSO-d6,400MHz) δ 8.48-8.50(d,1H),8.23(d,2H),8.16-8.18(m,2H),8.04(d,1H),7.77(d,1 H),7.51-7.59(m,3H),6.28(s,2H),4.52-4.55(m,1H),1.38-1.40(m,6H).

[0336] Example 25: Preparation of 5-amino-3-(2-phenylquinolin-7-yl)-1-(3-(piperazin-1-yl)cyclobutyl)-1H-pyrazole-4-carboxamide

[0337] [ka]

[0338] To a solution of 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (100 mg, 0.26 mmol, 1.0 equiv.) in DCM (20 mL) was added NaBHCN (24.9 mg, 0.40 mmol, 1.5 equiv.), AcOH (23.7 mg, 0.40 mmol, 1.5 equiv.), and tert-butyl piperazine-1-carboxylate (147.2 mg, 0.79 mmol, 3.0 equiv.). The mixture was stirred at 20 °C for 3 h, then quenched with water and concentrated in vacuo. The resulting residue was diluted with HO (20 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO, PE / EA=1 / 1, v / v) to give tert-butyl 4-(3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)piperazine-1-carboxylate (60 mg, 41.3%) as a yellow solid. LRMS (M+H + )m / z 550.3, calculatedfound 550.2.

[0339] [ka]

[0340] Tert-butyl 4-(3-(5-amino-4-cyano-3-(2-phenylquinolin-7-yl)-1H-pyrazol-1-yl)cyclobutyl)piperazine-1-carboxylate (60 mg, 0.11 mmol, 1.0 equiv) was added to concentrated HSO (5 mL) at room temperature. The mixture was stirred at room temperature for 3 hours, then slowly poured onto ice, adjusted to pH 7 by adding saturated NaHCO (aq), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-phenylquinolin-7-yl)-1-(3-(piperazin-1-yl)cyclobutyl)-1H-pyrazole-4-carboxamide (21.9 mg, 43.1%) as a white solid. LRMS (M+H): + )m / z 468.2, calculatedfound 468.1. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.31(d,2H),8.19(s,1H),8.18(d,1H),8.05(d,1H),7.77(dd,1H),7.49-7.59(m, 3H),6.31(s,2H),4.53-4.57(m,1H),2.63-2.68(m,4H),2.33-2.49(m,5H),2.19-2.22(m,4H).

[0341] Example 26: Preparation of 5-amino-1-(3-(4-methylpiperazin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0342] [ka]

[0343] To a solution of 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (100 mg, 0.26 mmol, 1.0 equiv.) in DCM (20 mL) was added NaBHCN (24.9 mg, 0.40 mmol, 1.5 equiv.), AcOH (23.7 mg, 0.40 mmol, 1.5 equiv.), and 1-methylpiperazine (79.1 mg, 0.79 mmol, 3.0 equiv.). The mixture was stirred for 3 h at 30 °C, then quenched with water and concentrated in vacuo. The resulting residue was diluted with HO (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (SiO2, PE / EA = 1 / 1, v / v) to give 5-amino-1-(3-(4-methylpiperazin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (70 mg, 57.3%) as a yellow solid. LRMS (M+H + )m / z 464.2, calculatedfound 464.1.

[0344] [ka]

[0345] 5-Amino-1-(3-(4-methylpiperazin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (60 mg, 0.11 mmol, 1.0 equiv) was added to concentrated HSO (5 mL), and the mixture was stirred at room temperature for 3 hours, then slowly poured onto ice, adjusted to pH 7 with saturated NaHCO (aq), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-(3-(4-methylpiperazin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (12.6 mg, 43.1%) as a white solid. LRMS (M+H): + )m / z 482.3, calculatedfound 482.2. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.30(d,2H),8.19(s,1H),8.18(d,1H),8.04(d,1H),7.77(dd,1H),7.49-7.59( m,3H),6.31(s,2H),4.51-4.60(m,1H),2.50-2.52(m,2H),2.31-2.41(m,11H),2.14(s,3H).

[0346] Example 27: Preparation of 5-amino-1-(3-(azetidin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0347] [ka]

[0348] To a stirred solution of 5-amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (200 mg, 0.5 mmol, 1.0 equiv.), AcOH (45.0 mg, 0.8 mmol, 1.5 equiv.), and azetidine (85.5 mg, 1.5 mmol, 3.0 equiv.) in DCM (5 mL) was added NaBHCN (64 mg, 1.0 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 4 h, then quenched with HO (20.0 mL), and the mixture was extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-1-(3-(azetidin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a pale yellow oil (50 mg, 22.5%). LRMS (M+H + )m / z 421.2, calculatedfound 421.2.

[0349] [ka]

[0350] A mixture of 5-amino-1-(3-(azetidin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (50 mg, 0.1 mmol, 1.0 equiv) in concentrated HSO (1.0 mL) was stirred at room temperature for 12 hours, then quenched with HO (20.0 mL), and the mixture was adjusted to pH 8.0 by the addition of saturated aqueous NaCO. The mixture was extracted with DCM / MeOH (10 / 1, 20 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford 5-amino-1-(3-(azetidin-1-yl)cyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (3.6 mg, 6.9%). LRMS(M+H +)m / z 439.2, calculatedfound 439.1. 1 H NMR(DMSO-d6,400MHz) δ 8.51(d,1H),8.29-8.31(m,2H),8.17-8.20(m,2H),8.06(d,1H),7.78(dd,1H),7.52-7.59(m,3H),6.30(s,2H),4 .50-4.55(m,1H),3.27-3.32(m,3H),3.18-3.19(m,1H),2.67-2.68(m,1H),2.33-2.46(m,4H),1.93-1.97(m,2H).

[0351] Example 28: Preparation of 5-amino-3-(8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0352] [ka]

[0353] A solution of 3-bromo-2-fluoroaniline (10 g, 52.9 mmol, 1.0 equiv.) and benzaldehyde (257 g, 2.40 mol, 1.2 equiv.) in toluene (1.5 L) was stirred at 150° C. for 16 hours. The reaction mixture was concentrated to dryness in vacuo to give N-(3-bromo-2-fluorophenyl)-1-phenylmethanimine (7.5 g, 51.3%) as a yellow oil, which was used in the next step without further purification. LRMS (M+H) + )m / z 278.0, calculatedfound 278.0. 1 H NMR (DMSO-d6,400MHz) δ 8.68(s,1H),7.95-7.98(m,2H),7.52-7.62(m,4H),7.32(t,1H),7.20(t,1H).

[0354] [ka]

[0355] A solution of N-(3-bromo-2-fluorophenyl)-1-phenylmethanimine (7 g, 25.2 mmol, 1.0 equiv.) and ethoxyethene (9.1 g, 125.9 mol, 5.0 equiv.) in TFE (100 mL) was stirred for 16 h at 35° C. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EA=10 / 1, v / v) to give 7-bromo-8-fluoro-2-phenyl-1,2-dihydroquinoline (2.8 g, 37.8%) as a yellow solid. LRMS (M+H) + )m / z 304.0, calculatedfound 304.0.

[0356] [ka]

[0357] A suspension of 7-bromo-8-fluoro-2-phenyl-1,2-dihydroquinoline (2.8 g, 9.5 mmol, 1.0 equiv.) and MnO (16.5 g, 190.1 mol, 5.0 equiv.) in DCM (50 mL) was stirred for 12 h at 35 °C. The reaction mixture was filtered, and the filtrate was concentrated in vacuo and purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give 7-bromo-8-fluoro-2-phenylquinoline (1.2 g, 42.8%) as a yellow solid. LRMS (M+H) + )m / z 302.0, calculatedfound 302.0.

[0358] [ka]

[0359] To a solution of 7-bromo-8-fluoro-2-phenylquinoline (500 mg, 1.7 mmol, 1.0 equiv.), DPPP (136.4 mg, 0.33 mmol, 0.2 equiv.), and Pd(OAc)2 (37.1 mg, 0.16 mmol, 0.1 equiv.) in DMSO / MeOH (300 mL / 300 mL) was added TEA (40 mL, 289.8 mmol, 3.0 equiv.). The mixture was stirred at 80°C under CO2 (1 atm) for 15 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl 8-fluoro-2-phenylquinoline-7-carboxylate (100 mg, 21.5%) as a yellow oil. LRMS (M+H) + )m / z 282.1, calculatedfound 282.1.

[0360] [ka]

[0361] To a solution of methyl 8-fluoro-2-phenylquinoline-7-carboxylate (100 mg, 0.36 mmol, 1.0 equiv.) in MeOH (30 mL) and HO (5 mL) was added NaOH (21.4 mg, 0.53 mmol, 1.5 equiv.). The mixture was stirred for 5 hours at 50° C., then concentrated in vacuo, diluted with water (20 mL), and adjusted to pH 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 8-fluoro-2-phenylquinoline-7-carboxylic acid (80 mg, 84.2%) as a white solid. LRMS (M+H + )m / z 268.1, calculatedfound 268.1.

[0362] [ka]

[0363] To a solution of 8-fluoro-2-phenylquinoline-7-carboxylic acid (80 mg, 0.30 mmol, 1.0 equiv) in DCM (10 mL) was added (COCl) (0.13 mL, 1.5 mmol, 5.0 equiv) and DMF (1 drop) at -78 °C. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 8-fluoro-2-phenylquinoline-7-carbonyl chloride as a yellow solid (95 mg, ca. 100.0%). LRMS (M+H + )m / z 282.1, calculatedfound 282.1 in MeOH.

[0364] [ka]

[0365] To a solution of 8-fluoro-2-phenylquinoline-7-carbonyl chloride (95 mg, 0.33 mmol, 1.0 equiv.) in THF (10 mL) was added malononitrile (22.0 mg, 0.33 mmol, 1.0 equiv.) and DIEA (0.2 mL, 1.0 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-(8-fluoro-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (60 mg, 54.5%). LRMS (M+H + )m / z 316.1, calculatedfound 316.1.

[0366] [ka]

[0367] To a solution of 2-(8-fluoro-2-phenylquinoline-7-carbonyl)malononitrile (60 mg, 0.19 mmol, 1.0 equiv.) in THF (10 mL) was added MeSO (48.0 mg, 0.38 mmol, 2.0 equiv.) and DIEA (49.1 mg, 0.38 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 hours, then concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-((8-fluoro-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (40 mg, 63.5%). LRMS (M+H + )m / z 330.1, calculatedfound 330.1.

[0368] [ka]

[0369] To a solution of 2-((8-fluoro-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (40 mg, 0.12 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (21.2 mg, 0.18 mmol, 1.5 equiv.) in EtOH (20 mL), TEA (0.2 mL, 0.97 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was stirred at 90 °C for 2 hours, after which the mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 5-amino-3-(8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (30 mg, 60.0%) as a yellow solid. LRMS(M+H + )m / z 414.2, calculatedfound 414.2.

[0370] [ka]

[0371] To a stirred solution of 5-amino-3-(8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (30 mg, 0.07 mmol, 1.0 equiv) and KCO (30.1 mg, 0.22 mmol, 3.0 equiv) in DMSO (10 mL) at room temperature was added HO (30%, 164.7 mg, 1.5 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred for 1 h at 60 °C. Water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-3-(8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (5.4 mg, 17.2%) as a white solid. LRMS (M+H + )m / z 432.2, calculatedfound 432.1. 1 H NMR(DMSO-d6,400MHz) δ 8.57(d,1H),8.27-8.33(m,3H),7.89(d,1H),7.51-7.63(m,4H),6.32(s,2H),5. 18(s,1H),4.45-4.50(m,1H),2.55-2.61(m,2H),2.36-2.41(m,2H),1.34(s,3H).

[0372] Example 29: Preparation of 5-amino-1-(oxetan-3-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0373] [ka]

[0374] To a stirred mixture of 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (400 mg, 1.3 mmol, 1.0 equiv) and KCO (107.6 mg, 0.8 mmol, 0.6 equiv) in DMF (5.0 mL) was added 3-iodooxetane (260.3 mg, 1.4 mmol, 1.1 equiv) at 0 °C. The mixture was stirred for 4 h at 35 °C, then quenched with HO (20.0 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-1-(oxetan-3-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile as a yellow oil (220 mg, 46.6%). + )m / z 368.1,calculatedfound 368.1.

[0375] [ka]

[0376] To a stirred solution of 5-amino-1-(oxetan-3-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (30 mg, 0.22 mmol, 1.0 equiv.) and KCO (90.2 mg, 0.65 mmol, 3.0 equiv.) in DMSO (10 mL) at room temperature was added HO (30%, 494.1 mg, 4.4 mmol, 20.0 equiv.). After the addition was complete, the reaction mixture was stirred for 2 h at 60 °C. Water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-1-(oxetan-3-yl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (15.4 mg, 18.3%) as a white solid. LRMS (M+H + )m / z 386.2, calculatedfound 386.0.1 H NMR(DMSO-d6,400MHz) δ 8.51(d,1H),8.29-8.32(m,2H),8.25(s,1H),8.19(d,1H),8.07(d,1H),7.82(dd,1H),7.5 0-7.60(m,3H),6.35(s,2H),6.05(brs,1H),5.58-5.62(m,1H),5.01(t,2H),4.88(t,2H).

[0377] Example 30: Preparation of 5-amino-1-(3,3-difluorocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0378] [ka]

[0379] 5-Amino-1-(3-oxocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (250 mg, 0.66 mmol, 1.0 equiv) was dissolved in DCM (30 mL) and cooled to 0 °C. DAST (531.0 mg, 3.3 mmol, 5.0 equiv) was added dropwise, and the reaction mixture was stirred at 35 °C for 1 h. The reaction mixture was quenched with water, neutralized to pH 7 with saturated aqueous sodium bicarbonate, and extracted with DCM (30 mL × 3). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give 5-amino-1-(3,3-difluorocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (160 mg, 60.6%) as a yellow solid. LRMS (M+H + )m / z 402.1, calculatedfound 402.0.

[0380] [ka]

[0381] 5-Amino-1-(3,3-difluorocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (80 mg, 0.20 mmol, 1.0 equiv) was added to concentrated HSO (5 mL), and the mixture was then stirred at 35 °C for 12 hours, then slowly poured onto ice, adjusted to pH 7 with saturated NaHCO (aq), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-(3,3-difluorocyclobutyl)-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (45.2 mg, 53.5%) as a white solid. LRMS (M+H): + )m / z 420.2, calculatedfound 420.0. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.29-8.32(m,2H),8.22(s,1H),8.18(d,1H),8.06(d,1H),7.78( dd,1H),7.49-7.59(m,3H),6.44(s,2H),4.87-4.92(m,1H),3.06-3.25(m,4H).

[0382] Example 31: Preparation of 2-(2-phenylquinolin-7-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide

[0383] [ka]

[0384] To a solution of 5-amino-3-(2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (120 mg, 0.39 mmol, 1.0 equiv.) in EtOH (10 mL) was added ethyl 2-formyl-3-oxopropanoate (61.1 mg, 0.42 mmol, 1.1 equiv.) and HOAc (5 drops). After stirring for 16 h at 25 °C, the mixture was filtered, washed with HO (10 mL), and dried in vacuo to give ethyl 3-cyano-2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (130 mg, 81.2%) as a yellow solid. LRMS (M+H) + )m / z 420.1, calculatedfound 420.0.

[0385] [ka]

[0386] Ethyl 3-cyano-2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (130 mg, 0.31 mmol, 1.0 equiv) was added to concentrated HSO (5 mL), and the mixture was stirred for 3 hours at 25 °C. It was then slowly poured onto ice, adjusted to pH 7 with saturated NaHCO solution, and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give ethyl 3-carbamoyl-2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (90 mg, 66.6%) as a yellow solid. LRMS (M+H) + )m / z 438.1, calculatedfound 438.0.

