Heterocyclic GLP-1 agonists

Abstract

The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and solvates: TIFF2023546054000383.tif68119 and pharmaceutical compositions containing them.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application No. PCT / CN2020 / 120605, filed October 13, 2020; and International Patent Application No. PCT / CN2021 / 118149, filed September 14, 2021, each of which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof. [Background technology]

[0003] Incretin metabolic hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important in regulating glucose homeostasis. Drugs that target this family of gastric peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, decrease gastric motility, and increase satiety.

[0004] Diabetes refers to a group of metabolic disorders characterized by persistent hyperglycemia. Type 2 diabetes mellitus (T2DM), the most common form, is an acquired disease that accounts for more than 90% of diabetes cases. The disease typically develops in obese or sedentary adults and begins with insulin resistance. While lifestyle changes can be helpful in managing the disease, T2DM patients may need to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.

[0005] In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose digestion. Although this incretin effect is significantly reduced (if present) in T2DM, GLP-1 retains insulinotropic properties even when the endocrine pancreatic response to GIP is effectively shut down. Thus, incretin mimetics and other GLP-1-based therapies can help activate insulin production in T2DM patients. Summary of the Invention

[0006] This application describes heterocyclic GLP-1 agonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating GLP-1-related diseases, disorders, and conditions are also provided.

[0007] Thus, Formula I: [ka] {In the formula, [ka] denotes a single or double bond, where permitted by valence; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 each independently represents C, CH, CR w and N, with the proviso that X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 at least two and at most four of are N; Each R wis independently selected from the group consisting of halogen; cyano; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) alkoxy; and (C1-C3) haloalkoxy; T 1 Ha-T 3 and -L a -(CR x R x ) q -T 3 selected from the group consisting of: T 3 teeth -N(R s )C(=O)R z ; -N(R s )C(=O)OR z ; -N(R s )C(=O)N(R s )R z ; -N(R s )S(O) 1-2 -R z ; -N(R s )S(=NR s )(=O)R z ; -S(O) 1-2 R z ; -P(=O)R z1 R z2 ; -C(=O)OH; -C(=O)N(R s )R z ; -S(O) 1-2 N(R s )R z ; -S(=NR s )(=O)N(R s )R z ; the below described: [ka] and 1 to 4 R which may optionally contain an endocyclic group selected from the group consisting of v5-10 membered heteroaryl optionally substituted with; the below described: [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R v (C1-C6)haloalkyl optionally further substituted with selected from the group consisting of: L a is a bond, -NH-, -N(C 1-3 alkyl)-, O or S(O) 0-2 and; q is 0, 1, 2 or 3, provided that when q is 0, L a is other than a bond; Each R s is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl; Each R x are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; or A pair of R x together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; R z , R z1 and R z2 are each independently hydrogen; 1 to 4 R v (C1-C6) alkyl optionally substituted with -R z3 ; and -L b -R z3 or R z1 and R z2 each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R z1 and R z2(in addition to the phosphorus bonded to) are heteroatoms each independently selected from O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected (C1-C6) alkyl; L b is 1 to 4 R v C optionally