Kinase modulators and methods of use thereof

Abstract

The invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions. In particular, compounds of the invention inhibitTYK2, a member of the Janus Kinase (JAK) family of non -receptor protein kinases.

Description

[0001] KINASE MODULATORS AND METHODS OF USE THEREOF I. Field of the Invention The invention provides compounds that modulate the activity of kinases, such as Tyrosine Kinase 2 (TYK2). II. Background A variety of medical conditions that affect millions of people are caused or exacerbated by unregulated activity of protein kinases. For example, aberrant kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorders, eye diseases, infectious diseases and hormone-related diseases. For many such disorders, however, no effective inhibitor or activator exists for the particular kinase that causes the disorder or its symptoms. Consequently, patients continue to suffer from an array of disorders due to the lack of suitable medicaments for their conditions. III. Summary The invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions. In particular, compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is implicated in autoimmune diseases, such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease. Thus, embodiments of the invention are useful as pharmaceutical compositions for treatment of such autoimmune conditions. The invention also provides methods of using the compounds to modulate kinase activity in cells and to treat conditions, such asautoimmune conditions, for which modulation of kinase activity provides a therapeutic benefit. For certaindiseases, especially the diseases of central nervous system, such as but not limited to multiple sclerosis, the desired compounds may need to be brain-penetrant in order to elicit desire pharmacological effects.Accordingly, in certain aspects, the invention provides compounds cross the blood -brain barrier fortreatment of conditions related to central nervous system and / or brain.In certain aspects, the invention provides compounds of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0002] wherein: X1is CH or N; R1is substituted or unsubstituted C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; L1 is absent or –C(=O)-(CH2)n, wherein n is 0, 1, or 2; A is substituted or unsubstituted alkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said heterocycloalkyl or heteroaryl comprises one or more N, O, or S as heteroatoms; said 4-10 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be fused;and wherein said substitutions are selected from the group consisting of: H, -OH, halogen, substituted or unsubstituted C1-C6alkyl, C1-C6alkenyl, partially halogenated C1-C6alkyl, partially halogenated C1-C6alkyl substituted with 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, hydroxyl-C1-C6alkyl, aminoalkyl, alkylaminoalkyl, C1-C6alkyl-S(=O)2-alkyl, alkyl- C(=O)-alkyl, -C(=O)NH2, -C(=O)NH-alkyl, C1-C6haloalkyl, and C3-C10cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said heterocycloalkyl and heteroaryl comprises one or more N, O, or S as heteroatoms, and wherein said C3-C10cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may have additional substitutions; B is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms and said optional substitutions on said 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are any of the above mentioned substitutions. In certain embodiments, in the compounds of Formula (I), X1is CH. In certain embodiments, in the compounds of Formula (I), X1is N. In certain embodiments, in the compounds of Formula (I), R1is methyl. In certain embodiments, in the compounds of Formula (I), R1is ethyl. In certain embodiments, in the compounds of Formula (I), R1is -CD3. In certain embodiments, in the compounds of Formula (I), L1is -C(=O)-. In certain embodiments, in the compounds of Formula (I), L1is -C(=O)-CH2. In certain embodiments, in the compounds of Formula (I), B is selected from the group consisting of: , In certain embodiments, in the compounds of Formula (I), B is optionally substituted cyclopropyl. In certain embodiments, in the compounds of Formula (I), B is cyclopropyl. In certain embodiments, in the compounds of Formula (I), B is cyclopropyl-methyl. In certain embodiments, in the compounds of Formula (I), B is substituted or unsubstituted pyridine and pyrimidine. In certain embodiments, in the compounds of Formula (I), A is substituted or unsubstituted phenyl. In certain embodiments, in the compounds of Formula (I), A is substituted or unsubstituted pyridine. In certain embodiments, in the compounds of Formula (I), A is fused heteroaryl or heterocycloalkyl. In certain embodiments, in the compounds of Formula (I), A is fused heteroaryl.In certain embodiments, in the compounds of Formula (I), A is heterocycloalkyl.In certain embodiments, in the compounds of Formula (I), A is fused heterocycloalkyl.In certain embodiments, in the compounds of Formula (I), A is substituted or unsubstituted 1H- pyrrole, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,2,4-triazole, oxazole, or 1,2,3-triazole. In certain embodiments, in the compounds of Formula (I), wherein the substitutions on A ring are selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, hydroxyl, halogen, aminoalkyl, alkylsulfonyl, oxo, C1-C6-oxyalkyl, or 4-7 membered heterocycloalkyl. In certain embodiments, the one or more substitution on A ring is methyl or cyclopropyl. In certain embodiments, A or optional substitutions on A are partially deuterated. In certain embodiments, in the compounds of Formula (I), one or more substitutions on A areoptionally substituted bridged cycloalkyl or heterocycloalkyl.In certain embodiments, in the compounds of Formula (I), one or more substitutions on A is 6 -membered spiro heterocycloalkyl comprising N or O as heteroatoms.In certain embodiments, in the compounds of Formula (I), A is: , wherein, R2and R3are independently selected from the group consisting of H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, and wherein C1-C6alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydroxy, oxo (=O), C1-C6 alkyl, C1-C6 oxyalkyl, C1-C6 alkylhydroxy, partially halogenated C1-C6 alkyl, cyano, and partially halogenated C1-C6oxyalkyl. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting of:

[0003] In certain embodiments, in the compounds of Formula (I), A is: wherein R4and R5are independently selected from the group consisting of H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, C1-C6aminoalkyl, 3-10 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl ring comprises N, O, or S as heteroatoms, said heteroaryl ring comprises N as heteroatom, and wherein C1-C6alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydroxy, oxo (=O), C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, partially halogenated C1-C6alkyl, cyano, and partially halogenated C1-C6oxyalkyl; and wherein R4and R5and said substitutions are optionally deuterated. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting of:

[0004] , , , , , , , , , , , ,

[0005] In certain embodiments, in the compounds of Formula (I), A is an optionally substituted 8-12 membered fused bicyclic ring. In certain embodiments, in the compounds of Formula (I), the fused bicyclic ring comprises N, O, and S as heteroatoms. In certain embodiments, said optional substitutions are selected from the group consisting of deuterium, cyclopropyl which may optionally be fused with said fused bicyclic ring, methyl, partially halogenated alkyl, oxo, 3-6 membered cycloalkyl or heterocycloalkyl wherein said N or O as heteroatoms. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting of: , . In certain embodiments, in the compounds of Formula (I), A is: wherein Y1, Y2, Y3, and Y4are independently CH, N, O, or S; and R6and R7are independently selected from H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, C1-C6aminoalkyl, 3-10 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl ring comprises N, O, or S as heteroatoms, said heteroaryl ring comprises N as heteroatom, and wherein C1-C6alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydroxy, oxo (=O), C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, partially halogenated C1-C6alkyl, cyano, and partially halogenated C1-C6oxyalkyl; and wherein R4and R5and said substitutions are optionally deuterated. In certain embodiments, in the compounds of Formula (I), A is: wherein Y1, Y2, Y3, and Y4are independently CH, or N, and R6and R7are discussed above. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting of:

[0006] In certain aspects, the invention provides compounds of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein X2is CH or N; X3is NH, N-CH3, CH2, CD2, O, S, -CHF, and -CF2; R8is H, D, halo, C1-C6alkyl, or oxy- C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated, partially halogenated C1-C6alkyl; L2 is a single bond, -CH=CH-, or -C≡C-; L3 is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; C is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms; said 4-10 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be fused;and wherein said substitutions are selected from the group consisting of: H, -OH, halogen, cyano, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl- oxyalkyl, oxy-C1-C6alkyl-cyano, optionally partially deuterated C1-C6alkyl, C1-C6alkyl-(optionallysubstituted C3-C8 cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), oxy-(optionallysubstituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), and oxy-C1-C6alkyl- (optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms) wherein said substitutions on C3-C8cycloalkyl or heterocycloalkyl are selected from the group consisting of H, -OH, halogen, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl-oxyalkyl, and optionally partially deuterated C1-C6alkyl; D is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4 alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms and said optional substitutions on said 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are any of the above mentioned substitutions. In certain embodiments, in the compounds of Formula (II), X2is CH. In certain embodiments, in the compounds of Formula (II), X2is N. In certain embodiments, in the compounds of Formula (II), X3is NH. In certain embodiments, in the compounds of Formula (II), X3is CH2. In certain embodiments, in the compounds of Formula (II), X3is CD2. In certain embodiments, in the compounds of Formula (II), X3 is O. In certain embodiments, in the compounds of Formula (II), X3 is S. In certain embodiments, in the compounds of Formula (II), X3 is CF2. In certain embodiments, in the compounds of Formula (II), R8is H. In certain embodiments, in the compounds of Formula (II), R8is methyl. In certain embodiments, in the compounds of Formula (II), R8 is -CD3. In certain embodiments, in the compounds of Formula (II), L3 is -NH- C(=O)-. In certain embodiments, in the compounds of Formula (II), L3 is a single bond. In certain embodiments, in the compounds of Formula (II), L3is -NH-. In certain embodiments, in the compounds of Formula (II), L3is: . In certain embodiments, in the compounds of Formula (II), D is selected from the group consisting of: In certain embodiments, in the compounds of Formula (II), D is cyclopropyl, which can be optionally substituted. In certain embodiments, in the compounds of Formula (II), D is: . In certain embodiments, in the compounds of Formula (II), D is . In certain embodiments, in the compounds of Formula (II), D is: . In certain embodiments, in the compounds of Formula (II), C is an optionally substituted 8-12 membered fused bicyclic ring. In certain embodiments, the fused bicyclic ring comprises N, O, and S as heteroatoms. In certain embodiments, said optional substitutions are selected from the group consisting of deuterium, halogen, cyclopropyl which may optionally be fused with said fused bicyclic ring, methyl, partially halogenated alkyl, oxo, 3-6 membered cycloalkyl or heterocycloalkyl wherein said N or O as heteroatoms. In certain embodiments, C is a 5-membered heteroaryl ring fused with 6-membered aryl or heteroaryl ring, wherein one or more heteroatom is N or O, wherein each of the ring is further optionally substituted. In certain embodiments, in the compounds of Formula (II), C is: . wherein R9and R10are independently selected from the group consisting of H, D, C1-C6alkyl or3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen or C 1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring. In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: wherein R9and R10are independently selected from the group consisting of H, D, OH, halogen, C1-C6alkyl, oxy- C1-C6alkyl, or 3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen, D, or C1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring. In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is selected from the group consisting of:

[0007] ,

[0008] ,

[0009] In certain embodiments, in the compounds of Formula (II), X3 is CF2 and R8 is F. In certain embodiments, in the compounds of Formula (II), X3is CF2and R8is H. In certain embodiments, in the compounds of Formula (II), X3is O and R8is methyl. In certain embodiments, in the compounds of Formula (II), X3is -CH2and R8is -CH3or CD3. In certain embodiments, in the compounds of Formula (II), X3is -CD2and R8is -CD3. In certain embodiments, in the compounds of Formula (II), X3is O. In certain embodiments, in the compounds of Formula (II), X3is -N-CH3and R8is -CH3. In certain embodiments, in the compounds of Formula (II), X2is N, X3is -NH, and R8is -CH3. In certain embodiments, in the compounds of Formula (II), X3is -NH and R8is -OCH3. In certain embodiments, in the compounds of Formula (II), X3is O and R8is CD2CD3. In certain embodiments, the compound is selected from the group consisting of the compounds provided in Table A: TABLE A: In certain aspects, the compounds of the invention are unexpectedly advantageous because they have an unexpectedly better metabolic profile and stability. In certain embodiments, these compounds have better bioavailability as compared to other compounds. In certain embodiments, this unexpected and enhanced bioavailability is a beneficial and desired property of the compound being developed as therapy for TYK2 related ailments. In certain embodiments, the compounds are selected from the group consisting of the compounds listed in Table B below. Table B:

[0010] In certain other aspects, the compounds of the invention are also unexpectedly advantageous because they have a better brain / plasma distribution upon administration to the patient. In certain preferred embodiments, the compounds of the current invention have a better blood brain penetration as compared to other contemporary compounds. In certain embodiments, the blood brain penetration of the compounds of the invention is beneficial because such compounds will be optimal for treatment of ailments of central nervous system. In certain embodiments, the compounds of the invention have better blood brain penetration and central nervous system as compared to the compounds provided in WO2023 / 244788, which is incorporated by reference in its entirety. In certain embodiments, the compounds are selected from the group consisting of the compounds listed in Table C below. Table C:

[0011] In certain embodiments, the compounds of the invention are selected from the group consisting of the compounds listed in Table D below: Table D:

[0012] In certain embodiments, the compounds of the invention are selected from the group consisting of the compounds listed in Table E below. Table E In certain embodiments, the compounds of the invention are selected from the group consisting of the compounds listed in Table F below: Table F:

[0013] In certain aspects, the compounds of the invention are selected from the group consisting of: In certain embodiments, the compounds of the invention do not include the compounds provided in WO2023 / 244788. In certain embodiments, the compounds of the invention do not include Examples 1 – 1142 provided in WO2023 / 244788, which is incorporated by reference in its entirety. In certain embodiments, the compounds of the invention do not include the compounds provided in Examples 1160 – Examples 1188. In certain embodiments, the compounds of the invention do not include the compounds wherein, in the compound of Formula (I), X1is CH. In certain embodiments, the invention provides compounds of Formula (II) with the proviso that the invention does not include the compounds wherein, in the compound of Formula (II), X2is CH. In certain aspects, the invention provides compounds of Formula (IIa), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein X3is NH, N-CH3, CH2, CD2, O, S, -CHF, and -CF2; R8is H, D, halo, C1-C6alkyl, or oxy- C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated, partially halogenated C1-C6alkyl; L3is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; C is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms; said 4-10 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be fused;and wherein said substitutions are selected from the group consisting of: H, -OH, halogen, cyano, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl- oxyalkyl, oxy-C1-C6alkyl-cyano, optionally partially deuterated C1-C6alkyl, C1-C6alkyl-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), oxy-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), and oxy-C1-C6alkyl- (optionally substituted C3-C8 cycloalkyl or heterocycloalkyl with N or O as the heteroatoms) wherein said substitutions on C3-C8cycloalkyl or heterocycloalkyl are selected from the group consisting of H, -OH, halogen, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl-oxyalkyl, and optionally partially deuterated C1-C6alkyl; D is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms and said optional substitutions on said 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are any of the above mentioned substitutions. In certain aspects, the invention provides compounds of Formula (IIb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein R8is H, D, halo, or C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; L3is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; D is 3-6 membered substituted or unsubstituted cycloalkyl, wherein said substitutions are H, C1-C4alkyl; and R9and R10are independently selected from the group consisting of H, D, OH, halogen, and C1-C6alkyl. In certain aspects, the invention provides compounds of Formula (IIc), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein R8is H, D, halo, or C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; L3is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; D is 3-6 membered substituted or unsubstituted cycloalkyl, wherein said substitutions are H, C1-C4alkyl; and R9and R10are independently selected from the group consisting of H, D, OH, halogen, or C1-C6alkyl. In certain aspects, the invention provides compounds of Formula (IId), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0014] wherein R8is H, D, halo, or C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; D is 3-6 membered substituted or unsubstituted cycloalkyl, wherein said substitutions are H, C1-C4alkyl; and R9and R10are independently selected from the group consisting of H, D, OH, halogen, or C1-C6 alkyl. In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -H.In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -CH3.In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -CD3.In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -CD3.In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently H. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently -CH3. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently H or D. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently H. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently -CD3. In certain embodiments, in the compounds of Formula (IIa), (IIb), or (IIc), L3is a single bond. In certain embodiments, the invention provides compounds of Formula (II), with the proviso that the invention does not include the compounds wherein in the compounds of Formula (II): X2is CH; L3is -C(=O); R8is CH3; and / or C is a 5-membered heteroaryl ring fused with 6-membered aryl or heteroaryl ring, wherein one ormore heteroatom is N or O, wherein each of the ring is further optionally substituted.In certain embodiments, the invention provides compounds of Formula (II), with the proviso that the invention does not include the compounds wherein in the compounds of Formula (II), wherein X2is CH R8is -CH3. In certain embodiments, the compound of the invention is a compound of Formula (II), wherein X2is N, and: X3is NH; R8is optionally deuterated C1-C3alkyl, wherein preferably R8is -CH3or -CD3; L2is a single bond; L3is -NH-C(=O)-; D is optionally substituted cyclopropyl, preferably methyl-cyclopropyl; C is: wherein R9and R10are independently selected from the group consisting of H, D, OH, halogen, C1- C6alkyl, oxy- C1-C6alkyl, or 3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen, D, or C1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring. In certain embodiments, the compound of the invention is a compound of Formula (II), wherein X2is N, and: X3is NH; R8is optionally deuterated C1-C3alkyl, wherein preferably R8is -CH3or -CD3; L2is a single bond; L3is -NH-C(=O)-; D is optionally substituted cyclopropyl, preferably methyl-cyclopropyl; C is selected from the group consisting of: In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that when X2is CH, C does not include:

[0015] In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that in the compounds of Formula (II), when X2is CH and L2is a single bond, C does not include: In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that when X2is CH, D does not include:

[0016] In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that when X2is CH, D does not include: . In certain beneficial aspects, the compounds of the invention are capable of crossing the blood brain barrier. Specifically, the compounds of the invention cross blood brain barrier as compared to other TYK2 inhibitors. Surprisingly, the compounds of the invention are significantly more brain penetrant as compared to other structurally analogous compounds. The beneficial properties of the compounds are important for treatment of conditions afflicting the brain and / or the central nervous system. In another aspect, the invention provides pharmaceutical compositions containing one or more compounds of the invention, such as any of the compounds described above. In certain embodiments, pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent. In another aspect, the invention provides methods of modulating the activity of a kinase by contacting cells containing a kinase with one or more compounds of the invention, such as any of those described above. The compound may inhibit activity of the kinase. The compound may increase activityof the kinase. The kinase may be a JAK family kinase. The kinase may be TYK2.In another aspect, the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above. The condition may be characterized by elevated activity of a kinase. The condition may be characterized by altered activity of a kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. The condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone- related disease. In another aspect, the invention provides use of a compound of the invention, such as any of those described above, for making a medicament. In embodiments of the use, the medicament is useful for treating a condition in a subject. In embodiments of the use the condition is characterized by elevated activity or altered activity of a kinase. In embodiments of the use, the kinase is a JAK family kinase. In embodiments of the use, the kinase isTYK2. In embodiments of the use, the condition is an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the invention provides a method of inhibiting TYK2 activity in a subject in need thereof with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the invention provides a method of treating a TYK2-mediated disease or disorder comprising administering to a subject in need thereof a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the TYK2-mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In certain embodiments, the TYK2-mediated disease or disorder is multiple sclerosis. Detailed Description: Chemical definitions: The expression alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C -10alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (- CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). The expression heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to asaturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-10 alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6alkyl”). The expression alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”). In someembodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1- butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-10alkenyl. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and l or 2 heteroatoms (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroCC2-6alkenyl”). The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings, e.g., 2 or 3 rings, and contains from 3 to 14 ring carbon atoms, such as from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3or NO2groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group. The expression cycloheteroalkyl or heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (e.g., 1, 2, or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom or a SO group or a SO2group. A cycloheteroalkyl or heterocycloalkyl group may have 1 or 2 rings containing from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms (e.g., C, O, N or S). Cycloheteroalkyl or heterocycloalkyl groups include cycloheteroalkenyl or heterocycloalkenyl groups. The expression cycloheteroalkyl or heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3or NO2groups. Examples are a piperidinyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotro pinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclic anhydrides. The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ringcarbon atoms, and one or two alkyl or alkynyl groups having 1 or 2 to 6 carbon atoms.The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (e.g., 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom or a SO group or a SO2group. A heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated. The expression aryl refers to an aromatic group that contains one or more rings, e.g., 2 or 3 rings, containing from 6 to 14 ring carbon atoms, such as from 6 to 10 ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH3, OH, SH, NH2, N3or NO2groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3- nitrophenyl or 4-hydroxyphenyl group. The expression heteroaryl refers to an aromatic group that contains one or more rings, e.g., 2 or 3 rings, containing from 5 to 14 ring atoms, such as from 5 to 10 ring atoms, and contains one or more (e.g., 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms. The expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH3, OH, SH, N3, NH2or NO2groups. Examples are pyridyl (e.g.4-pyridyl), imidazolyl (e.g.2-imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g.3- pyrazolyl) and isoquinolinyl groups. The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups in accordance with the above definitions, such as, for example, aryl- alkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups.Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o -fluorotoluene, lH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atomsand / or a cycloalkyl group containing 5 or 6 ring carbon atoms.The expression heteroaralkyl refers to an aralkyl group as defined above in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom, that is to say to groups containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms.Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl heterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylhetero cycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, hetero arylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, hetero arylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylhetero cycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4- carboxyphenylalkyl group. As stated above, the expressions cycloalkyl, cycloheteroalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH3, OH, =O, SH, =S, NH2, =NH, N3or NO2groups. The expression carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“ 0carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms 10 (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (G), and the like. Exemplary C3-10carbocyclyl groups include, without 20 limitation, the aforementioned G-s carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenvl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10carbocyclyl. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10cycloalkyl. The expression heterocyclyl or heterocyclic refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non- aromatic ring system having ring carbon atoms and 1¬4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ringheteroatom selected from nitrogen, oxygen, and sulfur.Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing oneheteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5 - memberedheterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups 5 containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing oneheteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5 -memberedheterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6- bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The expression optionally substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms, such as nitrogen, may have substituents, such as any suitable substituent described herein which satisfies the valencies of the heteroatoms and results in the formation of a stable moiety. For example and without limitation, optional substituents include fluorine, chlorine, bromine, and iodine atoms and CF3, CN, OH, =O, SH, = , NH2, =NH, N3and NO2groups. Optional substituents also include C1-C10alkyl, C2-C10alkenyl, C1-C10heteroalkyl, C3-C16cycloalkyl, C2-C17heterocycloalkyl, C4-C20alkylcycloalkyl, C2-C19heteroalkylcycloalkyl, C6-C18aryl, C1-17heteroaryl, C7-C20aralkyl or C2-C19heteroaralkyl, C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-C9heterocycloalkyl, C7- C12alkylcycloalkyl, C2-C11heteroalkylcycloalkyl, C6-C10aryl, C1-C9heteroaryl, C7-C12aralkyl, C2-C11heteroaralkyl, and C1-C10haloalkyl groups. Exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, amino, C1-4alkyl, C1-4heteroalkyl cyclopropyl, SF5, NO, NO2. Other exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, C1-4alkyl (e.g. methyl, ethyl, t- butyl), NMe2, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, NHCH2CH2OH, CH2CH2OCH3, SF5, SO2NMe2, NO, NO2, OCF3, SO2CF3, CN or CF3. Other exemplary substituents are F, Cl, Br, Me, OMe, CN or CF3. The term halogen preferably refers to F, Cl, Br or I. According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted. When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via asingle or double bond or these rings may be annulated. Other optional substituents include, but are not limited to, halogen, -CN, -NO2, -N3, - SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, - SSRCC, -C(O)Raa, -CO2H, -CHO, OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R bb)2,=NNRbbC(O)Raa, =NNRbbC(O)ORaa, =NNRbbS(O)2Raa, =NRbb, or =NORcc; in which: each instance of Raais, independently, selected from C1-10 alkyl, C1-10 heteroalkyl, C1-10 haloalkyl, C2-10alkenyl, C3-10cycloalkyl, C3-10cycloheteroalkyl, C3-10cycloalkenyl, C3-10cycloheteroalkenyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered cycloalkyl, 3-14 membered cycloheteroalkyl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, ca rbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 R dd groups;each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(Rcc)2, - CN, -C(O)Raa, -C(O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(NRcc)ORaa, -C(NRcc)N(Rcc)2, - SO2N(Rcc)2, -SO2Rcc, - SO2ORcc, -SORaa, -C(S)N(Rcc)2, -C(O)SRcc, -C(S)SRcc, - P(O)2Raa, -P(O)(Raa)2, -P(O)2N(Rcc)2, - P(O)(NRcc)2, C1-10alkyl, C1-10heteroalkyl, C1-10haloalkyl, C2-10alkenyl, C3-10cycloalkyl, C3-10cycloheteroalkyl, C3-10cycloalkenyl, C3-10cycloheteroalkenyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, - Si(Ree)3, -OSi(Ree)3, -C(S)N(Rff)2, -C(O)SRee, -C(S)SRee, -SC(S)SRee, -P(O)2Ree, -P(O)(Ree)2, -OP(O)(Ree)2, -OP(O)(ORee)2, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C2-6alkenyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; each instance of Reeis, independently, selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, - OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3+X-, -NH(C1-6alkyl)2+X-, -NH2(C1-6alkyl)+X-- MR+X-, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), - NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), - C(O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(O)NH2, -C(O)N(C1-6alkyl)2, - OC(O)NH(C1-6alkyl), -NHC(O)(C1-6alkyl), -N(C1-6alkyl)C(O)(C1-6alkyl), - NHCO2(C1-6alkyl), -NHC(O)N(C1-6alkyl)2, -NHC(O)NH(C1-6alkyl), -NHC(O)NH2, -C(NH)O(C1-6alkyl),-OC(NH)(C1-6alkyl), -OC(NH)OC1-6 alkyl, -C(NH)N(C1-6 alkyl)2, -C(NH)NH(C1-6 alkyl), -C(NH)NH2, -OC(NH)N(C1-6 alkyl)2, - OC(NH)NH(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(NH)NH2, - NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2,-SO2C1-6alkyl, - SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3- C(S)N(C1-6alkyl)2, C(S)NH(C1-6alkyl), C(S)NH2, - C(O)S(C1-6alkyl), -C(S)SC1-6alkyl, -SC(S)SC1-6alkyl, -P(O)2(C1-6alkyl), -P(O)(C1-6alkyl)2, -OP(O)(C1-6 alkyl)2, -OP(O)(OC1-6alkyl)2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C3-10carbocyclyl, C3-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X- is a counterion. Janus tyrosine kinase (JAK) family members are regulators of multiple signal transduction pathways initiated by membrane Type I and Type II cytokine receptors. There are 4 JAK family members including JAK1, JAK2, JAK3, and TYK2 (Schwartz et al, 2017). One such association is with signal transducer and activator of transcription (STAT) signal transduction mediated cytokine responses. The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation (Aaronson et al Science 2002). The binding of Type I and Type II cytokine receptor ligands, such as interferons and interleukins, to cell-surface receptors, causes the receptors to dimerize, which brings the receptor-associated JAKs into close proximity (Jalini et al, Genes and Cancer 2011), and sets off a sequence of downstream changes. There is a large body of evidence establishing the contribution of JAK-dependent cytokines to immunopathology, and clinical benefit can be provided by blocking these cytokines with biologics and small-molecule inhibitors. Some examples of this are the blockade of IL-6 in rheumatoid arthritis or IL- 12 / IL-23 in inflammatory bowel disease (IBD) (Schwartz et al 2017). The tyrosine kinase 2 (TYK2) member of the JAK family specifically plays a role in the downstream signaling of Interleukin (IL)-12, IL-23, and type I interferons (Baker and Isaacs, Ann Rheum Dis., 2018; Burke et al, Sci Trans Med, 2019). Like other JAK family members, TYK2 heterodimerizes with other JAK family members to provide ligand specificity and regulate downstream signal transduction pathways (Fig 1). Many of these pathways are altered in diseases and drive chronic inflammation in IBD, Psoriasis, and systemic lupus erythematosus (SLE) (Schwartz et al, Nat Rev Drug Dis, 2017). In addition to the role of TYK2 signaling cascades in disease there has been a strong body of genetic evidence of pointing to a role for TYK2. Genetic association studies have linked the TYK2 locus to an impact of the susceptibility in SLE, psoriasis, and multiple sclerosis (MS). This identification has been replicated and expanded in a number of recent analyses, and TYK2 is now recognized as a susceptibility gene in a variety of inflammatory and autoimmune diseases, including type I diabetes (T1D). The common characteristic of these diseases are changes in immunological function and activation, and downstream damage to target organs (Li et al, PLOS One, 2020). The use of small-molecule inhibitors of TYK2 have allowed for the confirmation of several of these hypotheses. Previous work in human derived PBMCs have demonstrated the ability of TYK2 inhibition to reduce IL-12 / IL-23 signaling in rodents and humans TYK2 inhibition has also proven efficacious in preclinical models of disease for psoriasis and ulcerative colitis (Burke et al, Sci Trans Med, 2020). The preclinical effects in rodents have since translated to humans with deucravacitinib demonstrating efficacy in Psoriasis patients (Armstrong et al, Ann of Rheu Dis, 2020). The genetic contribution of TYK2 has also been confirmed preclinically with the use of TYK2 knockout (KO) or transgenic (TG)animals. For example, Type I interferon signaling is reduced in in TYK2 KO animals as compared to WT mice (Karaghiosoff, Immunity, 2000) and TG animals with the P1104 protective variant of TYK2 are almost completely protected in the experimental autoimmune encephalitis (EAE) mouse model of MS (Gorman et al, Frnt in Immunology, 2019). Together, this large body of evidence provides supportive data for the role of cytokine signaling, and the support for the development of safe TYK2 inhibitors for a variety of inflammatory disorders. The invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions. In particular, compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is implicated in autoimmune diseases, such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease. Thus, embodiments of the invention are useful as pharmaceutical compositions for treatment of such autoimmune conditions. The invention also provides methods of using the compounds to modulate kinase activity in cells and to treat conditions, such as autoimmune conditions, for which modulation of kinase activity provides a therapeutic benefit. In certain aspects, the invention provides compounds of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein: X1is CH or N; R1is substituted or unsubstituted C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; L1 is absent or –C(=O)-(CH2)n, wherein n is 0, 1, or 2; A is substituted or unsubstituted alkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said heterocycloalkyl or heteroaryl comprises one or more N, O, or S as heteroatoms; said 4-10 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be fused;and wherein said substitutions are selected from the group consisting of: H, -OH, halogen, substituted or unsubstituted C1-C6alkyl, C1-C6alkenyl, partially halogenated C1-C6alkyl, partially halogenated C1-C6alkyl substituted with 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, hydroxyl-C1-C6alkyl, aminoalkyl, alkylaminoalkyl, C1-C6alkyl-S(=O)2-alkyl, alkyl- C(=O)-alkyl, -C(=O)NH2, -C(=O)NH-alkyl, C1-C6haloalkyl, and C3-C10cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said heterocycloalkyl and heteroaryl comprises one or more N, O, or S as heteroatoms, and wherein said C3-C10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may have additional substitutions; B is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms and said optional substitutions on said 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are any of the above mentioned substitutions. In certain embodiments, in the compounds of Formula (I), X1is CH. In certain embodiments, in the compounds of Formula (I), X1is N. In certain embodiments, in the compounds of Formula (I), R1is methyl. In certain embodiments, in the compounds of Formula (I), R1 is ethyl. In certain embodiments, in the compounds of Formula (I), R1 is -CD3. In certain embodiments, in the compounds of Formula (I), L1 is -C(=O)-. In certain embodiments, in the compounds of Formula (I), L1is -C(=O)-CH2. In certain embodiments, in the compounds of Formula (I), B is selected from the group consisting In certain embodiments, in the compounds of Formula (I), B is optionally substituted cyclopropyl. In certain embodiments, in the compounds of Formula (I), B is cyclopropyl. In certain embodiments, in the compounds of Formula (I), B is cyclopropyl-methyl. In certain embodiments, in the compounds of Formula (I), B is substituted or unsubstituted pyridine and pyrimidine. In certain embodiments, in the compounds of Formula (I), A is substituted or unsubstituted phenyl. In certain embodiments, in the compounds of Formula (I), A is substituted or unsubstituted pyridine. In certain embodiments, in the compounds of Formula (I), A is fused heteroaryl or heterocycloalkyl. In certain embodiments, in the compounds of Formula (I), A is fused heteroaryl.In certain embodiments, in the compounds of Formula (I), A is heterocycloalkyl.In certain embodiments, in the compounds of Formula (I), A is fused heterocycloalkyl.In certain embodiments, in the compounds of Formula (I), A is substituted or unsubstituted 1H- pyrrole, 2-pyrazoline, 2-imidazoline, pyrazole, imidazole, 1,2,4-triazole, oxazole, or 1,2,3-triazole. In certain embodiments, in the compounds of Formula (I), wherein the substitutions on A ring are selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, hydroxyl, halogen, aminoalkyl, alkylsulfonyl, oxo, C1-C6-oxyalkyl, or 4-7 membered heterocycloalkyl. In certain embodiments, the one or more substitution on A ring is methyl or cyclopropyl. In certain embodiments, A or optional substitutions on A are partially deuterated. In certain embodiments, in the compounds of Formula (I), one or more substitutions on A areoptionally substituted bridged cycloalkyl or heterocycloalkyl.In certain embodiments, in the compounds of Formula (I), one or more substitutions on A is 6 -membered spiro heterocycloalkyl comprising N or O as heteroatoms.In certain embodiments, in the compounds of Formula (I), A is: , wherein, R2and R3are independently selected from the group consisting of H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, and wherein C1-C6alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydoxy, oxo (=O), C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, partially halogenated C1-C6alkyl, cyano, and partially halogenated C1-C6oxyalkyl. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting of: . In certain embodiments, in the compounds of Formula (I), A is: wherein R4and R5are independently selected from the group consisting of H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, C1-C6aminoalkyl, 3-10 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl ring comprises N, O, or S as heteroatoms, said heteroaryl ring comprises N as heteroatom, and wherein C1-C6 alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydroxy, oxo (=O), C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, partially halogenated C1-C6alkyl, cyano, and partially halogenated C1-C6oxyalkyl; and wherein R4and R5and said substitutions are optionally deuterated. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting

[0017] . In certain embodiments, in the compounds of Formula (I), A is an optionally substituted 8-12 membered fused bicyclic ring. In certain embodiments, in the compounds of Formula (I), the fused bicyclic ring comprises N, O, and S as heteroatoms. In certain embodiments, said optional substitutions are selected from the group consisting of deuterium, cyclopropyl which may optionally be fused with said fused bicyclic ring, methyl, partially halogenated alkyl, oxo, 3-6 membered cycloalkyl or heterocycloalkyl wherein said N or O as heteroatoms. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting of:

[0018] . In certain embodiments, in the compounds of Formula (I), A is: wherein Y1, Y2, Y3, and Y4 are independently CH, N, O, or S; andR6and R7are independently selected from H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, C1-C6aminoalkyl, 3-10 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring, wherein said heterocycloalkyl ring comprises N, O, or S as heteroatoms, said heteroaryl ring comprises N as heteroatom, and wherein C1-C6alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydroxy, oxo (=O), C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, partially halogenated C1-C6alkyl, cyano, and partially halogenated C1-C6oxyalkyl; and wherein R4and R5and said substitutions are optionally deuterated. In certain embodiments, in the compounds of Formula (I), A is: wherein Y1, Y2, Y3, and Y4are independently CH, or N, and R6and R7are discussed above. In certain embodiments, in the compounds of Formula (I), A is selected from the group consisting , ,

[0019] In certain aspects, the invention provides compounds of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein X2is CH or N; X3 is NH, N-CH3, CH2, CD2, O, S, -CHF, and -CF2; R8is H, D, halo, C1-C6alkyl, or oxy- C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated, partially halogenated C1-C6alkyl; L2is a single bond, -CH=CH-, or -C≡C-; L3is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; C is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms; said 4-10 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be fused;and wherein said substitutions are selected from the group consisting of: H, -OH, halogen, cyano, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl- oxyalkyl, oxy-C1-C6alkyl-cyano, optionally partially deuterated C1-C6 alkyl, C1-C6 alkyl-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), oxy-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), and oxy-C1-C6alkyl- (optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms) wherein said substitutions on C3-C8cycloalkyl or heterocycloalkyl are selected from the group consisting of H, -OH, halogen, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl-oxyalkyl, and optionally partially deuterated C1-C6alkyl; D is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms and said optional substitutions on said 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are any of the above mentioned substitutions. In certain embodiments, in the compounds of Formula (II), X2is CH. In certain embodiments, in the compounds of Formula (II), X2is N. In certain embodiments, in the compounds of Formula (II), X3 is NH. In certain embodiments, in the compounds of Formula (II), X3 is CH2. In certain embodiments, in the compounds of Formula (II), X3 is CD2. In certain embodiments, in the compounds of Formula (II), X3is O. In certain embodiments, in the compounds of Formula (II), X3is S. In certain embodiments, in the compounds of Formula (II), X3is CF2. In certain embodiments, in the compounds of Formula (II), R8is H. In certain embodiments, in the compounds of Formula (II), R8is methyl. In certain embodiments, in the compounds of Formula (II), R8is -CD3. In certain embodiments, in the compounds of Formula (II), L3is -NH- C(=O)-. In certain embodiments, in the compounds of Formula (II), L3is a single bond. In certain embodiments, in the compounds of Formula (II), L3is -NH-. In certain embodiments, in the compounds of Formula (II), L3is: . In certain embodiments, in the compounds of Formula (II), D is selected from the group consisting of: In certain embodiments, in the compounds of Formula (II), D is cyclopropyl, which can be optionally substituted. In certain embodiments, in the compounds of Formula (II), D is: . In certain embodiments, in the compounds of Formula (II), D is . In certain embodiments, in the compounds of Formula (II), D is: . In certain embodiments, in the compounds of Formula (II), C is an optionally substituted 8-12 membered fused bicyclic ring. In certain embodiments, the fused bicyclic ring comprises N, O, and S as heteroatoms. In certain embodiments, said optional substitutions are selected from the group consisting of deuterium, halogen, cyclopropyl which may optionally be fused with said fused bicyclic ring, methyl, partially halogenated alkyl, oxo, 3-6 membered cycloalkyl or heterocycloalkyl wherein said N or O as heteroatoms. In certain embodiments, C is a 5-membered heteroaryl ring fused with 6-membered aryl or heteroaryl ring, wherein one or more heteroatom is N or O, wherein each of the ring is further optionally substituted. In certain embodiments, in the compounds of Formula (II), C is: . wherein R9and R10are independently selected from the group consisting of H, D, C1-C6alkyl or3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen or C 1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring. In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: wherein R9and R10are independently selected from the group consisting of H, D, OH, halogen, C1-C6alkyl, oxy- C1-C6alkyl, or 3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen, D, or C1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring. In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is: . In certain embodiments, in the compounds of Formula (II), C is selected from the group consisting of: , , , ,

[0020] In certain embodiments, in the compounds of Formula (II), X3is CF2and R8is F. In certain embodiments, in the compounds of Formula (II), X3is CF2and R8is H. In certain embodiments, in the compounds of Formula (II), X3 is O and R8 is methyl. In certain embodiments, in the compounds of Formula (II), X3 is -CH2and R8 is -CH3 or CD3. In certain embodiments, in the compounds of Formula (II), X3 is -CD2 and R8 is -CD3. In certain embodiments, in the compounds of Formula (II), X3is O. In certain embodiments, in the compounds of Formula (II), X3is -N-CH3and R8is -CH3. In certain embodiments, in the compounds of Formula (II), X2is N, X3is -NH, and R8is -CH3. In certain embodiments, in the compounds of Formula (II), X3is -NH and R8is -OCH3. In certain embodiments, in the compounds of Formula (II), X3is O and R8is CD2CD3. In certain aspects, the compounds of the invention are unexpectedly advantageous because they have an unexpectedly better metabolic profile and stability. In certain embodiments, these compounds have better bioavailability as compared to other compounds. In certain embodiments, this unexpected enhanced bioavailability is a beneficial and desired property of the compound being developed as therapy for TYK2 related ailments. In certain embodiments, the compound is selected from the group consisting of the compounds provided in Table A. In certain embodiments, the compounds are selected from the group consisting of the compounds listed in Table B. In certain other aspects, the compounds of the invention are also unexpectedly advantageous because they have a better brain / plasma distribution upon administration to the patient. In certain preferred embodiments, the compounds of the current invention have a better blood brain penetration as compared to other contemporary compounds. In certain embodiments, the blood brain penetration of the compounds of the invention is beneficial because such compounds will be optimal for treatment of ailments of central nervous system. In certain embodiments, the compounds of the invention have better blood brain penetration and central nervous system as compared to the compounds provided in WO2023 / 244788, which is incorporated by reference in its entirety. In certain embodiments, the compounds are selected from the group consisting of the compounds listed in Table C. In certain embodiments, the compounds are selected from the group consisting of the compounds listed in Table D: In certain embodiments, the compounds of the invention are selected from the group consisting of the compounds listed in Table E below. Table E In certain embodiments, the compounds of the invention are selected from the group consisting of the compounds listed in Table F below: Table F:

[0021] In certain aspects, the compounds of the invention are selected from the group consisting of: In certain embodiments, the compounds of the invention do not include the compounds provided in WO2023 / 244788. In certain embodiments, the compounds of the invention do not include Examples 1 – 1142 provided in WO2023 / 244788, which is incorporated by reference in its entirety. In certain embodiments, the compounds of the invention do not include the compounds provided in Examples 1160 – Examples 1188. In certain embodiments, the compounds of the invention do not include the compounds wherein, in the compound of Formula (I), X1is CH. In certain embodiments, the invention provides compounds of Formula (II) with the proviso that the invention does not include the compounds wherein, in the compound of Formula (II), X2is CH. In certain aspects, the invention provides compounds of Formula (IIa), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: wherein X3is NH, N-CH3, CH2, CD2, O, S, -CHF, and -CF2; R8is H, D, halo, C1-C6alkyl, or oxy- C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated, partially halogenated C1-C6alkyl; L3is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; C is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms;said 4-10 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may optionally be fused;and wherein said substitutions are selected from the group consisting of: H, -OH, halogen, cyano, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl- oxyalkyl, oxy-C1-C6alkyl-cyano, optionally partially deuterated C1-C6alkyl, C1-C6alkyl-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), oxy-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), and oxy-C1-C6alkyl- (optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms) wherein said substitutions on C3-C8cycloalkyl or heterocycloalkyl are selected from the group consisting of H, -OH, halogen, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl-oxyalkyl, and optionally partially deuterated C1-C6alkyl; D is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4 alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl or heteroaryl comprises N, O, or S as heteroatoms and said optional substitutions on said 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are any of the above mentioned substitutions. In certain aspects, the invention provides compounds of Formula (IIb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein R8is H, D, halo, or C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; L3 is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; D is 3-6 membered substituted or unsubstituted cycloalkyl, wherein said substitutions are H, C1-C4alkyl; and R9and R10are independently selected from the group consisting of H, D, OH, halogen, and C1-C6alkyl. In certain aspects, the invention provides compounds of Formula (IIc), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. wherein R8is H, D, halo, or C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; L3is a single bond, -NH-, -NH- C(=O)-(CH2)m, –C(=O)-(CH2)m, wherein m is 0, 1, or 2, or 4-6 membered heterocycloalkyl wherein N is the heteroatom; D is 3-6 membered substituted or unsubstituted cycloalkyl, wherein said substitutions are H, C1-C4alkyl; and R9and R10are independently selected from the group consisting of H, D, OH, halogen, or C1-C6alkyl. In certain aspects, the invention provides compounds of Formula (IId), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0022] wherein R8is H, D, halo, or C1-C6alkyl, wherein said C1-C6alkyl is optionally deuterated; D is 3-6 membered substituted or unsubstituted cycloalkyl, wherein said substitutions are H, C1-C4alkyl; and R9and R10are independently selected from the group consisting of H, D, OH, halogen, or C1-C6 alkyl. In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -H.In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -CH3.In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -CD3.In certain embodiments, in the compounds of Formula (IIa), (IIb), (IIc), or (IId), R 8 is -CD3.In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently H. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently -CH3. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently H or D. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently H. In certain embodiments, in the compounds of Formula (IIb), (IIc) or (IId), R9and R10are independently -CD3. In certain embodiments, in the compounds of Formula (IIa), (IIb), or (IIc), L3is a single bond. In certain embodiments, the invention provides compounds of Formula (II), with the proviso that the invention does not include the compounds wherein in the compounds of Formula (II): X2is CH; L3is -C(=O); R8is CH3; and / or C is a 5-membered heteroaryl ring fused with 6-membered aryl or heteroaryl ring, wherein one ormore heteroatom is N or O, wherein each of the ring is further optionally substituted.In certain embodiments, the invention provides compounds of Formula (II), with the proviso that the invention does not include the compounds wherein in the compounds of Formula (II), wherein X2is CH R8is -CH3. In certain embodiments, the compound of the invention is a compound of Formula (II), wherein X2is N, and: X3is NH; R8is optionally deuterated C1-C3alkyl, wherein preferably R8is -CH3or -CD3; L2is a single bond; L3is -NH-C(=O)-; D is optionally substituted cyclopropyl, preferably methyl-cyclopropyl; C is: wherein R9and R10are independently selected from the group consisting of H, D, OH, halogen, C1- C6alkyl, oxy- C1-C6alkyl, or 3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen, D, or C1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring. In certain embodiments, the compound of the invention is a compound of Formula (II), wherein X2is N, and: X3is NH; R8is optionally deuterated C1-C3alkyl, wherein preferably R8is -CH3or -CD3; L2is a single bond; L3is -NH-C(=O)-; D is optionally substituted cyclopropyl, preferably methyl-cyclopropyl; C is selected from the group consisting of: In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that when X2is CH, C does not include:

[0023] In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that in the compounds of Formula (II), when X2is CH and L2is a single bond, C does not include: In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that when X2is CH, D does not include:

[0024] In certain embodiments, the invention provides compounds of Formula (II), as described above, with the proviso that when X2is CH, D does not include: . In certain beneficial aspects, the compounds of the invention are capable of crossing the blood brain barrier. Specifically, the compounds of the invention cross blood brain barrier as compared to other TYK2 inhibitors. Surprisingly, the compounds of the invention are significantly more brain penetrant as compared to other structurally analogous compounds. The beneficial properties of the compounds are important for treatment of conditions afflicting the brain and / or the central nervous system. In certain embodiments, the invention provides pharmaceutically acceptable isotopically labeled compounds described herein. In certain embodiments, the isotopically labeled compounds are compounds where one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. In certain embodiments, the isotopically-labeled compounds of the disclosure, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in viewof their ease of incorporation and ready means of detection.Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art. In another aspect, the invention provides pharmaceutical compositions containing one or morecompounds of the invention, such as any of the compounds described above.In another aspect, the invention provides methods of modulating the activity of a kinase by contacting cells containing a kinase with one or more compounds of the invention, such as any of those described above. The compound may inhibit activity of the kinase. The compound may increase activity of the kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. In another aspect, the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above. The condition may be characterized by elevated activity of a kinase. The condition may be characterized by altered activity of a kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. The condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone- related disease. In another aspect, the invention provides use of a compound of the invention, such as any of those described above, for making a medicament. In embodiments of the use, the medicament is useful for treating a condition in a subject. In embodiments of the use the condition is characterized by elevated activity or altered activity of a kinase. In embodiments of the use, the kinase is a JAK family kinase. In embodiments of the use, the kinase is TYK2. In embodiments of the use, the condition is an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the invention provides a method of inhibiting TYK2 activity in a subject in need thereof with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the invention provides a method of treating a TYK2-mediated disease or disorder comprising administering to a subject in need thereof a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the TYK2-mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In certain embodiments, the TYK2-mediated disease or disorder is multiple sclerosis. Pharmaceutical compositions The present invention provides pharmaceutical compositions containing one or more compounds described above, or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt of such a compound, optionally in combination with a pharmaceutically acceptable carrier. The invention further provides such compounds for the preparation of a medicament for the treatment of one or more diseases mentioned herein. A pharmaceutical composition may contain one or more compounds of the invention in a therapeutically effective amount. A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered,the route of administration, the condition being treated, as well as the patient being treated.Compositions of the invention may include a vehicle for delivery of one or more compounds of the invention. For example, the composition may contain particles, such as nanoparticles, microparticles, liposomes, micelles, and virus particles. Examples of pharmacologically acceptable salts of sufficiently basic compounds of the invention are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of the invention may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2- hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the invention. Compounds of the invention may be solvated, especially hydrated. The hydratization / hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of the invention. The solvates and / or hydrates may e.g. be present in solid or liquid form. It should be appreciated that certain compounds of the invention may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis / trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R / S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of the invention may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio. According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and / or increases the formation of desired active metabolites. Accordingly, the present invention also encompasses the partially and fully deuterated compounds of the invention. The term hydrogen also encompasses deuterium. The therapeutic use of compounds according to the invention, their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention. The pharmaceutical compositions according to the present invention may comprise at least one compound of the invention as an active ingredient and, optionally, carrier substances and / or adjuvants. The present invention also relates to prodrugs which are composed of a compound of the invention and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of the invention, carrying a hydroxy group (-OH): a sulfate, a phosphate (-OPO3 or -OCH2OPO3) or an ester of an amino acid. For example, compositions may contain pro-drugs of the hydroxy group of a compound of the invention. As used herein, the term pharmaceutically acceptable ester especially refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of the invention. As mentioned above, therapeutically useful agents that contain compounds of the invention, their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of the invention will be administered by using the known and acceptable modes known in theart, either alone or in combination with any other therapeutic agent.For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatin capsules, the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skimmilk, and the like. For the production of soft capsules one may use excip ients as are e.g. vegetable,petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Particularly useful are lipids, such as phospholipids (e.g., natural origin and / or with a particle size between 300 to 350 nm) in phosphate buffered saline (pH = 7 to 8, e.g., 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants. In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, or from about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection. Methods of making compounds The invention also provides methods of making compounds of the invention, such as those described above. Synthesis schemes for making specific compounds of Formula (I) and Formula (II) are provided in the Examples below. Methods of treating conditions The compounds and compositions of the invention modulate activity of one or more protein kinases. The compounds and compositions may inhibit, activate, or otherwise alter kinase activity. Consequently, the compounds and compositions may be used to diagnose, treat, or prevent a condition, such as a disease, disorder, or other condition for which modulation of kinase activity provides therapeutic benefit. Diseases, disorders, and conditions that can be diagnosed and / or treated using compositions and methods of the invention include those associated with aberrant activity, e.g., increased activity or decreased activity, of one or more kinases. The kinase may be a serine-threonine kinase or a tyrosine kinase, e.g., a receptor tyrosine kinase or non-receptor tyrosine kinase. The kinase may be a member of the JAK family. For example and without limitation, the kinase may be non-receptor tyrosine-protein kinase TYK2 (TYK2), including mutants of any of the aforementioned kinases. The disease, disorder, or condition may be associated with aberrant TYK2 activity, such as autoimmune disorders, Crohn's disease, hyperimmunoglobulin E syndrome, inflammatory bowel disease, multiple sclerosis (MS), multiple sclerosis (MS), progressive supranuclear palsy (PSP), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes (T1D), or ulcerative colitis. The disease, disorder, or condition may be or include a respiratory tract / obstructive airways disease or disorder, such as rhinorrhea, tracheal constriction, airway contraction, acute-, allergic, atrophic rhinitis or chronic rhinitis (such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupous, fibrinous and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including rhinitis nervosa (hay fever) and vasomotor rhinitis), pollinosis, asthma (such as bronchial, atopic, allergic, intrinsic, extrinsic, exercise- induced, cold air-induced, occupational, bacterial infection-induced, and dust asthma particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness)), bronchitis (including chronic, acute, arachidic, catarrhal, croupous, pythonid and eosinophilic bronchitis), cardio bronchitis, pneumoconiosis, chronic inflammatory disease of the lung which result in interstitial fibrosis, such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (CORD, COAD, COLD or COPD, such as irreversible COPD), chronic sinusitis, conjunctivitis (e.g. allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (like farmer's lung and related diseases), fibroid lung, hypersensitivity lung diseases, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyposis, otitis media, and cough (chronic cough associated with inflammation or iatrogenic induced), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, lung fibrosis, including cryptogenic fibrosing alveolitis, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections, vasculitis and thrombotic disorders of the lung vasculature, and pulmonary hypertension, acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus, allergic bronchopulmonary mycosis, emphysema, diffuse pan bronchiolitis, systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and food related allergies which may have effects remote from the gut (such as migraine, rhinitis and eczema), anaphylactic shock, or vascular spasms. The disease, disorder, or condition may be or include a bone and joint related disease or disorder, such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathies (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Bechet's disease, Marie-Strumpell arthritis, arthritis of inflammatory bowel disease, and Reiter's disease), systemic sclerosis, osteoarthritis, osteoarthrosis, both primary and secondary to e.g.congenital hip dysplasia, cervical and lumbar spondylitis, and low back and neck pain, Sti ll's disease,reactive arthritis and undifferentiated spondarthropathy, septic arthritis and other infection -relatedarthropathies and bone disorders such as tuberculosis, including Pott's disease and Poncet's syndrome, acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursar and synovial inflammation, primary and secondary Sjogren's syndrome, systemic sclerosis and limited scleroderma, mixed connective tissue disease, and undifferentiated connective tissue disease, inflammatory myopathies including, polymalgia rheumatica, juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), rheumatic fever and its systemic complications, vasculitides including giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa, microscopic polyarteritis, and vasculitides to associated with viral infection, hypersensitivity reactions, cryoglobulins, paraproteins, low back pain, Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibenian Fever, Kikuchi disease, drug-induced arthalgias, tendonititides, polychondritis, and myopathies, osteoporosis, osteomalacia like osteoporosis, osteopenia, osteogenesis imperfects, osteopetrosis, osteofibrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, slack of artificial joint implant, sprain or strain of muscle or joint, tendinitis, fasciitis, periarthritis humeroscapularis, cervico-omo-brachial syndrome, or tenosynovitis. The disease, disorder, or condition may be or include a skin or eye related disease or disorder, such as glaucoma, ocular hypertension, cataract, retinal detachment, psoriasis (including psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, erythroderma psoriaticum), palmoplantar pustulosis, xerodoma, eczematous diseases (like atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis, and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilias, chronic skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity / allergic contact dermatitis (including sensitivity to poison ivy, sumac, or oak), and eosinophilic folliculitis (Ofuji's disease), pruritus, drug eruptions, urticaria (acute or chronic, allergic or non-allergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus et atrophica, pyodenna gangrenosum, skin sarcoid, pemphigus, ocular pemphigus, pemphigoid, epidermolysis bullosa, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Stevens-Johnson syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, both, infective and non infective, panniculitis, cutaneous Lymphomas, nonmelanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis including sympathetic ophthalmitis, sarcoidosis, xerosis infections including viral, fungal, and bacterial, allergic conjunctivitis, increased fibrosis, keloids, keloplasty, post-surgical scars, epidermolysis bullosa, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis, ocular angiogenesis, cornea damage and scar, all forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, scleritis, episcleritis, pachydermia, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasiveaspergillosis; conical cornea, dystorphia epithelialis comeae, or severe intraocular inflammation.The disease, disorder, or condition may be or include a gastrointestinal tract and abdominal related disease or disorder, such as celiac / coeliac disease (e.g. celiac sprue), cholecystitis, enteritis (including infectious, ischemic, radiation, drug-induced, and eosinophilic gastroenteritis), eosinophilic esophagitis, eosinophilic gastrointestinal inflammation, allergen induced diarrhea, enteropathy associated with seronegative arthropathies, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, gut ischemia, glossitis, gingivitis, periodontitis, oesophagitis, including reflex, proctitis, fibrosis and cirrhosis of the liver, pancreatitis, both acute and chronic, pancreatic fibrosis, pancreatic sclerosis, pancreatolithiasis, hepatic cirrhosis, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcoholic, lupoid, steatohepatitis and chronic viral), fatty liver, primary biliary cirrhosis, hepatic porphyria, and gastrointestinal related allergic disorders, spastic colon, diverticulitis, gastroenteric bleeding, Behcet's disease; partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), or hemolytic uremic syndrome. The disease, disorder, or condition may be or include a hematological disease or disorder, such as anemias, coagulation, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemias (e.g. myelogenous, lymphomas, plasma cell dyscrasias, disorders of the spleen, Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome. The disease, disorder, or condition may be or include a metabolic disease or disorder, such as obesity, amyloidosis, disturbances of the amino and acid metabolism like branched chain disease, hyperaminoacidemia, hyperaminoaciduria, disturbances of the metabolism of urea, hyperammonemia, mucopolysaccharidoses e.g. Maroteaux-Lamy syndrome, storage disease like glycogen storage diseases and lipid storage diseases, glycogenosis I diseases like Cori's disease, malabsorption diseases like intestinal carbohydrate malabsorption, oligosaccharidase deficiency like maltase-, lactase-, sucrase-insufficiency, disorders of the metabolism of fructose, disorders of the metabolism of galactose, galactosaemia, disturbances of carbohydrate utilization like diabetes, hypoglycemia, disturbances of pyruvate metabolism, hypolipidemia, hypolipoproteinemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, disturbances of the porphyrin metabolism, porphyrins, disturbances of the purine metabolism, lysosomal diseases, metabolic diseases of nerves and nervous systems like gangliosidoses,sphingolipidoses, sulfatidoses, leucodystrophies, or Lesch Nyhan syndrome.The disease, disorder, or condition may be or include a cerebellar dysfunction or disturbance of brain metabolism, such as dementia, Alzheimer's disease, Huntington's chores, Parkinson's disease, Pick's disease, toxic encepha-lopathy, demyelinating neuropathies like inflammatory neuropathy, Guillain-Barre syndrome; Meniere's disease and radiculopathy, primary and secondary metabolic disorders associated with hormonal defects like any disorder stemming from either an hyperfunction or hypofunction of some hormone- secreting endocrine gland and any combination thereof. Sipple's syndrome, pituitary gland dysfunction and its effects on other endocrine glands, such as the thyroid, adrenals, ovaries, and testes, acromegaly, hyper- and hypothyroidism, euthyroid goiter, euthyroid sick syndrome, thyroiditis, and thyroid cancer, over or underproduction of the adrenal steroid hormones, adrenogenital syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disturbances caused by the dysfunction of the parathyroid glands, pancreatic islet cell dysfunction, diabetes, disturbances of the endocrine system of the female like estrogen deficiency, resistant ovary syndrome; muscle weakness, myotonia. Duchenne's and other muscular dystrophies, dystrophia myotonica of Steinert, mitochondrial myopathies like disturbances of the catabolic metabolism in the muscle, carbohydrate and lipid storage myopathies, glycogenoses, myoglobinuria, malignant hyperthermia, polymyalgia rheumatics, dermatomyositis, multiple myositis, primary myocardial disease, cardiomyopathy; disorders of the ectoderm, neurofibromatosis, scleroderma and polyar teritis, Louis-Bar syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria; sexual dysfunction of the male and female; confused states and seizures due to inappropriate secretion of antidiuretic hormone from the pituitary gland, Liddle's syndrome, Bartter's syndrome, Fanconi's I syndrome, or renal electrolyte wasting. The disease, disorder, or condition may be or include a transplant rejection related condition, such as acute and chronic allograft rejection following solid organ transplant, for example, transplantation of kidney, heart, liver, lung, and cornea, chronic graft versus host disease, skin graft rejection, and bonemarrow transplant rejection, or immunosuppression.The disease, disorder, or condition may be or include a genitourinary related condition, such as nephritis (interstitial, acute interstitial (allergic), and glomerulonephritis), nephrotic syndrome, cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo vaginitis, vulvovaginal candidiasis, Peyronie's disease, and erectile dysfunction, renal disease, renal fibrosis, nephropyelitis, secondary contracted kidney, steroid dependent and steroid-resistant nephrosis, or Goodpasture's syndrome. The disease, disorder, or condition may be or include a CNS related disease or disorder, such as neurodegenerative diseases, Alzheimer's disease and other cementing disorders including CJD and nvCJD, amyloidosis, and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, acute and chronic so pain (acute, intermittent or persistent, whether of central or peripheral origin) including post-operative, visceral pain, headache, migraine, neuralgia (including trigeminal), atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies, neurosarcoidosis, to brain injuries, cerebrovascular diseases and their consequences, Parkinson's disease, corticobasal degeneration, motor neuron disease, dementia, including ALS (Amyotrophic-lateral sclerosis), multiple sclerosis, traumatic brain injury, stroke, post-stroke, post- traumatic brain injury, and small-vessel cerebrovascular disease, dementias, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and Parkinsonism linked 1 to chromosome 17, frontotemporal dementias, including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, HIV dementia, schizophrenia with dementia, and Korsakoffs psychosis, within the meaning of the definition are also considered to be CNS disorders central and peripheral nervous system complications of malignant, infectious or autoimmune processes, algesia, cerebral infarction, attack, cerebral ischemia, head injury, spinal cord injury, myelopathic muscular atrophy, Shy-Drager syndrome, Reye's syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe type dementia, acute anterior poliomyelitis (poliomyelitis), poliomyelitis neurosis, viral encephalitis, allergic encephalomyelitis, epileptic encephalopathies, Creutzfeldt-Jakob disease, Kuru disease, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, manic-depressive psychosis, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome, or Machado-Joseph disease. The disease, disorder, or condition may be or include an inflammatory or immunological disease or disorder, such as general inflammation (of the ocular, nasal, pulmonary, and gastrointestinal passages), mastocytosis / mast cell disorders (cutaneous, systemic, mast cell activation syndrome, and pediatric mast cell diseases), mastitis (mammary gland), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis), Wegener granulamatosis, myyositis (including polymyositis, dermatomyositis), basophil related diseases including basophilic leukemia and basophilic leukocytosis, and eosinophil related diseases such as Churg- Strauss syndrome, eosinophilic granuloma, lupus erythematosus (such as, systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus), chronic thyroiditis, Hashimoto's thyroiditis, Grave's disease, type I diabetes, complications arising from diabetes mellitus, other immune disorders, eosinophilia fasciitis, hyper IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency disease, acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, paraneoplastic syndromes, and other autoimmune disorders, fervescence, myositis, nervous diseases selected from multiple myositis, bursitis, Evans syndrome, leukotriene B4-mediated diseases, idiopathic hypoparathyroidism, nephrotic syndrome lupus, or immunosuppression. The disease, disorder, or condition may be or include a cardiovascular disease or disorder, such as congestive heart failure, myocardial infarction, ischemic diseases of the heart, all kinds of atrial and ventricular arrhythmias, hypertension, cerebral trauma, occlusive vascular disease, stroke, cerebrovascular disorder, atherosclerosis, restenosis, affecting the coronary and peripheral is circulation, pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, endocarditis, valvulitis, and aortitis including infective (e.g. syphilitic), hypertensive vascular diseases, peripheral vascular diseases, and atherosclerosis, vasculitides, disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins, aortic aneurism, periarteritis nodosa, cardiac fibrosis, post-myocardial infarction, idiopathic cardiomyopathy, or angioplasty. The disease, disorder, or condition may be or include an oncological disease or disorder, such as common cancers (prostate, breast, lung, ovarian, pancreatic, bowel and colon, abdomen, stomach (and any other digestive system cancers), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvic, skin, bone, soft tissue, spleen, thoracic, urogenital, and brain tumors), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma,ovarian cancer, pancreas cancer, neuroblastoma, malignancies affecting the bone marrow (includ ing theleukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrences, and paraneoplastic syndromes, as well as hypergammaglobulinemia, lymphoproliferative diseases, disorders, and / or conditions, paraproteinemias, purpura (including idiopathic thrombocytopenic purpura), Waldenstron's Macroglobulinemia, Gaucher's Disease, histiocytosis, retinoblastoma and any other hyperproliferative disease, sarcomata, cachexia, tumor growth, tumor invasion, metastasis, AIDS-related lymphomas, malignant immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type, leukemia of unspecified cell type, other and unspecified malignant neoplasms of lymphoid, haematopoietic and related tissues, for example diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma). Myeloid cancer includes e.g. acute or chronic myeloid leukaemia, or keratoleukoma. The disease, disorder, or condition may be or include another disease or disorder, such as pain, migraine, sleep disorders, fever, sepsis, idiopathic thrombocytopenia pupura, post- operative adhesions, flushing, ischemic / reperfusion injury in the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxin shock, septic shock, thermal regulation including fever, Raynaud's disease, gangrene, diseases requiring anti-coagulation therapy, congestive heart failure, mucus secretion disorders, pulmonary hypotension, prostanoid- induced smooth muscle contract associated with dysmenorrhea and premature labor, premature delivery, reperfusion injury, bum, thermal injury, hemorrhage or traumatic shock, menstrual pain, menstrual cramp, dysmenorrhea, periodontosis, rickettsial infectious disease, protozoal disease, reproduction disease, toothache, pain after tooth extraction, Herpeszoster, Herpes simplex, retroperitoneal fibrosis, or various radiation injuries.In certain embodiments, the disease is selected from the group consisting of an inflammatory disease, an autoimmune disease, an allergic disorder, and an ocular disorder. In certain embodiments, the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis and uveitis. The method may include modulating the activity of one or more kinases in a subject, such as any of the kinase described above. The method may include inhibiting a kinase. The method may include activating, e.g., stimulating or enhancing the activity of, a kinase. The method may include modulating activity of a single kinase or preferentially modulating activity of a specific kinase over others. The method may include modulating activity of multiple kinases or preferentially modulating activity of two more specific kinases over others. The method may include providing a compound of the invention. The method may include providing multiple compounds of the invention. The method may include contacting cells containing a kinase with one or more compounds of the invention. For example and without limitation, contacting a cell with a compound may include exposing a cell to a compound, e.g., in a formulation, such as any of those described above; delivering a compound inside a cell; providing a compound to a subject and allowing a cell in the subject to become exposed to the compound. Contacting may be performed in vivo or in vitro. In vitro contact may include exposure of cells or tissue isolated from a subject. The method may include contacting cells with a single compound of the invention. The method may include contact cells with multiple compounds of the invention. The method may include administration of a composition to a subject. The compositions may be provided by any suitable route of administration. For example and without limitation, the compositions may be administered buccally, by injection, dermally, enterally, intraarterially, intravenously, intranasally, e.g., by inhalation, intraocularly, orally, parenterally, pulmonarily, rectally, subcutaneously, systemically, topically, e.g., to the skin or eye, transdermally, or with or on an implantable medical device (e.g., stent or drug- eluting stent or balloon equivalents). Examples: Compounds of the invention can be synthesized through the following general synthetic schemes. The starting materials for the preparation of the compounds and other materials used in the methods described below may be readily obtained from commercial sources or may be prepared from the methods otherwise provided in the pertinent literature. Example 1: Synthesis of N-(5-((4-(2-hydroxy-2-methylpropyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70.0 mg; 0.263 mmol; 1.00 eq.), 1-(4-bromophenyl)-2-methylpropan-2-ol (60.2 mg; 0.263 mmol; 1.00 eq.), XPhos Pd G3(22.2 mg; 0.026 mmol; 0.10 eq.), XPhos (12.5 mg; 0.026 mmol; 0.10 eq.), CuI (5.0 mg; 0.026 mmol; 0.10 eq.) and Et3N (106.4 mg; 1.052 mmol; 4.00 eq.) in DMF (4 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 90 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 0-9% of MeOH in CH2Cl2as eluent to afford N-(5-((4-(2-hydroxy-2-methylpropyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (58.9 mg, 53.8%).LCMS (ESI) m / z 415.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.66 (s, 1H), 8.34 - 8.27 (m, 1H), 8.26 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.37 (s, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.69 (s, 2H), 2.13 - 2.03 (m, 1H), 1.08 (s, 6H), 0.93 - 0.81 (m, 4H). Examples 2-28: Each compound in Table 1 below was prepared using a similar experimental procedure to prepare Example 1 using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as the common intermediate and an appropriate aryl halide. Table 1:

[0025] Example 29: Synthesis of (R)-N-(5-((5-((3-methoxypyrrolidin-1-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: (R)-2-bromo-5-((3-methoxypyrrolidin-1-yl)methyl)pyridine To a stirred solution of 6-bromopyridine-3-carbaldehyde (200.0 mg; 1.075 mmol; 1.00 eq.), (R)-3- methoxypyrrolidine (163.1 mg; 1.612 mmol; 1.50 eq;) and AcOH (64.6 mg; 1.076 mmol; 1.00 eq.) in 1,2- dichloroethane (5 mL) was added NaBH(OAc)3(683.7 mg; 3.226 mmol; 3.00 eq.). The resulting mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-40% of EtOAc in petroleum ether as eluent to provide (R)-2- bromo-5-((3-methoxypyrrolidin-1-yl)methyl)pyridine as a yellow oil (200.0 mg, 65.2%). LCMS (ESI) m / z 271.2, [M+H]+. Each intermediate in Table 2 below was prepared using a similar experimental procedure to prepare (R)-2-bromo-5-((3-methoxypyrrolidin-1-yl)methyl)pyridine, where (R)-3-methoxypyrrolidine was replaced with the reagent as shown in Table 2 below. Table 2:

[0026] Step 2: (R)-N-(5-((5-((3-methoxypyrrolidin-1-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A stirred mixture of (R)-2-bromo-5-((3-methoxypyrrolidin-1-yl)methyl)pyridine (90.0 mg; 0.332 mmol; 1.00 eq.), N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (132.6 mg; 0.498 mmol; 1.50 eq.), XPhos Pd G3(84.3 mg; 0.100 mmol; 0.30 eq.), XPhos (47.5 mg; 0.100 mmol; 0.30 eq.), Et3N (134.4 mg; 1.328 mmol; 4.00 eq.) and CuI (19.0 mg; 0.100 mmol; 0.30 eq.) in DMF (3 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 90 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford a crude product. The crude product was purified by Prep-Achiral-SFC (Column: YMC-Actus Triart Diol-HILIC 3 × 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH); Flow rate: 75 mL / min; Gradient: 46% B to 46% B in 15 min) to afford (R)-N-(5-((5-((3-methoxypyrrolidin-1-yl)methyl)pyridin- 2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (29.2 mg, 18.8%). LCMS (ESI) m / z 457.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.39 (s, 1H), 8.63 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.47 - 8.39 (m, 1H), 8.35 (s, 1H), 7.78 (dd, J = 8.0, 2.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 3.94 - 3.86 (m, 1H), 3.63 (s, 2H), 3.17 (s, 3H), 3.04 (d, J = 4.4 Hz, 3H), 2.72 - 2.66 (m, 1H), 2.63 - 2.56 (m, 1H), 2.49 - 2.40 (m, 2H), 2.15 - 2.05 (m, 1H), 2.04 - 1.95 (m, 1H), 1.74 - 1.61 (m, 1H), 0.96 - 0.79 (m, 4H). Examples 30-40: Each compound in Table 3 below was prepared using a similar experimental procedure to prepare Example 29 using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl) cyclopropanecarboxamide as the common intermediate and the appropriate aryl halides. Table 3:

[0027] Example 41: Synthesis of N-(5-((4-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: N-(5-((4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarbox amide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (400.0 mg; 1.502 mmol; 1.00 eq.), 4-bromobenzaldehyde (416.8 mg; 2.253 mmol; 1.50 eq.), XPhos Pd G3(127.1 mg; 0.150 mmol; 0.10 eq.), XPhos (143.2 mg; 0.300 mmol; 0.20 eq.), CuI (28.6 mg; 0.150 mmol; 0.10 eq.) and Et3N (455.9 mg; 4.505 mmol; 3.00 eq.) in DMF (10 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 5- 10% of MeOH in CH2Cl2as eluent to provide N-(5-((4-formylphenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (350 mg, 59.7%). LCMS (ESI) m / z 371.1, [M+H]+. Step 2: N-(5-((4-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7 -naphthyridin-3-yl)cyclopropanecarboxamide To a stirred solution of N-(5-((4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (100.0 mg; 0.270 mmol; 1.00 eq.), 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (55.0 mg; 0.406 mmol; 1.50 eq.) and DIPEA (150.0 mg; 1.161 mmol; 4.30 eq.) in 1,2- dichloroethane (15 mL) was added NaBH(OAc)3(180.0 mg; 0.849 mmol; 3.15 eq.) at 0 ℃. The resulting solution was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with ice water and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 5 -10% ofMeOH in CH2Cl2 as eluent to afford a crude product. The crude product was purified by flash chromatography on pre-packed C18 column using 40-60% of MeOH / THF=1:1 in water (10 mmol / L NH4HCO3) as eluent to provide N-(5-((4-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)phenyl)ethynyl)- 8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (16.5 mg, 13.8%). LCMS (ESI) m / z 454.2, [M+H]+. Each compound in Table 4 below was prepared using a similar experimental procedure to prepare Example 41 using N-(5-((4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide as the common intermediate and appropriate amine. Examples 42-48: Table 4:

[0028] Example 49: Synthesis of N-(5-((4-((3-(difluoromethoxy)azetidin-1-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: benzyl 3-(difluoromethoxy)azetidine-1-carboxylate To a stirred solution of benzyl 3-hydroxyazetidine-1-carboxylate (2.00 g; 9.651 mmol; 1.00 eq.) and CuI(0.37 g; 1.930 mmol; 0.20 eq.) in MeCN (50 mL) was added a solution of 2,2 -difluoro-2-(fluorosulfonyl)acetic acid (2.58 g; 14.476 mmol; 1.50 eq.) in MeCN (50 mL) at 50 ℃. The resulting mixture was stirred at 50 ℃ for 30 minutes. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), the insoluble solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-50% of EtOAc in petroleum ether as eluent to afford benzyl 3-(difluoromethoxy)azetidine-1-carboxylate as a light yellow oil (1.6 g, 64.4%). LCMS (ESI) m / z 258.2, [M+H]+. Step 2: 3-(difluoromethoxy)azetidine hydrochloride To a stirred solution of benzyl 3-(difluoromethoxy)azetidine-1-carboxylate (1.60 g; 6.220 mmol; 1.00 eq.) in MeOH (20 mL) was added 10% Pd / C (1.60 g, 10% w / w) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 days under hydrogen atmosphere (30 atm). The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was filtered. The filtrate was diluted with HCl / MeOH (4 M, 10 mL) and stirred at room temperature for 0.5 hour. The resulting mixture was concentrated under reduced pressure to afford 3-(difluoromethoxy)azetidine hydrochloride as a light yellow oil (730.0 mg, crude). LCMS (ESI) m / z 124.1, [M+H]+. Step 3: N-(5-((4-((3-(difluoromethoxy)azetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-((3-(difluoromethoxy)azetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 41 by using N-(5-((4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Example 41, Step 1) and 3-(difluoromethoxy)azetidine hydrochloride as the starting material. LCMS (ESI) m / z 478.2, [M+H]+ Example 50: Synthesis of N-(5-((4-((3-ethoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: tert-butyl 3-ethoxyazetidine-1-carboxylate To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (200.0 mg; 1.155 mmol; 1.00 eq.) in DMF (4 mL) was added NaH (60% dispersion in mineral oil,55.5 mg; 2.313 mmol; 2.00 eq.) at 0 ℃ undernitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 hours. To the abovemixture was added iodoethane (360.7 mg; 2.313 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (10 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 10-30% of EtOAc in petroleum ether as eluent to provide tert-butyl 3-ethoxyazetidine-1-carboxylate as a yellow oil (193.0 mg, 83.0%). LCMS (ESI) m / z 202.1, [M+H]+. Step 2: 3-ethoxyazetidine hydrochloride To a solution of tert-butyl 3-ethoxyazetidine-1-carboxylate (50.0 mg; 0.248 mmol; 1.00 eq.) in MeOH (2 mL) was added HCl in1,4-dioxane (4.0 M, 0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was concentrated under vacuum to afford 3-ethoxyazetidine hydrochloride as a white solid (40.0 mg, crude). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z 102.1,+ Step 3: N-(5-((4-((3-ethoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide N-(5-((4-((3-ethoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 41 by using N-(5-((4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Example 41, Step 1) and 3-ethoxyazetidine hydrochloride as the starting material. LCMS (ESI) m / z 456.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.34 - 8.29 (m, 1H), 8.27 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.11 - 4.01 (m, 1H), 3.61 (s, 2H), 3.55 - 3.47 (m, 2H), 3.40 - 3.32 (m, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.95 - 2.80 (m, 2H), 2.14 - 2.03 (m, 1H), 1.10 (t, J = 7.0 Hz, 3H), 0.94 - 0.71 (m, 4H) Example 51: Synthesis of N-(5-((5-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)pyridin-2- yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: N-(5-((5-formylpyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.0 mg; 0.376 mmol; 1.00 eq.), 6-bromonicotinaldehyde (104.7 mg; 0.564 mmol; 1.50 eq.), XPhos Pd G3(31.7 mg; 0.038 mmol; 0.10 eq.), XPhos (35.8 mg; 0.075 mmol; 0.20 eq.), CuI (7.1 mg; 0.038 mmol; 0.10 eq.) and Et3N (114.0 mg; 1.127 mmol; 3.00 eq.) in DMF (5 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2- 10% of MeOH in CH2Cl2as eluent to afford N-(5-((5-formylpyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (120.0 mg, 81.7%). LCMS (ESI) m / z 372.2, [+. Step 2: N-(5-((5-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((5-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 41 by using N-(5-((5-formylpyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide and 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride as the starting material. LCMS (ESI) m / z 455.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.39 (s, 1H), 8.63 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.48 - 8.40 (m, 1H), 8.35 (s, 1H), 7.84 (dd, J = 8.0, 2.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 3.78 - 3.63 (m, 2H), 3.53 - 3.48 (m, 3H), 3.03 (d, J = 4.4 Hz, 3H), 2.60 - 2.55 (m, 1H), 2.31 - 2.20 (m, 2H), 2.12 - 2.02 (m, 1H), 0.94 - 0.80 (m, 4H), 0.76 - 0.67 (m, 1H), 0.38 - 0.29 (m, 1H). Example 52: Synthesis of N-(5-((2-((3-methoxyazetidin-1-yl)methyl)pyridin-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: N-(5-((2-formylpyridin-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide To a stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (150.0 mg; 0.564 mmol; 1.00 eq.), 4-bromopicolinaldehyde (156.5 mg; 0.846 mmol; 1.50 eq.), XPhos (53.8 mg; 0.113 mmol; 0.20 eq.), XPhos Pd G3(47.7 mg; 0.056 mmol; 0.10 eq.) and CuI (10.7 mg; 0.056 mmol; 0.10 eq.) in DMF (1 mL) was added Et3N (170.9 mg; 1.692 mmol; 3.00 eq.). The resulting mixture was degassed and purged with N2for 3 times and stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 0-4% of MeOH in CH2Cl2as eluent to afford N-(5-((2-formylpyridin-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (250.0 mg, 51.4%). LCMS (ESI) m / z 372.1, [M+H]+. Step 2: N-(5-((2-((3-methoxyazetidin-1-yl)methyl)pyridin-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((2-((3-methoxyazetidin-1-yl)methyl)pyridin-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 41 by using N-(5-((2-formylpyridin-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and 3-methoxyazetidine hydrochloride as the starting material. LCMS (ESI) m / z 443.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.38 (s, 1H), 8.69 (s, 1H), 8.57 - 8.43 (m, 2H), 8.34 (s, 1H), 7.49 - 7.43 (m, 1H), 7.37 - 7.30 (m, 1H), 4.08 - 3.98 (m, 1H), 3.71 (s, 2H), 3.67 - 3.58 (m, 2H), 3.17 (s, 3H), 3.03 (d, J = 4.4 Hz, 3H), 3.00 - 2.91 (m, 2H), 2.15 - 2.04 (m, 1H), 0.98 - 0.79 (m, 4H). Example 53: Synthesis of N-(5-((3-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: N-(5-((3-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarbox amide A stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.0 mg; 0.311 mmol; 1.00 eq.), 3-ethynylbenzaldehyde (101.3 mg; 0.777 mmol; 2.50 eq.), XPhos Pd G3(26.3 mg; 0.031 mmol; 0.10 eq.), XPhos (14.8 mg; 0.031 mmol; 0.10 eq.), CuI (5.9 mg; 0.031 mmol; 0.10 eq.) and Et3N (126.0 mg; 1.244 mmol; 4.00 eq.) in DMF (6 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 90 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated undervacuum. The residue was purified by flash chromatography on silica gel column using 0 -5% of MeOH inCH2Cl2as eluent to provide N-(5-((3-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (100.1 mg, 78.4%). LCMS (ESI) m / z 371.1, [M+H] +.Step 2: N-(5-((3-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((3-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 41 by using N-(5-((3-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and 3-methoxyazetidine hydrochloride as the starting material. LCMS (ESI) m / z 442.2, [M+H]+Example 54: Synthesis of N-(5-((4-((6-oxa-1-azaspiro[3.3]heptan-1-yl)methyl)-2- fluorophenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: N-(5-((2-fluoro-4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide To a stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.1 mg; 0.376 mmol; 1.50 eq.), XPhos Pd G3 (42.4 mg; 0.050 mmol; 0.20 eq.), XPhos (23.8 mg; 0.050 mmol; 0.20 eq.), CuI (9.5 mg; 0.050 mmol; 0.20 eq.) and 4-bromo-3-fluorobenzaldehyde (50.8 mg; 0.251 mmol; 1.00 eq.) in DMF (3 mL) was added Et3N (76.0 mg; 0.752 mmol; 3.00 eq.) at room temperature. The resulting mixture was degassed and purged with N2for 3 times and stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford N-(5-((2-fluoro- 4-formylphenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (80.1 mg, 82.2%). LCMS (ESI) m / z 389.1, [M+H]+. Step 2: N-(5-((4-((6-oxa-1-azaspiro[3.3]heptan-1-yl)methyl)-2-fluorophenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0029] N-(5-((4-((6-oxa-1-azaspiro[3.3]heptan-1-yl)methyl)-2-fluorophenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 41 by using N-(5-((2-fluoro-4-formylphenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide and 6-oxa-1-azaspiro[3.3]heptane as the starting material. LCMS (ESI) m / z 472.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.38 (s, 1H), 8.61 (s, 1H), 8.40 - 8.33 (m, 1H), 8.29 (s, 1H), 7.60 - 7.53 (m, 1H), 7.32 - 7.22 (m, 2H), 4.84 (d, J = 7.2 Hz, 2H), 4.52 (d, J = 7.2 Hz, 2H), 3.85 (s, 2H), 3.05 - 2.98 (m, 5H), 2.33 (t, J = 6.6 Hz, 2H), 2.12 - 2.02 (m, 1H), 0.92 - 0.76 (m, 4H). Example 55: Synthesis of N-(5-((2-(hydroxymethyl)furo[2,3-c]pyridin-5-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: methyl 5-chlorofuro[2,3-c]pyridine-2-carboxylate A solution of 2-chloro-5-hydroxyisonicotinaldehyde (200.0 mg; 1.270 mmol; 1.00 eq.), methyl 2 -bromoacetate (313.6 mg; 1.396 mmol; 1.10 eq.) and K2CO3(701.8 mg; 5.078 mmol; 4.00 eq.) in DMF (5 mL) was stirred at 80 ℃ for 1 hour under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature. The crude mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers werewashed with brine (50 mL) just once, dried over anhydrous Na 2SO4. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-50% of EtOAc in petroleum ether as eluent to afford methyl 5-chlorofuro[2,3-c]pyridine- 2-carboxylate as a white solid (120.0 mg, 44.6%). LCMS (ESI) m / z 212.1, [M+H]+. Step 2: (5-chlorofuro[2,3-c]pyridin-2-yl)methanol To a stirred solution of methyl 5-chlorofuro[2,3-c]pyridine-2-carboxylate (110.0 mg; 0.520 mmol; 1.00 eq.) in THF (10 mL) was added LiBH4(2.0 M in THF, 1.0 mL) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction was quenched with a saturated aqueous solution of NH4Cl at 0 ℃. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layerswere washed with brine (50 mL) just once, dried over anhydrous Na 2SO4. After filtration, the filtrate wasconcentrated under reduced pressure to afford (5-chlorofuro[2,3-c]pyridin-2-yl)methanol as a white solid (100.0 mg, crude). LCMS (ESI) m / z 184.2, [M+H]+. Step 3: N-(5-((2-(hydroxymethyl)furo[2,3-c]pyridin-5-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((2-(hydroxymethyl)furo[2,3-c]pyridin-5-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and (5-chlorofuro[2,3-c]pyridin-2-yl)methanol as the starting material. LCMS (ESI) m / z 414.1, [M+H]+. Example 56: Synthesis of N-(5-((2-(fluoromethyl)furo[2,3-c]pyridin-5-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide To a stirred solution of N-(5-((2-(hydroxymethyl)furo[2,3-c]pyridin-5-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Example 55) (110.0 mg; 0.266 mmol; 1.00 eq.) in dichloromethane (20 mL) was added DAST (128.6 mg; 0.798 mmol; 3.00 eq.) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The desired productwas detected via LCMS. After the completion of reaction, the reaction was quenched with a saturatedaqueous solution of NaHCO3and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 20-60% of MeCN / THF = 3:1 in water (10 mmol / L NH4HCO3) to provide N-(5-((2- (fluoromethyl)furo[2,3-c]pyridin-5-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide as a yellow solid (1.9 mg, 1.6%). LCMS (ESI) m / z 416.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.39 (s, 1H), 9.03 (s, 1H), 8.65 (s, 1H), 8.42 - 8.37 (m, 1H), 8.36 (s 1H), 8.03 (s, 1H), 7.29 (d, J = 4.4 Hz, 1H), 5.66 (d, J = 47.6 Hz, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.17 - 2.00 (m, 1H), 0.91 - 0.82 (m, 4H). Example 57: Synthesis of N-(5-((5-((1-methyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-((6-chloropyridin-3-yl)methyl)malononitrile To a solution of malononitrile (2.46 g; 37.282 mmol; 3.00 eq.) and K2CO3(5.14 g; 37.158 mmol; 3.00 eq.) in DMF (40 mL) was added a solution of 2-chloro-5-(chloromethyl)pyridine (2.00 g; 12.345 mmol; 1.00 eq.) in DMF (60 mL) dropwise at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was diluted with water (200 mL) and acidified to pH = 2 with concentrated hydrochloric acid. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-13% of EtOAc in CH2Cl2as eluent to provide 2-((6-chloropyridin-3-yl)methyl)malononitrile as a brown solid (700.0 mg, 29.5%). LCMS (ESI) m / z 192.0, [M+H]+. Step 2: 4-((6-chloropyridin-3-yl)methyl)-1H-pyrazole-3,5-diamine A solution of 2-((6-chloropyridin-3-yl)methyl)malononitrile (700.2 mg; 4.071 mmol; 1.00 eq.) and hydrazine hydrate (80%; 328 mg; 5.248 mmol; 1.29 eq.) in EtOH (8 mL) was stirred at 80 ℃ for 4 hours. Then additional amount of hydrazine hydrate (80%; 164 mg) was added at room temperature and stirred at 80 ℃ for another 4 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature. The resulting mixture was purified by flash chromatography on pre-packed C18 column using 0-25% of MeCN in water (10 mmol / L NH4HCO3) as eluent to provide 4-((6-chloropyridin-3-yl)methyl)-1H-pyrazole-3,5-diamine as a yellow solid (280.0 mg, 30.7%). LCMS (ESI) m / z 224.1, [M+H]+. Step 3: 5-((1H-pyrazol-4-yl)methyl)-2-chloropyridine To a stirred solution of 4-((6-chloropyridin-3-yl)methyl)-1H-pyrazole-3,5-diamine (260.3 mg; 1.162 mmol; 1.00 eq.) and phosphinic acid (50% in water; 3.77 mL) in water (3 mL) was added a solution of NaNO2(177.2 mg; 2.568 mmol; 2.20 eq.) in water (1 mL) dropwise at 0 ℃. The resulting mixture was stirred at 0 ℃ for 0.5 hour and then allowed to warm to room temperature and stirred for 4.5 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction was diluted with water (20 mL) and neutralized to pH = 7 with an aqueous solution of NaOH (2 M). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-2% of MeOH in CH2Cl2as eluent to provide 5-((1H-pyrazol-4-yl)methyl)-2-chloropyridine as a white solid (90.3 mg, 39.9%). LCMS (ESI) m / z 194.0, [M+H]+. Step To a stirred solution of 5-((1H-pyrazol-4-yl)methyl)-2-chloropyridine (90.3 mg; 0.516 mmol; 1.00 eq.) and K2CO3(214.8 mg; 1.554 mmol; 3.00 eq.) in DMF (1 mL) was added iodomethane (366.5 mg; 2.582 mmol; 5.00 eq.). The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)pyridine as a yellow solid (50.1 mg, 46.6%). LCMS (ESI) m / z 208.1, [M+H]+. Step 5: N-(5-((5-((1-methyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((5-((1-methyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)pyridine as the starting material. LCMS (ESI) m / z 438.2, [M+H]+Example 58: Synthesis of N-(8-(methylamino)-5-((5-(1-morpholinoethyl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4-(1-(6-bromopyridin-3-yl)ethyl)morpholine A solution of 1-(6-bromopyridin-3-yl)ethan-1-one (300.0 mg; 1.500 mmol; 1.00 eq.), morpholine (195.9 mg; 2.250 mmol; 1.50 eq.), DIPEA (387.6 mg; 3.000 mmol; 2.00 eq.) and NaBH(OAc)3(953.5 mg; 4.500 mmol; 3.00 eq.) in 1,2-dichloroethane (6 mL) was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated solution of NaHCO3(10 mL). The crude mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on pre- packed C18 column using 40-60% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide 4-(1-(6- bromopyridin-3-yl)ethyl)morpholine as a colorless oil (87.5 mg, 21.0%). LCMS (ESI) m / z 271.0, [M+H]+. Step 2: N-(8-(methylamino)-5-((5-(1-morpholinoethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)c yclopropanecarboxamide N-(8-(methylamino)-5-((5-(1-morpholinoethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-(1-(6-bromopyridin-3-yl)ethyl)morpholine as the starting material. LCMS (ESI) m / z 457.2, [M+H]+. Each isomer in the table below was obtained by chiral SFC purification from Example 58 the configuration has been arbitrarily assigned.