[0387] [ka]

[0388] Ethyl 3-carbamoyl-2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (75 mg, 0.17 mmol, 1.0 equiv) was added to concentrated HCl (15 mL) and the mixture was stirred for 15 hours at 50°C. The reaction mixture was concentrated in vacuo to give 3-carbamoyl-2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (40 mg, 57.1%) as a yellow solid. LRMS (M+H) + )m / z 410.1, calculatedfound 410.0.

[0389] [ka]

[0390] To a solution of 3-carbamoyl-2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (40 mg, 0.10 mmol, 1.0 equiv.), NH4Cl (52.8 mg, 1.0 mmol, 10.0 equiv.), and HATU (55.7 mg, 0.15 mmol, 1.5 equiv.) in DMF (10 mL) was added DIEA (63.1 mg, 0.50 mmol, 5.0 equiv.), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL), extracted with DCM (50 mL × 2), and washed with water (50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide as a yellow solid (15 mg, 37.5%). + )m / z 409.1, calculatedfound 409.0.

[0391] [ka]

[0392] To a solution of 2-(2-phenylquinolin-7-yl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide (15 mg, 0.037 mmol, 1.0 equiv.) in DCM (5 mL) and MeOH (5 mL) was added NaBH (14.0 mg, 0.37 mmol, 10.0 equiv.). After stirring for 16 h at room temperature, the mixture was partitioned between DCM / MeOH (50 mL / 3 mL) and brine (30 mL). The organic layer was dried over NaSO and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 2-(2-phenylquinolin-7-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide (5.1 mg, 34.0%) as a white solid. LRMS (M+H) + )m / z 413.2, calculatedfound 413.1. 1 H NMR(DMSO-d6,400MHz) δ 8.48(d,1H),8.28-8.31(m,2H),8.20(s,1H),8.17(d,1H),8.03(d,1H),7.77(dd,1H),7.51 -7.59(m,3H),4.20-4.25(m,1H),4.06-4.12(m,1H),3.46-3.57(m,2H),2.96-2.99(m,1H).

[0393] Example 32: Preparation of 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(4-methoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide

[0394] [ka]

[0395] To a solution of 7-bromo-4-methoxyquinoline (34 g, 143.4 mmol, 1.0 equiv.), DPPP (11.8 g, 28.7 mmol, 0.2 equiv.), and Pd(OAc)2 (3.2 g, 14.3 mmol, 0.1 equiv.) in DMSO / MeOH (1000 mL / 500 mL) was added TEA (59.5 mL, 430.4 mmol, 3.0 equiv.). The mixture was stirred at 80°C under CO2 (1 atm) for 15 h and then concentrated in vacuo. The resulting residue was added to water (300 mL), and the mixture was extracted with EtOAc (550 mL x 3). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 4-methoxyquinoline-7-carboxylate (21.2 g, 67.8%) as a yellow oil. + )m / z 218.1, calculatedfound 218.1.

[0396] [ka]

[0397] To a solution of methyl 4-methoxyquinoline-7-carboxylate (21.2 g, 97.6 mmol, 1.0 equiv.) in DCM (300 mL) was added m-CPBA (42.1 g, 244.2 mmol, 2.5 equiv.) at room temperature. The mixture was stirred for 12 hours at room temperature, then poured onto ice, adjusted to pH 13 with saturated aqueous Na2CO3, and extracted with DCM (500 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-methoxy-7-(methoxycarbonyl)quinoline 1-oxide (15.2 g, 66.8%) as a yellow oil. LRMS (M+H) + )m / z 234.1, calculatedfound 234.2.

[0398] [ka]

[0399] A mixture of 4-methoxy-7-(methoxycarbonyl)quinoline 1-oxide (15.2 g, 65.2 mmol, 1.0 equiv.), POBr3 (28.1 g, 97.8 mmol, 1.5 equiv.), and DMF (2.4 g, 32.6 mmol, 0.5 equiv.) in DCM (500 mL) was stirred at room temperature for 15 h. The mixture was then cooled to room temperature, poured onto ice, and adjusted to pH 12–13 with aqueous Na2CO3. The aqueous layer was extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give methyl 2-bromo-4-methoxyquinoline-7-carboxylate (8.6 g, 44.8%) as a yellow solid. LRMS (M+H) + )m / z 296.0, calculatedfound 297.1.

[0400] [ka]

[0401] To a solution of methyl 2-bromo-4-methoxyquinoline-7-carboxylate (8.6 g, 29.0 mmol, 1.0 equiv.) in dioxane (300 mL) was added phenylboronic acid (7.1 g, 58.1 mmol, 2.0 equiv.), Pd(PPh3)4 (3.4 g, 2.9 mmol, 0.1 equiv.), and Cs2CO3 (18.9 g, 58.0 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 15 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 4-methoxy-2-phenylquinoline-7-carboxylate (11 g, approximately 100%) as a white solid. +)m / z 294.1, calculatedfound 294.1.

[0402] [ka]

[0403] To a solution of methyl 4-methoxy-2-phenylquinoline-7-carboxylate (11 g, 37.5 mmol, 1.0 equiv.) in MeOH (300 mL) and HO (50 mL) was added NaOH (2.3 g, 56.3 mmol, 1.5 equiv.). The mixture was stirred for 5 h at 50 °C, then concentrated in vacuo and diluted with water (100 mL). The pH was adjusted to 2 by adding 37% HCl. The resulting mixture was stirred for 5 min, filtered, and dried to give 4-methoxy-2-phenylquinoline-7-carboxylic acid (10 g, 95%) as a white solid. LRMS (M+H + )m / z 280.1, calculatedfound 280.1.

[0404] [ka]

[0405] To a solution of 4-methoxy-2-phenylquinoline-7-carboxylic acid (10 g, 35.8 mmol, 1.0 equiv) in DCM (100 mL) was added (COCl) (9.1 mL, 107.5 mmol, 3.0 equiv) and DMF (0.1 mL) at -78 °C. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 4-methoxy-2-phenylquinoline-7-carbonyl chloride as a yellow solid (12.5 g, ca. 100.0%). LRMS (M+H + )m / z 294.1, calculatedfound 294.1 in MeOH.

[0406] [ka]

[0407] To a solution of 4-methoxy-2-phenylquinoline-7-carbonyl chloride (12.5 g, 41.9 mmol, 1.0 equiv.) in THF (200 mL) was added malononitrile (2.8 g, 41.9 mmol, 1.0 equiv.) and DIEA (21.9 mL, 125.8 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and diluted with water (200 mL). The resulting mixture was extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-(4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (11.6 g, 84%). LRMS(M+H + )m / z 328.1, calculatedfound 328.1.

[0408] [ka]

[0409] To a solution of 2-(4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile (11.6 g, 35.3 mmol, 1.0 equiv.) in THF (100 mL) was added MeSO (8.9 g, 70.7 mmol, 2.0 equiv.) and DIEA (18.5 mL, 106.1 mmol, 3.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (200 mL), and extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-(methoxy(4-methoxy-2-phenylquinolin-7-yl)methylene)malononitrile as a yellow oil (4.8 g, 34%). LRMS(M+H + )m / z 342.1, calculatedfound 342.1.

[0410] [ka]

[0411] To a solution of 2-(methoxy(4-methoxy-2-phenylquinolin-7-yl)methylene)malononitrile (800 mg, 2.3 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (408.2 mg, 3.5 mmol, 1.5 equiv.) in MeOH (50 mL), TEA (2.6 mL, 18.7 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was stirred at 90 °C for 2 hours, and then the mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(4-methoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (800 mg, 80.0%) as a yellow solid. LRMS(M+H + )m / z 426.2, calculatedfound 426.2.

[0412] [ka]

[0413] To a stirred solution of 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(4-methoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (800 mg, 1.9 mmol, 1.0 equiv) and KCO (779.3 mg, 5.6 mmol, 3.0 equiv) in DMSO (50 mL) was added HO (30%, 3.0 mL, 37.6 mmol, 20.0 equiv) at room temperature. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by preparative HPLC to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(4-methoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (464.2 mg, 56%) as a white solid. LRMS (M+H + )m / z 444.2, calculatedfound 444.2. 1 H NMR(DMSO-d6,400MHz) δ 8.31(d,2H),8.17(d,1H),8.14(s,1H),7.15(dd,1H),7.48-7.57(m,4H),6.30(s,2H),5.20 (s,1H),4.44-4.49(m,1H),4.19(s,3H),2.59-2.64(m,2H),2.36-2.41(m,2H),1.34(s,3H).

[0414] Example 33: Preparation of 5-amino-3-(4-ethoxy-8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0415] [ka]

[0416] To a solution of 3-bromo-2-fluoroaniline (25.0 g, 132.2 mmol, 1.0 equiv.) in Tol (300 mL) was added ethyl 3-oxo-3-phenylpropanoate (25.4 g, 132.2 mmol, 1.0 equiv.) at room temperature. The mixture was stirred at 120° C. for 15 hours. The mixture was cooled to room temperature and diluted with PE (500 mL). The precipitate was filtered and dried under vacuum to give 3-((3-bromo-2-fluorophenyl)imino)-3-phenylpropanoic acid (7 g, 15.9%) as a yellow solid. LRMS (M+H) + )m / z 336.0, calculatedfound 336.1.

[0417] [ka]

[0418] A mixture of 3-((3-bromo-2-fluorophenyl)imino)-3-phenylpropanoic acid (15 g, 44.6 mmol, 1.0 equiv) and PhO (150 mL) was stirred for 1 h at 240 °C. The mixture was cooled to room temperature and diluted with PE (200 mL). The precipitate was filtered and dried to give 7-bromo-8-fluoro-2-phenylquinolin-4(1H)-one (3 g, 21.1%) as a brown solid. LRMS (M+H) + )m / z 318.0, calculatedfound 318.1.

[0419] [ka]

[0420] To a solution of 7-bromo-8-fluoro-2-phenylquinolin-4(1H)-one (8 g, 25.2 mmol, 1.0 equiv.) in MeCN (120 mL) was added POBr (14.4 g, 50 mmol, 2.0 equiv.). The mixture was stirred at 100 °C for 2 h. The mixture was then cooled to room temperature, poured onto ice, adjusted to pH 13 with saturated aqueous NaCO solution, and extracted with DCM (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give 4,7-dibromo-8-fluoro-2-phenylquinoline (6 g, 62.3%) as a yellow solid. LRMS (M+H) + )m / z 381.9,calculatedfound 381.9.

[0421] [ka]

[0422] A mixture of 4,7-dibromo-8-fluoro-2-(2-fluorophenyl)quinoline (970 mg, 2.4 mmol, 1.0 equiv.), EtONa (216.0 mg, 3.2 mmol, 1.3 equiv.), and EtOH (30 mL) was stirred at reflux for 15 hours. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give 7-bromo-4-ethoxy-8-fluoro-2-phenylquinoline (420 mg, 51%) as a yellow solid. LRMS (M+H) + )m / z 346.0, calculatedfound 346.0.

[0423] [ka]

[0424] To a solution of 7-bromo-4-ethoxy-8-fluoro-2-phenylquinoline (420 mg, 1.2 mmol, 1.0 equiv.), DPPP (200.0 mg, 0.49 mmol, 0.4 equiv.), and Pd(OAc)2 (54.3 mg, 0.24 mmol, 0.2 equiv.) in DMSO / MeOH (100 mL / 100 mL) was added TEA (0.9 mL, 6.1 mmol, 5.0 equiv.). The mixture was stirred at 80 °C under CO2 (1 atm) for 15 h, after which the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give methyl 4-ethoxy-8-fluoro-2-phenylquinoline-7-carboxylate (420 mg, approximately 100%) as a yellow solid. + )m / z 326.1, calculatedfound 326.1.

[0425] [ka]

[0426] To a solution of methyl 4-ethoxy-8-fluoro-2-phenylquinoline-7-carboxylate (420 mg, 1.3 mmol, 1.0 equiv.) in MeOH (30 mL) and HO (3 mL) was added NaOH (77.5 mg, 1.9 mmol, 1.5 equiv.). The mixture was stirred at 80° C. for 15 hours, then concentrated in vacuo, diluted with water (10 mL), and adjusted to pH=2 with 37% aqueous HCl. The resulting mixture was stirred for 5 minutes, filtered, and dried under vacuum to give 4-ethoxy-8-fluoro-2-phenylquinoline-7-carboxylic acid (349 mg, 87%) as a white solid. LRMS (M+H + )m / z 312.1, calculatedfound 312.1.

[0427] [ka]

[0428] To a solution of 4-ethoxy-8-fluoro-2-phenylquinoline-7-carboxylic acid (349 mg, 1.1 mmol, 1.0 equiv) in DCM (30 mL) was added (COCl) (0.5 mL, 5.6 mmol, 5.0 equiv) and DMF (2 drops) at −78° C. The mixture was stirred at room temperature for 7 hours and then concentrated in vacuo to give 4-ethoxy-8-fluoro-2-phenylquinoline-7-carbonyl chloride as a yellow solid (550 mg, ca. 100.0%), which was used directly in the next step. LRMS (M+H + )m / z 326.1, calculatedfound 326.1.

[0429] [ka]

[0430] To a solution of 4-ethoxy-8-fluoro-2-phenylquinoline-7-carbonyl chloride (550 mg, 1.7 mmol, 1.0 equiv.) in THF (70 mL) was added malononitrile (110 mg, 1.7 mmol, 1.0 equiv.) and DIEA (0.9 mL, 5 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours, then concentrated and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-(4-ethoxy-8-fluoro-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (320 mg, 79%). LRMS (M+H + )m / z 360.1, calculatedfound 360.0.

[0431] [ka]

[0432] To a solution of 2-(4-ethoxy-8-fluoro-2-phenylquinoline-7-carbonyl)malononitrile (320 mg, 0.90 mmol, 1.0 equiv) in THF (50 mL) was added MeSO (224.5 mg, 1.8 mmol, 2.0 equiv) and DIEA (574.9 mg, 4.5 mmol, 5.0 equiv). The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((4-ethoxy-8-fluoro-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (110 mg, 33%). LRMS (M+H + )m / z 374.1, calculatedfound 374.1.

[0433] [ka]

[0434] To a solution of 2-((4-ethoxy-8-fluoro-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (110 mg, 0.29 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (41.1 mg, 0.35 mmol, 1.2 equiv.) in MeOH (50 mL) was added TEA (0.33 mL, 2.4 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 80° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-3-(4-ethoxy-8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (40 mg, 30%) as a yellow solid. LRMS (M+H +)m / z 458.2, calculatedfound 458.2.

[0435] [ka]

[0436] To a stirred solution of 5-amino-3-(4-ethoxy-8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (30 mg, 0.065 mmol, 1.0 equiv) in DMSO (20 mL) was added KCO (45.3 mg, 0.33 mmol, 5.0 equiv) and HO (30%, 0.1 mL, 1.3 mmol, 20.0 equiv). After the addition was complete, the mixture was stirred at 60 °C for 2 h, then diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to give 5-amino-3-(4-ethoxy-8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide as a white solid (340.2 mg, 43%). LRMS (M+H + )m / z 476.2, calculatedfound 476.2. 1 H NMR(DMSO-d6,400MHz) δ 8.32(d,2H),7.99(d,1H),7.67(s,1H),7.52-7.60(m,4H),6.34(s,2H),5.21(s,1H) ,4.49-4.53(m,3H),2.54-2.60(m,2H),2.35-2.41(m,2H),1.54(t,3H),1.34(s,3H).