substituted with 1-3 is alkylene; R z3 is (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v optionally substituted with; R in each case v are independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, CN, -O(C1-C6) alkylene-O(C1-C6) alkyl, phenyl, -S(O) 0-2 -C1-C6 alkyl and halogen; T 2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R T are independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is (C1-C3) alkylene optionally substituted with; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L each together with the atom to which it is attached forms a (C3-C6)cycloalkyl ring; Ring A is [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] [ka] [During the ceremony, W 2 is CR Y2 or N, L w is (C1-C3) alkylene. 1 to 4 R Y phenylene optionally substituted by; 1 to 3 R Y 5-6 membered heteroarylene optionally substituted by 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with selected from the group consisting of: Here, mm is L2 represents a point of attachment to L 3 represents the attachment point to; R in each case Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 When R Y1 and R Y2 The groups taken together form a (C1-C4) alkylene, wherein one of the CH2 units of said (C1-C4) alkylene is selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; L 3 is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; R in each case a are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or A pair of R a together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or Ring A [ka] and;W 2 is CRY2 and;L 3 -C(R a R a )-, then one R a is R Y2 Combined with W 2 and L 3 A double bond is formed between the remaining R a is selected from the group consisting of hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C3) haloalkyl, and (C3-C8) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (BV): [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 1 , B 2 , B 3 and B 4 Each of these is independently 1 and N; B 5A and B 5B each is independently selected from the group consisting of C and N; B 6A , B 6B and B 6C Each of these is independently O, S, CR 1 , N.R. N and N; (B-III) ----- are independently a single bond or a double bond; However, B 5A , B 5B , B 6A , B 6B and B 6C at least one of B is an independently selected heteroatom; 5A , B 5B , B 6A , B 6B and B 6C At least one of is C or CR 1 and B 5A, B 5B , B 6A , B 6B and B 6C A ring containing is a heteroaryl. [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 7 and B 8 are independently -O- and -NR N - and -C(R 1 )2- is selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 independently, CR 1 and N. selected from the group consisting of: Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl; (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl) and -C(O)NR 2 R 3 selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; R aa , R ab and R ac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 4is a bond or -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; Z 1 and Z 2 are independently a bond, NH, N(C1-C6 alkyl), O, C(=O), or S(O) 0-2 and 1-2 R c C optionally substituted with 1-3 selected from the group consisting of alkylene; However, Z 1 and Z 2 is not a bond at the same time; Furthermore, however, Z 1 is NH, N(C1-C6 alkyl), -O- or -S-, Z 2 is a bond, C(=O), S(O) 1-2 or 1-2 R c C optionally substituted with 1-3 is alkylene; Z 2 is NH, N(C1-C6 alkyl), -O- or -S-, Z 1 is a bond, C(=O), S(O) 1-2 or 1 to 3 R c C optionally substituted with 1-3 is alkylene; Each R c are independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl, or a pair of R c together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, and CN; b is an integer between 0 and 3 or a pharmaceutically acceptable salt or solvate thereof.