[0030] Example 61: Synthesis of N-(8-(methylamino)-5-((4-((1-methylazetidin-3-yl)oxy)phenyl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate To a solution of 4-bromophenol (2.00 g; 11.560 mmol; 1.00 eq.) and Cs2CO3(7.53 g; 23.120 mmol; 2.00 eq.) in DMF (40 mL) was added tert-butyl 3-bromoazetidine-1-carboxylate (4.09 g; 17.340 mmol; 1.50 eq.) at 0 ℃. The resulting solution was stirred at 120 ℃ for 1 hour. The desired product was detected via LCMS. After completion of reaction, the resulting mixture was cooled to room temperature. The reaction was diluted with water (50 mL), extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 10-20% of EtOAc in petroleum ether as eluent to provide tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate as a white oil (4.60 g, 86.6%). LCMS (ESI) m / z 328.0, [M+H]+. Step 2: 3-(4-bromophenoxy)azetidine hydrochloride A solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (300.0 mg; 0.914 mmol; 1.00 eq.) and HCl in 1,4-dioxane (4.0 M, 8 mL) in methanol (4 mL) was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After completion of reaction, the resulting mixture was concentrated under reduced pressure to afford 3-(4-bromophenoxy)azetidine hydrochloride as a white solid (264.0 mg, crude). The crude product was used in the next step without further purification. LCMS (ESI) m / z 228.0, [M+H]+. Step 3: 3-(4-bromophenoxy)-1-methylazetidine To a stirred solution of 3-(4-bromophenoxy)azetidine hydrochloride (250.0 mg; 0.945 mmol; 1.00 eq.) and formaldehyde (37% in water,588.5 mg; 7.256 mmol; 7.68 eq.) in CH2Cl2(10 mL) was added NaBH(OAc)3(600.8 mg; 2.835 mmol; 3.00 eq.) at 0 ℃. The resulting solution was stirred at room temperature for 1.5 hours. The desired product was detected via LCMS. After completion of reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 1-5% of MeOH in CH2Cl2as eluent to provide 3-(4-bromophenoxy)-1-methylazetidine as a white oil (228.0 mg, 99.6%). LCMS (ESI) m / z 242.0, [M+H]+. Step 4: N-(8-(methylamino)-5-((4-((1-methylazetidin-3-yl)oxy)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(8-(methylamino)-5-((4-((1-methylazetidin-3-yl)oxy)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 3-(4-bromophenoxy)-1-methylazetidine as the starting material. LCMS (ESI) m / z 428.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.37 (s, 1H), 8.63 (s, 1H), 8.30 - 8.25 (m, 1H), 8.24 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 4.84 - 4.74 (m, 1H), 3.79 - 3.68 (m, 2H), 3.05 - 2.93 (m, 5H), 2.30 (s, 3H), 2.12 - 2.01 (m, 1H), 0.92 - 0.78 (m, 4H). Example 62: Synthesis of N-(5-(([1,3]dioxolo[4,5-c]pyridin-6-yl-2,2-d2)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 6-bromopyridine-3,4-diol To a stirred solution of 2-bromo-5-methoxypyridin-4-ol (300.0 mg; 1.470 mmol; 1.00 eq.) in dichloromethane (6 mL) was added tribromoborane (1.0 M in CH2Cl2, 2.2 mL) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with an aqueous solution of sodium hyposulfite (6 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 30- 100% of MeCN in water (0.5% trifluoroacetic acid) as eluent to afford 6-bromopyridine-3,4-diol as an off-white solid (300 mg, crude). LCMS (ESI) m / z 189.9, [M+H]+. Step 2: 6-bromo-[1,3]dioxolo[4,5-b]pyridine-2,2-d2 A mixture of 6-bromopyridine-3,4-diol (300.1 mg; 1.579 mmol; 1.00 eq.), Cs2CO3(771.7 mg; 2.369 mmol; 1.50 eq.) and dibromomethane-d2(416.4 mg; 2.369 mmol; 2.00 eq.) in DMF (3 mL) was stirred at 110 ℃ for 1 hour under nitrogen atmosphere. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-35% of EtOAc in petroleum ether as eluent to afford 6-bromo- [1,3]dioxolo[4,5-b]pyridine-2,2-d2as an off-white solid (66.1 mg, 20.4%). LCMS (ESI) m / z 204.0, [M+H]+. Step 3: N-(5-(([1,3]dioxolo[4,5-c]pyridin-6-yl-2,2-d2)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-y l)cyclopropanecarboxamide N-(5-(([1,3]dioxolo[4,5-c]pyridin-6-yl-2,2-d2)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 6-bromo-[1,3]dioxolo[4,5-b]pyridine-2,2-d2 as the starting material. LCMS (ESI) m / z 390.1, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.38 (s, 1H), 8.62 (s, 1H), 8.42 - 8.35 (m, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 7.29 (s, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.13 - 2.02 (m, 1H), 0.94 - 0.80 (m, 4H). Example 63: Synthesis of N-(8-(methylamino)-5-((5-((tetrahydrofuran-2-yl)methyl)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4-(trifluoromethyl)benzenesulfonohydrazide To a stirred solution of 4-(trifluoromethyl)benzenesulfonyl chloride (3.00 g; 12.264 mmol; 1.00 eq.) in THF (45 mL) was added hydrazine hydrate (80%) (2.29 g; 36.669 mmol; 3.00 eq.) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at 0 ℃ for 0.5 hour. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(trifluoromethyl)benzenesulfonohydrazide as an off-white solid (2.90 g, 98.4%). LCMS (ESI) m / z 241.0, [M+H]+. Step 2: (Z)-N'-((6-chloropyridin-3-yl)methylene)-4-(trifluoromethyl)benzenesulfonohydrazide To a stirred solution of 4-(trifluoromethyl)benzenesulfonohydrazide (410.0 mg; 1.707 mmol; 1.00 eq.) in EtOH (2.2 mL) was added 6-chloronicotinaldehyde (241.6 mg; 1.707 mmol; 1.00 eq.) at room temperature. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the precipitated solids were collected by filtration, washed with hexane and dried under vacuum to afford (Z)-N'-((6-chloropyridin-3-yl)methylene)-4- (trifluoromethyl)benzenesulfonohydrazide as a white solid (510 mg, 82.1%). LCMS (ESI) m / z 364.0, [M+H]+. Step 3: N'-((6-chloropyridin-3-yl)(tetrahydrofuran-2-yl)methyl)-4-(trifluoromethyl)benzenesulfono hydrazide A solution of (Z)-N'-((6-chloropyridin-3-yl)methylene)-4-(trifluoromethyl)benzenesulfonohydrazide (450.0 mg; 1.237 mmol; 1.00 eq.) and bis(4-chlorophenyl)methanone (62.1 mg; 0.247 mmol; 0.20 eq.) in a mixture solvent of THF / TFT (1:1, 12 mL) was degassed and purged with N2for 3 times. The resulting mixture was placed in the photoreactor (Kessil PR160390 nm lamp) and stirred at 30 ℃ for 12 hours. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was concentrated under reduced pressure to afford N'-((6-chloropyridin-3-yl)(tetrahydrofuran-2-yl)methyl)-4- (trifluoromethyl)benzenesulfonohydrazide (538.9 mg, crude). The crude product was used in the next step without further purification. LCMS (ESI) m / z 436.1, [M+H]+. Step 4: 2-chloro-5-((tetrahydrofuran-2-yl)methyl)pyridine A mixture N'-((6-chloropyridin-3-yl)(tetrahydrofuran-2-yl)methyl)-4- (trifluoromethyl)benzenesulfonohydrazide (538.9 mg; 1.236 mmol; 1.00 eq.) and Et3N (375.3 mg; 3.709 mmol; 3.00 eq.) in EtOH (12 mL) was stirred at 80 ℃ for 1 hour under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-50% of EtOAc in petroleum ether as eluent to afford 2-chloro-5- ((tetrahydrofuran-2-yl)methyl)pyridine as an off-white solid (184.0 mg, 75.2%). LCMS (ESI) m / z 198.1, [M+H]+. Step 5: N-(8-(methylamino)-5-((5-((tetrahydrofuran-2-yl)methyl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(8-(methylamino)-5-((5-((tetrahydrofuran-2-yl)methyl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using 2-chloro-5-((tetrahydrofuran-2-yl)methyl)pyridine and N-(5-ethynyl-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as the starting material. LCMS (ESI) m / z 428.2, [M+H]+. Example 64: Synthesis of N-(8-(methylamino)-5-((5-(tetrahydrofuran-3-yl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4-(6-bromopyridin-3-yl)tetrahydrofuran-2-ol A solution of 2-bromo-5-iodopyridine (500.0 mg; 1.761 mmol; 1.00 eq.), (Z)-but-2-ene-1,4-diol (186.2 mg; 2.113 mmol; 1.20 eq.), Pd(OAc)2(7.9 mg; 0.035 mmol; 0.02 eq.), NaHCO3(295.9 mg; 3.522 mmol; 2.00 eq.) and tetrabutylazanium chloride (489.4 mg; 1.761 mmol; 1.00 eq.) in MeCN (5.0 mL) was stirred at 60 ℃ overnight under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature. The resulting mixture was diluted with diethyl ether (60 mL) and washed with brine (3 × 5 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 4-(6- bromopyridin-3-yl)tetrahydrofuran-2-ol as a brown solid (623.2 mg, 39.5%). LCMS (ESI) m / z 244.0, [M+H]+. Step 2: 2-bromo-5-(tetrahydrofuran-3-yl)pyridine To a stirred solution of 4-(6-bromopyridin-3-yl)tetrahydrofuran-2-ol (620.0 mg; 2.540 mmol; 1.00 eq.) in CH2Cl2 (5.0 mL) were added triethylsilane (324.8 mg; 2.794 mmol; 1.10 eq.) and BF3 OEt2 (396.5 mg; 2.794 mmol; 1.10 eq.) dropwise at 0 ℃. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3(20 mL). The resulting mixture was extracted with CH2Cl2(3 × 15 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 20-30% of EtOAc in petroleum ether as eluent to provide 2-bromo-5-(tetrahydrofuran-3-yl)pyridine as a yellow oil (92.9 mg, 15.1%). LCMS (ESI) m / z 228.0, [M+H]+Step 3: N-(8-(methylamino)-5-((5-(tetrahydrofuran-3-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-y l)cyclopropanecarboxamide N-(8-(methylamino)-5-((5-(tetrahydrofuran-3-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-bromo-5-(tetrahydrofuran-3-yl)pyridine as the starting material. LCMS (ESI) m / z 414.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.38 (s, 1H), 8.62 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.43 - 8.37 (m, 1H), 8.34 (s, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 4.08 - 4.02 (m, 1H), 4.01 - 3.94 (m, 1H), 3.86 - 3.78 (m, 1H), 3.64 - 3.58 (m, 1H), 3.51 - 3.42 (m, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.42 - 2.29 (m, 1H), 2.13 - 2.04 (m, 1H), 2.02 - 1.90 (m, 1H), 0.92 - 0.80 (m, 4H). Example 65: Synthesis of N-(5-((5-(3-methoxyazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0031] Step 1: 2-bromo-5-(3-methoxyazetidin-1-yl)pyridine A stirred mixture of 3-methoxyazetidine hydrochloride (200.0 mg; 1.618 mmol; 1.00 eq.), 2-bromo-5- iodopyridine (460.0 mg; 1.620 mmol; 1.00 eq.), Pd2(dba)3(148.2 mg; 0.162 mmol; 0.10 eq.), XantPhos (187.2 mg; 0.324 mmol; 0.20 eq.) and Cs2CO3(1055.0 mg; 3.238 mmol; 2.00 eq.) in 1,4-dioxane (4 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 70 ℃ for 16 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 20-60% of EtOAc in petroleum ether as eluent to provide 2-bromo-5-(3- methoxyazetidin-1-yl)pyridine as a white oil (273.0 mg, 69.3%). LCMS (ESI) m / z 243.0, [M+H]+. Step 2: N-(5-((5-(3-methoxyazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide N-(5-((5-(3-methoxyazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-bromo-5-(3-methoxyazetidin-1-yl)pyridine as the starting material. LCMS (ESI) m / z 429.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.61 (s, 1H), 8.35 - 8.29 (m, 1H), 8.27 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 4.42 - 4.32 (m, 1H), 4.21 - 4.13 (m, 2H), 3.80 - 3.72 (m, 2H), 3.26 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.13 - 2.03 (m, 1H), 0.93 - 0.79 (m, 4H). Example 66: Synthesis of N-(5-((5-(3-fluoroazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-bromo-5-(3-fluoroazetidin-1-yl)pyridine A stirred mixture of 2-bromo-5-iodopyridine (200.0 mg; 0.704 mmol; 1.00 eq.), 3-fluoroazetidine hydrochloride (78.5 mg; 0.704 mmol; 1.00 eq.), Pd2(dba)3(64.5 mg; 0.070 mmol; 0.10 eq.), XantPhos (81.5 mg; 0.141 mmol; 0.20 eq.) and Cs2CO3(459.1 mg; 1.409 mmol; 2.00 eq.) in 1,4-dioxane (5 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 70 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-25% of EtOAc in petroleum ether as eluent to afford 2-bromo-5-(3- fluoroazetidin-1-yl)pyridine as a yellow oil (107.5 mg, 66.0%). LCMS (ESI) m / z 231.0, [M+H]+. Step 2: N-(5-((5-(3-fluoroazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(5-((5-(3-fluoroazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-bromo-5-(3-fluoroazetidin-1-yl)pyridine as the starting material. LCMS (ESI) m / z 417.2, [M+H]+. Example 67: Synthesis of N-(5-((5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-bromo-5-(3,3-difluoroazetidin-1-yl)pyridine A stirred mixture of 3,3-difluoroazetidine hydrochloride (200.0 mg; 1.549 mmol; 4.00 eq.), 2-bromo-5- iodopyridine (110.0 mg; 0.387 mmol; 1.00 eq.), Pd2(dba)3 (70.9 mg; 0.077 mmol; 0.20 eq.), XantPhos (89.6 mg; 0.155 mmol; 0.40 eq.) and Cs2CO3(252.4 mg; 0.775 mmol; 2.00 eq.) in 1,4-dioxane (6 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 70 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-10% of EtOAc in petroleum ether as eluent to provide 2-bromo-5-(3,3- difluoroazetidin-1-yl)pyridine as a red solid (170 mg, 50.9%). LCMS (ESI) m / z 249.0, [M+H]+. Step 2: N-(5-((5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide N-(5-((5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-bromo-5-(3,3-difluoroazetidin-1-yl)pyridine as the starting material. LCMS (ESI) m / z 435.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.37 (s, 1H), 8.62 (s, 1H), 8.37 - 8.30 (m, 1H), 8.29 (s, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.8 Hz, 1H), 4.47 - 4.38 (m, 4H), 3.03 (d, J = 4.4 Hz, 3H), 2.12 - 2.03 (m, 1H), 0.92 - 0.79 (m, 4H). Example 68: Synthesis of N-(5-((5-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)pyridin-2- yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: tert-butyl 7-((6-bromopyridin-3-yl)methyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate To a stirred solution of 6-bromonicotinaldehyde (300.0 mg; 1.613 mmol; 1.00 eq.), tert-butyl 3,7- diazabicyclo[3.3.1]nonane-3-carboxylate (365.0 mg; 1.613 mmol; 1.00 eq.) in 1,2-dichloroethane (10 mL) was added NaBH(OAc)3(1.03 g; 4.839 mmol; 3.00 eq.) under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford tert-butyl 7-((6-bromopyridin-3-yl)methyl)-3,7- diazabicyclo[3.3.1]nonane-3-carboxylate as a light yellow oil (450.0 mg, 64.7%). LCMS (ESI) m / z 396.2, [M+H]+. Step 2: 3-((6-bromopyridin-3-yl)methyl)-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate To a stirred solution of tert -butyl 7-((6-bromopyridin-3-yl)methyl)-3,7-diazabicyclo[3.3.1]nonane-3- carboxylate (440.0 mg; 1.110 mmol; 1.00 eq.) in CH2Cl2(20 mL) was added 2,2,2-trifluoroacetic acid (2 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was concentrated under reduced pressure to afford 3-((6-bromopyridin-3-yl)methyl)-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate as a brown oil. (450.0 mg, crude). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z 296.1, [M+H]+. Step 3: 3-((6-bromopyridin-3-yl)me To a stirred solution of 3-((6-bromopyridin-3-yl)methyl)-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate (450.0 mg; 1.141 mmol; 1.00 eq.) and HCHO (37 wt% in water, 68.9 mg) in CH 2Cl2 (20mL) were added DIEA (1.48 g; 11.414 mmol; 10.00 eq.) and NaBH(OAc)3(725.7 mg; 3.424 mmol; 3.00 eq.). The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 20-60% of MeOH in water (10 mmol / L NH4HCO3) to afford 3-((6-bromopyridin-3-yl)methyl)-7-methyl-3,7- diazabicyclo[3.3.1]nonane as a white solid (340.0 mg, 91.2%). LCMS (ESI) m / z 310.2, Step 4: N-(5-((5-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((5-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and 3-((6-bromopyridin-3-yl)methyl)-7-methyl-3,7- diazabicyclo[3.3.1]nonane as the starting material. LCMS (ESI) m / z 496.3, [M+H]+. Example 69: Synthesis of N-(5-((4-((3-fluoroazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 1-(4-bromobenzyl)-3-fluoroazetidine To a stirred solution of 3-fluoroazetidine hydrochloride (452.1 mg; 4.053 mmol; 1.50 eq.), DIPEA (1.04 g; 8.106 mmol; 3.00 eq.) and 4-bromobenzaldehyde (500.0 mg; 2.702 mmol; 1.00 eq.) in dichloroethane (5 mL) was added NaBH(OAc)3(1.71 g; 8.106 mmol; 3.00 eq.) in portions at 0 ℃. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water at 0 ℃ and basified to pH = 8 with an aqueous solution of NaOH (1.0 M). The resulting mixture was extracted with CH2Cl2(3 × 20 mL). The combinedorganic layers were washed with brine (3 × 5 mL), dried over anhydrous Na 2SO4. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 1-9% of MeOH in CH2Cl2 as eluent to provide1-(4-bromobenzyl)-3-fluoroazetidine as a yellow oil (540.0 mg, 78.0%). LCMS (ESI) m / z 244.0, [M+H]+. Step 2: N-(5-((4-((3-fluoroazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide N-(5-((4-((3-fluoroazetidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(4-bromobenzyl)-3-fluoroazetidine as the starting material. LCMS (ESI) m / z 430.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.36 - 8.29 (m, 1H), 8.27 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.32 - 5.05 (m, 1H), 3.69 (s, 2H), 3.65 - 3.52 (m, 2H), 3.26 - 3.09 (m, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.13 - 2.03 (m, 1H), 0.94 - 0.79 (m, 4H). Example 70: Synthesis of N-(5-((4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 1-(4-bromobenzyl) To a stirred solution of 4-bromobenzaldehyde (200.0 mg; 1.081 mmol; 1.00 eq.) and 3,3-difluoropiperidine hydrochloride (196.4 mg; 1.621 mmol; 1.50 eq.) in 1,2-dichloroethane (10 mL) were added AcOH (64.9 mg; 1.081 mmol; 1.00 eq.) and NaBH(OAc)3(687.3 mg; 3.243 mmol; 3.00 eq.) at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3at 0 ℃. The mixture was extracted with CH2Cl2(3 × 15 mL). The combinedorganic layers were washed with water (3 × 10 mL), dried over anhydrous Na 2SO4. After filtration, thefiltrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 50-60% of ethyl acetate in petroleum ether as eluent to provide 1-(4-bromobenzyl)- 3,3-difluoropiperidine as a colorless oil (248 mg, 79.0%). LCMS (ESI) m / z 290.0, [M+H]+. Step 2: N-(5-((4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(4-bromobenzyl)-3,3-difluoropiperidine as the starting material. LCMS (ESI) m / z 476.2, Example 71: Synthesis of N-(5-((5-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-bromo-5-((4-fluoropiperidin-1-yl)methyl)pyridine To a stirred solution of 6-bromonicotinaldehyde (200 mg; 1.075 mmol; 1.00 eq.), 4-fluoropiperidine hydrochloride (224.2 mg; 1.606 mmol; 1.49 eq.) and DIEA (277.4 mg; 2.146 mmol; 2.00 eq.) in 1,2- dichloroethane (5 mL) was added NaBH(OAc)3(683.9 mg; 3.227 mmol; 3.00 eq.) in portions at 0 ℃. The resulting mixture was stirred at room temperature for 3 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (20 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-50% of EtOAc in petroleum ether as eluent to afford 2-bromo-5-((4-fluoropiperidin-1- yl)methyl)pyridine as a white solid (193.0 mg, 65.7%). LCMS (ESI) m / z 273.0, [M+H]+. Step 2: N-(5-((5-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((5-((4-fluoropiperidin-1-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-bromo-5-((4-fluoropiperidin-1-yl)methyl)pyridine as the starting material. LCMS (ESI) m / z 459.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.39 (s, 1H), 8.63 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.47 - 8.39 (m, 1H), 8.34 (s, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 4.81 - 4.58 (m, 1H), 3.55 (s, 2H), 3.03 (d, J = 4.4 Hz, 3H), 2.62 - 2.58 (m, 2H), 2.38 - 2.28 (m, 2H), 2.14 - 2.03 (m, 1H), 1.96 - 1.80 (m, 2H), 1.80 - 1.76 (m, 2H), 0.94 - 0.79 (m, 4H). Example 72: Synthesis of N-(5-((5-((4H-1,2,4-triazol-4-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin Step 1: 5-((4H-1,2,4-triazol-4-yl)methyl)-2-chloropyridine and 5-((1H-1,2,4-triazol-1-yl)methyl)-2- chloropyridine A solution of 2-chloro-5-(chloromethyl)pyridine (1.00 g; 6.172 mmol; 1.00 eq.), 4H-1,2,4-triazole (429.0 mg; 6.211 mmol; 1.01 eq.) and K2CO3(1.70 g; 12.301 mmol; 1.99 eq.) in DMF (6 mL) was stirred at 75 ℃ for 5 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL), extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 20-50% of EtOAc in petroleum ether as eluent to provide 5-((4H-1,2,4-triazol-4-yl)methyl)-2-chloropyridine as a white oil (50.0 mg, 4.1%) and 5-((1H- 1,2,4-triazol-1-yl)methyl)-2-chloropyridine as a white solid (550.0 mg, 45.6%). LCMS (ESI) m / z 195.0, [M+H]+. Step 2: N-(5-((5-((4H-1,2,4-triazol-4-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((5-((4H-1,2,4-triazol-4-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 5-((4H-1,2,4-triazol-4-yl)methyl)-2-chloropyridine as the starting material. LCMS (ESI) m / z 425.2, [M+H]+. Example 73: Synthesis of N-(5-((5-((1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((5-((1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 5-((1H-1,2,4-triazol-1-yl)methyl)-2-chloropyridine (Example 72, Step 1) as the starting material. LCMS (ESI) m / z 425.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.38 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.49 - 8.41 (m, 1H), 8.35 (s, 1H), 8.03 (s, 1H), 7.76 (dd, J = 8.0, 2.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 5.53 (s, 2H), 3.03 (d, J = 4.4 Hz, 3H), 2.13 - 2.03 (m, 1H), 0.93 - 0.80 (m, 4H). Example 74: Synthesis of N-(5-((2-((3-methoxyazetidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazol- 6-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 6-bromo-1-methyl-1H-benzo[d]imidazole-2-carbaldehyde To a stirred solution of (6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)methanol (WO 2023 / 244788, which is incorporated by reference in its entirety) (300.0 mg; 1.24 mmol; 1.00 eq.) in CH2Cl2(10 mL) was added Dess-Martin (633.3 mg; 1.49 mmol; 1.20 eq.) in portions at 0-5 ℃. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the mixture was quenched with a saturated aqueous solution of sodium bicarbonate (10 mL) and stirred for 0.5 hours. The crude mixture was extracted with CH2Cl2(3 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 20-30% of EtOAc in petroleum ether as eluent to provide 6-bromo-1-methyl-1H- benzo[d]imidazole-2-carbaldehyde as a purple solid (279.6 mg, 93.9%). LCMS (ESI) m / z 239.0, [M+H]+. Step 2: 6-bromo-2-((3-methoxyazetidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazole To a stirred solution of 6-bromo-1-methyl-1H-benzo[d]imidazole-2-carbaldehyde (250.0 mg; 1.04 mmol; 1.00 eq.), 3-methoxyazetidine hydrochloride (129.2 mg; 1.04 mmol; 1.00 eq.) and DIPEA (405.5 mg; 3.13 mmol; 3.00 eq.) in 1, 2-dichloroethane (8 mL) was added NaBH(OAc)3(664.8 mg; 3.13 mmol; 3.00 eq.) in portions. The resulting mixture was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3(20 mL) at room temperature. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 10-20% of EtOAc in petroleum ether as eluent to provide 6- bromo-2-((3-methoxyazetidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazole as a yellow oil (353.6 mg, 81.7%). LCMS (ESI) m / z 310.0, [M+H]+. Step 3: N-(5-((2-((3-methoxyazetidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((2-((3-methoxyazetidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and 6-bromo-2-((3-methoxyazetidin-1-yl)methyl)-1-methyl-1H- benzo[d]imidazole as the starting material. LCMS (ESI) m / z 496.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.38 (s, 1H), 8.79 (s, 1H), 8.32 - 8.28 (m, 1H), 8.27 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 1.2 Hz, 1H), 4.03 - 3.94 (m, 1H), 3.89 (s, 2H), 3.84 (s, 3H), 3.58 - 3.50 (m, 2H), 3.15 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 3.01 - 2.97 (m, 2H), 2.15 - 2.06 (m, 1H), 0.94 - 0.81 (m, 4H). Example 75 and Example 76: Synthesis of (R)-N-(5-((4-(1-(3-methoxyazetidin-1- yl)ethyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 75) and (S)-N-(5-((4-(1-(3-methoxyazetidin-1-yl)ethyl)phenyl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 76) Step 1: 1-(1-(4-bromophenyl)ethyl)-3-methoxyazetidine To a stirred solution of 1-(4-bromophenyl)ethan-1-one (300.0 mg; 1.507 mmol; 1.00 eq.), 3- methoxyazetidine hydrochloride (131.3 mg; 1.507 mmol; 1.00 eq.) and DIPEA (584.4 mg; 4.521 mmol; 3.00 eq.) in 1,2-dichloroethane (6 mL) was added NaBH(OAc)3(958.3 mg; 4.521 mmol; 3.00 eq.). The resulting mixture was stirred at room temperature for 3 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3(10 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on pre-packed C18 column using 50-70% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide 1-(1-(4-bromophenyl)ethyl)- 3-methoxyazetidine as a yellow oil (200.1 mg, 48.7%). LCMS (ESI) m / z 270.0, Step 2: (R)-N-(5-((4-(1-(3-methoxyazetidin-1-yl)ethyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide and (S)-N-(5-((4-(1-(3-methoxyazetidin-1- yl)ethyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-(1-(3-methoxyazetidin-1-yl)ethyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(1-(4-bromophenyl)ethyl)-3-methoxyazetidine as the starting material. The racemate was separated by Prep-Chiral-SFC (Column: CHIRAL ART Cellulose-SZ, 3×25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 50% B; RT1(min): 4.58; RT2(min): 6) to provide -(3-methoxyazetidin-1-yl)ethyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 75, the faster peak) as a yellow solid (47.5 mg, 27.7%) and (S)-N-(5-((4-(1-(3-methoxyazetidin-1-yl)ethyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 76, the slower peak) as a yellow solid (35.1 mg, 20.5%). The two configurations were arbitrarily assigned. LCMS and HNMR for Example 75: LCMS (ESI) m / z 456.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.64 (s, 1H), 8.35 - 8.28 (m, 1H), 8.26 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.96 - 3.87 (m, 1H), 3.59 - 3.51 (m, 1H), 3.30 - 3.21 (m, 2H), 3.14 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.86 - 2.79 (m, 1H), 2.71 - 2.64 (m, 1H), 2.13 - 2.04 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 0.92 - 0.80 (m, 4H). LCMS and HNMR for Example 76: LCMS (ESI) m / z 456.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.64 (s, 1H), 8.35 - 8.28 (m, 1H), 8.26 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.96 - 3.87 (m, 1H), 3.59 - 3.51 (m, 1H), 3.30 - 3.21 (m, 2H), 3.14 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.86 - 2.79 (m, 1H), 2.71 - 2.64 (m, 1H), 2.13 - 2.04 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 0.92 - 0.80 (m, 4H). Example 77: Synthesis of N-(5-((2-(azetidin-1-ylmethyl)pyridin-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-(azetidin-1-ylmethyl)-4-bromopyridine To a stirred solution of 4-bromopicolinaldehyde (200.0 mg; 1.075 mmol; 1.00 eq.) and azetidine (92.1 mg; 1.613 mmol; 1.50 eq.) in 1,2-dichloroethane (10 mL) were added AcOH (64.5 mg; 1.074 mmol; 1.00 eq.) and NaBH(OAc)3(683.7 mg; 3.226 mmol; 3.00 eq.) at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3at 0 ℃. The mixture was extracted with CH2Cl2(3 × 15 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 50-60% of ethyl acetate in petroleum ether as eluent to provide 2-(azetidin-1-ylmethyl)-4-bromopyridine as a colorless oil (220.0 mg; 90.0%). LCMS (ESI) m / z 227.0, [M+H]+. Step 2: N-(5-((2-(azetidin-1-ylmethyl)pyridin-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(5-((2-(azetidin-1-ylmethyl)pyridin-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using 2-(azetidin-1-ylmethyl)-4-bromopyridine and N-(5-ethynyl-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as the starting material. LCMS (ESI) m / z 413.2, [M+H]+. Example 78: Synthesis of N-(8-(methylamino)-5-((4-(piperidin-1-ylmethyl)phenyl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 1-(4-bromobenzyl)piperidine To a stirred solution of 4-bromobenzaldehyde (200.0 mg; 1.081 mmol; 1.00 eq.) and piperidine (138.1 mg; 1.622 mmol; 1.50 eq.) in 1,2-dichloroethane (10 mL) were added AcOH (64.9 mg; 1.081 mmol; 1.00 eq.) and NaBH(OAc)3(687.3 mg; 3.243 mmol; 3.00 eq.) at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3at 0 ℃. The mixture was extracted with CH2Cl2(3 × 15 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 50-60% of ethyl acetate in petroleum ether as eluent to provide 1-(4-bromobenzyl)piperidine as a colorless oil (246 mg, 89.5%). LCMS (ESI) m / z 254.0, [M+H]+. Step 2: N-(8-(methylamino)-5-((4-(piperidin-1-ylmethyl)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(8-(methylamino)-5-((4-(piperidin-1-ylmethyl)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(4-bromobenzyl)piperidine as the starting material. LCMS (ESI) m / z 440.2, [ . Example 79: Synthesis of N-(5-((4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 1-(4-bromobenzyl)- To a stirred solution of 4,4-difluoropiperidine hydrochloride (127.7 mg; 0.810 mmol; 1.50 eq.), DIPEA (209.1 mg; 1.620 mmol; 3.00 eq.) and 4-bromobenzaldehyde (100.2 mg; 0.540 mmol; 1.00 eq.) in 1,2- dichloroethane (5 mL) was added NaBH(OAc)3(343.6 mg; 1.620 mmol; 3.00 eq.) in portions at 0 ℃. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction was quenched with water at 0 ℃ and basified to pH = 8 with an aqueous solution of NaOH (1.0 M). The resulting mixture was extracted with CH2Cl2(3 × 10 mL). Thecombined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na 2SO4. After filtration,the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-60% of EtOAc in petroleum ether as eluent to afford 1-(4-bromobenzyl)-4,4- difluoropiperidine as a light yellow oil (80.0 mg, 51.0%). LCMS (ESI) m / z 290.0, [M+H]+. Step 2: N-(5-((4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(4-bromobenzyl)-4,4-difluoropiperidine as the starting material. LCMS (ESI) m / z 476.2, [M+H]+. Example 80: Synthesis of N-(5-((4-((7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3- yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: tert-butyl 7-(4-bromobenzyl carboxylate To a stirred solution of 4-bromobenzaldehyde (150.0 mg; 0.811 mmol; 1.00 eq.) and tert-butyl 9-oxa-3,7- diazabicyclo[3.3.1]nonane-3-carboxylate (185.1 mg; 0.811 mmol; 1.00 eq.) in 1,2-dichloroethane (15 mL) was added NaBH(OAc)3(515.5 mg; 2.432 mmol; 3.00 eq.) under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford tert-butyl 7-(4- bromobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a white solid (240.0 mg, 73.7%). LCMS (ESI) m / z 397.0, [M+H]+. Step 2: 3-(4-bromobenzyl)-9-oxa- -trifluoroacetate To a stirred solution of tert-butyl 7-(4-bromobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (240.0 mg; 0.604 mmol; 1.00 eq.) in CH2Cl2(10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under reduced pressure to afford 3- (4-bromobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate as a brown solid (230.0 mg, crude). LCMS (ESI) m / z 297.0, [M+H]+. Step 3: 3-(4-bromobenzyl)-7-methyl- nonane To a stirred solution of 3-(4-bromobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate (230.0 mg; 0.582 mmol; 1.00 eq.), HCHO (37 wt% in water, 472.3 mg) and DIEA (225.7 mg; 1.746 mmol; 3.00 eq.) in CH2Cl2(10 mL) was added NaBH(OAc)3(370.0 mg; 1.746 mmol; 3.00 eq.) at 0 ℃. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 5-60% of MeCN in water (10 mmol / L NH4HCO3) to provide 3-(4- bromobenzyl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane as a yellow solid (120.0 mg, 66.3%). LCMS (ESI) m / z 311.1, [M+H]+. Step 4: N-(5-((4-((7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-8-(meth ylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-((7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and 3-(4-bromobenzyl)-7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane as the starting material. LCMS (ESI) m / z 497.3, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.38 (s, 1H), 8.67 (s, 1H), 8.37 - 8.29 (m, 1H), 8.27 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 3.82 - 3.79 (m, 2H), 3.45 (s, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.82 - 2.74 (m, 4H), 2.46 - 2.40 (m, 2H), 2.31 - 2.23 (m, 2H), 2.16 (s, 3H), 2.13 - 2.07 (m, 1H), 0.91 - 0.82 (m, 4H). Example 81: Synthesis of N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3- yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: tert-butyl 7-(4-bromobenzyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate To a stirred solution of 4-bromobenzaldehyde (350.0 mg; 1.892 mmol; 1.00 eq.) and tert-butyl 3,7- diazabicyclo[3.3.1]nonane-3-carboxylate (428.1 mg; 1.892 mmol; 1.00 eq.) in 1,2-dichloroethane (6 mL) was added NaBH(OAc)3(1.20 g; 5.676 mmol; 3.00 eq.) in portions. The resulting mixture was stirred at room temperature for 1.5 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 0-10% EtOAc in petroleum ether as eluent to provide tert-butyl 7-(4-bromobenzyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a white solid (635.6 mg, 83.9%). LCMS (ESI) m / z 395.1, [M+H]+. Step 2: 3-(4-bromobenzyl)-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate A solution of tert-butyl 7-(4-bromobenzyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (600.0 mg; 1.518 mmol; 1.00 eq.) and 2,2,2-trifluoroacetic acid (1 mL) in CH2Cl2(6 mL) was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under vacuum to provide 3-(4-bromobenzyl)-3,7-diazabicyclo[3.3.1]nonane 2,2,2- trifluoroacetate as a white oil (650 mg, crude). The crude product was used in the next step without further purification. LCMS (ESI) m / z 295.1, [M+H]+. Step onane To a solution of 3-(4-bromobenzyl)-3,7-diazabicyclo[3.3.1]nonane 2,2,2-trifluoroacetate (470.0 mg; 1.195 mmol; 1.00 eq.) and DIPEA (308.9 mg; 2.390 mmol; 2.00 eq.) in CH2Cl2(5 mL) were added formaldehyde (37% in water) (145.4 mg; 1.792 mmol; 1.50 eq.) and NaBH(OAc)3(759.9 mg; 3.585 mmol; 3.00 eq.). The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silica gel column using 0 -20% ofMeOH in CH2Cl2(0.1% Et3N) as eluent to provide 3-(4-bromobenzyl)-7-methyl-3,7- diazabicyclo[3.3.1]nonane as a colorless oil (400.1 mg, 92.1%). LCMS (ESI) m / z 309.1, [M+H]+. Step 4: N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and 3-(4-bromobenzyl)-7-methyl-3,7-diazabicyclo[3.3.1]nonane as the starting material. LCMS (ESI) m / z 495.3, Example 82: Synthesis of N-(8-(methylamino)-5-((4-(4-oxopyridin-1(4H)-yl)phenyl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 1-(4-bromophenyl)pyridin-4(1H)-one A mixture of 1,4-dibromobenzene (500.0 mg; 5.258 mmol; 1.00 eq.), Cs2CO3(3.42 g; 10.516 mmol; 2.00 eq.), CuI (100.1 mg; 0.526 mmol; 0.10 eq.) and pyridin-4-ol (1.24 g; 5.258 mmol; 1.00 eq.) in DMF (5 mL) was stirred at 120 ℃ overnight under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine (2 ×10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2 as eluent to afford 1-(4-bromophenyl)pyridin-4(1H)-one as an off-white solid (300.2 mg, 22.8%). LCMS (ESI) m / z 250.0, [M+H]+. Step 2: N-(8-(methylamino)-5-((4-(4-oxopyridin-1(4H)-yl)phenyl)ethynyl)-2,7-naphthyridin-3-yl)cyc lopropanecarboxamide N-(8-(methylamino)-5-((4-(4-oxopyridin-1(4H)-yl)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(4-bromophenyl)pyridin-4(1H)-one as the starting material. LCMS (ESI) m / z 436.2, [M+H]+. Example 83: Synthesis of N-(8-(methylamino)-5-((2-(oxetan-3-yl)-2H-1,2,3-triazol-4-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4,5-dibromo-2-(oxetan-3-yl)-2H-1,2,3-triazole A solution of 4,5-dibromo-2H-1,2,3-triazole (1.00 g; 4.408 mmol; 1.00 eq.), 3-bromooxetane (604.4 mg; 4.412 mmol; 1.00 eq.) and K2CO3(2.45 g; 17.727 mmol; 4.02 eq.) in DMF (10 mL) was stirred at 80 ℃ for 16 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4,5-dibromo-2-(oxetan-3-yl)- 2H-1,2,3-triazole as a white oil (180.0 mg, crude). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z 281.9, [M+H]+. Step 2: 4-bromo-2-(oxetan-3-yl)-2H-1,2,3-triazole To a stirred solution of 4,5-dibromo-2-(oxetan-3-yl)-2H-1,2,3-triazole (180.0 mg; 0.636 mmol; 1.00 eq.) in THF (5 mL) was added chloro(isopropyl)magnesium (2.0 M in THF, 0.96 mL) at 0 ℃. The resulting mixture was stirred at -20 ℃ for 0.5 hour and at 0 ℃ for 2 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL) at 0 ℃. The crude mixture was extracted with CH2Cl2(3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of EtOAc in petroleum ether as eluent to provide 4- bromo-2-(oxetan-3-yl)-2H-1,2,3-triazole as a white oil (90.0 mg, crude). LCMS (ESI) m / z 204.0, [M+H]+. Step 3: N-(8-(methylamino)-5-((2-(oxetan-3-yl)-2H-1,2,3-triazol-4-yl)ethynyl)-2,7-naphthyridin-3- N-(8-(methylamino)-5-((2-(oxetan-3-yl)-2H-1,2,3-triazol-4-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-bromo-2-(oxetan-3-yl)-2H-1,2,3-triazole as the starting material. LCMS (ESI) m / z 390.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.39 (s, 1H), 8.55 (s, 1H), 8.49 - 8.41 (m, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 5.98 - 5.87 (m, 1H), 5.07 - 5.00 (m, 2H), 5.00 - 4.93 (m, 2H), 3.03 (d, J = 4.4 Hz, 3H), 2.13 - 2.02 (m, 1H), 0.91 - 0.79 (m, 4H). Example 84: Synthesis of N-(5-((2-(2,2-difluoroethyl)-2H-1,2,3-triazol-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4,5-dibromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole To a stirred mixture of 4,5-dibromo-2H-1,2,3-triazole (1.00 g; 4.408 mmol; 1 eq.) and K2CO3(1.02 g; 7.380 mmol; 1.67 eq.) in DMF (5 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (792.6 mg; 3.702 mmol; 0.84 eq.) at 0 ℃. The resulting mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water (10 mL) and extracted with diethyl ether (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of EtOAc in petroleum ether as eluent to provide 4,5-dibromo-2-(2,2- difluoroethyl)-2H-1,2,3-triazole as a white oil (220.0 mg, 17.1%). LCMS (ESI) m / z 290.1, [M+H]+. Step 2: 4-bromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole To a stirred solution of 4,5-dibromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole (220.0 mg; 0.756 mmol; 1.00 eq.) in THF (6 mL) was added chloro(isopropyl)magnesium (2.0 M in THF, 1.33 mL) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1.5 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL). The crude mixture was extracted with diethyl ether (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-bromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole as a colorless oil (90.0 mg, crude). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z 212.0, [M+H]+. Step 3: N-(5-((2-(2,2-difluoroethyl)-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((2-(2,2-difluoroethyl)-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-bromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole as the starting material. LCMS (ESI) m / z 398.1, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.39 (s, 1H), 8.55 (s, 1H), 8.53 (s, 1H), 8.45 - 8.37 (m, 1H), 8.33 (s, 1H), 6.67 - 6.39 (m, 1H), 5.09 - 4.96 (m, 2H), 3.03 (d, J = 4.4 Hz, 3H), 2.11 - 2.02 (m, 1H), 0.92 - 0.78 (m, 4H). Example 85: Synthesis of N-(8-(methylamino)-5-((5-methylthiophen-2-yl)ethynyl)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.0 mg; 0.376 mmol; 1.00 eq.), 2-bromo-5-methylthiophene (99.7 mg; 0.564 mmol; 1.50 eq.), Pd(PPh3)4(65.1 mg; 0.056 mmol; 0.15 eq.), Et3N (114.0 mg; 1.128 mmol; 3.00 eq.) and CuI (7.2 mg; 0.038 mmol; 0.10 eq.) in DMF (1 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 50 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 3-8% of MeOH in CH2Cl2as eluent to provide N-(8-(methylamino)-5-((5-methylthiophen-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide as a light yellow solid (95.1 mg, 69.0%). LCMS (ESI) m / z 363.1, [M+H]+. Example 86: Synthesis of N-(5-((4-((2H-1,2,3-triazol-2-yl)methyl)phenyl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-(4-bromobenzyl)-2H-1,2,3-triazole and 1-(4-bromobenzyl)-1H-1,2,3-triazole A mixture of 1-bromo-4-(bromomethyl)benzene (2.17 g; 8.687 mmol; 1.20 eq.), K2CO3(3.00 g; 21.717 mmol; 3.00 eq.) and 1H-1,2,3-triazole (500.2 mg; 7.239 mmol; 1.00 eq.) in DMF (5 mL) was stirred at room temperature overnight under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-50% of EtOAc in petroleum ether as eluent to afford 2- (4-bromobenzyl)-2H-1,2,3-triazole as an off-white solid (170.0 mg, 9.8%) and 1-(4-bromobenzyl)-1H- 1,2,3-triazole as an off-white solid (300.0 mg, 17.3%). LCMS (ESI) m / z 238.0, [M+H]+. Step 2: N-(5-((4-((2H-1,2,3-triazol-2-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide N-(5-((4-((2H-1,2,3-triazol-2-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-(4-bromobenzyl)-2H-1,2,3-triazole as the starting material. LCMS (ESI) m / z 424.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.38 - 8.31 (m, 1H), 8.27 (s, 1H), 7.86 (s, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.72 (s, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.14 - 2.02 (m, 1H), 0.93 - 0.78 (m, 4H). Example 87: Synthesis of N-(5-((4-((1H-1,2,3-triazol-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((4-((1H-1,2,3-triazol-1-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 1-(4-bromobenzyl)-1H-1,2,3-triazole (Example 86, Step 1) as the starting material. LCMS (ESI) m / z 424.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.38 - 8.31 (m, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.78 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.68 (s, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.12 - 2.02 (m, 1H), 0.93 - 0.76 (m, 4H). Example 88: Synthesis of N-(8-(methylamino)-5-((4-(4-methylmorpholin-3-yl)phenyl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 3-(4-bromophenyl)-4-methylmorpholin-2-ol To a stirred solution of (4-bromophenyl)boronic acid (1.00 g; 4.979 mmol; 1.00 eq.) and 2- (methylamino)ethan-1-ol (0.45 g; 5.975 mmol; 1.20 eq.) in a mixture solvent of EtOH / water (2:1, 7.5 mL) was added oxalaldehyde (40% in water; 0.87 g; 1.20 eq.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 ℃ for 14 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-50% of EtOAc in petroleum ether as eluent to provide 3-(4-bromophenyl)-4- methylmorpholin-2-ol as a white solid (1.10 g, 81.1%). LCMS (ESI) m / z 272.0, [M+H]+. Step 2: 5-(4-bromophenyl)-4-methyl-3,4-dihydro-2H-1,4-oxazine To a stirred solution of 3-(4-bromophenyl)-4-methylmorpholin-2-ol (500.0 mg; 1.837 mmol; 1.00 eq.) and Et3N (557.7 mg; 5.511 mmol; 3.00 eq.) in 1,2-dichloroethane (15 mL) was added Ms2O (448.1 mg; 2.572 mmol; 1.40 eq.) in portions at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with a saturated aqueous solution of KH2PO4(20 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were washed with saturated KH2PO4aqueous solution (2 × 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-(4-bromophenyl)-4-methyl-3,4-dihydro-2H- 1,4-oxazine as a white solid (500.2 mg, crude). The crude product was used in the next step without further purification. LCMS (ESI) m / z 254.0, [M+H]+. Step 3: 3-(4-bromophenyl)-4-methylmorpholine A mixture of 5-(4-bromophenyl)-4-methyl-3,4-dihydro-2H-1,4-oxazine (500.0 mg; 1.968 mmol; 1.00 eq.), NaBH(OAc)3(708.8 mg; 3.346 mmol; 1.70 eq.) and AcOH (118.1 mg; 1.968 mmol; 1.00 eq.) in 1,2- dichloroethane (5 mL) was stirred at room temperature for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction was quenched with water at 0 ℃ and basified to pH = 8 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with CH2Cl2(3 ×10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na 2SO4.After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-60% of EtOAc in petroleum ether as eluent to provide 3-(4- bromophenyl)-4-methylmorpholine as a light yellow oil (256.1 mg, 50.8%). LCMS (ESI) m / z 256.0, [M+H]+. Step 4: N-(8-(methylamino)-5-((4-(4-methylmorpholin-3-yl)phenyl)ethynyl)-2,7-naphthyridin-3-yl)c yclopropanecarboxamide N-(8-(methylamino)-5-((4-(4-methylmorpholin-3-yl)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 3-(4-bromophenyl)-4-methylmorpholine as the starting material. LCMS (ESI) m / z 442.2, [M+H]+. Examples 89 and 90: Each isomer in the table below was obtained by chiral SFC purification from Example 88, the configuration has been arbitrarily assigned. Example 91: Synthesis of (R)-N-(8-(methylamino)-5-((4-((4-methylmorpholin-2- yl)methoxy)phenyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: (R)-2-((4-bromophenoxy)methyl)-4-methylmorpholine To a solution of 4-bromophenol (300.0 mg; 1.734 mmol; 1.00 eq.), (R)-(4-methylmorpholin-2-yl)methanol (456.9 mg; 3.483 mmol; 2.01 eq.) and PPh3 (914.1 mg; 3.485 mmol; 2.01 eq.) in THF (6 mL) was added DIAD (704.7 mg; 3.485 mmol; 2.01 eq.) at 0 ℃. The mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 10-20% of THF in CH2Cl2as eluent to afford (R)-2-((4- bromophenoxy)methyl)-4-methylmorpholine as a white oil (120 mg, 24.1%). LCMS (ESI) m / z 286.0, [M+H]+. Step 2: (R)-N-(8-(methylamino)-5-((4-((4-methylmorpholin-2-yl)methoxy)phenyl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (R)-N-(8-(methylamino)-5-((4-((4-methylmorpholin-2-yl)methoxy)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and (R)-2-((4-bromophenoxy)methyl)-4-methylmorpholine as the starting material. LCMS (ESI) m / z 472.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.37 (s, 1H), 8.64 (s, 1H), 8.29 - 8.25 (m, 1H), 8.24 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 4.03 - 3.99 (m, 2H), 3.84 - 3.76 (m, 2H), 3.58 - 3.51 (m, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.82 - 2.75 (m, 1H), 2.64 - 2.57 (m, 1H), 2.21 (s, 3H), 2.12 - 1.95 (m, 2H), 1.92 - 1.83 (m, 1H), 0.93 - 0.79 (m, 4H). Example 92: Synthesis of (S)-N-(8-(methylamino)-5-((4-((4-methylmorpholin-2- yl)methoxy)phenyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: (S)-2-((4-bromophenoxy)methyl)-4-methylmorpholine To a solution of 4-bromophenol (400.0 mg; 2.312 mmol; 1.00 eq.), (S)-(4-methylmorpholin-2-yl)methanol (606.6 mg; 4.624 mmol; 2.00 eq.) and PPh3(1212.9 mg; 4.624 mmol; 2.00 eq.) in THF (4 mL) was added DIAD (935.0 mg; 4.624 mmol; 2.00 eq.) at 0 ℃. The mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 15-20% of THF in CH2Cl2as eluent to afford (S)-2-((4- bromophenoxy)methyl)-4-methylmorpholine as a colorless oil (80.0 mg, 12.1%). LCMS (ESI) m / z 286.0, [M+H]+. Step 2: (S)-N-(8-(methylamino)-5-((4-((4-methylmorpholin-2-yl)methoxy)phenyl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide

[0032] (S)-N-(8-(methylamino)-5-((4-((4-methylmorpholin-2-yl)methoxy)phenyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and (S)-2-((4-bromophenoxy)methyl)-4-methylmorpholine as the starting material. LCMS (ESI) m / z 472.2, [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.36 (s, 1H), 8.64 (s, 1H), 8.29 - 8.25 (m, 1H), 8.24 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 4.05 - 3.99 (m, 2H), 3.86 - 3.73 (m, 2H), 3.62 - 3.49 (m, 1H), 3.02 (d, J = 4.2 Hz, 3H), 2.83 - 2.74 (m, 1H), 2.66 - 2.55 (m, 1H), 2.21 (s, 3H), 2.14 - 1.95 (m, 2H), 1.94 - 1.83 (m, 1H), 0.94 - 0.77 (m, 4H). Example 93: Synthesis of N-(5-((1-cyclopropyl-1H-indazol-5-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 5-bromo-1-cyclopropyl-1H-indazole To a stirred mixture of 5-bromo-1H-indazole (500.0 mg; 2.538 mmol; 1.00 eq.), cyclopropylboronic acid (435.9 mg; 5.076 mmol; 2.00 eq.), Cu(OAc)2(460.9 mg; 2.538 mmol; 1.00 eq.), Na2SO3(639.6 mg; 5.076 mmol; 2.00 eq.) in 1,2-dichloroethane (20 mL) was added 2,2'-bipyridine (396.3 mg; 2.538 mmol; 1.00 eq.) at room temperature. The resulting mixture was degassed and purged with O2for 3 times and stirred at 70 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-18% of EtOAc in petroleum ether as eluent to provide 5-bromo-1-cyclopropyl-1H-indazole as an orange oil (500 mg, 83.1%). LCMS (ESI) m / z 237.0, [M+H]+. Step 2: N-(5-((1-cyclopropyl-1H-indazol-5-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(5-((1-cyclopropyl-1H-indazol-5-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 5-bromo-1-cyclopropyl-1H-indazole as the starting material. LCMS (ESI) m / z 423.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.38 (s, 1H), 8.69 (s, 1H), 8.33 - 8.27 (m, 2H), 8.07 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8, 1.2 Hz, 1H), 3.84 - 3.76 (m, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.13 - 2.04 (m, 1H), 1.18 - 1.09 (m, 4H), 0.96 - 0.80 (m, 4H). Example 94: Synthesis of N-(5-((2-(methyl-d3)-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4,5-dibromo-2-(methyl-d3)-2H-1,2,3-triazole A solution of 4,5-dibromo-2H-1,2,3-triazole (1.00 g; 4.408 mmol; 1.00 eq.), iodomethane-d3(2.00 g; 13.797 mmol; 3.13 eq.) and K2CO3(1.20 g; 8.683 mmol; 1.97 eq.) in DMF (15 mL) was stirred at room temperature for 12 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 10-20% of EtOAc in petroleum ether as eluent to provide 4,5-dibromo-2-(methyl-d3)-2H-1,2,3-triazole as a white solid (700 mg, 65.1%). LCMS (ESI) m / z 242.9, [M+H]+. Step 2: 4-bromo-2-(methyl-d3)-2H-1,2,3-triazole To a stirred solution of 4,5-dibromo-2-(methyl-d3)-2H-1,2,3-triazole (500.0 mg; 2.050 mmol; 1.00 eq.) in THF (8 mL) was added i-PrMgCl (2.0 M in THF, 3.3 mL) at -20 ℃ and stirred for 0.5 hour under nitrogen atmosphere. Then the mixture was stirred at 0 ℃ for another 2 hours. The desired product was detected via LCMS. After the completion of reaction, the mixture was quenched with ice water (10 mL). The resulting mixture was extracted with diethyl ether (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 4-bromo-2-(methyl-d3)-2H- 1,2,3-triazole as a colorless oil (350 mg, crude). LCMS (ESI) m / z 165.0, [M+H]+. Step 3: N-(5-((2-(methyl- -1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)c yclopropanecarboxamide N-(5-((2-(methyl-d3)-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-bromo-2-(methyl-d3)-2H-1,2,3-triazole as the starting material. LCMS (ESI) m / z 351.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.40 (s, 1H), 8.65 - 8.44 (m, 2H), 8.30 (s, 1H), 8.04 (s, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.13 - 2.03 (m, 1H), 0.96 - 0.74 (m, 4H). Example 95: Synthesis of N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 3-bromo-1-cyclopropyl-5-methyl-1H-pyrazole A solution of 3-bromo-5-methyl-1H-pyrazole (300.0 mg; 1.863 mmol; 1.00 eq.), cyclopropylboronic acid (320.1 mg; 3.726 mmol; 2.00 eq.), 2,2'-bipyridine (291.0 mg; 1.863 mmol; 1.00 eq.), Cu(OAc)2(338.4 mg; 1.863 mmol; 1.00 eq.) and Na2CO3(394.9 mg; 3.726 mmol; 2.00 eq.) in 1,2-dichloroethane (8 mL) was stirred at 70 ℃ overnight under air atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 0- 40% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide 3-bromo-1-cyclopropyl-5-methyl-1H- pyrazole as a yellow oil (212.9 mg, 21.3%). LCMS (ESI) m / z 201.0, [M+H]+. Step 2: N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 3-bromo-1-cyclopropyl-5-methyl-1H-pyrazole as the starting material. LCMS (ESI) m / z 387.2. [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.36 (s, 1H), 8.52 (s, 1H), 8.33 - 8.26 (m, 1H), 8.24 (s, 1H), 6.29 (s, 1H), 3.59 - 3.51 (m, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.36 (s, 3H), 2.11 - 2.02 (m, 1H), 1.01 - 0.96 (m, 4H), 0.91 - 0.77 (m, 4H). Example 96: Synthesis of N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4-bromo-1-cyclopropyl-5-methyl-1H-pyrazole To a stirred solution of 4-bromo-1-cyclopropyl-1H-pyrazole (500.0 mg; 2.673 mmol; 1.00 eq.) in THF (10 mL) was added LDA (2.0 M in THF, 2.67 mL) dropwise at -78 ℃. The resulting mixture was stirred at - 78 ℃ for 1 hour under nitrogen atmosphere. To the above mixture was added a solution of iodomethane (569.1 mg; 4.010 mmol; 1.50 eq.) in THF (10 mL) at -78 ℃ and stirred for another 0.5 hour at -78 ℃. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was allowed to warm to room temperature and quenched with a saturated aqueous solution of NH4Cl (30 mL). The crude mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 40-50% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide 4-bromo-1-cyclopropyl-5-methyl-1H-pyrazole as a yellow oil (370.2 mg, 68.8%). LCMS (ESI) m / z 201.0, [M+H]+. Step 2: N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide

[0033] N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-bromo-1-cyclopropyl-5-methyl-1H-pyrazole as the starting material. LCMS (ESI) m / z 387.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.36 (s, 1H), 8.60 (s, 1H), 8.25 - 8.21 (m, 1H), 8.20 (s, 1H), 7.53 (s, 1H), 3.61 - 3.52 (m, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.49 (s, 3H), 2.11 - 2.02 (m, 1H), 1.10 - 0.98 (m, 4H), 0.89 - 0.78 (m, 4H). Example 97 and Example 98: Synthesis of N-(5-((3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)- 8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 97) and N-(5-((5- methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Example 98) Step 1: 4-bromo-3-methyl-1-(methyl-d3)-1H-pyrazole and 4-bromo-5-methyl-1-(methyl-d3)-1H- pyrazole (mixture) To a stirred solution of 4-bromo-3-methyl-1H-pyrazole (500.0 mg; 3.106 mmol; 1.00 eq.) in THF (10 mL) was added NaH (60% dispersion in mineral oil,149.0 mg; 6.209 mmol; 2.00 eq.) at 0 ℃. The resulting mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. To the above mixture was added iodomethane-d3(450.1 mg; 3.105 mmol; 1.00 eq.). The resulting mixture was stirred at room temperature for 3 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water (10 mL) at 0 ℃. The resulting mixture was extracted with CH2Cl2(3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford a mixture of 4-bromo-3-methyl-1-(methyl-d3)-1H-pyrazole and 4-bromo-5-methyl-1-(methyl-d3)-1H- pyrazole as a light yellow oil (300.0 mg, 54.2%). LCMS (ESI) m / z 179.1, [M+H]+. Step 2: N-(5-((3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide and N-(5-((5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide N-(5-((3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide and N-(5-((5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide were synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide and a mixture of 4-bromo-3-methyl-1-(methyl-d3)-1H- pyrazole and 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole as the starting material. The mixture was separated by Prep-Achiral-SFC (Column: DAICEL DCpak P4VP 3 × 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (20mM NH3); Flow rate: 60 mL / min; Gradient: 37% B to 37% B in 15 min) to afford N-(5-((3-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Example 97, the faster peak) as a yellow solid (2.0 mg, 0.7%) and N-(5-((5- methyl-1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 98, the slower peak) as a yellow solid (2.1 mg, 0.8%).LCMS and HNMR for Example 97: LCMS (ESI) m / z 364.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.36 (s, 1H), 8.59 (s, 1H), 8.25 - 8.20 (m, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.28 (s, 3H), 2.12 - 2.02 (m, 1H), 0.90 - 0.78 (m, 4H). LCMS and HNMR for Example 98: LCMS (ESI) m / z 364.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.36 (s, 1H), 8.61 (s, 1H), 8.39 - 8.00 (m, 2H), 7.56 (s, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.41 (s, 3H), 2.13 - 2.02 (m, 1H), 0.91 - 0.79 (m, 4H). Example 99: Synthesis of N-(5-((5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 4-bromo-5-chloro-1,3-dimethyl-1 To a stirred solution of 1,3-dimethyl-5-chloropyrazole (300.0 mg; 2.297 mmol; 1.00 eq.) in CCl4(3 mL) was added NBS (450.0 mg; 2.528 mmol; 1.10 eq.) at 0 ℃. The resulting solution was stirred at room temperature for 24 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 20- 30% of EtOAc in petroleum ether as eluent to provide 4-bromo-5-chloro-1,3-dimethyl-1H-pyrazole as a white solid (400.0 mg, 83.1%). LCMS (ESI) m / z 208.9, [M+H]+. Step 2: N-(5-((5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(5-((5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-bromo-5-chloro-1,3-dimethyl-1H-pyrazole as the starting material. LCMS (ESI) m / z 395.1, [M+H]+.1 1.05 (s, 1H), 9.37 (s, 1H), 8.59 (s, 1H), 8.33 - 8.27 (m, 1H), 8.23 (s, 1H), 3.77 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.29 (s, 3H), 2.11 - 2.01 (m, 1H), 0.88 - 0.78 (m, 4H). Example 100: Synthesis of N-(5-((5-(1-cyanoethyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 2-(6-chloropyridin-3-yl)propanenitrile To a stirred solution of 2-(6-chloropyridin-3-yl)acetonitrile (600.0 mg; 3.932 mmol; 1.00 eq.) in THF (6 mL) was added NaH (60% dispersion in mineral oil ) (157.3 mg; 3.933 mmol; 1.00 eq.) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 10 minutes under nitrogen atmosphere. To the above mixture was added iodomethane (558.2 mg; 3.933 mmol; 1.00 eq.) at 0 ℃ and stirred at 0 ℃ for another 0.5 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction was quenched with a saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-33% of EtOAc in petroleum ether as eluent to provide 2-(6-chloropyridin-3- yl)propanenitrile as a white solid (296.6 mg, 45.2%). LCMS (ESI) m / z 167.0, [M+H]+. Step 2: N-(5-((5-(1-cyanoethyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide N-(5-((5-(1-cyanoethyl)pyridin-2-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 2-(6-chloropyridin-3-yl)propanenitrile as the starting material. LCMS (ESI) m / z 397.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.39 (s, 1H), 8.69 - 8.59 (m, 2H), 8.48 - 8.40 (m, 1H), 8.36 (s, 1H), 7.94 (dd, J = 8.0, 2.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 4.52 - 4.38 (m, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.14 - 2.03 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 0.95 - 0.78 (m, 4H). Example 101 and Example 102: Synthesis of N-(5-((1-cyclopropyl-3-methyl-1H-pyrazol-4- yl)ethynyl)-8-((methyl-d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 101) and N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)ethynyl)-8-((methyl-d3)amino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Example 102) Step 1: 4-bromo-1-cyclopropyl-3-methyl-1H-pyrazole and 4-bromo-1-cyclopropyl-5-methyl-1H- pyrazole A solution of 4-bromo-3-methyl-1H-pyrazole (1.00 g; 6.211 mmol; 1.00 eq.), cyclopropylboronic acid (1.07 g; 12.422 mmol; 2.00 eq.), 2,2'-bipyridine (970.1 mg; 6.211 mmol; 1.00 eq.), Cu(OAc)2(1.13 g; 6.211 mmol; 1.00 eq.) and Na2CO3(1.32 g; 12.422 mmol; 2.00 eq.) in 1,2-dichloroethane (30 mL) was stirred at 70 ℃ overnight under oxygen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and diluted with EtOAc (200 mL). The solids were removed via filtration, the filtrate was washed with brine (2 × 50 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 30-40% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide a mixture of 4-bromo-1-cyclopropyl-3-methyl-1H-pyrazole and 4-bromo-1- cyclopropyl-5-methyl-1H-pyrazole as a yellow oil (625.4 mg, 50.0%). LCMS (ESI) m / z 201.0, [M+H]+. Step 2: N-(8-((methyl-d3)amino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarb oxamide To a stirred mixture of N-(5-bromo-8-((methyl-d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.00 g; 3.085 mmol; 1.00 eq.), Pd(dppf)Cl2CH2Cl2(1.26 g; 1.542 mmol; 0.5 eq.) and CuI (293.7 mg; 1.542 mmol; 0.5 eq.) in DMF (10 mL) were added trimethylsilylacetylene (605.9 mg; 6.170 mmol; 2.00 eq.) andDIPEA (2.39 g; 18.510 mmol; 6.00 eq.). The resulting mixture was stirred at 50 ℃ for 2 hours undernitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 1-5% of MeOH in CH2Cl2as eluent to provide N-(8-((methyl-d3)amino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (931 mg, 84.5%). LCMS (ESI) m / z 342.2, [M+H]+.Step 3: N-(5-ethynyl-8-((methyl- yl)cyclopropanecarboxamide To a solution of N-(8-((methyl-d3)amino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (920.0 mg; 2.694 mmol; 1.00 eq.) in MeOH (10.0 mL) was added K2CO3(994.0 mg; 7.193 mmol; 2.67 eq.). The resulting mixture was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 1-5% of MeOH in CH2Cl2as eluent to provide N-(5-ethynyl-8-((methyl-d3)amino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (416.4 mg, 56.5%). LCMS (ESI) m / z 270.1, [M+H]+. Step 4: N-(5-((1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)ethynyl)-8-((methyl-d3)amino)-2,7-naphthyri din-3-yl)cyclopropanecarboxamide and N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)ethynyl)-8- ((methyl-d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0034] The mixture of N-(5-((1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)ethynyl)-8-((methyl-d3)amino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide and N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4- yl)ethynyl)-8-((methyl-d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 1 by using N-(5-ethynyl-8-((methyl- d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and a mixture of 4-bromo-1-cyclopropyl-3- methyl-1H-pyrazole and 4-bromo-1-cyclopropyl-5-methyl-1H-pyrazole as the starting materials. The mixture was separated by Prep-Achiral-SFC (Column: GreenSep Nitro, 30 × 150 mm 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH (20 mM NH3); Flow rate: 60 mL / min; Gradient: isocratic 40% B; RT1(min): 9.93; RT2(min): 12.45) to afford N-(5-((1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)ethynyl)-8- ((methyl-d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 101, the faster peak) as a yellow solid (9.4 mg, 6.5%) and N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)ethynyl)-8-((methyl- d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 102, the slower peak) as a yellow solid (4.1 mg, 2.8%). LCMS and HNMR for example Example 101: LCMS (ESI) m / z 390.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.35 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 3.70 - 3.62 (m, 1H), 2.27 (s, 3H), 2.10 - 2.02 (m, 1H), 1.07 - 1.01 (m, 2H), 0.97 - 0.90 (m, 2H), 0.88 - 0.80 (m, 4H). LCMS and HNMR for Example 102: LCMS (ESI) m / z 390.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.36 (s, 1H), 8.60 (s, 1H), 8.20 (s, 2H), 7.53 (s, 1H), 3.61 - 3.53 (m, 1H), 2.49 (s, 3H), 2.12 - 1.99 (m, 1H), 1.10 - 0.98 (m, 4H), 0.88 - 0.80 (m, 4H). Example 103: Synthesis of N-(5-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-((methyl- d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide Step 1: 1-(4-ethynylbenzyl)-3-methoxyazetidine To a stirred solution of 4-ethynylbenzaldehyde (500.0 mg; 3.842 mmol; 1.00 eq.), 3-methoxyazetidine hydrochloride (712.2 mg; 5.763 mmol; 1.50 eq.) and DIEA (993.1 mg; 7.684 mmol; 2.00 eq.) in 1,2- dichloroethane (30 mL) was added NaBH(OAc)3(2.44 g; 11.525 mmol; 3.00 eq.) in portions. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was basified to pH = 7 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with CH2Cl2(3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2- 10% of MeOH in CH2Cl2as eluent to afford 1-(4-ethynylbenzyl)-3-methoxyazetidine as a yellow oil (700.0 mg, 90.5%). LCMS (ESI) m / z 202.2, [M+H]+. Step 2: N-(5-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-((methyl-d3)amino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A stirred mixture of 1-(4-ethynylbenzyl)-3-methoxyazetidine (74.7 mg; 0.371 mmol; 1.50 eq.), N-(5- bromo-8-((methyl-d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (80.0 mg; 0.248 mmol; 1.00 eq.), XPhos Pd G3(20.9 mg; 0.025 mmol; 0.10 eq.), XPhos (23.6 mg; 0.050 mmol; 0.20 eq.), Et3N (75.1 mg; 0.742 mmol; 3.00 eq.) and CuI (4.7 mg; 0.025 mmol; 0.10 eq.) in DMF (2 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford a crude product. The crude product was purified by flash chromatography on pre-packed C18 column using 20-60% of MeCN / THF = 3:1 in water (10 mmol / L NH4HCO3) to provide N-(5-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)-8-((methyl- d3)amino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (18.2 mg, 16.4%). LCMS (ESI) m / z 445.3, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.32 - 8.29 (m, 1H), 8.27 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.04 - 3.93 (m, 1H), 3.60 (s, 2H), 3.53 - 3.45 (m, 2H), 3.15 (s, 3H), 2.90 - 2.82 (m, 2H), 2.14 - 2.03 (m, 1H), 0.94 - 0.80 (m, 4H). Example 104: Synthesis of N-(8-(methylamino)-5-((2-methyloxazol-4-yl)ethynyl)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide Step 1: 4-ethynyl-2-methyloxazole A solution of 2-methyloxazole-4-carbaldehyde (300.0 mg; 2.700 mmol; 1.00 eq.), K2CO3(745.8 mg; 5.396 mmol; 2.00 eq.) and dimethyl (1-diazo-2-oxopropyl)phosphonate (519.0 mg; 2.702 mmol; 1.00 eq.) in MeOH (9 mL) was stirred at room temperature for 5 hours. The desired product was detected via LCMS. After the completion of reaction, the resulting mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with water (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-ethynyl- 2-methyloxazole as a white oil (200.0 mg, 69.1%). LCMS (ESI) m / z 108.0, [M+H]+. Step 2: N-(8-(methylamino)-5-((2-methyloxazol-4-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropaneca rboxamide N-(8-(methylamino)-5-((2-methyloxazol-4-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was synthesized using a similar procedure that was previously described in Example 103 by using N-(5- bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and 4-ethynyl-2-methyloxazole as the starting material. LCMS (ESI) m / z 348.1, [M+H]+.1H NMR NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.51 (s, 1H), 8.39 - 8.33 (m, 2H), 8.27 (s, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.45 (s, 3H), 2.12 - 2.02 (m, 1H), 0.91 - 0.79 (m, 4H). Example 105 and Example 106: Synthesis of N-(5-((4-((1-((3S,4S)-4-hydroxy-3- methyltetrahydrofuran-3-yl)azetidin-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Example 105) and N-(5-((4-((1-((3R,4R)-4-hydroxy-3- methyltetrahydrofuran-3-yl)azetidin-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Example 106) Step 1: tetrahydrofuran-3,4-diol (trans racemate) A solution of 3,6-dioxabicyclo[3.1.0]hexane (10.00 g; 116.158 mmol; 1.00 eq.) and H2SO4(36.00 g; 367.085 mmol; 3.16 eq.) in water (200.0 mL) was stirred at 100 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with THF (100 mL) at room temperature for 3 hours. After filtration, the filtrate was concentrated under reduced pressure to afford tetrahydrofuran-3,4- diol (trans racemate) as a brown oil (12.0 g, 99.2%). LCMS (ESI) m / z 105.0, [M+H]+. Step 2: 4-((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-3-ol (trans racemate) To a solution of tetrahydrofuran-3,4-diol (trans isomer) (12.00 g; 115.384 mmol; 1.00 eq.) and tert-butylchlorodiphenylsilane (31.71 g; 115.384 mmol; 1.01 eq.) in MeCN (300 mL) was added 1H-imidazole (11.78 g; 173.076 mmol; 1.50 eq.) at room temperature. The resulting mixture was stirred at 70 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc(500 mL) and washed with brine (2 × 200 mL). The organic layer was dried over anhydrous Na 2SO4. Afterfiltration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 25-60% of EtOAc in petroleum ether as eluent to afford 4- ((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-3-ol (trans racemate) as a white solid (28.0 g, 71.6%). LCMS (ESI) m / z 343.2, [M+H]+. Step 3: 4-((tert-butyldiphenylsilyl)oxy) -one A solution of 4-((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-3-ol (trans isomer) (28.00 g; 81.749 mmol; 1.00 eq.) and Dess-Martin (40.00 g; 94.308 mmol; 1.15 eq.) in CH2Cl2(280.0 mL) was stirred at room temperature for 3 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction was quenched with a saturated aqueous solution of NaHCO3(500 mL) at room temperature. The resulting mixture was extracted with CH2Cl2(2 × 200 mL). The combined organic layers were washed with water (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 25-60% of EtOAc in petroleum ether as eluent to afford 4-((tert-butyldiphenylsilyl)oxy)dihydrofuran-3(2H)-one as a colorless oil (22.0 g, 79.0%). LCMS (ESI) m / z 341.1, [M+H]+. Step 4: 3-(3-(4-bromobenzyl)azetidin-1-yl)-4-((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-3- carbonitrile A solution of 3-(4-bromobenzyl)azetidine hydrochloride (1.00 g; 3.808 mmol; 1.00 eq.) and AcOH (249.2 mg; 4.151 mmol; 1.09 eq.) in 1,2-dichloroethane (100.0 mL) was stirred at 50 ℃ for 1 hour. To the above mixture were added DIPEA (1.60 g; 12.376 mmol; 3.25 eq.) and 4-((tert- butyldiphenylsilyl)oxy)dihydrofuran-3(2H)-one (1.40 g; 4.265 mmol; 1.12 eq.). The resulting mixture was stirred at 50 ℃ for another 1 hour. To the above mixture was added trimethylsilanecarbonitrile (1.20 g; 12.096 mmol; 1.59 eq.) and stirring was continued at 50 ℃ overnight under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the mixture was cooled to room temperature and quenched with a saturated solution of NH4HCO3(50 mL). The resulting mixture was extracted with CH2Cl2(2 × 50 mL). The combined organic layers were washed with water (100 mL) just once and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(3-(4-bromobenzyl)azetidin-1-yl)-4-((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-3- carbonitrile as a colorless oil (2.7 g, crude). LCMS (ESI) m / z 575.2, [M+H]+. Step 5: 3-(4-bromobenzyl)-1-(4-((tert-butyldiphenylsilyl)oxy)-3-methyltetrahydrofuran-3-yl)azetidin e (cis racemate) To a stirred solution of 3-(3-(4-bromobenzyl)azetidin-1-yl)-4-((tert- butyldiphenylsilyl)oxy)tetrahydrofuran-3-carbonitrile (2.20 g; 3.822 mmol; 1.00 eq.) in THF (50.0 mL) was added methylmagnesium bromide (1.0 M in THF, 20.0 mL) dropwise at 0 ℃. The resulting mixture was stirred at 50 ℃ for 3 hours under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the mixture was cooled to room temperature and quenched with a saturated aqueous solution of NH4HCO3(50 mL). The resulting mixture was extracted with EtOAc (2 × 20 mL). Thecombined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2SO4. Afterfiltration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-10% of EtOAc in petroleum ether as eluent to afford 3-(4- bromobenzyl)-1-(4-((tert-butyldiphenylsilyl)oxy)-3-methyltetrahydrofuran-3-yl)azetidine (cis racemate) as a colorless oil (930.0 mg, 43.0%). LCMS (ESI) m / z 564.2, [M+H]+. Step 6: N-(5-((4-((1-(4-((tert-butyldiphenylsilyl)oxy)-3-methyltetrahydrofuran-3-yl)azetidin-3-yl)met hyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (cis racemat e) A solution of 3-(4-bromobenzyl)-1-(4-((tert-butyldiphenylsilyl)oxy)-3-methyltetrahydrofuran-3- yl)azetidine (cis racemate) (358.7 mg; 0.636 mmol; 1.41 eq.), N-(5-ethynyl-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (120.0 mg; 0.451 mmol; 1.00 eq.), Et3N (96.2 mg; 0.952 mmol; 2.11 eq.), XPhos Pd G3 (38.1 mg; 0.045 mmol; 0.10 eq.), XPhos (47.2 mg; 0.099 mmol; 0.22 eq.) and CuI (12.0 mg; 0.063 mmol; 0.14 eq.) in DMF (5 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. Afterthe completion of reaction, the reaction mixture was cooled to room temperature and concentrated undervacuum. The residue was purified by flash chromatography on silica gel column using 0-5% of MeOH in CH2Cl2as eluent to afford N-(5-((4-((1-(4-((tert-butyldiphenylsilyl)oxy)-3-methyltetrahydrofuran-3- yl)azetidin-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (cis racemate) as a yellow solid (158.0 mg, 46.7%). LCMS (ESI) m / z 750.4, [M+H]+. Step 7: N-(5-((4-((1-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)azetidin-3-yl)methyl)phenyl)e thynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and N-(5-((4-((1-((3R,4R) -4-hydroxy-3-methyltetrahydrofuran-3-yl)azetidin-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2, 7-naphthyridin-3-yl)cyclopropanecarboxamide A solution of N-(5-((4-((1-(4-((tert-butyldiphenylsilyl)oxy)-3-methyltetrahydrofuran-3-yl)azetidin-3- yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (cis racemate) (148 mg; 0.197 mmol; 1.00 eq.) and TBAF (1.0 M in THF, 1 mL) in THF (5 mL) was stirred at 60 ℃ for 1 hour under nitrogen atmosphere. The desired product was detected via LCMS. After the completion of reaction, the mixture was cooled to room temperature and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel column using 0 -5% of MeOH in CH2Cl2 aseluent to afford 80 mg of the cis racemate. The cis racemate was separated by Prep-Chiral-HPLC (Column: CHIRALPAK IC, 2 × 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH: CH2Cl2=1: 1; Flow rate: 20 mL / min; Gradient: 40% B to 40% B in 7 min; RT1(min): 5.08; RT2(min): 5.93) to afford N-(5-((4-((1-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)azetidin-3- yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 105, the faster peak) as a yellow solid (13.2 mg, 16.5%) and N-(5-((4-((1-((3R,4R)-4-hydroxy-3- methyltetrahydrofuran-3-yl)azetidin-3-yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (Example 106, the slower peak) as a yellow solid (17.0 mg, 21.2%). The two configurations were arbitrarily assigned. LCMS and HNMR for Example 105: LCMS (ESI) m / z 512.3, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.34 - 8.28 (m, 1H), 8.26 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.75 - 4.51 (m, 1H), 3.88 - 3.80 (m, 1H), 3.71 - 3.61 (m, 2H), 3.55 - 3.49 (m, 1H), 3.42 - 3.33 (m, 3H), 3.16 - 3.07 (m, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.86 (d, J = 7.6 Hz, 2H), 2.74 - 2.64 (m, 1H), 2.14 - 2.04 (m, 1H), 1.02 (s, 3H), 0.94 - 0.80 (m, 4H). LCMS and HNMR for Example 106: LCMS (ESI) m / z 512.3, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.65 (s, 1H), 8.34 - 8.28 (m, 1H), 8.26 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.75 - 4.51 (m, 1H), 3.88 - 3.80 (m, 1H), 3.71 - 3.61 (m, 2H), 3.55 - 3.49 (m, 1H), 3.42 - 3.33 (m, 3H), 3.16 - 3.07 (m, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.86 (d, J = 7.6 Hz, 2H), 2.74 - 2.64 (m, 1H), 2.14 - 2.04 (m, 1H), 1.02 (s, 3H), 0.94 - 0.80 (m, 4H). Example 107: Synthesis of 4-((6-((6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin- 4-yl)ethynyl)pyridin-3-yl)amino)butanoic acid Step 1: 1-(6-bromopyridin-3-yl)pyrrolidin-2-one A stirred mixture of 2-bromo-5-iodopyridine (2.00 g; 7.067 mmol; 1.00 eq.), pyrrolidin-2-one (500.0 mg; 5.882 mmol; 0.83 eq.), K3PO4(3745.6 mg; 17.668 mmol; 2.50 eq.), CuI (134.6 mg; 0.707 mmol; 0.10 eq.) and ethane-1,2-diol (65.7 mg; 1.060 mmol; 0.15 eq.) in isopropanol (10 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ overnight. The desired product was detected viaLCMS. After the completion of reaction, the mixture was cooled to room temperature and concentratedunder vacuum. The residue was purified by flash chromatography on silica gel column using 0 -2% ofMeOH in CH2Cl2as eluent to afford 1-(6-bromopyridin-3-yl)pyrrolidin-2-one as an off-white solid (450.0 mg, 26.4%). LCMS (ESI) m / z 241.0, [M+H]+. Step 2: 1-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrrolidin-2-one To a solution of 1-(6-bromopyridin-3-yl)pyrrolidin-2-one (450.0 mg; 1.875 mmol; 1.00 eq.), Pd(dppf)Cl2.CH2Cl2(305.6 mg; 0.375 mmol; 0.20 eq.) and CuI (71.4 mg; 0.375 mmol; 0.20 eq.) in DMF (4.5 mL) was added DIPEA (1.45 g; 11.250 mmol; 6.00 eq.). The mixture was degassed and purged with N2for 3 times. To the above mixture was added ethynyltrimethylsilane (367.5 mg; 3.750 mmol; 2.00 eq.) at room temperature and the reaction mixture was stirred at 50 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 10-30% of EtOAc in petroleum as eluent to afford 1-(6-((trimethylsilyl)ethynyl)pyridin-3- yl)pyrrolidin-2-one as a brown solid (300.0 mg, 61.9%). LCMS (ESI) m / z 259.1, [M+H]+. Step 3: 1-(6-ethynylpyridin-3-yl)pyrrolidin-2-one A solution of 1-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrrolidin-2-one (300.0 mg; 1.163 mmol; 1.00 eq.) and K2CO3(320.9 mg; 2.325 mmol; 2.00 eq.) in MeOH (20 mL) was stirred at room temperature for 20 minutes. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 50-60% of EtOAc in petroleum ether as eluent to afford 1-(6-ethynylpyridin-3-yl)pyrrolidin-2-one as a brown solid (150.0 mg, 69.2%). LCMS (ESI) m / z 187.1, [M+H]+. Step 4: N-(8-(methylamino)-5-((5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide

[0035] A solution of 1-(6-bromopyridin-3-yl)pyrrolidin-2-one (448.5 mg; 1.861 mmol; 1.50 eq.), N-(5-ethynyl-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (330.0 mg; 1.241 mmol; 1.00 eq.), XPhos Pd G3(105.1 mg; 0.124 mmol; 0.10 eq.), XPhos (118.4 mg; 0.248 mmol; 0.20 eq.), Et3N (375.9 mg; 3.722 mmol; 3.00 eq.) and CuI (23.6 mg; 0.124 mmol; 0.10 eq.) in DMF (3.0 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected viaLCMS. After the completion of reaction, the reaction mixture was cooled to room temperature andconcentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 0-10% of MeOH in CH2Cl2as eluent to afford N-(8-(methylamino)-5-((5-(2-oxopyrrolidin-1-yl)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (120.0 mg, 22.6%). LCMS (ESI) m / z 427.2, [M+H]+. Step 5: 4-((6-((6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4- yl)ethynyl)pyridin-3-yl)amino)butanoic acid A solution of N-(8-(methylamino)-5-((5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (150.0 mg; 0.352 mmol; 1.00 eq.) and NaOH (140.7 mg; 3.517 mmol; 10.00 eq.) in a mixture solvent of MeOH / DMSO / water (10:1:1, 58 mL) was stirred at 80 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting mixture was diluted with water (20 mL) to precipitate solids. The precipitated solids were collected by filtration, washed with water (20 mL) just once. The crude product was purified by flash chromatography on pre-packed C18 column using 10-30% of MeCN / THF = 3:1 in water (10 mmol / L NH4HCO3) to afford 4-((6-((6-(cyclopropanecarboxamido)-1- (methylamino)-2,7-naphthyridin-4-yl)ethynyl)pyridin-3-yl)amino)butanoic acid as a yellow solid (15.1 mg, 9.2%). LCMS (ESI) m / z 445.2, [M+H]+. Example 108: Synthesis of N6-(2,6-dimethylpyrimidin-4-yl)-4-((5-methoxypyridin-2-yl)ethynyl)-N1- methyl-2,7-naphthyridine-1,6-diamine A stirred mixture of 4-((5-methoxypyridin-2-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine (90.0 mg; 0.295 mmol; 1.00 eq.), 4-chloro-2,6-dimethylpyrimidine (37.8 mg; 0.265 mmol; 0.90 eq.), Pd2(dba)3(64.8 mg; 0.071 mmol; 0.24 eq.), XantPhos (81.9 mg; 0.142 mmol; 0.48 eq.) and Cs2CO3(192.1 mg; 0.590 mmol; 2.00 eq.) in 1,4-dioxane (4 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 130 ℃ for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to afford N6-(2,6-dimethylpyrimidin-4-yl)-4-((5-methoxypyridin-2-yl)ethynyl)-N1-methyl-2,7- naphthyridine-1,6-diamine as a yellow solid (37.8 mg, 30.9%). LCMS (ESI) m / z 412.2, [M+H]+. Example 109: Synthesis of N6-(2,6-dimethylpyrimidin-4-yl)-N1-methyl-4-((5- (morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6-diamine Step 1: N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6-diamine To a stirred solution of N-(8-(methylamino)-5-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (WO 2023 / 244788, which is incorporated by reference in its entirety) (250.0 mg; 0.565 mmol; 1.00 eq.) in MeOH (21 mL) was added a solution of NaOH (225.9 mg; 5.648 mmol; 10.00 eq.) in water (7 mL). The resulting mixture was stirred at 60 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL) to precipitate solids. The solids were collected by filtration, washed with water (3 × 10 mL) and dried under vacuum to provide N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine- 1,6-diamine as a yellow solid (180.0 mg, 80.8%). LCMS (ESI) m / z 375.2, [M+H]+. Step 2: N6-(2,6-dimethylpyrimidin-4-yl)-N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)- 2,7-naphthyridine-1,6-diamine N6-(2,6-dimethylpyrimidin-4-yl)-N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7- naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 108 by using N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6- diamine and 4-chloro-2,6-dimethylpyrimidine as the starting material. LCMS (ESI) m / z 481.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.37 (s, 1H), 8.68 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.40 - 8.33 (m, 1H), 8.32 (s, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 3.66 - 3.59 (m, 4H), 3.55 (s, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.41 - 2.35 (m, 7H), 2.32 (s, 3H). Example 110: Synthesis of 1-(3-(4-((6-((2,6-dimethylpyrimidin-4-yl)amino)-1-(methylamino)-2,7- naphthyridin-4-yl)ethynyl)phenoxy)azetidin-1-yl)ethan-1-one Step 1: tert-butyl 3-(4-((6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4- yl)ethynyl)phenoxy)azetidine-1-carboxylate To a stirred mixture of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (500.0 mg; 1.523 mmol; 1.00 eq.), XPhos Pd G3(257.9 mg; 0.305 mmol; 0.20 eq.), XPhos (145.2 mg; 0.305 mmol; 0.20 eq.), CuI (58.0 mg; 0.305 mmol; 0.20 eq.) and (5-ethynyl-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (608.5 mg; 2.284 mmol; 1.50 eq. ) in DMF (4 mL) was added Et3N (616.6 mg; 6.092 mmol; 3.00 eq.) at room temperature. The resulting mixture was degassed and purged with N2for 3 times and stirred at 90 ℃ for 2 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was purified by flash chromatography on silica gel column using 2 -10% ofMeOH in CH2Cl2as eluent to afford tert-butyl 3-(4-((6-(cyclopropanecarboxamido)-1-(methylamino)-2,7- naphthyridin-4-yl)ethynyl)phenoxy)azetidine-1-carboxylate as a yellow solid (720.0 mg, 92.0%). LCMS (ESI) m / z 514.2, [M+H]+. Step 2: 4-((4-(azetidin-3-yloxy)phenyl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine To a stirred solution of tert-butyl 3-(4-((6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin- 4-yl)ethynyl)phenoxy)azetidine-1-carboxylate (700.0 mg; 1.363 mmol; 1.00 eq.) in a mixture solvent of MeOH / THF / DMSO / water (5:5:2:2, 25 mL) was added NaOH (545.1 mg; 13.630 mmol; 10.00 eq.). The resulting mixture was stirred at 60 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 20- 60% of MeCN in water (10 mmol / L NH4HCO3) as eluent to provide 4-((4-(azetidin-3- yloxy)phenyl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (320.0 mg, 67.9%). LCMS (ESI) m / z 346.2, [M+H]+. Step 3: 1-(3-(4-((6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)ethynyl)phenoxy)azetidin-1-yl)eth an-1-one To a stirred solution of 4-((4-(azetidin-3-yloxy)phenyl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine (320.0 mg; 0.966 mmol; 1.00 eq.) and DIPEA (374.4 mg; 2.898 mmol; 3.00 eq.) in a mixture solvent of CH2Cl2 / DMF (7:1, 4 mL) was added a solution of acetic anhydride (98.5 mg; 0.966 mmol; 1.00 eq.) in CH2Cl2(1 mL) at 0 ℃ under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 30-100% of MeOH in water (10 mmol / L NH4HCO3) as eluent to afford 1-(3-(4-((6-amino-1-(methylamino)-2,7-naphthyridin-4- yl)ethynyl)phenoxy)azetidin-1-yl)ethan-1-one as a yellow solid (255.0 mg, 68.1%). LCMS (ESI) m / z 388.2, [M+H]+. Step 4: 1-(3-(4-((6-((2,6-dimethylpyrimidin-4-yl)amino)-1-(methylamino)-2,7-naphthyridin-4- yl)ethynyl)phenoxy)azetidin-1-yl)ethan-1-one 1-(3-(4-((6-((2,6-dimethylpyrimidin-4-yl)amino)-1-(methylamino)-2,7-naphthyridin-4- yl)ethynyl)phenoxy)azetidin-1-yl)ethan-1-one was synthesized using a similar procedure that was previously described in Example 108 by using 1-(3-(4-((6-amino-1-(methylamino)-2,7-naphthyridin-4- yl)ethynyl)phenoxy)azetidin-1-yl)ethan-1-one and 4-chloro-2,6-dimethylpyrimidine as the starting material. LCMS (ESI) m / z 494.2, [M+H]+. Example 111: Synthesis of 1-(3-(4-((1-(methylamino)-6-(pyridin-2-ylamino)-2,7-naphthyridin-4- yl)ethynyl)phenoxy)azetidin-1-yl)ethan-1-one 1-(3-(4-((1-(methylamino)-6-(pyridin-2-ylamino)-2,7-naphthyridin-4-yl)ethynyl)phenoxy)azetidin-1- yl)ethan-1-one was synthesized using a similar procedure that was previously described in Example 108 by using 1-(3-(4-((6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)ethynyl)phenoxy)azetidin-1-yl)ethan- 1-one (Example 110, Step 3) and 2-chloropyridine as the starting material. LCMS (ESI) m / z 465.2, [M+H]+. Example 112: Synthesis of N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A mixture of 4-bromo-2-ethyl-2H-1,2,3-triazole (39.7 mg; 0.225 mmol; 1.00 eq.), N-(5-ethynyl-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (90.0 mg; 0.338 mmol; 1.50 eq.), XPhos Pd G3(57.2 mg; 0.068 mmol; 0.30 eq.), XPhos (32.2 mg; 0.068 mmol; 0.30 eq.), Et3N (91.2 mg; 0.901 mmol; 4.00 eq.) and CuI (12.9 mg; 0.068 mmol; 0.30 eq.) in DMF (3 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to provide a crude product. The crude product was purified by flash chromatography on pre-packed C18 column using 20-60% of MeCN in water (10 mmol / L NH4HCO3) as eluent to provide N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (31.1 mg, 37.7%). LCMS (ESI) m / z 362.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.39 (s, 1H), 8.55 (s, 1H), 8.52 - 8.40 (m, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.12 - 2.02 (m, 1H), 1.49 (t, J = 7.2 Hz, 3H), 0.92 - 0.78 (m, 4H). Example 113: Synthesis of 4-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)- 2,7-naphthyridine-1,6-diamine Step 1: N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopr opanecarboxamide A mixture of 4-bromo-2-ethyl-2H-1,2,3-triazole (39.7 mg; 0.225 mmol; 1.00 eq.), N-(5-ethynyl-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (90.0 mg; 0.338 mmol; 1.50 eq.), XPhos Pd G3(57.2 mg; 0.068 mmol; 0.30 eq.), XPhos (32.2 mg; 0.068 mmol; 0.30 eq.), Et3N (91.2 mg; 0.901 mmol; 4.00 eq.) and CuI (12.9 mg; 0.068 mmol; 0.30 eq.) in DMF (3 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected viaLCMS. After the completion of reaction, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to provide a crude product. The crude product was purified by flash chromatography on pre-packed C18 column using 20-60% of MeCN in water (10 mmol / L NH4HCO3) as eluent to provide N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (31.1 mg, 37.7%). LCMS (ESI) m / z 362.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.39 (s, 1H), 8.55 (s, 1H), 8.52 - 8.40 (m, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.12 - 2.02 (m, 1H), 1.49 (t, J = 7.2 Hz, 3H), 0.92 - 0.78 (m, 4H). Step 2: 4-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine To a stirred solution of N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (180.0 mg; 0.498 mmol; 1.00 eq.) in a mixture solvent of MeOH / DMSO (10:1, 22 mL) was added a solution of NaOH (199.2 mg; 4.980 mmol; 10.00 eq.) in water (8 mL) at room temperature. The resulting mixture was stirred at 70 ℃ for 1.5 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration, washed with water (1 × 20 mL) and dried under vacuum to afford 4-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a brown solid (120.0 mg, 78.0%). LCMS (ESI) m / z 294.2, [M+H]+. Step 3: 4-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine- 1,6-diamine 4-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 108 by using 4-((2- ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine and 2-chloropyridine as the starting material. LCMS (ESI) m / z 371.2, [M+H]+. Example 114: Synthesis of 4-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-N1-methyl-N6- (pyridin-2-yl)-2,7-naphthyridine-1,6-diamine