[0437] Example 34: Preparation of 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0438] [ka]

[0439] To a solution of 4,7-dibromo-8-fluoro-2-phenylquinoline (6 g, 15.5 mmol, 1.0 equiv.) in MeOH (100 mL) was added MeONa (1.7 g, 30.1 mmol, 2.0 equiv.). The mixture was stirred at 70° C. for 15 hours. The mixture was concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL×2). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give 7-bromo-8-fluoro-4-methoxy-2-phenylquinoline (4.5 g, 88.2%) as a white solid. LRMS (M+H + )m / z 332.0, calculatedfound 332.0.

[0440] [ka]

[0441] To a solution of 7-bromo-8-fluoro-4-methoxy-2-phenylquinoline (2 g, 6.0 mmol, 1.0 equiv.), DPPP (1 g, 2.4 mmol, 0.4 equiv.), and Pd(OAc) (270 mg, 1.2 mmol, 0.2 equiv.) in DMSO / MeOH (50 mL / 50 mL) was added TEA (9.6 mL, 30 mmol, 5.0 equiv.). The mixture was stirred at 80° C. under CO (1 atm) for 15 hours, after which the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 8-fluoro-4-methoxy-2-phenylquinoline-7-carboxylate (1.3 g, 72.2%) as a white solid. LRMS (M+H + )m / z 312.1, calculatedfound 312.2.

[0442] [ka]

[0443] To a solution of methyl 8-fluoro-4-methoxy-2-phenylquinoline-7-carboxylate (1.3 g, 4.1 mmol, 1.0 equiv.) in MeOH (30 mL) and HO (10 mL) was added NaOH (501 mg, 12.3 mmol, 3.0 equiv.). The mixture was stirred for 15 hours at 50° C., then concentrated in vacuo and diluted with water (60 mL). The mixture was adjusted to pH 2 with 37% aqueous HCl. The resulting mixture was stirred for 5 minutes, filtered, and dried to give 8-fluoro-4-methoxy-2-phenylquinoline-7-carboxylic acid (1.1 g, 90.2%) as a white solid. LRMS (M+H + )m / z 298.1, calculatedfound 298.2.

[0444] [ka]

[0445] To a solution of 8-fluoro-4-methoxy-2-phenylquinoline-7-carboxylic acid (1.1 g, 3.7 mmol, 1.0 equiv.) in DCM (30 mL) was added (COCl) (0.7 mL, 18.5 mmol, 5.0 equiv.) and DMF (5 drops) at 0° C. The mixture was stirred at room temperature for 7 hours and then concentrated in vacuo to give 8-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl chloride (1.3 g, ca. 100%) as a yellow solid, which was used directly in the next step. LRMS (M+H) + )m / z 312.1, calculatedfound 312.2 in MeOH.

[0446] [ka]

[0447] To a solution of 8-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl chloride (1.3 g, 4.1 mmol, 1.0 equiv.) in THF (30 mL) was added malononitrile (817 mg, 12.3 mmol, 3.0 equiv.) and DIEA (3.5 mL, 20.5 mmol, 5.0 equiv.). The mixture was stirred at room temperature for 3 hours, then concentrated and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give 2-(8-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (1.2 g, 82.9%). LRMS (M+H + )m / z 346.1, calculatedfound 346.2.

[0448] [ka]

[0449] To a solution of 2-(8-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile (1.2 g, 3.4 mmol, 1.0 equiv.) in THF (30 mL) was added MeSO (0.9 mL, 17 mmol, 5.0 equiv.) and DIEA (3.1 mL, 34 mmol, 10 equiv.). The mixture was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give 2-((8-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (800 mg, 66.6%). LRMS(M+H + )m / z 360.1, calculatedfound 360.2.

[0450] [ka]

[0451] To a solution of 2-((8-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (800 mg, 2.2 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (384 mg, 3.3 mmol, 1.5 equiv.) in MeOH (20 mL) was added TEA (3.4 mL, 17.2 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours, after which the mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (500 mg, 50.9%) as a white solid. LRMS (M+H +)m / z 444.2, calculatedfound 444.3.

[0452] [ka]

[0453] To a stirred solution of 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (500 mg, 1.12 mmol, 1.0 equiv) and KCO (467 mg, 3.36 mmol, 3.0 equiv) in DMSO (5 mL) at room temperature was added HO (30%, 1.3 mL, 11.2 mmol, 10.0 equiv). The mixture was stirred at 60 °C for 2 hours, then diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (374 mg, 72.4%) as a white solid. LRMS (M+H + )m / z calculated 462.2, 1 H NMR(DMSO-d6,400MHz) δ 8.33(d,2H),7.98(d,1H),7.68(s,1H),7.52-7.59(m,4H),6.32(s,2H),5.19(s,1H) ,4.45-4.50(m,1H),4.21(s,3H),2.55-2.60(m,2H),2.36-2.40(m,2H),1.33(s,3H).

[0454] Example 35: Preparation of 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0455] [ka]

[0456] To a solution of 3-bromo-2-fluoroaniline (50 g, 264.6 mmol, 1.0 equiv.) in toluene (800 mL) was added ethyl 3-(2-fluorophenyl)-3-oxopropanoate (55.6 g, 264.6 mmol, 1.0 equiv.) and p-toluenesulfonic acid (4.6 g, 26.5 mmol, 0.1 equiv.). The reaction mixture was stirred at reflux for 3 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give ethyl 3-((3-bromo-2-fluorophenyl)imino)-3-(2-fluorophenyl)propanoate (8.4 g, 8.4%) as a yellow oil. LRMS (M+H): + )m / z 381.0, calculatedfound 381.1.

[0457] [ka]

[0458] A mixture of ethyl 3-((3-bromo-2-fluorophenyl)imino)-3-(2-fluorophenyl)propanoate (8.4 g, 22.1 mmol, 8.4%) and Eaton's reagent was stirred at 80 °C for 3 h. The mixture was then cooled to room temperature, poured onto ice, and adjusted to pH 12-13 with aqueous Na2CO3. The aqueous phase was extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give 7-bromo-8-fluoro-2-(2-fluorophenyl)quinolin-4(1H)-one (9.4 g, ca. 100%) as a yellow solid. LRMS (M+H) + )m / z 336.0, calculatedfound 336.1.

[0459] [ka]

[0460] A mixture of 7-bromo-8-fluoro-2-(2-fluorophenyl)quinolin-4(1H)-one (9.4 g, 27.9 mmol, 1.0 equiv.), POBr3 (24.1 g, 83.9 mmol, 3.0 equiv.), and MeCN (200 mL) was stirred under reflux for 15 hours. The mixture was cooled to room temperature, poured onto ice, and the pH was adjusted to 12-13 with aqueous Na2CO3. The aqueous phase was extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give 4,7-dibromo-8-fluoro-2-(2-fluorophenyl)quinoline (14.7 g, ca. 100%) as a yellow solid. LRMS (M+H) + )m / z 399.9, calculatedfound 401.0.

[0461] [ka]

[0462] A mixture of 4,7-dibromo-8-fluoro-2-(2-fluorophenyl)quinoline (14.7 g, 36.8 mmol, 1.0 equiv.), MeONa (6.0 g, 110.5 mmol, 3.0 equiv.), and MeOH (200 mL) was stirred at reflux for 15 hours. The mixture was then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give 7-bromo-8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline (10.8 g, 83.7%) as a yellow solid. LRMS (M+H) + )m / z 350.0, calculatedfound 350.0.

[0463] [ka]

[0464] To a solution of 7-bromo-8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline (10.8 g, 30.9 mmol, 1.0 equiv.), DPPP (5.1 g, 12.3 mmol, 0.4 equiv.), and Pd(OAc) (1.4 g, 6.2 mmol, 0.2 equiv.) in DMSO / MeOH (200 mL / 300 mL) was added TEA (21.3 mL, 154.3 mmol, 5.0 equiv.). The mixture was stirred at 80 °C under CO (1 atm) for 15 hours, after which the reaction mixture was diluted with water (2000 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give methyl 8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylate (10.5 g, approximately 100%) as a yellow solid. LRMS (M+H + )m / z 330.1, calculatedfound 330.1.

[0465] [ka]

[0466] To a solution of methyl 8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylate (10.5 g, 31.9 mmol, 1.0 equiv.) in MeOH (100 mL) and HO (30 mL) was added NaOH (1.9 g, 47.8 mmol, 1.5 equiv.). The mixture was stirred for 15 hours at 80° C., concentrated in vacuo, diluted with water (60 mL), and adjusted to pH 2 with 37% aqueous HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylic acid (9.9 g, 98%) as a white solid. LRMS (M+H) + )m / z 316.1, calculatedfound 316.0.

[0467] [ka]

[0468] To a solution of 8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylic acid (9.9 g, 31.4 mmol, 1.0 equiv.) in DCM (100 mL) was added (COCl) (13.3 mL, 157.1 mmol, 5.0 equiv.) and DMF (0.25 mL, 3.1 mmol, 0.1 equiv.) at −78° C. The mixture was stirred at room temperature for 7 hours and then concentrated in vacuo to give 8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carbonyl chloride as a yellow solid (12.5 g, ca. 100.0%), which was used directly in the next step. LRMS (M+H + )m / z 330.1, calculatedfound 330.1 in MeOH.

[0469] [ka]

[0470] To a solution of 8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carbonyl chloride (12.5 g, 37.5 mmol, 1.0 equiv.) in THF (100 mL) was added malononitrile (2.5 g, 37.5 mmol, 1.0 equiv.) and DIEA (19.6 mL, 112.6 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours, then concentrated and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give 2-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carbonyl)malononitrile as a yellow oil (11.7 g, 86%). + )m / z 364.1,calculatedfound 364.0.

[0471] [ka]

[0472] To a solution of 2-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinoline-7-carbonyl)malononitrile (11.7 g, 32.2 mmol, 1.0 equiv) in THF (200 mL) was added MeSO (6.3 mL, 64.4 mmol, 2.0 equiv) and DIEA (28.1 mL, 161.2 mmol, 5.0 equiv). The mixture was stirred at 80 °C for 3 h, concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (7.1 g, 58.5%). LRMS (M+H +)m / z 378.1, calculatedfound 378.1.

[0473] [ka]

[0474] To a solution of 2-((8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile (1.1 g, 2.9 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (406 mg, 3.5 mmol, 1.2 equiv.) in MeOH (50 mL) was added TEA (3.2 mL, 23.3 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 80° C. for 2 hours and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (760 mg, 55.1%) as a yellow solid. LRMS (M+H + )m / z 462.2, calculatedfound 462.4.

[0475] [ka]

[0476] To a stirred solution of 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (760 mg, 1.6 mmol, 1.0 equiv) in DMSO (50 mL) was added KCO (1.1 g, 8.2 mmol, 5.0 equiv) and HO (30%, 3.7 mL, 33.0 mmol, 20.0 equiv). After the addition was complete, the mixture was stirred at 60 °C for 3 h, then diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide as a white solid (340.2 mg, 43%). LRMS (M+H + )m / z 480.2, calculatedfound 480.1. 1 H NMR(DMSO-d6,400MHz) δ 7.99-8.05(m,2H),7.55-7.62(m,2H),7.47(d,1H),7.38-7.43(m,2H),6.32(s,2H),5.19( s,1H),4.44-4.49(m,1H),4.14(s,3H),2.54-2.60(m,2H),2.35-2.41(m,2H),1.33(s,3H).

[0477] Example 36: Preparation of 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0478] [ka]

[0479] To a solution of 7-bromo-4-chloroquinoline (45 g, 185.6 mmol, 1.0 equiv) in MeOH (500 mL) was added NaOEt (37.8 g, 556.7 mmol, 3.0 equiv). The mixture was stirred at 70° C. for 15 hours. The mixture was concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 7-bromo-4-ethoxyquinoline (40 g, 85.1%) as a white solid. LRMS (M+H) + )m / z 252.0, calculatedfound 252.0.

[0480] [ka]

[0481] To a solution of 7-bromo-4-methoxyquinoline (40 g, 159.3 mmol, 1.0 equiv.), DPPP (26.3 g, 63.7 mmol, 0.4 equiv.), and Pd(OAc) (7.2 g, 31.8 mmol, 0.2 equiv.) in DMSO / MeOH (500 mL / 500 mL) was added TEA (110.3 mL, 796.8 mmol, 5.0 equiv.). The mixture was stirred at 80 °C under CO (1 atm) for 15 h, after which the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 4-ethoxyquinoline-7-carboxylate (25 g, 67.5%) as a white solid. LRMS (M+H + )m / z 232.1, calculatedfound 232.2.

[0482] [ka]

[0483] To a stirred solution of methyl 4-ethoxyquinoline-7-carboxylate (25 g, 99.6 mmol, 1.0 equiv.) in DCM (500 mL) was added m-CPBA (51.5 g, 298.8 mmol, 3.0 equiv.) at room temperature. The mixture was stirred for 12 hours at room temperature, then poured onto ice, adjusted to pH 13 by the addition of saturated aqueous Na2CO3, and extracted with DCM (500 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-ethoxy-7-(methoxycarbonyl)quinoline 1-oxide (36 g, >100%) as a yellow oil. LRMS (M+H) + )m / z 248.1, calculatedfound 248.1.

[0484] [ka]

[0485] To a solution of 4-ethoxy-7-(methoxycarbonyl)quinoline 1-oxide (36 g, 145.7 mmol, 1.0 equiv.) in DCM (1000 mL) was added POBr (54.4 g, 189.5 mmol, 1.3 equiv.) and DMF (5.7 mL, 72.9 mmol, 0.5 equiv.) at 0 °C. The mixture was stirred for 15 h at 40 °C, then poured onto ice, adjusted to pH 13 with saturated aqueous NaCO solution, and extracted with DCM (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl 2-bromoquinoline-7-carboxylate (16 g, 47.9%, 2 steps) as a yellow solid. LRMS (M+H) + )m / z 310.0, calculatedfound 310.0.

[0486] [ka]

[0487] To a solution of methyl 2-bromo-4-methoxyquinoline-7-carboxylate (16 g, 51.6 mmol, 1.0 equiv.) in dioxane (300 mL) was added phenylboronic acid (12.6 g, 103.2 mmol, 2.00 equiv.), Pd(PPh3)4 (6.0 g, 5.1 mmol, 0.1 equiv.), and Cs2CO3 (33.6 g, 103.2 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 2 h, then concentrated in vacuo, diluted with water (200 mL), and extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 4-methoxy-2-phenylquinoline-7-carboxylate (14 g, 88.6%) as a white solid. LRMS (M+H + )m / z 308.1, calculatedfound 308.1

[0488] [ka]

[0489] To a solution of methyl 4-ethoxy-2-phenylquinoline-7-carboxylate (14 g, 45.6 mmol, 1.0 equiv.) in MeOH (300 mL) and HO (50 mL) was added NaOH (2.7 g, 68.4 mmol, 1.5 equiv.). The mixture was stirred for 6 h at 50 °C, then concentrated in vacuo, diluted with water (100 mL), and adjusted to pH 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 min, filtered, and dried to give 4-ethoxy-2-phenylquinoline-7-carboxylic acid (12 g, ca. 100%) as a white solid. LRMS (M+H + )m / z 294.1, calculatedfound 294.1.