[0008] Additionally, Formula I: [ka] {In the formula, [ka] denotes a single or double bond, where permitted by valence; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 each independently represents C, CH, CR w and N, with the proviso that X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 at least two and at most four of are N; Each R w is independently selected from the group consisting of halogen; cyano; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) alkoxy; and (C1-C3) haloalkoxy; T 1 Ha-T 3 and -L a -(CR x R x ) q -T 3 selected from the group consisting of: T 3 teeth -N(R s )C(=O)R z ; -N(R s )C(=O)OR z ; -N(R s )C(=O)N(R s )R z ; -N(R s )S(O) 1-2 -R z ; -N(R s )S(=NR s )(=O)R z ; -S(O) 1-2 R z ; -P(=O)R z1 R z2 ; -C(=O)OH; -C(=O)N(R s )R z ; -S(O) 1-2 N(R s )R z ; -S(=NR s )(=O)N(R s )R z ; the below described: [ka] and 1 to 4 R which may optionally contain an endocyclic group selected from the group consisting of v 5-10 membered heteroaryl optionally substituted with; the below described: [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R v (C1-C6)haloalkyl optionally further substituted with selected from the group consisting of: L a is a bond, -NH-, -N(C 1-3 alkyl)-, O or S(O) 0-2 and; q is 0, 1, 2 or 3, provided that when q is 0, L a is other than a bond; Each R s is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl; Each R x are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; or A pair of R x together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Or, when q is 2 or 3, a pair of R on adjacent carbon atoms x together form double bonds between adjacent carbon atoms; R z , R z1 and R z2 are each independently hydrogen; 1 to 4 R v (C1-C6) alkyl optionally substituted with -R z3 ; and -L b -R z3 or R z1 and R z2 each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R z1 and R z2 (in addition to the phosphorus bonded to) are heteroatoms each independently selected from O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected (C1-C6) alkyl; L b is 1 to 4 R v C optionally substituted with 1-3 is alkylene; R z3 is (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v optionally substituted with; R in each case v are independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, CN, -O(C1-C6) alkylene-O(C1-C6) alkyl, phenyl, -S(O) 0-2 -C1-C6 alkyl and halogen; T 2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R T are independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is (C1-C3) alkylene optionally substituted with; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L each together with the atom to which it is attached forms a (C3-C6)cycloalkyl ring; Ring A is [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] [ka] [During the ceremony, W 2 is CR Y2 or N, L w is (C1-C3) alkylene. 1 to 4 R Y phenylene optionally substituted by; 1 to 3 R Y 5-6 membered heteroarylene optionally substituted by 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with selected from the group consisting of: Here, mm is L 2 represents a point of attachment to L 3 represents the attachment point to; R in each case Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W1 is CR Y1 and W 2 is CR Y2 When R Y1 and R Y2 The groups taken together form a (C1-C4) alkylene, wherein one of the CH2 units of said (C1-C4) alkylene is selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; L 3 is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; R in each case a are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or A pair of R a together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or Ring A [ka] and;W 2 is CR Y2 and;L 3 -C(R a R a )-, 1 R a is R Y2 Combined with W 2 and L 3 A double bond is formed between the remaining R a is selected from the group consisting of hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C3) haloalkyl, and (C3-C8) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (BV): [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 1 , B 2 , B 3 and B 4 Each of these is independently 1 and N; B 5A and B 5B each is independently selected from the group consisting of C and N; B 6A , B 6B and B 6C Each of these is independently O, S, CR 1 , N.R. N and N; (B-III) ----- are independently a single bond or a double bond; However, B 5A , B 5B , B 6A , B 6B and B 6C at least one of B is an independently selected heteroatom; 5A , B 5B , B 6A , B 6B and B 6C At least one of is C or CR 1 and B 5A , B 5B , B 6A , B 6B and B 6C A ring containing is a heteroaryl. [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 7 and B 8 are independently -O- and -NR N - and -C(R 1 )2- is selected from the group consisting of; B9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 independently, CR 1 and N. selected from the group consisting of: Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl; (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl) and -C(O)NR 2 R 3 selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; R aa , R ab and R ac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 4 is a bond or -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; Z 1 and Z 2 are independently a bond, NH, N(C1-C6 alkyl), O, C(=O), or S(O) 0-2 and 1-2 R c C optionally substituted with 1-3 selected from the group consisting of alkylene; However, Z 1 and Z 2 is not a bond at the same time; Furthermore, however, Z1 is NH, N(C1-C6 alkyl), -O- or -S-, Z 2 is a bond, C(=O), S(O) 1-2 or 1-2 R c C optionally substituted with 1-3 is alkylene; Z 2 is NH, N(C1-C6 alkyl), -O- or -S-, Z 1 is a bond, C(=O), S(O) 1-2 or 1 to 3 R c C optionally substituted with 1-3 is alkylene; Each R c are independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl, or a pair of R c together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, and CN; b is an integer between 0 and 3 or a pharmaceutically acceptable salt or solvate thereof.