[0036] Step 1: 4-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6- diamine To a stirred solution of N-(5-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (Example 95) (140.0 mg; 0.362 mmol; 1.00 eq.) in a mixture solvent of MeOH / DMSO (1:5, 6 mL) was added a solution of NaOH (144.9 mg; 3.623 mmol; 10.00 eq.) in water (1.5 mL). The resulting mixture was stirred at 70 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature. The crude mixture was purified by flash chromatography on pre-packed C18 column using 70-80% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide 4-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-N1- methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (110 mg, 95.6%). LCMS (ESI) m / z 319.2, [M+H]+. Step 2: 4-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7- naphthyridine-1,6-diamine 4-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1,6- diamine was synthesized using a similar procedure that was previously described in Example 108 by using 4-((1-cyclopropyl-5-methyl-1H-pyrazol-3-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine and 2- chloropyridine as the starting material. LCMS (ESI) m / z 396.2, [M+H]+. Example 115: Synthesis of 4-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)- 2,7-naphthyridine-1,6-diamine Step 1: N-(5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide To a solution of 4-iodo-1,3-dimethyl-1H-pyrazole (170.0 mg; 0.766 mmol; 1.00 eq.) and N-(5-ethynyl-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (305.9 mg; 1.149 mmol; 1.50 eq.), XPhos Pd G3(194.4 mg; 0.230 mmol; 0.30 eq.), XPhos (109.5 mg; 0.230 mmol; 0.30 eq.) and CuI (43.8 mg; 0.230 mmol; 0.30 eq.) in DMF (5 mL) was added Et3N (309.9 mg; 3.062 mmol; 4.00 eq.). The resulting mixture was degassed and purged with N2for 3 times and stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 5-10% of methanol in CH2Cl2as eluent to provide N-(5-((1,3-dimethyl-1H-pyrazol-4- yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (250 mg, 90.9%). LCMS (ESI) m / z 361.2, Step 2: 4-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine To a stirred solution of N-(5-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide (250.0 mg; 0.694 mmol; 1.00 eq.) in a mixture solvent of MeOH / DMSO (5:1, 18 mL) was added a solution of NaOH (277.7 mg; 6.944 mmol; 10.00 eq.) in water (3 mL) at 0 ℃. The resulting mixture was stirred at 60 ℃ for 15 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on pre-packed C18 column using 0-60% of MeCN / THF / MeOH = 3:1:1 in water (10 mmol / L NH4HCO3) as eluent to provide 4-((1,3- dimethyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (120.0 mg, 59.4%). LCMS (ESI) m / z 293.1, [M+H]+. Step 3: 4-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1, 6-diamine 4-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 108, by using 4-((1,3- dimethyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine and 2-chloropyridine as the starting material. LCMS (ESI) m / z 370.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.30 (s, 1H), 8.56 (s, 1H), 8.19 (dd, J = 4.8, 1.2 Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.72 - 7.65 (m, 1H), 7.40 - 7.35 (m, 1H), 6.95 - 6.89 (m, 1H), 3.81 (s, 3H), 3.01 (d, J = 4.4 Hz, 3H), 2.33 (s, 3H). Example 116: Synthesis of 4-((5-methoxypyridin-2-yl)ethynyl)-N1-methyl-N6-(1-methyl-1H-pyrazol- 3-yl)-2,7-naphthyridine-1,6-diamine A stirred mixture of 4-((5-methoxypyridin-2-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine (60.0 mg; 0.197 mmol; 1.00 eq.), EPhos Pd G4(18.0 mg; 0.020 mmol; 0.10 eq.), EPhos (10.5 mg; 0.020 mmol; 0.10 eq.), Cs2CO3(256.5 mg; 0.787 mmol; 4.01 eq.) and 3-bromo-1-methyl-1H-pyrazole (31.5 mg; 0.196 mmol; 1.00 eq.) in 1,4-dioxane (3 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 120 ℃ for 3 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 2-15% of MeOH in CH2Cl2as eluent to provide a crude product. The crude product was purified by flash chromatography on pre -packed C18column using 20-80% of THF / MeCN = 3:1 in water (10 mmol / L NH4HCO3) as eluent to provide 4-((5- methoxypyridin-2-yl)ethynyl)-N1-methyl-N6-(1-methyl-1H-pyrazol-3-yl)-2,7-naphthyridine-1,6-diamine as a yellow solid (38.8 mg, 51.2%). LCMS (ESI) m / z 386.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.22 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 8.20 - 8.12 (m, 2H), 8.04 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.8, 2.8 Hz, 1H), 6.10 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.01 (d, J = 4.4 Hz, 3H). Each compound in Table 5 below was prepared using a similar experimental procedure to prepare Example 116 using 4-((5-methoxypyridin-2-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine as the common intermediate and an appropriate aryl halide. Table 5: Example 119: Synthesis of N1-methyl-N6-(1-methyl-1H-pyrazol-3-yl)-4-((5- (morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6-diamine N1-methyl-N6-(1-methyl-1H-pyrazol-3-yl)-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7- naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 116 by using N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6- diamine (Example 109, step 1) and 3-bromo-1-methyl-1H-pyrazole as the starting material. LCMS (ESI) m / z 455.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.22 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.22 - 8.19 (m, 2H), 8.05 (s, 1H), 7.79 (d, J = 8.0, 2.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 6.10 (d, J = 2.0 Hz, 1H), 3.79 (s, 3H), 3.61 - 3.59 (m, 4H), 3.54 (s, 2H), 3.01 (d, J = 4.4 Hz, 3H), 2.41 - 2.33 (m, 4H). Example 120: Synthesis of 4-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)- 2,7-naphthyridine-1,6-diamine Step 1: N-(5-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (300.0 mg; 1.127 mmol; 1.00 eq.), XPhos Pd G3(286.2 mg; 0.338 mmol; 0.30 eq.), XPhos (161.0 mg; 0.338 mmol; 0.30 eq.), Et3N (341.7 mg; 3.377 mmol; 3.00 eq.), CuI (21.5 mg; 0.113 mmol; 0.10 eq.) and 4- bromo-1,2-dimethyl-1H-imidazole (294.4 mg; 1.682 mmol; 1.49 eq.) in DMF (3 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 2-15% of MeOH in CH2Cl2 as eluent to provide N-(5-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (143.0 mg, 35.2%). LCMS (ESI) m / z 361.2, [M+H]+. Step 2: 4-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine To a stirred solution of N-(5-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide (143.0 mg; 0.397 mmol; 1.00 eq.) in MeOH (5 mL) was added a solution of NaOH (159.0 mg; 3.975 mmol; 10.02 eq.) in water (1.5 mL). The resulting mixture was stirred at 60 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on pre-packed C18 column using 20-100% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide 4-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (80.0 mg, 68.9%). LCMS (ESI) m / z 293.1, [M+H]+. Step 3: 4-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine- 1,6-diamine 4-((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 116 by using 4- ((1,2-dimethyl-1H-imidazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine and 2-chloropyridine as the starting material. LCMS (ESI) m / z 370.2, [M+H]+. Example 121: Synthesis of 2-(6-((8-(methylamino)-5-(pyridin-2-ylethynyl)-2,7-naphthyridin-3- yl)amino)pyridin-3-yl)propan-2-ol Step 1: N-(8-(methylamino)-5-(pyridin-2-ylethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamid e A stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (200.0 mg; 0.62 mmol; 1.00 eq.), 2-ethynylpyridine (64.2 mg; 0.62 mmol; 1.00 eq.), XPhos Pd G3(52.7 mg; 0.06mmol; 0.10 eq.), XPhos (29.6 mg; 0.06 mmol; 0.10 eq.), CuI (11.8 mg; 0.06 mmol; 0.10 eq.) and Et 3N(252.1 mg; 2.49 mmol; 4.00 eq.) in DMF (8 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 90 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 0-5% of MeOH in CH2Cl2as eluent to provide N-(8-(methylamino)-5-(pyridin-2-ylethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide as a brown solid (181.2 mg, 83.2%). LCMS (ESI) m / z 344.1, [M+H]+. Step 2: N1-methyl-4-(pyridin-2-yleth To a stirred solution of N-(8-(methylamino)-5-(pyridin-2-ylethynyl)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (160.0 mg; 0.46 mmol; 1.00 eq.) in a mixture solvent of DMSO / MeOH (1:3, 5 mL) was added a solution of NaOH (186.3 mg; 4.65 mmol; 10.00 eq.) in water (0.3 mL). The resulting mixture was stirred at 60 ℃ overnight. The desired product was detected via LCMS. After the completionof reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography on pre-packed C18 column using 50-60% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide N1-methyl-4-(pyridin-2-ylethynyl)-2,7-naphthyridine-1,6- diamine as a yellow solid (91.4 mg, 71.2%). LCMS (ESI) m / z 276.1, +. Step 3: 2-(6-((8-(methylamino)-5-(pyridin-2-ylethynyl)-2,7-naphthyridin-3-yl)amino)pyridin-3-yl)pr opan-2-ol 2-(6-((8-(methylamino)-5-(pyridin-2-ylethynyl)-2,7-naphthyridin-3-yl)amino)pyridin-3-yl)propan-2-ol was synthesized using a similar procedure that was previously described in Example 116 by using N1- methyl-4-(pyridin-2-ylethynyl)-2,7-naphthyridine-1,6-diamine and 2-(6-bromopyridin-3-yl)propan-2-ol as the starting material. LCMS (ESI) m / z 411.2, [M+H]+. Example 122: Synthesis of 4-((1-allyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7- naphthyridine-1,6-diamine Step 1: N-(5-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (400.0 mg; 1.502 mmol; 1.00 eq.), 4-bromo-1-cyclopropyl-1H-pyrazole (335.6 mg; 1.794 mmol; 1.19 eq.), XPhos Pd G3(381.6 mg; 0.451 mmol; 0.30 eq.), XPhos (214.7 mg; 0.450 mmol; 0.30 eq.), Et3N (455.6 mg; 4.502 mmol; 3.00 eq.) and CuI (28.6 mg; 0.150 mmol; 0.10 eq.) in DMF (4 mL) was degassed and purged with N2for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to provide a crude product. The residue was purified by flash chromatography on pre-packed C18 column using 20-70% of THF / MeCN = 1:3 in water (10 mmol / L NH4HCO3) to provide N-(5-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide as a yellow solid (410.0 mg, 73.2%). LCMS (ESI) m / z 373.2, [M+H]+. Step 2: 4-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine To a stirred mixture of N-(5-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin- 3-yl)cyclopropanecarboxamide (180.0 mg; 0.483 mmol; 1.00 eq.) in a mixture solvent of MeOH / DMSO (10:1, 22 mL) was added a solution of NaOH (193.3 mg; 4.833 mmol; 10.00 eq.) in water (8 mL) at room temperature. The resulting mixture was stirred at 60 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration, washed with water (1 × 20 mL) and dried under vacuum to afford 4-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (120.0 mg, 78.3%). LCMS (ESI) m / z 305.2, [M+H]+. Step 3: 4-((1-allyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1,6-diam ine 4-((1-allyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-N6-(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 116 by using 4-((1- cyclopropyl-1H-pyrazol-4-yl)ethynyl)-N1-methyl-2,7-naphthyridine-1,6-diamine and 2-chloropyridine as the starting material. LCMS (ESI) m / z 382.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.29 (s, 1H), 8.57 (s, 1H), 8.26 - 8.20 (m, 1H), 8.18 - 8.07 (m, 3H), 7.76 (s, 1H), 7.73 - 7.65 (m, 1H), 7.50 - 7.42 (m, 1H), 6.96 - 6.88 (m, 1H), 6.14 - 6.00 (m, 1H), 5.26 (d, J = 10.4 Hz, 1H), 5.17 (d, J = 17.2 Hz, 1H), 4.83 (d, J = 5.6 Hz, 2H), 3.00 (d, J = 4.4 Hz, 3H). Example 123: Synthesis of N1-methyl-N6-(pyridin-2-yl)-4-((1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)ethynyl)-2,7-naphthyridine-1,6-diamine Step 1: N-(8-(methylamino)-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (400.0 mg; 1.502 mmol; 1.00 eq.), XPhos Pd G3(381.6 mg; 0.451 mmol; 0.30 eq.), XPhos (214.8 mg; 0.451 mmol; 0.30 eq.), Et3N (455.6 mg; 4.502 mmol; 3.00 eq.), CuI (28.6 mg; 0.150 mmol; 0.10 eq.) and 4- bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (520.0 mg; 2.250 mmol; 1.50 eq.) in DMF (4 mL) was degassed and purged with N2 for 3 times. The resulting mixture was stirred at 110 ℃ for 1 hour. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-10% of MeOH in CH2Cl2as eluent to provide N-(8-(methylamino)-5-((1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (367.0 mg, 58.6%). LCMS (ESI) m / z 417.2, [M+H]+. Step 2: N1-methyl-4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7-naphthyridine- 1,6-diamine To a stirred solution of N-(8-(methylamino)-5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide (367.0 mg; 0.881 mmol; 1.00 eq.) in MeOH (20 mL) was added a solution of NaOH (353.0 mg; 8.826 mmol; 10.02 eq.) in water (6 mL) at room temperature. The resulting mixture was stirred at 60 ℃ for 16 hours. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 20- 70% of THF / MeCN = 1:3 in water (10 mmol / L NH4HCO3) to provide N1-methyl-4-((1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7-naphthyridine-1,6-diamine as a yellow solid (300.0 mg, 97.7%). LCMS (ESI) m / z 349.2, [M+H]+. Step 3: N1-methyl-N6-(pyridin-2-yl)-4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7- naphthyridine-1,6-diamine N1-methyl-N6-(pyridin-2-yl)-4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7- naphthyridine-1,6-diamine was synthesized using a similar procedure that was previously described in Example 116 by using N1-methyl-4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)ethynyl)-2,7- naphthyridine-1,6-diamine and 2-chloropyridine as the starting material. LCMS (ESI) m / z 426.2, [M+H]+. Example 124: Synthesis of 2-cyclopropyl-N-(8-(methylamino)-5-((5-(morpholinomethyl)pyridin-2- yl)ethynyl)-2,7-naphthyridin-3-yl)acetamide To a stirred solution of N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6- diamine (Example 109, step 1) (60.0 mg; 0.160 mmol; 1.00 eq.) and 2-cyclopropylacetic acid (14.4 mg; 0.144 mmol; 0.90 eq.) in pyridine (5 mL) was added POCl3(73.7 mg; 0.480 mmol; 3.00 eq.) dropwise at 0 ℃. The resulting mixture was stirred at room temperature for 30 minutes. The desired product was detected via LCMS. After the completion of reaction, the reaction was quenched with water (1 mL) at 0 ℃. The crude mixture was purified by flash chromatography on pre-packed C18 column using 20-60% of MeCN / THF = 3:1 in water (10 mmol / L NH4HCO3) to provide 2-cyclopropyl-N-(8-(methylamino)-5-((5- (morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridin-3-yl)acetamide as a yellow solid (24.5 mg, 32.6%). LCMS (ESI) m / z 457.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.38 (s, 1H), 8.69 (s, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.46 - 8.40 (m, 1H), 8.36 (s, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 3.61 - 3.58 (m, 4H), 3.55 (s, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.43 - 2.38 (m, 4H), 2.36 (d, J = 6.8 Hz, 2H), 1.16 - 1.00 (m, 1H), 0.58 - 0.40 (m, 2H), 0.29 - 0.12 (m, 2H). Each compound in Table 6 below was prepared using a similar experimental procedure to prepare Example 124 using N1-methyl-4-((5-(morpholinomethyl)pyridin-2-yl)ethynyl)-2,7-naphthyridine-1,6-diamine as the common intermediate and appropriate acid. Table 6:

[0037] Example 127: Synthesis of (1S,2R)-2-methyl-N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)m ethyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide Step 1: N1-methyl-4-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-2,7-na phthyridine-1,6-diamine To a stirred solution of N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 81) (262.0 mg; 0.530 mmol; 1.00 eq.) in MeOH (5 mL) was added a solution of NaOH (212.0 mg; 5.300 mmol; 10.01 eq.) in water (1.5 mL) at room temperature. The resulting mixture was stirred at 60 ℃ overnight. The desired product was detected via LCMS. After the completion of reaction, the reaction mixture was cooled to room temperature and concentrated under vacuum. The precipitated solids were collected by filtration, washed with water (5 × 10 mL) and dried under vacuum to afford N1-methyl-4-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3- yl)methyl)phenyl)ethynyl)-2,7-naphthyridine-1,6-diamine as a yellow solid (110.0 mg, 48.6%). LCMS (ESI) m / z 427.3, [M+H]+. Step 2: (1S,2R)-2-methyl-N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3- yl)methyl)phenyl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (1S,2R)-2-methyl-N-(5-((4-((7-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide was synthesized using a similar procedure that was previously described in Example 124, by using N1-methyl-4-((4-((7-methyl-3,7- diazabicyclo[3.3.1]nonan-3-yl)methyl)phenyl)ethynyl)-2,7-naphthyridine-1,6-diamine and (1S,2R)-2- methylcyclopropane-1-carboxylic acid as the starting material. LCMS (ESI) m / z 509.3, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.37 (s, 1H), 8.71 (s, 1H), 8.37 - 8.31 (m, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.51 (s, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.90 - 2.64 (m, 4H), 2.64 - 2.60 (m, 2H), 2.40 - 2.30 (m, 5H), 2.16 - 2.06 (m, 1H), 1.99 - 1.90 (m, 2H), 1.52 - 1.48 (m, 2H), 1.38 - 1.26 (m, 1H), 1.17 (d, J = 6.0 Hz, 3H), 1.06 - 0.97 (m, 1H), 0.91 - 0.82 (m, 1H). Example 128: Synthesis of (1S,2R)-N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)- 2,7-naphthyridin-3-yl)-2-methylcyclopropane-1-carboxamide (1S,2R)-N-(5-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)-2- methylcyclopropane-1-carboxamide was synthesized using a similar procedure that was previously described in Example 124, by using 4-((2-ethyl-2H-1,2,3-triazol-4-yl)ethynyl)-N1-methyl-2,7- naphthyridine-1,6-diamine (Example 113, Step 1) and (1S,2R)-2-methylcyclopropane-1-carboxylic acid as the starting material. LCMS (ESI) m / z 376.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 8.45 - 8.39 (m, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 4.58 - 4.45 (m, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.14 - 2.03 (m, 1H), 1.49 (t, J = 7.2 Hz, 3H), 1.37 - 1.27 (m, 1H), 1.13 (d, J = 6.0 Hz, 3H), 1.03 - 0.95 (m, 1H), 0.88 - 0.79 (m, 1H). Example 129: Synthesis of (1S,2R)-2-methyl-N-(5-((2-methyl-2H-1,2,3-triazol-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide Step 1: N-(5-((2-methyl-2H-1,2,3-triazol-4-yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide A stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyrid...

Claims

B is C1-C8alkyl, 3-6 membered substituted or unsubstituted cycloalkyl, C1-C3-(substituted or unsubstituted cycloalkyl); 4-6 membered heteroaryl comprising N as the heteroatom, wherein said substitutions are H, C1-C4alkyl, and said 3-6 membered substituted or unsubstituted cycloalkyl may be spiro; optionally substituted, fused, bridged, or spiro 3-8 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said h as heteroatoms and said optional substitutions on s r heteroaryl are any of the above mentioned substit 2. The compound o 3. The compound o 4. The compound o5. The compound of claim 1, wherein R1is ethyl.

6. The compound of claim 1, wherein R1is -CD3.

7. The compound of claim 1, wherein L1is -C(=O)-.

8. The compound of claim 1, wherein L1is -C(=O)-CH2.

9. The compound of claim 1, wherein B is selected from the group consisting of: , , , , , , , , , , and .

10. The compound of claim 1, wherein B is optionally substituted cyclopropyl.

11. The compound of claim 1, wherein B is cyclopropyl.

12. The compound of claim 1, wherein B is cyclopropyl-methyl.

13. The compound of claim 1, wherein B is substituted or unsubstituted pyridine and pyrimidine.

14. The compound of claim 1, wherein A is substituted or unsubstituted phenyl.

15. The compound of claim 1, wherein A is substituted or unsubstituted pyridine.

16. The compound of claim 1, wherein A is fused heteroaryl or heterocycloalkyl.

17. The compound of claim 1, wherein A is fused heteroaryl.

18. The compound of claim 1, wherein A is heterocycloalkyl.

19. The compound of claim 1, wherein A is fused heterocycloalkyl.

20. The compound of claim 1, wherein A is substituted or unsubstituted 1H-pyrrole, 2-pyrazoline, 2- imidazoline, pyrazole, imidazole, 1,2,4-triazole, oxazole, or 1,2,3-triazole.

21. The compound of claim 1, wherein said substitutions on A ring are selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl, halogen, aminoalkyl, alkylsulfonyl, oxo, C1- C6-oxyalkyl, or 4-7 membered heterocycloalkyl.

22. The compound of claim 1, wherein said one or more substitution on A is methyl or cyclopropyl.

23. In certain embodiments, A or optional substitutions on A are partially deuterated.

26. The compound of claim 1, wherein A is: ,wherein, R2and R3are independently selected from the group consisting of H, halo, C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, and wherein C1-C6alkyl is optionally substituted with alkylsulfonyl, 3-10 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl comprises N or O as heteroatoms, said cycloalkyl or heterocycloalkyl are optionally bridged or spiro, and are optionally further substituted with halo, hydoxy, oxo (=O), C1-C6alkyl, C1-C6oxyalkyl, C1-C6alkylhydroxy, partially halogenated C1-C6alkyl, cyano, and partially halogenated C1-C6oxyalkyl.

27. The compound of claim 1, wherein A is selected from the group consisting of: ,, , , ,, , , , , , , , , , , , , , , , ,, , ,, , , ,, , , , ,, , , , ,,C1-C6aryl, S as or or halo, C1-C6, , , , ,, , , ,, , , , , , , , , , , , , , , , , ,, , , ,ic r s. p c l, p d h,, , , , , , , , , , , , , , , , , , , , , , , ,o, C6, , , , , , , , , , , ,, , , , , , , , , , , , , ,, , , , , , , , , , , ,, , , , , ,, .C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6alkyl-S(=O)2-alkyl, C1-C6haloalkyl, alkyl- oxyalkyl, oxy-C1-C6alkyl-cyano, optionally partially deuterated C1-C6alkyl, C1-C6alkyl-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), oxy-(optionally substituted C3-C8cycloalkyl or heterocycloalkyl with N or O as the heteroatoms), and oxy-C1-C6alkyl- (optionally substituted C3-C8 cycloalkyl or heterocycloalkyl with N or O as the heteroatoms) wherein said substitutions on C3-C8 cycloalkyl or heterocycloalkyl are selected from the group consisting of H, -OH, halogen, C1-C6alkyl, oxy-C1-C6alkyl, amino-C1-C6alkyl, C1-C6y partially deuterated C1-C6alkyl, C1-C3-(substituted or heteroatom, wherein said bstituted cycloalkyl may be yl, heterocycloalkyl, aryl, or r S as heteroatoms and said yl, or heteroaryl are any of39. The compound of claim 37, wherein X2is N.

40. The compound of claim 37, wherein X3is NH.

41. The compound of claim 37, wherein X3 is CH2.

42. The compound of claim 37, wherein X3is CD2.

43. The compound of claim 37, wherein X3is O.

44. The compound of claim 37, wherein X3is S.

45. The compound of claim 37, wherein X3is CF2.

46. The compound of claim 37, wherein R8is H.

47. The compound of claim 37, wherein R8is methyl.

48. The compound of claim 37, wherein R8is -CD3.

49. The compound of claim 37, wherein L3is -NH- C(=O)-.

50. The compound of claim 37, wherein L3is a single bond.

51. The compound of claim 37, wherein L3is -NH-.

52. The compound of claim 37, wherein L3 is: .

53. The compound of claim 37, wherein D is selected from the group consisting of: , , , , , , , , , , , , , , ,. , , , , , , and .

54. The compound of claim 37, wherein D is cyclopropyl, which can be optionally substituted.

55. The compound of claim 37, wherein D is: .

56. The compound of claim 37, wherein D is .

57. The compound of claim 37, wherein D is: .

58. The compound of claim 37, wherein C is an optionally substituted 8-12 membered fused bicyclic ring.

59. The compound of claim 58, wherein said the fused bicyclic ring comprises N, O, and S as heteroatoms.

60. The compound of claim 58, wh substitutions are selected from the group consisting of deuterium, halogen, cyclo rther optionally be fused with said fused bicyclic ring, methyl, partially halogen membered cycloalkyl or heterocycloalkyl wherein said N or O as heteroatoms.

61. The compound of claim 37, wherein C is a 5-membered heteroaryl ring fused with 6-membered3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with halogen or C 1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring.

63. The compound of claim 37, wherein C is:.

64. The compound of claim 37, wherein C is:wherein R9and R10are independently seom the group consisting of H, D, OH, halogen, C1-C6alkyl, oxy- C1-C6alkyl, or 3-7 membered cycloalkyl, wherein the alkyl or cycloalkyl are optionallysubstituted with halogen, D, or C1-C3alkyl or cycloalkyl, and R9and R10can optionally form a heterocycloalkyl ring.

65. The compound of claim 37, wherein C is: .

66. The compound of claim 37, wherein C is: .

67. The compound of claim 37, wherein C is:

68. The compound of claim 37, wherein C is: .

69. The compound of claim 37, wherein C is:

70. The compound of consisting of:, , , , ,, , , , ,,, , ,,, , , , ,, , , , , , ,, , , , , , , ,,. , .

80. The compound of claim 37, wherein X3is O and R8is CD2CD3.in theclaims 1-93.. , .

97. The method of claims 94, 95, or 96, wherein the compound is administered parenterally.

98. The method of claims 94, 95, or 96, wherein the compound is administered intravenously.

99. The method of claims 94, 95, or 96, wherein the compound is administered via an injection.

100. The method of claims 94, 95, or 96, wherein the compound is administered orally.

101. A pharmaceutical composition comprising a therapeutically effective amount of compound of any of claims 1-93.

102. The pharmaceutical composition of claim 95, wherein the composition comprises at least one additional excipient.

103. Use of the compounds of any of claims 1 – 93 in the manufacture of a medicament for treatment of a medical condition associated with the central nervous system.

104. The use according to claim 103, wherein the medical condition is multiple sclerosis.

95. The method of claim 94, wherein the neurological condition is a condition associated with TYK2 signaling.

96. The method of claim 94. wherein the medical condition is multiple sclerosis.

97. The method of claims 94, 95, or 96, wherein the compound is administered parenterally.

98. The method of claims 94, 95, or 96, wherein the compound is administered intravenously.

99. The method of claims 94, 95, or 96, wherein the compound is administered via an injection.

100. 'lire method of claims 94, 95, or 96. wherein the compound is administered orally.

101. A pharmaceutical composition comprising a therapeutically effective amount of compound of any of claims 1 -93.

102. The pharmaceutical composition of claim 95, wherein the composition comprises at least one additional excipient.

103. Use of the compo unds of any of claims 1 - 93 in the manufacture of a medicament for treatment of a medical condition associated with the central nervous system.

104. The use according to claim 103. wherein the medical condition is multiple sclerosis

Images