[0490] [ka]

[0491] To a solution of 4-ethoxy-2-phenylquinoline-7-carboxylic acid (12 g, 40.9 mmol, 1.0 equiv) in DCM (200 mL) was added (COCl) (10.4 mL, 122.9 mmol, 3.0 equiv) and DMF (0.1 mL) at -78 °C. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 4-ethoxy-2-phenylquinoline-7-carbonyl chloride as a yellow solid (15 g, ca. 100.0%). LRMS (M+H + )m / z 308.1, calculatedfound 308.1 in MeOH.

[0492] [ka]

[0493] To a solution of 4-ethoxy-2-phenylquinoline-7-carbonyl chloride (15 g, 48.2 mmol, 1.0 equiv.) in THF (400 mL) was added malononitrile (3.2 g, 48.2 mmol, 1.0 equiv.) and DIEA (19.9 mL, 144.7 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and diluted with water (200 mL). The resulting mixture was extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-(4-ethoxy-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (9 g, 62%). LRMS (M+H + )m / z 342.1, calculatedfound 342.1.

[0494] [ka]

[0495] To a solution of 2-(4-ethoxy-2-phenylquinoline-7-carbonyl)malononitrile (3 g, 8.8 mmol, 1.0 equiv.) in THF (100 mL) was added MeSO (1.7 mL, 17.6 mmol, 2.0 equiv.) and DIEA (4.6 mL, 26.4 mmol, 3.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (200 mL), and extracted with EtOAc (500 mL × 2). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-((4-ethoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (1 g, 32%). LRMS(M+H + )m / z 356.1, calculatedfound 356.1.

[0496] [ka]

[0497] To a solution of 2-((4-ethoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (150 mg, 0.42 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (73.5 mg, 0.63 mmol, 1.5 equiv.) in MeOH (50 mL), TEA (0.5 mL, 3.4 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was stirred at 90° C. for 2 hours, after which the mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (120 mg, 64%) as a yellow solid. LRMS (M+H + )m / z 440.2, calculatedfound 440.2.

[0498] [ka]

[0499] To a stirred solution of 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (120 mg, 0.27 mmol, 1.0 equiv) and KCO (113.3 mg, 0.82 mmol, 3.0 equiv) in DMSO (20 mL) was added HO (30%, 0.6 mL, 5.5 mmol, 20.0 equiv) at room temperature. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by preparative HPLC to give 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (14.1 mg, 11%) as a white solid. LRMS (M+H + )m / z 458.2, calculatedfound 458.2. 1 H NMR(DMSO-d6,400MHz) δ 8.29(d,2H),8.18(d,1H),8.12(d,1H),7.69(dd,1H),7.50-7.58(m,4H),6.31(s,2H),5.20 (s,1H),4.43-4.52(m,3H),2.59-2.64(m,2H),2.36-2.41(m,2H),1,53(t,3H),1.34(s,3H).

[0500] Example 37: Preparation of 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0501] [ka]

[0502] To a solution of 7-bromoquinoline (20 g, 96.6 mmol, 1.0 equiv.), DPPP (8.0 g, 19.3 mmol, 0.2 equiv.), and Pd(OAc)2 (2.1 g, 9.7 mmol, 0.1 equiv.) in DMSO / MeOH (300 mL / 300 mL) was added TEA (40 mL, 289.8 mmol, 3.0 equiv.). The mixture was stirred at 120 °C under CO2 (5 atm) for 15 h and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl quinoline-7-carboxylate (16.4 g, 91.1%) as a yellow solid. LRMS (M+H) + )m / z 188.1, calculatedfound 188.0.

[0503] [ka]

[0504] To a stirred solution of methyl quinoline-7-carboxylate (16.4 g, 87.7 mmol, 1.0 equiv.) in DCM (300 mL) was added m-CPBA (22.7 g, 131.6 mmol, 1.5 equiv.) at room temperature. The mixture was stirred for 2 hours at room temperature, then poured onto ice, adjusted to pH 13 by adding saturated aqueous Na2CO3, and extracted with DCM (500 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 7-(methoxycarbonyl)quinoline 1-oxide (17.5 g, 98.3%) as a yellow oil. LRMS (M+H) + )m / z 204.1, calculatedfound 204.1.

[0505] [ka]

[0506] To a solution of 7-(methoxycarbonyl)quinoline 1-oxide (17.5 g, 86.2 mmol, 1.0 equiv.) in DCM (500 mL) was added POBr (32.1 g, 112.1 mmol, 1.3 equiv.) and DMF (3.3 mL, 43.1 mmol, 0.5 equiv.) at −78° C. The mixture was stirred at room temperature for 2 hours, then poured onto ice, adjusted to pH 13 by adding saturated aqueous NaCO solution, and extracted with DCM (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl 2-bromoquinoline-7-carboxylate (17.2 g, 75.4%) as a yellow solid. LRMS (M+H) + )m / z 266.0, calculatedfound 266.0. 1 H NMR (DMSO-d6,400MHz) δ 8.50(s,1H),8.45(d,1H),8.12-8.21(m,2H),8.86(d,1H),3.95(s,3H).

[0507] [ka]

[0508] To a solution of methyl 2-bromoquinoline-7-carboxylate (12 g, 45.2 mmol, 1.0 equiv.) in dioxane (300 mL) was added (2-fluorophenyl)boronic acid (12.7 g, 90.5 mmol, 2.0 equiv.), Pd(PPh3)4 (2.6 g, 2.2 mmol, 0.05 equiv.), and Cs2CO3 (29.5 g, 90.4 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 1 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-(2-fluorophenyl)quinoline-7-carboxylate (12.8 g, approximately 100%) as a white solid. LRMS (M+H + )m / z 282.1, calculatedfound 282.1.

[0509] [ka]

[0510] To a solution of methyl 2-(2-fluorophenyl)quinoline-7-carboxylate (12.8 g, 45.6 mmol, 1.0 equiv.) in MeOH (200 mL) and HO (30 mL) was added NaOH (2.7 g, 68.3 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 15 hours, then concentrated in vacuo, diluted with water (60 mL), and adjusted to pH=2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 2-(2-fluorophenyl)quinoline-7-carboxylic acid (10.7 g, 88.5%) as a white solid. LRMS (M+H + )m / z 268.1, calculatedfound 268.1.

[0511] [ka]

[0512] To a solution of 2-(2-fluorophenyl)quinoline-7-carboxylic acid (10.7 g, 40.1 mmol, 1.0 equiv) in DCM (200 mL) was added (COCl) (3.4 mL, 42.1 mmol, 5.0 equiv) and DMF (5 drops) at -78 °C. The mixture was stirred at room temperature for 7 h and then concentrated in vacuo to give 2-(2-fluorophenyl)quinoline-7-carbonyl chloride as a yellow solid (12.6 g, ca. 100.0%). LRMS (M+H + )m / z 282.1, calculatedfound 282.1 in MeOH.

[0513] [ka]

[0514] To a solution of 2-(2-fluorophenyl)quinoline-7-carbonyl chloride (12.7 g, 44.6 mmol, 1.0 equiv.) in THF (200 mL) was added malononitrile (2.9 g, 44.5 mmol, 1.0 equiv.) and DIEA (23.3 mL, 133.7 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated and diluted with water (120 mL). The resulting mixture was extracted with EtOAc (350 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give 2-((2-(2-fluorophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile as a yellow oil (14.7 g, approximately 100%). LRMS (M+H + )m / z 316.1, calculatedfound 316.1.

[0515] [ka]

[0516] To a solution of 2-((2-(2-fluorophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile (14.7 g, 46.7 mmol, 1.0 equiv) in THF (300 mL) was added MeSO (9.0 mL, 93.3 mmol, 2.0 equiv) and DIEA (40.6 mL, 233.3 mmol, 5.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (120 mL), and extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((2-(2-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (5 g, 33%). LRMS (M+H + )m / z 330.1, calculatedfound 330.1.

[0517] [ka]

[0518] To a solution of 2-((2-(2-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile (100 mg, 0.30 mmol, 1.0 equiv) and 3-hydrazinyl-1-methylcyclobutan-1-ol (52.9 mg, 0.46 mmol, 1.5 equiv) in MeOH (50 mL) was added TEA (0.4 mL, 2.4 mmol, 8.0 equiv) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours, after which the mixture was concentrated under vacuum and purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (40 mg, 32%) and 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (45 mg, 36%) as yellow solids. LRMS (M+H + )m / z 414.2, calculatedfound 414.3.

[0519] [ka]

[0520] To a stirred solution of 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (40 mg, 0.096 mmol, 1.0 equiv) and KCO (40.1 mg, 0.29 mmol, 3.0 equiv) in DMSO (20 mL) at room temperature was added HO (30%, 0.2 mL, 1.9 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred for 1 h at 60 °C. The mixture was diluted with water (80 mL), and the mixture was extracted with EtOAc (200 mL). The organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (11.8 mg, 33%) as a white solid. LRMS (M+H + )m / z calculated 432.2,found 432.2. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.22(s,1H),8.05-8.10(m,2H),7.94(d,1H),7.82(d,1H),7.55-7.59(m,1H),7.37-7.43( m,2H),6.29(s,2H),5.19(s,1H),4.42-4.51(t,1H),2.59-2.65(m,2H),2.36-2.42(m,2H),1.35(s,3H).

[0521] Example 38: Preparation of 5-amino-3-(2-(2-bromophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0522] [ka]

[0523] To a solution of methyl 2-bromoquinoline-7-carboxylate (3.1 g, 11.7 mmol, 1.0 equiv.) in dioxane (300 mL) was added (2-bromophenyl)boronic acid (4.7 g, 23.4 mmol, 2.0 equiv.), Pd(PPh3)4 (68.0 mg, 0.059 mmol, 0.05 equiv.), and Cs2CO3 (7.6 g, 23.4 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 4 hours and then concentrated in vacuo. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-(2-bromophenyl)quinoline-7-carboxylate (2.8 g, 70%) as a white solid. + )m / z 342.0, calculatedfound 342.1.

[0524] [ka]

[0525] To a solution of methyl 2-(2-bromophenyl)quinoline-7-carboxylate (2.8 g, 8.2 mmol, 1.0 equiv) in MeOH (200 mL) and HO (30 mL) was added NaOH (492 mg, 12.3 mmol, 1.5 equiv). The mixture was stirred for 2 hours at 50° C., then concentrated in vacuo, diluted with water (20 mL), and adjusted to pH=2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 2-(2-bromophenyl)quinoline-7-carboxylic acid (2.6 g, 97%) as a white solid. LRMS (M+H + )m / z 328.0, calculatedfound 328.0.

[0526] [ka]

[0527] To a solution of 2-(2-bromophenyl)quinoline-7-carboxylic acid (2.6 g, 7.9 mmol, 1.0 equiv) in DCM (50 mL) was added (COCl) (499 mg, 39.6 mmol, 5.0 equiv) and DMF (5 drops) at -78 °C. The mixture was stirred at room temperature for 7 h and then concentrated in vacuo to give crude 2-(2-bromophenyl)quinoline-7-carbonyl chloride as a yellow solid (4 g, ca. 100%). LRMS (M+H + )m / z 342.0, calculatedfound 342.1 in MeOH.

[0528] [ka]

[0529] To a solution of 2-(2-bromophenyl)quinoline-7-carbonyl chloride (4 g crude, 7.92 mmol, 1.0 equiv.) in THF (50 mL) was added malononitrile (523 mg, 7.92 mmol, 1.0 equiv.) and DIEA (3.06 g, 23.7 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give 2-((2-(2-bromophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile as a yellow oil (3.4 g, 70%). LRMS (M+H + )m / z 376.0, calculatedfound 376.1.

[0530] [ka]

[0531] To a solution of 2-((2-(2-bromophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile (3.4 g crude, 7.92 mmol, 1.0 equiv) in THF (100 mL) was added MeSO (2.0 g, 15.8 mmol, 2.0 equiv) and DIEA (5.11 g, 39.6 mmol, 5.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 h and then concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((2-(2-bromophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (130 mg, 4% over three steps). LRMS (M+H + )m / z 390.0, calculatedfound 390.1.

[0532] [ka]

[0533] To a solution of 2-((2-(2-bromophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile (130 mg, 0.33 mmol, 1.0 equiv.) and 3-hydrazinyl-1-methylcyclobutan-1-ol (58 mg, 0.50 mmol, 1.5 equiv.) in MeOH (50 mL) was added TEA (267 mg, 2.64 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours, after which the mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-3-(2-(2-bromophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (90 mg, 57%) as a yellow solid. LRMS (M+H) + )m / z 474.1, calculatedfound 474.2.

[0534] [ka]

[0535] To a stirred solution of 5-amino-3-(2-(2-bromophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (90 mg, 0.19 mmol, 1.0 equiv) and KCO (79 mg, 0.57 mmol, 3.0 equiv) in DMSO (10 mL) was added HO (30% in water, 430 mg, 3.8 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h at 60 °C, then diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-3-(2-(2-bromophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (51 mg, 0.10 mmol, 55%) as a white solid. LRMS (M+H + )m / z 492.1, calculatedfound 492.0. 1 H NMR(DMSO-d6,400MHz) δ 8.49(d,1H),8.19(s,1H),8.09(d,1H),7.74-7.85(m,3H),7.64(d,1H),7.56(td,1H),7.44(td,1H) ),6.29(s,2H),5.19(s,1H),4.42-4.51(m,1H),2.59-2.65(m,2H),2.36-2.42(m,2H),1.34(s,3H).

[0536] Example 39: Preparation of 5-amino-3-(2-(4-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0537] [ka]

[0538] To a solution of methyl 2-bromoquinoline-7-carboxylate (2 g, 7.5 mmol, 1.0 equiv.) in dioxane (100 mL) was added (4-fluorophenyl)boronic acid (2.1 g, 15.1 mmol, 2.0 equiv.), Pd(PPh3)4 (436.2 mg, 0.38 mmol, 0.05 equiv.), and Cs2CO3 (11.1 g, 15.0 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 1 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-(4-fluorophenyl)quinoline-7-carboxylate (1.5 g, 71.4%) as a white solid. LRMS (M+H + )m / z 282.1, calculatedfound 282.1.

[0539] [ka]

[0540] To a solution of methyl 2-(4-fluorophenyl)quinoline-7-carboxylate (1.5 g, 5.3 mmol, 1.0 equiv.) in MeOH (100 mL) and HO (10 mL) was added NaOH (320.3 mg, 8.0 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 15 hours, then concentrated in vacuo, diluted with water (60 mL), and adjusted to pH 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 2-(4-fluorophenyl)quinoline-7-carboxylic acid (1.4 g, ca. 100%) as a white solid. LRMS (M+H) + )m / z 268.1, calculatedfound 268.1.

[0541] [ka]

[0542] To a solution of 2-(4-fluorophenyl)quinoline-7-carboxylic acid (1.4 g, 5.2 mmol, 1.0 equiv.) in DCM (100 mL) was added (COCl) (2.2 mL, 26.2 mmol, 5.0 equiv.) and DMF (5 drops) at -78 °C. The mixture was stirred at room temperature for 7 h and then concentrated in vacuo to give 2-(4-fluorophenyl)quinoline-7-carbonyl chloride as a yellow solid (2.3 g, ca. 100.0%). LRMS (M+H + )m / z 282.1, calculatedfound 282.1 in MeOH.

[0543] [ka]

[0544] To a solution of 2-(4-fluorophenyl)quinoline-7-carbonyl chloride (1.3 g, 4.6 mmol, 1.0 equiv.) in THF (100 mL) was added malononitrile (301.1 mg, 4.6 mmol, 1.0 equiv.) and DIEA (2.3 mL, 13.7 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated and diluted with water (120 mL). The resulting mixture was extracted with EtOAc (350 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-((2-(4-fluorophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile as a yellow oil (1.3 g, 86%). LRMS(M+H + )m / z 316.1, calculatedfound 316.1.