[0009] Additionally, Formula I: [ka] {In the formula, [ka] denotes a single or double bond, where permitted by valence; X1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 each independently represents C, CH, CR w and N, with the proviso that X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 at least two and at most four of are N; Each R w is independently selected from the group consisting of halogen; cyano; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) alkoxy; and (C1-C3) haloalkoxy; T 1 Ha-T 3 and -L a -(CR x R x ) q -T 3 selected from the group consisting of: T 3 teeth -N(R s )C(=O)R z ; -N(R s )C(=O)OR z ; -N(R s )C(=O)N(R s )R z ; -N(R s )S(O) 1-2 -R z ; -N(R s )S(=NR s )(=O)R z ; -S(O) 1-2 R z ; -P(=O)R z1 R z2 ; -C(=O)OH; -C(=O)N(R s )R z ; -S(O) 1-2 N(R s )R z ; -S(=NR s )(=O)N(R s )R z ; the below described: [ka] and 1 to 4 R which may optionally contain an endocyclic group selected from the group consisting of v 5-10 membered heteroaryl optionally substituted with; the below described: [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R v (C1-C6)haloalkyl optionally further substituted with selected from the group consisting of: L a is a bond, -NH-, -N(C 1-3 alkyl)-, O or S(O) 0-2 and; q is 0, 1, 2 or 3, provided that when q is 0, L a is other than a bond; Each R s is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl; Each R x are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; or A pair of R x together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Or, when q is 2 or 3, a pair of R on adjacent carbon atoms x together form double bonds between adjacent carbon atoms; R z , R z1 and R z2 are each independently hydrogen; 1 to 4 R v (C1-C6) alkyl optionally substituted with -R z3 ; and -L b -R z3 or R z1 and R z2 each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R z1 and R z2 (in addition to the phosphorus bonded to) are heteroatoms each independently selected from O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected (C1-C6) alkyl; L b is 1 to 4 R v C optionally substituted with 1-3 is alkylene; R z3 is (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v optionally substituted with; R in each case v are independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, CN, -O(C1-C6) alkylene-O(C1-C6) alkyl, phenyl, -S(O) 0-2 -C1-C6 alkyl and halogen; T 2is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R T are independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is (C1-C3) alkylene optionally substituted with; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L each together with the atom to which it is attached forms a (C3-C6)cycloalkyl ring; Ring A is [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] [ka] [During the ceremony, W 2 is CR Y2 or N, L w is (C1-C3) alkylene. 1 to 4 R Y phenylene optionally substituted by; 1 to 3 R Y 5-6 membered heteroarylene optionally substituted by 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] selected from the group consisting of: Here, mm is L 2 represents a point of attachment to L 3 represents the attachment point to; R in each case Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W1 is CR Y1 and W 2 is CR Y2 When R Y1 and R Y2 The groups taken together form a (C1-C4) alkylene, wherein one of the CH2 units of said (C1-C4) alkylene is selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; L 3 is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; R in each case a are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or A pair of R a together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or Ring A [ka] and;W 2 is CR Y2 and;L 3 -C(R a R a )-, then one R a is R Y2 Combined with W 2 and L 3 A double bond is formed between the remaining R a is selected from the group consisting of hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C3) haloalkyl, and (C3-C8) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (BV): [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 1 , B 2 , B 3 and B 4 Each of these is independently 1 and N; B 5A and B 5B each is independently selected from the group consisting of C and N; B 6A , B 6B and B 6C Each of these is independently O, S, CR 1 , N.R. N and N; (B-III) ----- are independently a single bond or a double bond; However, B 5A , B 5B , B 6A , B 6B and B 6C at least one of B is an independently selected heteroatom; 5A , B 5B , B 6A , B 6B and B 6C At least one of is C or CR 1 and B 5A , B 5B , B 6A , B 6B and B 6C A ring containing is a heteroaryl. [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 7 and B 8 are independently -O-, -NR N - and -C(R 1 )2- is selected from the group consisting of; B9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 independently, CR 1 and N. selected from the group consisting of: Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl; (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl) and -C(O)NR 2 R 3 selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; R aa , R ab and R ac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 4 is a bond or -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; Z 1 and Z 2 are independently a bond, NH, N(C1-C6 alkyl), O, C(=O), or S(O) 0-2 and 1-2 R c C optionally substituted with 1-3 selected from the group consisting of alkylene; However, Z 1 and Z 2 is not a bond at the same time; Furthermore, however, Z1 is NH, N(C1-C6 alkyl), -O- or -S-, Z 2 is a bond, C(=O), S(O) 1-2 or 1-2 R c C optionally substituted with 1-3 is alkylene; Z 2 is NH, N(C1-C6 alkyl), -O- or -S-, Z 1 is a bond, C(=O), S(O) 1-2 or 1 to 3 R c C optionally substituted with 1-3 is alkylene; Each R c are independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl, or a pair of R c together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, and CN; b is an integer between 0 and 3 or a pharmaceutically acceptable salt or solvate thereof.

[0010] Also provided is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0011] Also provided herein is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0012] Also provided herein is a method for treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to a patient identified or diagnosed as having type 2 diabetes.

[0013] Also provided is a method for treating diabetes in a patient, comprising determining that the patient has type 2 diabetes; and then administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, determining that the patient has type 2 diabetes includes performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof. In some embodiments, the HbA1c level is about 6.5% or higher. In some embodiments, the fasting blood glucose level is about 126 mg / dL or higher. In some embodiments, the non-fasting blood glucose level is about 200 mg / dL or higher.

[0014] In one embodiment, the method further comprises obtaining a sample from the patient. In one embodiment, the sample is a body fluid sample. In one embodiment, the patient is about 40 to about 70 years old and is overweight or obese. In one embodiment, the patient is about 22 kg / m 2 In certain embodiments, the patient has a body mass index (BMI) of about 30 kg / m or greater. 2 or have a BMI of 18.5 or higher.

[0015] In certain embodiments, the method for treating type 2 diabetes comprises reducing fasting blood glucose levels, hi certain embodiments, the fasting blood glucose levels are reduced to about 100 mg / dL or less.

[0016] In certain embodiments, the method for treating type 2 diabetes comprises reducing HbA1c levels, hi certain embodiments, the HbA1c levels are reduced to about 5.7% or less.

[0017] In certain embodiments, the method for treating type 2 diabetes comprises reducing glucagon levels.

[0018] In certain embodiments, the method for treating type 2 diabetes comprises reducing insulin levels.

[0019] In certain embodiments, the method for treating type 2 diabetes comprises reducing BMI. In certain embodiments, the BMI is about 25 kg / m 2 or less.

[0020] In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0021] In some embodiments, the method for treating type 2 diabetes further comprises administering an additional therapy or therapeutic agent to the patient. In some embodiments, the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic drug, an antiobesity drug, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) drug, an antiemetic drug, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic drug is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic polypeptide (GIP), insulin or an insulin analog, an alpha-glucosidase inhibitor, a sodium-dependent glucose transporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In certain embodiments, the antiobesity agent is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, human proislet peptide (HIP), or a combination thereof. peptide) (HIP), cannabinoid receptor type 1 (CB1R) antagonist, lipase inhibitor, melanocortin receptor 4 agonist, farnesoid X receptor (FXR) agonist, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitor, GDF-15 analog, opioid receptor antagonist, cholecystokinin agonist, serotonergic agent, methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulator, AMP-activated protein kinase (AMPK) activator, sodium-glucose transporter 1 (SGLT-1) inhibitor, or any combination thereof.In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof. In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, and the additional therapeutic agent are administered sequentially in any order as separate preparations.

[0022] Also provided herein is a method for modulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation results in increased insulin levels.

[0023] Also provided herein is a method for modulating glucose levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation results in a decrease in glucose levels.

[0024] Also provided herein is a method for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, or kidney disease. , adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia In some embodiments, the inflammatory bowel disease is selected from the group consisting of: diabetes, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, and glucose metabolism. abnormalities, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, Syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0025] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications, patents, and patent applications incorporated by reference conflict with the disclosure contained herein, the present specification shall take precedence and / or supersede any such conflicting document.

[0026] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0027] Detailed Description Provided herein are heterocyclic GLP-1 agonists for use in the treatment of T2DM and other conditions in which activation of GLP-1 action is beneficial.

[0028] definition When numerical values ​​are described as ranges, it is understood that all possible subranges within such ranges, as well as the recitation of specific numerical values ​​within such ranges, are included, whether or not a specific numerical value or specific subrange is explicitly stated.

[0029] As used herein, the term "halo" or "halogen" means -F (also referred to herein as "fluoro"), -Cl (also referred to herein as "chloro"), -Br (also referred to herein as "bromo"), and -I (also referred to herein as "iodo").

[0030] As used herein, the term "alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C1-C6 alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical of 1 to 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0031] As used herein, the term "alkylene" refers to a divalent alkyl containing the indicated number of carbon atoms. For example, "C-C alkylene" refers to a divalent alkyl having 1 to 3 carbon atoms (e.g., -CH-, -CH(CH)-, -CHCH-, or -CHCHCH-). Similarly, the terms "cycloalkylene," "heterocycloalkylene," "arylene," and "heteroarylene" refer to divalent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.

[0032] As used herein, the term "alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "C2-C6 alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain of 2 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, or pentenyl.