[0545] [ka]

[0546] To a solution of 2-((2-(4-fluorophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile (1.3 g, 4.1 mmol, 1.0 equiv) in THF (70 mL) was added MeSO (0.8 mL, 8.3 mmol, 2.0 equiv) and DIEA (2.7 mL, 20.6 mmol, 5.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (120 mL), and extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((2-(4-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (410 mg, 31.4%). LRMS (M+H + )m / z 330.1, calculatedfound 330.1.

[0547] [ka]

[0548] To a solution of 2-((2-(4-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile (230 mg, 0.70 mmol, 1.0 equiv) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (121.6 mg, 1.0 mmol, 1.5 equiv) in MeOH (50 mL) was added TEA (0.8 mL, 5.6 mmol, 8.0 equiv) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours, after which the mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-3-(2-(4-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (140 mg, 48%) as a yellow solid. LRMS (M+H+ )m / z 414.2, calculatedfound 414.3.

[0549] [ka]

[0550] To a stirred solution of 5-amino-3-(2-(4-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (140 mg, 0.34 mmol, 1.0 equiv) and KCO (140.1 mg, 1.0 mmol, 3.0 equiv) in DMSO (20 mL) at room temperature was added HO (30%, 0.8 mL, 6.8 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred for 1 h at 60 °C. The reaction was diluted with water (80 mL) and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-3-(2-(4-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (34.4 mg, 23%) as a white solid. LRMS (M+H + )m / z calculated 432.2,found 432.2. 1 H NMR(DMSO-d6,400MHz) δ 8.49(d,1H),8.35-8.39(m,2H),8.16-8.20(m,2H),8.05(d,1H),7.77(dd,1H),7.36-7.43(m,2H) ,6.30(s,2H),5.19(s,1H),4.42-4.51(m,1H),2.59-2.65(m,2H),2.36-2.42(m,2H),1.34(s,3H).

[0551] Example 40: Preparation of 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0552] [ka]

[0553] To a stirred solution of 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (45 mg, 0.11 mmol, 1.0 equiv) and KCO (40.1 mg, 0.29 mmol, 3.0 equiv) in DMSO (10 mL) at room temperature was added HO (30%, 0.2 mL, 2.2 mmol, 20.0 equiv). After the addition was complete, the reaction mixture was stirred for 1 h at 60 °C. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL). The organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-3-(2-(2-fluorophenyl)quinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (15 mg, 0.034 mmol, 32%) as a white solid. LRMS (M+H + )m / z calculated 432.2,found 432.2. 1 H NMR(DMSO-d6,400MHz) δ 8.50(d,1H),8.22(s,1H),8.05-8.10(m,2H),7.94(dd,1H),7.82(d,1H),7.55-7.59(m,1H),7. 37-7.43(m,2H),6.27(s,2H),4.98(s,1H),4.92-4.96(m,1H),2.39-2.55(m,4H),1.35(s,3H).

[0554] Example 41: Preparation of 5-amino-3-(2-(3-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0555] [ka]

[0556] To a solution of methyl 2-bromoquinoline-7-carboxylate (6 g, 22.6 mmol, 1.0 equiv.) in dioxane (100 mL) was added (3-fluorophenyl)boronic acid (6.3 g, 45.3 mmol, 2.0 equiv.), Pd(PPh3)4 (1.3 g, 1.1 mmol, 0.05 equiv.), and Cs2CO3 (14.7 g, 45.2 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 1 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-(3-fluorophenyl)quinoline-7-carboxylate (2.2 g, 35%) as a white solid. LRMS (M+H + )m / z 282.1, calculatedfound 282.1.

[0557] [ka]

[0558] To a solution of methyl 2-(3-fluorophenyl)quinoline-7-carboxylate (2.2 g, 7.8 mmol, 1.0 equiv.) in MeOH (100 mL) and HO (10 mL) was added NaOH (469.8 mg, 11.7 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 15 hours, then concentrated in vacuo, diluted with water (60 mL), and adjusted to pH 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 2-(3-fluorophenyl)quinoline-7-carboxylic acid (1.4 g, 62%) as a white solid. LRMS (M+H) + )m / z 268.1, calculatedfound 268.1.

[0559] [ka]

[0560] To a solution of 2-(3-fluorophenyl)quinoline-7-carboxylic acid (1.4 g, 5.2 mmol, 1.0 equiv.) in DCM (100 mL) was added (COCl) (2.2 mL, 26.2 mmol, 5.0 equiv.) and DMF (5 drops) at -78 °C. The mixture was stirred at room temperature for 7 h and then concentrated in vacuo to give 2-(3-fluorophenyl)quinoline-7-carbonyl chloride as a yellow solid (2.0 g, ca. 100.0%). LRMS (M+H + )m / z 282.1, calculatedfound 282.1 in MeOH.

[0561] [ka]

[0562] To a solution of 2-(3-fluorophenyl)quinoline-7-carbonyl chloride (2 g, 7.0 mmol, 1.0 equiv.) in THF (100 mL) was added malononitrile (463.2 mg, 7.0 mmol, 1.0 equiv.) and DIEA (3.7 mL, 21.1 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated and diluted with water (120 mL). The resulting mixture was extracted with EtOAc (350 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-((2-(3-fluorophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile as a yellow oil (1.0 g, 66%). LRMS(M+H + )m / z 316.1, calculatedfound 316.1.

[0563] [ka]

[0564] To a solution of 2-((2-(3-fluorophenyl)quinolin-7-yl)(hydroxy)methylene)malononitrile (1.0 g, 3.2 mmol, 1.0 equiv) in THF (70 mL) was added MeSO (0.6 mL, 6.3 mmol, 2.0 equiv) and DIEA (2.7 mL, 15.9 mmol, 5.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 hours, then concentrated in vacuo, diluted with water (120 mL), and extracted with EtOAc (250 mL × 2). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-((2-(3-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (100 mg, 10%). LRMS(M+H + )m / z 330.1, calculatedfound 330.1.

[0565] [ka]

[0566] To a solution of 2-((2-(3-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile (100 mg, 0.30 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (52.9 mg, 0.46 mmol, 1.5 equiv.) in MeOH (50 mL) was added TEA (0.4 mL, 2.4 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 85° C. for 2 hours, after which the mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-3-(2-(3-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (50 mg, 40%) as a yellow solid. LRMS(M+H +)m / z 414.2, calculatedfound 414.3.

[0567] [ka]

[0568] To a stirred solution of 5-amino-3-(2-(3-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (50 mg, 0.12 mmol, 1.0 equiv) and KCO (50.1 mg, 0.36 mmol, 3.0 equiv) in DMSO (20 mL) was added HO (30%, 0.3 mL, 2.4 mmol, 20.0 equiv) at room temperature. After the addition was complete, the reaction mixture was stirred at 60 °C for 1 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by preparative HPLC to give 5-amino-3-(2-(3-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (21.3 mg, 44%) as a white solid. LRMS (M+H + )m / z 432.2, calculatedfound 432.1. 1 H NMR(DMSO-d6,400MHz) δ 8.52(d,1H),8.21-8.24(m,2H),8.16(d,1H),8.11(d,1H),8.07(d,1H),7.79(dd,1H),7.60-7.64(m,1H),7.35 -7.39(m,1H),6.30(s,2H),5.19(s,1H),4.42-4.51(m,1H),2.59-2.65(m,2H),2.36-2.42(m,2H),1.34(s,3H).

[0569] Example 42: Preparation of 5-amino-3-(8-fluoro-4-hydroxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0570] [ka]

[0571] To a stirred solution of 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (60 mg, 0.13 mmol, 1.0 equiv) in ACN (3 mL) was added TMSI (42 mg, 0.39 mmol, 3.0 equiv) and NaI (20 mg, 0.39 mmol, 3.0 equiv). The reaction mixture was stirred at 80° C. under N for 16 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 5-amino-3-(8-fluoro-4-hydroxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (30 mg, 51%) as a white solid. LRMS (M+H + )m / z 448.2, calculatedfound 448.2. 1 H NMR(MeOD,400MHz) δ 8.18(d,1H),7.85(t,2H),7.48-7.58(m,4H),6.69(brs,1H),4.43-4.48(m,1H),2.73-2.79(m,2H),2.57-2.62(m,2H),1.46(s,3H).

[0572] Example 43: Preparation of 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1-(3-oxocyclobutyl)-1H-pyrazole-4-carboxamide

[0573] [ka]

[0574] To a solution of 2-((4-ethoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (600 mg, 1.7 mmol, 1.0 equiv) in EtOH (50 mL) was added NH2NH2.H2O (810 mg, 16.9 mmol, 10.0 equiv) at room temperature. The reaction mixture was stirred at 90 °C for 2 h, then concentrated in vacuo and diluted with water (20 mL). The resulting mixture was stirred for 5 min and filtered. The solid was dried to give 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (520 mg, 86%) as a yellow solid. LRMS (M+H + )m / z 356.1, calculatedfound 356.2.

[0575] [ka]

[0576] A stirred solution of 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carbonitrile (420 mg, 1.18 mmol, 1.0 equiv) was dissolved in concentrated HSO (5 mL) at 0 °C under N. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was carefully added to water (100 mL) at 0 °C. NaCO was added to adjust the pH to 12-13, and then the mixture was extracted with DCM (80 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (370 mg, 84%) as a white solid. LRMS (M+H + )m / z calculatedfound 374.2.

[0577] [ka]

[0578] To a solution of 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1H-pyrazole-4-carboxamide (420 mg, 1.1 mmol, 1.0 equiv.) in DMF (10 mL) was added 3-bromocyclobutan-1-one (200.0 mg, 1.4 mmol, 1.2 equiv.) and K2CO3 (93.2 mg, 0.68 mmol, 0.6 equiv.). After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-1-(3-oxocyclobutyl)-1H-pyrazole-4-carboxamide (170 mg, 34%). + )m / z 442.2, calculatedfound 442.6. 1 H NMR(DMSO-d6,400MHz) δ 8.28-8.31(m,2H),8.18(d,1H),8.14(d,1H),7.71(dd,1H),7.50-7.57(m,4H) ,6.44(s,2H),5.12-5.16(m,1H),4.48(q,2H),3.59-3.62(m,4H),1.53(t,3H).

[0579] Example 44: Preparation of 5-amino-3-(4-(difluoromethoxy)-8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0580] [ka]

[0581] To a solution of 5-amino-3-(8-fluoro-4-hydroxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (15.0 mg, 0.033 mmol, 1.0 equiv) in DMF (10 mL) was added KCO (9.3 mg, 0.067 mmol, 2.0 equiv) and sodium 2-chloro-2,2-difluoroacetate (7.7 mg, 0.05 mmol, 1.5 equiv). After the addition was complete, the mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(4-(difluoromethoxy)-8-fluoro-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (2.5 mg, 15.6%). LRMS (M+H + )m / z 498.2, calculatedfound 498.1. 1 H NMR(DMSO-d6,400MHz) δ 8.32(d,2H),7.95-7.98(m,2H),7.56-7.74(m,4H),6.31(s,2H),5.19(s,1 H),4.42-4.49(m,1H),2.55-2.61(m,2H),2.36-2.39(m,2H),1.33(s,3H).

[0582] Example 45: Preparation of 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0583] [ka]

[0584] To a solution of 2-((8-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (500 mg, 1.39 mmol, 1.0 equiv.) and 3-hydrazinyl-1-methylcyclobutan-1-ol (242 mg, 2.08 mmol, 1.5 equiv.) in MeOH (15 mL), TEA (1.12 g, 11.1 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was stirred at 90° C. for 2 hours and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (100 mg, 16%) as a white solid. LRMS(M+H + )m / z 444.2, calculatedfound 444.3.

[0585] [ka]

[0586] To a stirred solution of 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (80 mg, 0.18 mmol, 1.0 equiv) and KCO (75 mg, 0.54 mmol, 3.0 equiv) in DMSO (3 mL) was added HO (30%, 203 mg, 1.8 mmol, 10.0 equiv) at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 2 h, then diluted with water (15 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(8-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (24 mg, 29%) as a white solid. LRMS (M+H + )m / z calculated 462.2, 1 H NMR(DMSO-d6,400MHz) δ 8.32-8.35(m,2H),7.98(d,1H),7.68(s,1H),7.52-7.59(m,4H),6.29(s,2H), 4.97(s,1H),4.94-4.96(m,1H),4.21(s,3H),2.40-2.50(m,4H),1.33(s,3H).

[0587] Example 46: Preparation of 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0588] [ka]

[0589] To a solution of methyl 2-bromo-4-methoxyquinoline-7-carboxylate (5.0 g, 16.9 mmol, 1.0 equiv.) in dioxane (100 mL) was added (2-fluorophenyl)boronic acid (4.7 g, 33.9 mmol, 2.0 equiv.), Pd(PPh3)4 (979 mg, 0.8 mmol, 0.05 equiv.), and Cs2CO3 (11.1 g, 33.9 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 15 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylate (4.5 g, 86%) as a white solid. LRMS (M+H + )m / z 312.1, calculatedfound 312.1.

[0590] [ka]

[0591] To a solution of methyl 2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylate (4.5 g, 14.5 mmol, 1.0 equiv.) in MeOH (100 mL) and HO (10 mL) was added NaOH (868.2 mg, 21.7 mmol, 1.5 equiv.). The mixture was stirred for 6 hours at 50° C., then concentrated in vacuo, diluted with water (100 mL), and adjusted to pH 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and dried to give 2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylic acid (4 g, 93%) as a white solid. LRMS (M+H) + )m / z 298.1, calculatedfound 298.1.

[0592] [ka]

[0593] To a solution of 2-(2-fluorophenyl)-4-methoxyquinoline-7-carboxylic acid (4 g, 13.5 mmol, 1.0 equiv.) in DCM (100 mL) was added (COCl) (3.4 mL, 40.4 mmol, 3.0 equiv.) and DMF (0.1 mL) at −78° C. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 2-(2-fluorophenyl)-4-methoxyquinoline-7-carbonyl chloride as a yellow solid (5 g, ca. 100.0%). LRMS (M+H + )m / z 312.1, calculatedfound 312.1 in MeOH.

[0594] [ka]

[0595] To a solution of 2-(2-fluorophenyl)-4-methoxyquinoline-7-carbonyl chloride (5.0 g, 15.9 mmol, 1.0 equiv.) in THF (200 mL) was added malononitrile (1.0 g, 15.8 mmol, 1.0 equiv.) and DIEA (8.3 mL, 47.6 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and diluted with water (200 mL). The resulting mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give 2-((2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(hydroxy)methylene)malononitrile as a yellow oil (10.0 g, approximately 100%). LRMS (M+H + )m / z 346.1, calculatedfound 346.1.

[0596] [ka]

[0597] To a solution of 2-((2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(hydroxy)methylene)malononitrile (3.1 g, 9.0 mmol, 1.0 equiv) in THF (100 mL) was added MeSO (1.7 mL, 18.0 mmol, 2.0 equiv) and DIEA (4.7 mL, 26.9 mmol, 3.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (200 mL), and extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (1.2 g, approximately 37%). LRMS (M+H + )m / z 360.1, calculatedfound 360.1.