[0033] As used herein, the term "alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "C2-C6 alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing from 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0034] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "C3-C6 cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyls include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0035] As used herein, the term "heterocycloalkyl" means a mono-, bi-, tri-, or polycyclic non-aromatic ring group containing the indicated number of ring atoms (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring group) having 1 to 3 heteroatoms (in the case of a monocycle), 1 to 6 heteroatoms (in the case of a bicycle), or 1 to 9 heteroatoms (in the case of a tricycle or polycycle), wherein the heteroatoms are O, N, S, or S(O). 1~2(e.g., in the case of monocyclic, bicyclic, or tricyclic rings, carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms (N, O, S, or S(O)), respectively) 1~2)), where 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Non-limiting examples of partially unsaturated heterocycloalkyls include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, dihydropyranyl, and the like. Heterocycloalkyls can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocycloalkyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxa ... .2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0036] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, in which at least one ring is aromatic (e.g., C6 monocyclic, C 10 Bicyclic, or C 14 Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0037] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5-6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms), in which at least one ring is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl)) and at least one ring in the group contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2, 3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxone, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]xathiin, isoindoline, and the like.

[0038] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

[0039] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is on an oxygen atom. For example, "C 1-6 "Alkoxy" is -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl group in which the group is on the oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group in which the group is on the oxygen atom.

[0040] As used herein, " [ka] " indicates any single or double bond, as valence allows. As used herein, " [ka] " indicates the point of attachment to the parent molecule.

[0041] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

[0042] As used herein, when a ring is described as "aromatic," it means that the ring has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. When a ring group containing at least two rings is described as "aromatic," it means that the ring group contains one or more aromatic rings. Thus, when a ring group containing at least two rings is described as "non-aromatic," it means that none of the constituent rings of the ring group are aromatic.

[0043] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation associated with the ring itself; for example, one or more double bonds between constituent ring atoms), but the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring group containing at least two rings is described as "partially unsaturated," it means that the ring group contains one or more partially unsaturated rings, but none of the constituent rings of the ring group are aromatic.

[0044] As used herein, the term "carboxylic acid bioisostere" refers to a group having chemical and physical similarities that result in biological properties closely resembling those of carboxylic acids (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p. 283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38 25 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres"). Examples of suitable carboxylic acid bioisosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

[0045] The term "tautomer" as used herein means a compound whose structure differs significantly in the arrangement of atoms but exists in ready and rapid equilibrium; the compounds provided herein may be represented as different tautomers; it is understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present invention, and the name of the compound does not exclude the tautomers.

[0046] As used herein, the term "GLP-1R" or "GLP-1 receptor" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0047] As used herein, the term "GLP-1 associated disease" is meant to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide 1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0048] As used herein, the term "GLP-1 agonist" or "GLP-1RA" refers to an agonist of the glucagon-like peptide 1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RAs have been shown to treat type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, albiglutide (TANZEMM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXMMIA®), semaglutide (OZEMPIC®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in U.S. Patent Nos. 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE45313.

[0049] As used herein, the term "pharmaceutically acceptable" indicates that a compound, or a salt thereof, or a composition thereof is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient being treated.

[0050] As used herein, the term "therapeutic compound" is meant to include, but is not limited to, any compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof), and any composition (e.g., pharmaceutical composition) in which any compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is a component.

[0051] The term "administration" or "administering" refers to a method for providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0052] As used herein, the terms "effective amount," "effective dose," "pharmaceutically effective amount," or "therapeutically effective amount" refer to a sufficient quantity of an administered chemical entity (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof)) to relieve to some extent one or more of the symptoms of the disease or condition being treated, and may include curing the disease. "Cure" refers to the elimination of active disease symptoms. Such results include the reduction and / or alleviation of the signs, symptoms, or pathogenesis of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0053] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0054] The term "pharmaceutical composition" refers to a mixture of a compound of Formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or fillers. Pharmaceutical compositions facilitate administration of the compound to an organism. Many techniques exist for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0055] The terms "treat," "treating," and "treatment," in the context of treating a disease, disorder, or condition, include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with said disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0056] As used herein, the term "preventing" refers to the prevention of the onset, recurrence or spread, in whole or in part, of a disease or condition as described herein, or a symptom thereof.

[0057] As used herein, the terms "subject," "patient," or "individual" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the terms refer to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or required. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0058] The terms "treatment regimen" and "administration regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the invention.

[0059] As used herein, the term "pharmaceutical combination" means a pharmaceutical treatment that results in the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0060] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., components or combination partners of the combination), which are administered together or separately as desired by a medical practitioner or in accordance with regulatory authorities, as defined herein.

[0061] As used herein, the term "modulation" means regulation or modulation (eg, increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0062] compound Thus, Formula I: [ka] {In the formula, [ka] denotes a single or double bond, where permitted by valence; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 each independently represents C, CH, CR w and N, with the proviso that X 1 , X 2 , X 3 , X 4 , X 5, X 6 , X 7 and X 8 at least two and at most four of are N; Each R w is independently selected from the group consisting of halogen; cyano; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) alkoxy; and (C1-C3) haloalkoxy; T 1 Ha-T 3 and -L a -(CR x R x ) q -T 3 selected from the group consisting of: T 3 teeth -N(R s )C(=O)R z ; -N(R s )C(=O)OR z ; -N(R s )C(=O)N(R s )R z ; -N(R s )S(O) 1-2 -R z ; -N(R s )S(=NR s )(=O)R z ; -S(O) 1-2 R z ; -P(=O)R z1 R z2 ; -C(=O)OH; -C(=O)N(R s )R z ; -S(O) 1-2 N(R s )R z ; -S(=NR s )(=O)N(R s )R z ; the below described: [ka] and 1 to 4 R which may optionally contain an endocyclic group selected from the group consisting of v 5-10 membered heteroaryl optionally substituted with; the below described: [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R v (C1-C6)haloalkyl optionally further substituted with selected from the group consisting of: L a is a bond, -NH-, -N(C 1-3 alkyl)-, O or S(O) 0-2 and; q is 0, 1, 2 or 3, provided that when q is 0, L a is other than a bond; Each R s is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl; Each R x are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; or A pair of R x together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; R z , R z1 and R z2 are each independently hydrogen; 1 to 4 R v (C1-C6) alkyl optionally substituted with -R z3 ; and -L b -R z3 or R z1 and R z2each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R z1 and R z2 (in addition to the phosphorus bonded to) are heteroatoms each independently selected from O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected (C1-C6) alkyl; L b is 1 to 4 R v C optionally substituted with 1-3 is alkylene; R z3 is (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v optionally substituted with; R in each case v is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, CN, and halogen; T 2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R Tare independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is (C1-C3) alkylene optionally substituted with; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L each together with the atom to which it is attached forms a (C3-C6)cycloalkyl ring; Ring A is [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] [ka] [During the ceremony, W 2 is CR Y2 or N, L w is (C1-C3) alkylene. 1 to 4 R Y phenylene optionally substituted by; 1 to 3 R Y5-6 membered heteroarylene optionally substituted by 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with selected from the group consisting of: Here, mm is L 2 represents a point of attachment to L 3 represents the attachment point to; R in each case Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 When R Y1 and R Y2 The groups taken together form a (C1-C4) alkylene, wherein one of the CH2 units of said (C1-C4) alkylene is selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; L 3 is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; R in each case aare independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or A pair of R a together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or Ring A [ka] and;W 2 is CR Y2 and;L 3 -C(R a R a )-, then one R a is R Y2 Combined with W 2 and L 3 A double bond is formed between the remaining R a is selected from the group consisting of hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C3) haloalkyl, and (C3-C8) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (BV): [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 1 , B 2 , B 3 and B 4 Each of these is independently 1 and N; B 5A and B 5B each is independently selected from the group consisting of C and N; B 6A , B 6B and B 6C Each of these is independently O, S, CR 1 , N.R. N and N; (B-III) ----- are independently a single bond or a double bond; However, B 5A , B 5B , B 6A , B 6B and B 6C at least one of B is an independently selected heteroatom; 5A , B 5B , B 6A , B 6B and B 6C At least one of is C or CR 1 and B 5A , B 5B , B 6A , B 6B and B 6C A ring containing is a heteroaryl. [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 7 and B 8 are independently -O-, -NR N - and -C(R 1 )2- is selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 independently, CR 1 and N. selected from the group consisting of: Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl; (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl) and -C(O)NR 2 R 3 selected from the group consisting of: Each R 2 and R 3is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; R aa , R ab and R ac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 4 is a bond or -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; Z 1 and Z 2 are independently a bond, NH, N(C1-C6 alkyl), O, C(=O), or S(O) 0-2 and 1-2 R c C optionally substituted with 1-3 selected from the group consisting of alkylene; However, Z 1 and Z 2 is not a bond at the same time; Furthermore, however, Z 1 is NH, N(C1-C6 alkyl), -O- or -S-, Z 2 is a bond, C(=O), S(O) 1-2 or 1-2 R c C optionally substituted with 1-3 is alkylene; Z 2 is NH, N(C1-C6 alkyl), -O- or -S-, Z 1 is a bond, C(=O), S(O) 1-2 or 1 to 3 R c C optionally substituted with 1-3 is alkylene; Each R c are independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl, or a pair of R ctogether with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, and CN; b is an integer between 0 and 3 or a pharmaceutically acceptable salt or solvate thereof.