[0598] [ka]

[0599] To a solution of 2-((2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile (1.2 g, 3.3 mmol, 1.0 equiv.) and (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (581.6 mg, 5.0 mmol, 1.5 equiv.) in MeOH (80 mL) was added TEA (3.7 mL, 26.7 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 80° C. for 2 h and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (1.2 g, 75%) as a yellow solid. LRMS (M+H + )m / z 444.2, calculatedfound 444.2.

[0600] [ka]

[0601] To a stirred solution of 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (1.2 g, 2.7 mmol, 1.0 equiv.) and KCO (1.1 g, 8.1 mmol, 3.0 equiv.) in DMSO (50 mL) at room temperature was added HO (30%, 6.1 mL, 54.2 mmol, 20.0 equiv.). After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. Water (150 mL) was added, and the mixture was extracted with EtOAc (150 mL x 2). The organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (720 mg, 60%) as a white solid. LRMS (M+H + )m / z calculatedfound 462.2. 1 H NMR(DMSO-d6,400MHz) δ 8.20(d,1H),8.14(d,1H),7.99-8.04(m,1H),7.77(dd,1H),7.53-7.59(m,1H),7.37-7.42(m,3H),6.29( s,2H),5.20(s,1H),4.44-4.49(m,1H),4.12(s,3H),2.59-2.64(m,2H),2.36-2.41(m,2H),1.34(s,3H).

[0602] Example 47: Preparation of 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0603] [ka]

[0604] To a solution of 2-((2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile (100 mg, 0.28 mmol, 1.0 equiv) and 3-hydrazinyl-1-methylcyclobutan-1-ol (48.5 mg, 0.42 mmol, 1.5 equiv) in MeOH (15 mL) was added TEA (225.1 mg, 2.2 mmol, 8.0 equiv) at room temperature. The reaction mixture was stirred at 90° C. for 2 hours and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (100 mg, 81%) as a white solid. LRMS(M+H + )m / z 444.2, calculatedfound 444.3.

[0605] [ka]

[0606] To a stirred solution of 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol, 1.0 equiv) and KCO (30 mg, 0.66 mmol, 3.0 equiv) in DMSO (3 mL) was added HO (30%, 248 mg, 2.2 mmol, 10.0 equiv) at room temperature. The mixture was stirred at 60 °C for 1 hour, then diluted with water (15 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (20 mg, 0.043 mmol, 20% yield) as a white solid. LRMS (M+H+ )m / z 462.2, calculatedfound 462.3, 1 H NMR(DMSO-d6,400MHz) δ 8.19(d,1H),8.13(d,1H),8.01(td,1H),7.76(dd,1H),7.53-7.59(m,1H),7.37-7.41(m,3H) ,6.26(s,2H),4.97(s,1H),4.91-4.96(m,1H),4.12(s,3H),2.38-2.54(m,4H),1.35(s,3H).

[0607] Examples 48 and 49: Preparation of 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide and 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0608] [ka]

[0609] To a solution of methyl 2-bromo-4-methoxyquinoline-7-carboxylate (4.0 g, 13.6 mmol, 1.0 equiv.) in dioxane (100 mL) was added (3-fluorophenyl)boronic acid (3.8 g, 27.1 mmol, 2.0 equiv.), Pd(PPh3)4 (783.7 mg, 0.7 mmol, 0.05 equiv.), and Cs2CO3 (8.8 g, 27.1 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 15 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-(3-fluorophenyl)-4-methoxyquinoline-7-carboxylate (1.9 g, 45%) as a yellow solid. + )m / z 312.1, calculatedfound 312.1.

[0610] [ka]

[0611] To a solution of methyl 2-(3-fluorophenyl)-4-methoxyquinoline-7-carboxylate (1.9 g, 6.1 mmol, 1.0 equiv.) in MeOH (100 mL) and HO (10 mL) was added NaOH (366.6 mg, 9.1 mmol, 1.5 equiv.). The mixture was stirred for 6 hours at 50° C., then concentrated in vacuo, diluted with water (20 mL), and adjusted to pH 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and dried to give 2-(3-fluorophenyl)-4-methoxyquinoline-7-carboxylic acid (1.4 g, 78%) as a white solid. LRMS (M+H) + )m / z 298.1, calculatedfound 298.1.

[0612] [ka]

[0613] To a solution of 2-(3-fluorophenyl)-4-methoxyquinoline-7-carboxylic acid (800 mg, 2.7 mmol, 1.0 equiv) in DCM (50 mL) was added (COCl) (0.7 mL, 8.1 mmol, 3.0 equiv) and DMF (0.1 mL) at −78° C. The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give 2-(3-fluorophenyl)-4-methoxyquinoline-7-carbonyl chloride as a yellow solid (848 mg, ca. 100.0%). LRMS (M+H + )m / z 312.1, calculatedfound 312.1 in MeOH.

[0614] [ka]

[0615] To a solution of 2-(3-fluorophenyl)-4-methoxyquinoline-7-carbonyl chloride (848 mg, 2.7 mmol, 1.0 equiv.) in THF (50 mL) was added malononitrile (177.7 mg, 2.7 mmol, 1.0 equiv.) and DIEA (1.4 mL, 8.1 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give 2-((2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)(hydroxy)methylene)malononitrile as a yellow oil (600 mg, approximately 64.6%). LRMS (M+H + )m / z 346.1, calculatedfound 346.1.

[0616] [ka]

[0617] To a solution of 2-((2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)(hydroxy)methylene)malononitrile (600 mg, 1.7 mmol, 1.0 equiv) in THF (50 mL) was added MeSO (0.4 mL, 3.5 mmol, 2.0 equiv) and DIEA (0.9 mL, 5.2 mmol, 3.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to give 2-((2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (200 mg, 32%). LRMS (M+H + )m / z 360.1, calculatedfound 360.1.

[0618] [ka]

[0619] To a solution of 2-((2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)(methoxy)methylene)malononitrile (200 mg, 0.56 mmol, 1.0 equiv.) and 3-hydrazinyl-1-methylcyclobutan-1-ol (96.9 mg, 0.84 mmol, 1.5 equiv.) in MeOH (80 mL) was added TEA (0.6 mL, 4.5 mmol, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours, then concentrated in vacuo and purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (128.0 mg, 50%) as a yellow solid. LRMS (M+H +)m / z 444.2, calculatedfound 444.2.

[0620] [ka]

[0621] To a stirred solution of 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (120 mg, 0.27 mmol, 1.0 equiv) and KCO (112 mg, 0.81 mmol, 3.0 equiv) in DMSO (5 mL) was added HO (30%, 612 mg, 5.4 mmol, 20.0 equiv) at room temperature. After the addition was complete, the reaction mixture was stirred for 15 h at room temperature. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 2). The organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (25.5 mg, 50%) and 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (22 mg, 18%) as white solids.

[0622] 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide: LRMS (M+H + )m / z 462.2, calculatedfound 462.3. 1H NMR(DMSO-d6,400MHz) δ 8.13-8.21(m,4H),7.73(dd,1H),7.63(s,1H),7.57-7.62(m,1H),7.34-7.38(m,1H),6.29(s,2H) ,5.20(s,1H),4.44-4.49(m,1H),4.20(s,3H),2.59-2.64(m,2H),2.36-2.41(m,2H),1.34(s,3H).

[0623] 5-amino-3-(2-(3-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide: LRMS (M+H + )m / z 462.2, calculatedfound 462.3. 1 H NMR(DMSO-d6,400MHz) δ 8.13-8.21(m,4H),7.73(dd,1H),7.63(s,1H),7.57-7.62(m,1H),7.34-7.38(m,1 H),6.27(s,2H),4.92-4.98(m,2H),4.20(s,3H),2.38-2.54(m,4H),1.35(s,3H).

[0624] Example 50: Preparation of 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0625] [ka]

[0626] To a solution of 2-((8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl(methoxy)methylene)malononitrile (1.1 g, 2.9 mmol, 1.0 equiv.) and 3-hydrazinyl-1-methylcyclobutan-1-ol (406 mg, 3.5 mmol, 1.2 equiv.) in MeOH (50 mL), TEA (3.2 mL, 23.3 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was heated at 80° C. for 2 h. The mixture was stirred and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (PE / EA=2 / 1, v / v) to give 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (240 mg, 18%) as a yellow solid. LRMS (M+H + )m / z 462.2, calculatedfound 462.4.

[0627] [ka]

[0628] To a stirred solution of 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (220 mg, 0.48 mmol, 1.0 equiv) in DMSO (6 mL) was added KCO (331 mg, 2.4 mmol, 5.0 equiv) and HO (30%, 1.1 g, 9.6 mmol, 20.0 equiv). After the addition was complete, the mixture was stirred at 60 °C for 2 h, then diluted with water (20 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(8-fluoro-2-(2-fluorophenyl)-4-methoxyquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide as a white solid (135 mg, 59%). LRMS (M+H + )m / z 480.2, calculatedfound 480.3. 1 H NMR(DMSO-d6,400MHz) δ 7.99-8.05(m,2H),7.55-7.62(m,2H),7.47(d,1H),7.38-7.43(m,2H),6.29(s,2) H),4.98(s,1H),4.92-4.97(m,1H),4.14(s,3H),2.38-2.51(m,4H),1.33(s,3H).

[0629] Examples 51 and 52: Preparation of 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide and 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0630] [ka]

[0631] A mixture of 3-bromo-4-fluoroaniline (13.0 g, 68.4 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (12.7 g, 132.2 mmol, 1.0 equiv.) in dioxane (200 mL) was stirred at 120 °C for 1 h, then cooled to room temperature and diluted with PE (500 mL). The precipitate was filtered to give 5-(((3-bromo-4-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (21 g, 88%) as a yellow solid.

[0632] [ka]

[0633] A mixture of 5-(((3-bromo-4-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (21 g, 61.2 mmol, 1.0 equiv) and PhO (250 mL) was stirred for 1 h at 240 °C. The mixture was cooled to room temperature, diluted with PE (200 mL), and the precipitate was filtered to give 7-bromo-6-fluoroquinolin-4-ol and 5-bromo-6-fluoroquinolin-4-ol (11.6 g, 79%) as brown solids. LRMS (M+H) + )m / z 242.0, calculatedfound 242.1.

[0634] [ka]

[0635] To a solution of 7-bromo-6-fluoroquinolin-4-ol and 5-bromo-6-fluoroquinolin-4-ol (11.6 g, 48.1 mmol, 1.0 equiv.) in Tol (120 mL) was added POCl (9.2 mL, 96.2 mmol, 2 equiv.). The mixture was stirred at 100 °C for 1 hour, then poured onto ice, adjusted to pH 13 with saturated aqueous NaCO, and extracted with DCM (500 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give 7-bromo-4-chloro-6-fluoroquinoline (5.5 g, 50.0%) as a yellow solid. LRMS (M+H) + )m / z 259.9, calculatedfound 260.0. 1 H NMR (DMSO-d6,400MHz) δ 8.86(d,1H),8.52(d,1H),8.03(d,1H),7.85(d,1H).

[0636] [ka]

[0637] To a solution of 7-bromo-4-chloro-6-fluoroquinoline (1.9 g, 7.3 mmol, 1.0 equiv.) in MeOH (80 mL) was added MeONa (789.2 mg, 14.6 mmol, 2.0 equiv.). The mixture was stirred at 40° C. for 15 hours, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL×2). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give 7-bromo-6-fluoro-4-methoxyquinoline (850 mg, 50%) as a white solid. LRMS (M+H + )m / z 256.0, calculatedfound 256.0.

[0638] [ka]

[0639] To a solution of 7-bromo-6-fluoro-4-methoxyquinoline (850 mg, 3.3 mmol, 1.0 equiv.), DPPP (547.2 mg, 1.3 mmol, 0.4 equiv.), and Pd(OAc) (148.8 mg, 0.66 mmol, 0.2 equiv.) in DMSO / MeOH (50 mL / 50 mL) was added TEA (2.3 mL, 16.6 mmol, 5.0 equiv.). The mixture was stirred at 80° C. under CO (1 atm) for 15 hours, after which the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 6-fluoro-4-methoxyquinoline-7-carboxylate (468 mg, 61%) as a white solid. + )m / z 236.1, calculatedfound 236.2.

[0640] [ka]

[0641] A mixture of methyl 6-fluoro-4-methoxyquinoline-7-carboxylate (468 mg, 2.0 mmol, 1.0 equiv.) and hydrogen peroxide (0.9 mL of a 30% solution, 0.34 mol, 4.0 equiv.) in AcOH (20 mL) was stirred at 90° C. for 15 hours, then concentrated in vacuo to give 6-fluoro-4-methoxy-7-(methoxycarbonyl)quinoline 1-oxide (400 mg, 80%) as a yellow solid. LRMS (M+H + )m / z 252.1, calculatedfound 252.2.

[0642] [ka]

[0643] To a solution of 6-fluoro-4-methoxy-7-(methoxycarbonyl)quinoline 1-oxide (400 mg, 1.6 mmol, 1.0 equiv.) in DCM (80 mL) was added POBr (594.5 mg, 2.1 mmol, 1.3 equiv.) and DMF (2 drops) at 0 °C. The mixture was stirred at room temperature for 15 h, then poured onto ice, adjusted to pH 13 with saturated aqueous NaCO solution, and extracted with DCM (100 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give methyl 2-bromo-6-fluoro-4-methoxyquinoline-7-carboxylate (124.7 mg, 24%) as a yellow solid. LRMS (M+H + )m / z 314.0, calculatedfound 314.0.

[0644] [ka]

[0645] To a solution of methyl 2-bromo-6-fluoro-4-methoxyquinoline-7-carboxylate (125 mg, 0.40 mmol, 1.0 equiv.) in dioxane (30 mL) was added phenylboronic acid (97.4 mg, 0.80 mmol, 2.0 equiv.), Pd(PPh3)4 (46.2 mg, 0.04 mmol, 0.1 equiv.), and Cs2CO3 (260.4 mg, 0.80 mmol, 2.0 equiv.). The mixture was stirred at 120 °C for 5 h, then concentrated in vacuo, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 6-fluoro-4-methoxy-2-phenylquinoline-7-carboxylate (100 mg, 80%) as a yellow solid. +)m / z 312.1, calculatedfound 312.1.

[0646] [ka]

[0647] To a solution of methyl 6-fluoro-4-methoxy-2-phenylquinoline-7-carboxylate (100 mg, 0.32 mmol, 1.0 equiv.) in MeOH (50 mL) and HO (10 mL) was added NaOH (19.3 mg, 0.48 mmol, 1.5 equiv.). The mixture was stirred for 6 hours at 50° C., then concentrated in vacuo, diluted with water (20 mL), and adjusted to pH=2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and dried to give 6-fluoro-4-methoxy-2-phenylquinoline-7-carboxylic acid (100 mg, 100%) as a yellow solid. LRMS (M+H) + )m / z 298.1, calculatedfound 298.1.

[0648] [ka]

[0649] To a solution of 6-fluoro-4-methoxy-2-phenylquinoline-7-carboxylic acid (100 mg, 0.33 mmol, 1.0 equiv) in DCM (50 mL) was added (COCl) (0.1 mL, 1.0 mmol, 3.0 equiv) and DMF (2 drops) at -78 °C. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 6-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl chloride as a yellow solid (120 mg, ca. 100.0%). LRMS (M+H) + )m / z 312.1, calculatedfound 312.1 in MeOH.

[0650] [ka]

[0651] To a solution of 6-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl chloride (120 mg, 0.38 mmol, 1.0 equiv.) in THF (20 mL) was added malononitrile (25.1 mg, 0.38 mmol, 1.0 equiv.) and DIEA (0.2 mL, 1.1 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give 2-(6-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (91 mg, 70%). LRMS(M+H + )m / z 346.1, calculatedfound 346.1.

[0652] [ka]

[0653] To a solution of 2-(6-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile (91 mg, 0.26 mmol, 1.0 equiv.) in THF (30 mL) was added MeSO (66.5 mg, 0.53 mmol, 2.0 equiv.) and DIEA (0.2 mL, 0.8 mmol, 3.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 hours, then concentrated in vacuo, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-((6-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (50 mg, 53%). LRMS(M+H+ )m / z 360.1, calculatedfound 360.1.

[0654] [ka]

[0655] To a solution of 2-((6-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (50 mg, 0.14 mmol, 1.0 equiv.) and 3-hydrazinyl-1-methylcyclobutan-1-ol (24.2 mg, 0.21 mmol, 1.5 equiv.) in MeOH (30 mL), TEA (0.2 mL, 1.1 mmol, 8.0 equiv.) was added at room temperature. The reaction mixture was stirred at 80 °C for 2 hours, after which the mixture was concentrated in vacuo and purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (20.0 mg, 32.7%) as a yellow solid. LRMS (M+H + )m / z 444.2, calculatedfound 444.2.

[0656] [ka]

[0657] To a stirred solution of 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (20 mg, 0.045 mmol, 1.0 equiv.) and KCO (18.6 mg, 0.14 mmol, 3.0 equiv.) in DMSO (20 mL) at room temperature was added HO (30%, 0.1 mL, 0.9 mmol, 20.0 equiv.). After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (2.2 mg, 11%) and 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (4.2 mg, 12%) as white solids.

[0658] 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide: LRMS (M+H + )m / z 462.2, calculatedfound 462.1. 1 H NMR(DMSO-d6,400MHz) δ 8.31(d,2H),8.07(d,1H),7.82(d,1H),7.63(s,1H),7.51-7.59(m,3H),6.28(s,2H) ,4.44-4.49(m,1H),4.20(s,3H),2.59-2.64(m,2H),2.36-2.41(m,2H),1.34(s,3H). 19 F NMR(DMSO-d6, 377 MHz) δ -115.5(s,1F).

[0659] 5-amino-3-(6-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide: LRMS (M+H + )m / z 462.2, calculatedfound 462.1. 1 H NMR(DMSO-d6,400MHz) δ 8.31(d,2H),8.07(d,1H),7.82(d,1H),7.63(s,1H),7.51-7.59(m,3H),6. 25(s,2H),4.92-4.97(m,1H),4.20(s,3H),2.38-2.51(m,4H),1.33(s,3H). 19 F NMR(DMSO-d6,377 MHz) δ -115.5(s,1F).

[0660] Example 53: Preparation of 5-amino-3-(4-(difluoromethoxy)-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0661] [ka]

[0662] To a solution of 5-amino-3-(4-hydroxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (40.0 mg, 0.09 mmol, 1.0 equiv) in DMF (10 mL) was added KCO (25.6 mg, 0.18 mmol, 2.0 equiv) and sodium 2-chloro-2,2-difluoroacetate (21.6 mg, 0.14 mmol, 1.5 equiv). The mixture was stirred for 1 h at 50 °C. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(4-(difluoromethoxy)-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide (1.8 mg, 5%). LRMS (M+H + )m / z 480.2, calculatedfound 480.1. 1 H NMR(400MHz,DMSO) δ 8.29.8.32(m,2H),8.24(d,1H),8.16(d,1H),7.84-7.90(m,2H),7.54-7.93(m,3H),6.28( s,2H),5.21(s,1H),4.44-4.49(m,1H),2.57-2.68(m,2H),2.32-2.41(m,2H),1.34(s,3H).

[0663] Example 54: Preparation of 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinazolin-7-yl)-1H-pyrazole-4-carboxamide

[0664] [ka]

[0665] To a solution of methyl 2-chloroquinazoline-7-carboxylate (1.0 g, 4.5 mmol, 1.0 equiv.) in DME / EtOH / HO (10 mL / 10 mL / 10 mL), phenylboronic acid (823.5 mg, 6.8 mmol, 1.5 equiv.), Pd(PPh3)2Cl2 (315.9 mg, 0.45 mmol, 0.1 equiv.), and K2CO3 (1.8 g, 13.5 mmol, 3.0 equiv.) were added. The mixture was stirred at 120 °C for 15 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 2-phenylquinazoline-7-carboxylic acid (500 mg, 44.2%) as a yellow solid. + )m / z 251.1, calculatedfound 251.1.

[0666] [ka]

[0667] To a solution of 2-phenylquinazoline-7-carboxylic acid (500 mg, 2.0 mmol, 1.0 equiv) in DCM (10 mL) was added (COCl) (0.9 mL, 10.0 mmol, 5.0 equiv) and DMF (2 drops) at -78 °C. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 2-phenylquinazoline-7-carbonyl chloride as a yellow solid (500 mg, ca. 100.0%). LRMS (M+H + )m / z 265.1, calculatedfound 265.1 in MeOH.

[0668] [ka]

[0669] To a solution of 2-phenylquinazoline-7-carbonyl chloride (500 mg, 1.9 mmol, 1.0 equiv.) in THF (10 mL) was added malononitrile (250.8 mg, 3.8 mmol, 2.0 equiv.) and DIEA (1.0 mL, 5.7 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 2 hours, then concentrated and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to give 2-(hydroxy(2-phenylquinazolin-7-yl)methylene)malononitrile as a yellow oil (400 mg, 71.9%). LRMS (M+H + )m / z 299.1, calculatedfound 299.1.

[0670] [ka]

[0671] To a solution of 2-(hydroxy(2-phenylquinazolin-7-yl)methylene)malononitrile (400 mg, 1.3 mmol, 1.0 equiv.) in THF (10 mL) was added MeSO (0.3 mL, 2.6 mmol, 2.0 equiv.) and DIEA (0.5 mL, 2.6 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 h, then concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give 2-(methoxy(2-phenylquinazolin-7-yl)methylene)malononitrile as a yellow oil (200 mg, 47.8%). LRMS (M+H + )m / z 313.1, calculatedfound 313.1.

[0672] [ka]

[0673] A mixture of 2-(methoxy(2-phenylquinazolin-7-yl)methylene)malononitrile (200 mg, 0.64 mmol, 1.0 equiv.), (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (111.2 mg, 0.96 mmol, 1.5 equiv.), and TEA (0.4 mL, 1.92 mmol, 3.0 equiv.) in 5.0 mL of EtOH was stirred at 80 °C for 2 h. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinazolin-7-yl)-1H-pyrazole-4-carbonitrile as a yellow oil (150 mg, 59.3%). LRMS (M+H) + )m / z 397.2, calculatedfound 397.2.

[0674] [ka]

[0675] To a solution of 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinazolin-7-yl)-1H-pyrazole-4-carbonitrile (50 mg, 0.13 mmol, 1.0 equiv) in DMSO (3.0 mL) was added KCO (54 mg, 0.39 mmol, 3.0 equiv) and HO (1 mL) at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 1 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(2-phenylquinazolin-7-yl)-1H-pyrazole-4-carboxamide as a white solid (8.0 mg, 15.4%). LRMS (M+H + )m / z 415.2, calculatedfound 415.2. 1 H NMR(DMSO-d6,400MHz) δ 9.71(s,1H),8.58-8.60(m,2H),8.18-8.20(d,2H),7.92-7.95(m,1H),7.56-7.59(m,3H),6.2 6(s,2H),5.19(s,1H),4.45-4.49(m,1H),2.59-2.67(m,2H),2.37-2.41(m,2H),1.34(s,3H).

[0676] Example 55: Preparation of 5-amino-3-(5-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0677] [ka]

[0678] A mixture of 3-bromo-5-fluoroaniline (5.0 g, 26.4 mmol, 1.0 equiv.) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.9 g, 26.4 mmol, 1.0 equiv.) in dioxane (100 mL) was stirred at 120° C. for 1 h. The mixture was cooled to room temperature and diluted with PE (100 mL). The precipitate was filtered to give 5-(((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.2 g, >100%) as a yellow solid. LRMS (M+H) + )m / z 344.0, calculatedfound 286.0, 304.1.

[0679] [ka]

[0680] A mixture of 5-(((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.2 g, 23.9 mmol, 1.0 equiv.) and PhO (100 mL) was stirred at 240 °C for 1 h. The mixture was cooled to room temperature and diluted with PE (100 mL). The precipitate was filtered to give a mixture of 7-bromo-5-fluoroquinolin-4-ol and 5-bromo-7-fluoroquinolin-4-ol (4.5 g, 78%) as a brown solid. LRMS (M+H) + )m / z 242.0, calculatedfound 242.1.

[0681] [ka]

[0682] To a solution of 7-bromo-5-fluoroquinolin-4-ol and 5-bromo-7-fluoroquinolin-4-ol (4.5 g, 18.7 mmol, 1.0 equiv.) in Tol (120 mL) was added POCl (5.7 g, 37.3 mmol, 2 equiv.). The mixture was stirred at 100 °C for 1 hour, then poured onto ice, adjusted to pH 13 with saturated aqueous NaCO, and extracted with DCM (500 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give a mixture of 7-bromo-4-chloro-5-fluoroquinoline and 5-bromo-4-chloro-7-fluoroquinoline (3.9 g, 79%) as a yellow solid. LRMS (M+H) + )m / z 259.9, calculatedfound 260.0

[0683] [ka]

[0684] A mixture of 7-bromo-4-chloro-5-fluoroquinoline and 5-bromo-4-chloro-7-fluoroquinoline (3.1 g, 12 mmol, 1.0 equiv.) and MeONa (970 mg, 18 mmol, 1.5 equiv.) in MeOH (50 mL) was stirred at 40° C. for 1 hour. LCMS showed the reaction was complete. The reaction was quenched with HO (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc=10 / 1, v / v) to give a mixture of 7-bromo-5-fluoro-4-methoxyquinoline and 5-bromo-7-fluoro-4-methoxyquinoline as a yellow oil (2.4 g, 80%). LRMS (M+H + )m / z 256.0, calculatedfound 256.0.

[0685] [ka]

[0686] To a solution of 7-bromo-5-fluoro-4-methoxyquinoline and 5-bromo-7-fluoro-4-methoxyquinoline (2.4 g, 9.4 mmol, 1.0 equiv.), DPPP (780 mg, 1.8 mmol, 0.2 equiv.), and Pd(OAc) (210.6 mg, 0.94 mmol, 0.1 equiv.) in DMSO / MeOH (20 mL / 20 mL) was added TEA (3.8 mL, 28.2 mmol, 3.0 equiv.). The mixture was stirred at 80 °C under CO (5 atm) for 15 h and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give a mixture of methyl 5-fluoro-4-methoxyquinoline-7-carboxylate and methyl 7-fluoro-4-methoxyquinoline-5-carboxylate (1.8 g, 72%) as a yellow oil. LRMS(M+H + )m / z 236.1, calculatedfound 236.1.

[0687] [ka]

[0688] To a stirred solution of methyl 5-fluoro-4-methoxyquinoline-7-carboxylate and methyl 7-fluoro-4-methoxyquinoline-5-carboxylate (1.8 g, 7.7 mmol, 1.0 equiv.) in DCM (20 mL) was added m-CPBA (1.9 g, 11.5 mmol, 1.5 equiv.) at room temperature. The mixture was stirred for 12 hours at room temperature, then poured onto ice, adjusted to pH 13 with saturated aqueous Na2CO3, and extracted with DCM (30 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a mixture of 5-fluoro-4-methoxy-7-(methoxycarbonyl)quinoline 1-oxide and 7-fluoro-4-methoxy-5-(methoxycarbonyl)quinoline 1-oxide (1.5 g, 78.9%) as a yellow oil. LRMS (M+H) +)m / z 252.1, calculatedfound 252.1.

[0689] [ka]

[0690] To a solution of 5-fluoro-4-methoxy-7-(methoxycarbonyl)quinoline 1-oxide and 7-fluoro-4-methoxy-5-(methoxycarbonyl)quinoline 1-oxide (1.5 g, 5.9 mmol, 1.0 equiv.) in DCM (20 mL) was added POBr (2.2 g, 7.8 mmol, 1.3 equiv.) and DMF (2.3 mL, 2.9 mmol, 0.5 equiv.) at −78° C. The mixture was stirred for 15 hours at 45° C., then poured onto ice, adjusted to pH 13 by adding saturated aqueous NaCO solution, and extracted with DCM (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 2-bromo-5-fluoro-4-methoxyquinoline-7-carboxylate (600 mg, 31.6%) as a yellow solid. + )m / z 314.0, calculatedfound 314.0. 1 H NMR (DMSO-d6,400MHz) δ 8.16(s,1H),7.66(dd,1H),7.37(s,1H),4.07(s,3H),3.94(s,3H).

[0691] [ka]

[0692] To a solution of methyl 2-bromo-5-fluoro-4-methoxyquinoline-7-carboxylate (600 mg, 1.9 mmol, 1.0 equiv.) in dioxane (10 mL) was added phenylboronic acid (467.7 mg, 3.8 mmol, 2.00 equiv.), Pd(PPh3)4 (219 mg, 0.19 mmol, 0.1 equiv.), and Cs2CO3 (1.8 g, 5.7 mmol, 3.0 equiv.). The mixture was stirred at 80 °C for 5 h, then concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give methyl 5-fluoro-4-methoxy-2-phenylquinoline-7-carboxylate (410 mg, approximately 68.3%) as a white solid. LRMS (M+H + )m / z 312.1, calculatedfound 312.1.

[0693] [ka]

[0694] To a solution of methyl 5-fluoro-4-methoxy-2-phenylquinoline-7-carboxylate (410 mg, 1.3 mmol, 1.0 equiv.) in MeOH (6.0 mL) and HO (2.0 mL) was added NaOH (80 mg, 2.0 mmol, 1.5 equiv.). The mixture was stirred for 15 hours at 50° C., then concentrated in vacuo and diluted with water (50 mL). The pH was adjusted to 2 by adding 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 5-fluoro-4-methoxy-2-phenylquinoline-7-carboxylic acid (350 mg, 89.7%) as a white solid. LRMS (M+H + )m / z 298.1, calculatedfound 298.1.

[0695] [ka]

[0696] To a solution of 5-fluoro-4-methoxy-2-phenylquinoline-7-carboxylic acid (350 mg, 1.2 mmol, 1.0 equiv) in DCM (10 mL) was added (COCl) (0.6 mL, 6.0 mmol, 5.0 equiv) and DMF (2 drops) at 0 °C. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 5-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl chloride as a yellow solid (340 mg, 91.9%). LRMS (M+H + )m / z 312.1, calculatedfound 312.1 in MeOH.

[0697] [ka]

[0698] To a solution of 5-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl chloride (340 mg, 1.1 mmol, 1.0 equiv.) in THF (10 mL) was added malononitrile (145.2 mg, 2.2 mmol, 2.0 equiv.) and DIEA (0.6 mL, 3.3 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 2 hours, then concentrated and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to give 2-(5-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile as a yellow oil (350 mg, 94.1%). LRMS (M+H + )m / z 346.1, calculatedfound 346.1.

[0699] [ka]

[0700] To a solution of 2-(5-fluoro-4-methoxy-2-phenylquinoline-7-carbonyl)malononitrile (350 mg, 1.0 mmol, 1.0 equiv.) in THF (10 mL) was added MeSO (0.2 mL, 2.0 mmol, 2.0 equiv.) and DIEA (0.5 mL, 2.0 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 hours, then concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give 2-((5-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (130 mg, 36.1%). LRMS(M+H + )m / z 360.1, calculatedfound 360.1.

[0701] [ka]

[0702] To a solution of 2-((5-fluoro-4-methoxy-2-phenylquinolin-7-yl)(methoxy)methylene)malononitrile (130 mg, 0.36 mmol, 1.0 equiv) in EtOH (5.0 mL) was added (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (63 mg, 0.54 mmol, 1.5 equiv) and TEA (1.4 mL, 10.1 mmol, 3.0 equiv). The reaction mixture was stirred at 80° C. for 2 hours, then concentrated in vacuo and purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-3-(5-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile as a yellow oil (100 mg, 62.5%). LRMS (M+H +)m / z 444.2, calculatedfound 444.2.

[0703] [ka]

[0704] To a stirred solution of 5-amino-3-(5-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (100 mg, 0.22 mmol, 1.0 equiv) in DMSO (3.0 mL) was added KCO (93.4 mg, 0.66 mmol, 3.0 equiv) and HO (2.0 mL) at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 2 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(5-fluoro-4-methoxy-2-phenylquinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide as a white solid (76.0 mg, 73.1%). LRMS (M+H + )m / z calculatedfound 462.2. 1 H NMR(DMSO-d6,400MHz) δ 8.30-8.32(m,2H),8.00-8.01(d,1H),7.52-7.59(m,4H),7.42-7.45(d,1H),6.25(s,2H),5.2 0(s,1H),4.50-4.59(m,1H),4.16(s,3H),2.58-2.63(m,2H),2.35-2.40(m,2H),1.33(s,3H).

[0705] Example 56: Preparation of 5-amino-3-(8-fluoro-2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0706] [ka]

[0707] A mixture of 2-fluorobenzaldehyde (5.0 g, 40.3 mmol, 1.0 equiv) and 2-(triphenyl-phosphanylidene)acetaldehyde (12.3 g, 40.3 mmol, 1.0 equiv) in toluene (50.0 mL) was stirred for 4 hours at 80° C. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give (£)-3-(2-fluorophenyl)acrylaldehyde as a yellow oil (3.9 g, 65%).

[0708] [ka]

[0709] A mixture of (£)-3-(2-fluorophenyl)acrylaldehyde (3.9 g, 26 mmol, 1.0 equiv.) and 3-bromo-2-fluoroaniline (4.9 g, 26 mmol, 1.0 equiv.) in toluene (40.0 mL) and 6N HCl (40 mL) was heated to reflux for 40 hours. The mixture was concentrated, and the residue was diluted with HO (50 mL). The mixture was adjusted to pH 13 with saturated NaHCO and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give 7-bromo-8-fluoro-2-(2-fluorophenyl)quinoline as a yellow oil (3.1 g, 37.3%). LRMS (M+H + )m / z 320.0, calculatedfound 320.0.

[0710] [ka]

[0711] To a solution of 7-bromo-8-fluoro-2-(2-fluorophenyl)quinoline (3.1 g, 9.7 mmol, 1.0 equiv.), DPPF (799 mg, 1.9 mmol, 0.2 equiv.), and Pd(OAc)2 (217.6 mg, 0.97 mmol, 0.1 equiv.) in DMSO / MeOH (30 mL / 30 mL) was added TEA (3.9 mL, 29.1 mmol, 3.0 equiv.). The mixture was stirred at 80 °C under CO2 (5 atm) for 20 h and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give methyl 8-fluoro-2-(2-fluorophenyl)quinoline-7-carboxylate (960 mg, 33.1%) as a yellow solid. LRMS (M+H) + )m / z 300.1, calculatedfound 300.1

[0712] [ka]

[0713] To a solution of methyl 8-fluoro-2-(2-fluorophenyl)quinoline-7-carboxylate (960 mg, 3.2 mmol, 1.0 equiv.) in MeOH (6.0 mL) and HO (2.0 mL) was added NaOH (192.6 mg, 4.8 mmol, 1.5 equiv.). The mixture was stirred for 15 hours at 50° C., then concentrated in vacuo and diluted with water (50 mL). The pH was adjusted to 2 by the addition of 37% HCl. The resulting mixture was stirred for 5 minutes, filtered, and concentrated in vacuo to give 8-fluoro-2-(2-fluorophenyl)quinoline-7-carboxylic acid (800 mg, 87.4%) as a white solid. LRMS (M+H + )m / z 286.1, calculatedfound 286.1.

[0714] [ka]

[0715] To a solution of 8-fluoro-2-(2-fluorophenyl)quinoline-7-carboxylic acid (800 mg, 2.8 mmol, 1.0 equiv.) in DCM (10 mL) was added (COCl) (1.4 mL, 14 mmol, 5.0 equiv.) and DMF (2 drops) at 0° C. The mixture was stirred at room temperature for 2 h and concentrated in vacuo to give 8-fluoro-2-(2-fluorophenyl)quinoline-7-carbonyl chloride as a yellow solid (800 mg, ca. 94.1%). LRMS (M+H + )m / z 300.1, calculatedfound 300.1 in MeOH.

[0716] [ka]

[0717] To a solution of 8-fluoro-2-(2-fluorophenyl)quinoline-7-carbonyl chloride (800 mg, 2.6 mmol, 1.0 equiv.) in THF (10 mL) was added malononitrile (348.5 mg, 5.2 mmol, 2.0 equiv.) and DIEA (1.4 mL, 7.8 mmol, 3.0 equiv.) in an ice bath. The mixture was stirred at room temperature for 2 hours, then concentrated and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to give 2-(8-fluoro-2-(2-fluorophenyl)quinoline-7-carbonyl)malononitrile as a yellow oil (300 mg, 34.1%). LRMS(M+H + )m / z 334.1, calculatedfound 334.1

[0718] [ka]

[0719] To a solution of 2-(8-fluoro-2-(2-fluorophenyl)quinoline-7-carbonyl)malononitrile (300 mg, 0.9 mmol, 1.0 equiv.) in THF (10 mL) was added MeSO (0.2 mL, 1.8 mmol, 2.0 equiv.) and DIEA (0.5 mL, 1.8 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at 80 °C for 3 hours, then concentrated in vacuo, diluted with water (20 mL), and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give 2-((8-fluoro-2-(2-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile as a yellow oil (90 mg, 28.8%). LRMS(M+H + )m / z 348.1, calculatedfound 348.1.

[0720] [ka]

[0721] To a solution of 2-((8-fluoro-2-(2-fluorophenyl)quinolin-7-yl)(methoxy)methylene)malononitrile (90 mg, 0.26 mmol, 1.0 equiv) in EtOH (5.0 mL) was added (1s,3s)-3-hydrazinyl-1-methylcyclobutan-1-ol (64 mg, 0.39 mmol, 1.5 equiv) and TEA (0.1 mL, 0.78 mmol, 3.0 equiv). The reaction mixture was stirred at 80° C. for 2 hours, then concentrated in vacuo and purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to give 5-amino-3-(8-fluoro-2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile as a yellow oil (100 mg, 90.1%). LRMS (M+H + )m / z calculated 432.2,found 432.2.

[0722] [ka]

[0723] To a solution of 5-amino-3-(8-fluoro-2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carbonitrile (100 mg, 0.23 mmol, 1.0 equiv) in DMSO (3.0 mL) was added KCO (94.2 mg, 0.69 mmol, 3.0 equiv) and HO (2.0 mL). After the addition was complete, the mixture was stirred at 60 °C for 2 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 5-amino-3-(8-fluoro-2-(2-fluorophenyl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide as a white solid (13.4 mg, 12.9%). LRMS (M+H + )m / z 450.2, calculatedfound 450.2. 1 H NMR(DMSO-d6,400MHz) δ 8.57-8.59(d,1H),8.02-8.09(m,2H),7.90-7.92(d,1H),7.44-7.67(m,2H),7.39-7.41(m,2H), 6.31(s,2H),5.18(s,1H),4.45-4.49(m,1H),2.50-2.60(m,2H),2.36-2.40(m,2H),1.33(s,3H).

[0724] Example 57: Preparation of 5-amino-3-(8-fluoro-2-(pyridin-2-yl)quinolin-7-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide

[0725] [ka]

[0726] To a solution of 3-bromo-2-fluoroaniline (50.0 g, 0.26 mol, 1.0 equiv.), sodium 3-nitrobenzenesulfonate (105.3 g, 0.47 mol, 1.8 equiv.), and propane-1,2,3-triol (66.9 g, 0.73 mol, 2.8 equiv.) in HO (56.0 mL) was added concentrated HSO (105.5 mL). The mixture was stirred at 150 °C for 2 hours. The mixture was poured into ice water and acidified to pH 14 with 5 N aqueous sodium hydroxide solution. The mixture was extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1, v / v) to give 7-bromo-8-fluoroquinoline (26.0 g, 43.3%) as a yellow solid. LRMS (M+H + )m / z 226.0, calculatedfound 226.0.

[0727] [ka]

[0728] To a solution of 7-bromo-8-fluoroquinoline (26.0 g, 0.12 mol, 1.0 equiv.), DPPP (9.5 g, 23.1 mmol, 0.2 equiv.), and Pd(OAc)2 (2.7 g, 0.012 mol, 0.1 equiv.) in DMSO / MeOH (260 mL / 260 mL) was added TEA (49.0 mL, 0.36 mol, 3.0 equiv.). The mixture was stirred at 80 °C under CO2 (5 atm) for 15 h and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give methyl 8-fluoroquinoline-7-carboxylate (11.2 g, 47.5%) as a yellow oil. LRMS (M+H) +)m / z 206.1, calculatedfound 206.1.

[0729] [ka]

[0730] To a stirred solution of methyl 8-fluoroquinoline-7-carboxylate (6.5 g, 31.7 mmol, 1.0 equiv.) in DCM (80 mL) was added m-CPBA (8.17 g, 47.6 mmol, 1.5 equiv.) at room temperature. The mixture was stirred for 12 hours at room temperature, then poured onto ice, adjusted to pH 13 by the addition of saturated aqueous Na2CO3, and extracted with DCM (100 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 8-fluoro-7-(methoxycarbonyl)quinoline 1-oxide (6.3 g, 90%) as a yellow oil. LRMS (M+H) + )m / z 222.1, calculatedfound 222.1.

[0731] [ka]

[0732] To a solution of 8-fluoro-7-(methoxycarbonyl)quinoline 1-oxide (3.1 g, 14.0 mmol, 1.0 equiv.) in DCM (30 mL) was added POBr (5.2 g, 18.2 mmol, 1.3 equiv.) and DMF (0.5 mL, 7.0 mmol, 0.5 equiv.) at −78° C. The mixture was stirred for 15 hours at 45° C., then poured onto ice, adjusted to pH 13 with saturated aqueous NaCO solution, and extracted with DCM (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The result...

Claims

1. Formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; L is a bond, or optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; R ２ is an optionally substituted carbocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl, and the optional substitutions of the optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl are cyano, halo, hydroxy, azido, amino, nitro, —CO ２ H, -S(O)-R １０ , -S-R １０ , -S(O) ２ -R １０ , optionally substituted C1-C6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted (heterocyclyl)-O-, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R １１ ) ２ , -CO-R １０ , -CO ２ -R １０ , -CON(R １１ ) ２ , -NR １１ CO-R １０ , -NR １１ CO ２ -R １０ , -SO ２ N (R １１ ) ２ , -C(=NR １２ )-N(R １１ ) ２ , -NR １１ CO-N (R １０ ) ２ , or -NR １１ SO ２ -N(R １０ ) ２ is selected from the group consisting of X ３ is N or C-R ３ and X ４ is N or C-R ４ and X ５ is N or C-R ５ and X ６ is N or C-R ６ and X ８ is N or C-R ８ and R ３ , R ４ , R ５ , R ６ , and R ８ are independently hydrogen, cyano, halo, hydroxy, azido, amino, nitro, —CO ２ H, -S(O)-R １０ , -S-R １０ , -S(O) ２ -R １０ , optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted heterocyclyl, -N(R １１ ) ２ , -CO-R １０ , -CO ２ -R １０ , -CON(R １１ ) ２ , -NR １１ CO-R １０ , -NR １１ CO ２ -R １０ , -SO ２ N (R １１ ) ２ , -C(=NR １２ )-N(R １１ ) ２ , -NR １１ CO-N (R １０ ) ２ , and -NR １１ SO ２ -N(R １０ ) ２ is selected from the group consisting of R １０ are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R １１ are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R １２ is H or optionally substituted C1-C6 alkyl; R ９ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted C4-C10 carbocyclylalkyl; R ９ and L, or R ９ and X may be taken together with any intervening atom to form an optionally substituted heterocyclyl ring, or a pharmaceutically acceptable salt or solvate thereof.

2. X ３ is N, and X ４ is C-R ４ 2. The compound of claim 1, wherein:

3. X ３ is C-R ３ and X ４ is N, or a pharmaceutically acceptable salt or solvate thereof.

4. X ３ is C-R ３ and X ４ is C-R ４ 2. The compound of claim 1, wherein:

5. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a bond.

6. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted C3-C7 cycloalkyl.

7. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted C4 cycloalkyl.

8. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted heterocyclyl.

9. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted piperidine or pyrrolidine.

10. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted piperidin-4-yl.

11. 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted C1-C8 alkyl.

12. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted cycloalkyl.

13. 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted C3-C7 cycloalkyl.

14. 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted heterocyclyl.

15. 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted C1-C8 alkyl.

16. 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein X is an optionally substituted C4-C10 cycloalkylalkyl.

17. 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein X is optionally substituted heterocyclylalkyl.

18. R ３ is H, or a pharmaceutically acceptable salt or solvate thereof.

19. R ４ is H, or a pharmaceutically acceptable salt or solvate thereof.

20. R ４ 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted C1-C4 alkoxy.

21. X ８ is N, or a pharmaceutically acceptable salt or solvate thereof.

22. X ８ is C-R ８ 6. The compound of claim 5, wherein:

23. R ８ is H, or a pharmaceutically acceptable salt or solvate thereof.

24. R ８ 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen.

25. R ８ is F, or a pharmaceutically acceptable salt or solvate thereof.

26. R ９ is H, or a pharmaceutically acceptable salt or solvate thereof.

27. R ２ 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted aryl.

28. R ２ 28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted phenyl.

29. R ２ 28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein is phenyl substituted with at least one halogen.

30. R ２ 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted heteroaryl.

31. R ２ 31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein is an optionally substituted pyridine.

32. X ６ is N, or a pharmaceutically acceptable salt or solvate thereof.

33. X ６ is C-R ６ 6. The compound of claim 5, wherein:

34. R ６ is H, or a pharmaceutically acceptable salt or solvate thereof.

35. X ５ is N, or a pharmaceutically acceptable salt or solvate thereof.

36. X ５ is C-R ５ 6. The compound of claim 5, wherein:

37. R ５ is H, or a pharmaceutically acceptable salt or solvate thereof.

38. A compound having the structure of a compound provided in Table 1A or Table 1B, or a pharmaceutically acceptable salt or solvate thereof.

39. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

40. 10. A method for preparing a pharmaceutical composition, comprising the step of mixing a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

41. 10. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the human or animal body.

42. Use of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

43. A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, for treating cancer in a patient in need of treatment.

44. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

45. A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, for treating an autoimmune disease in a patient in need of such treatment.

46. ​​Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of thyroid eye disease.

47. A composition for treating thyroid eye disease in a patient in need of treatment, comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

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