[0063] Additionally, Formula I: [ka] {In the formula, [ka] denotes a single or double bond, where permitted by valence; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 each independently represents C, CH, CR w and N, with the proviso that X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 at least two and at most four of are N; Each R wis independently selected from the group consisting of halogen; cyano; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) alkoxy; and (C1-C3) haloalkoxy; T 1 Ha-T 3 and -L a -(CR x R x ) q -T 3 selected from the group consisting of: T 3 teeth -N(R s )C(=O)R z ; -N(R s )C(=O)OR z ; -N(R s )C(=O)N(R s )R z ; -N(R s )S(O) 1-2 -R z ; -N(R s )S(=NR s )(=O)R z ; -S(O) 1-2 R z ; -P(=O)R z1 R z2 ; -C(=O)OH; -C(=O)N(R s )R z ; -S(O) 1-2 N(R s )R z ; -S(=NR s )(=O)N(R s )R z ; the below described: [ka] and 1 to 4 R which may optionally contain an endocyclic group selected from the group consisting of v5-10 membered heteroaryl optionally substituted with; the below described: [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R v (C1-C6)haloalkyl optionally further substituted with selected from the group consisting of: L a is a bond, -NH-, -N(C 1-3 alkyl)-, O or S(O) 0-2 and; q is 0, 1, 2 or 3, provided that when q is 0, L a is other than a bond; Each R s is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl; Each R x are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; or A pair of R x together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or when q is 2 or 3, a pair of R on adjacent carbon atoms x together form double bonds between adjacent carbon atoms; R z , R z1 and R z2 are each independently hydrogen; 1 to 4 R v (C1-C6) alkyl optionally substituted with -R z3 ; and -L b -R z3 or R z1 and R z2each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R z1 and R z2 (in addition to the phosphorus bonded to) are heteroatoms each independently selected from O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected (C1-C6) alkyl; L b is 1 to 4 R v C optionally substituted with 1-3 is alkylene; R z3 is (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v optionally substituted with; R in each case v are independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, CN, -O(C1-C6) alkylene-O(C1-C6) alkyl, phenyl, -S(O) 0-2 -C1-C6 alkyl and halogen; T 2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R Tare independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is (C1-C3) alkylene optionally substituted with; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L each together with the atom to which it is attached forms a (C3-C6)cycloalkyl ring; Ring A is [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] [ka] [During the ceremony, W 2 is CR Y2 or N, L w is (C1-C3) alkylene. 1 to 4 R Y phenylene optionally substituted by; 1 to 3 R Y5-6 membered heteroarylene optionally substituted by 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with selected from the group consisting of: Here, mm is L 2 represents a point of attachment to L 3 represents the attachment point to; R in each case Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 When R Y1 and R Y2 The groups taken together form a (C1-C4) alkylene, wherein one of the CH2 units of said (C1-C4) alkylene is selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; L 3 is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; R in each case aare independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or A pair of R a together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or Ring A [ka] and;W 2 is CR Y2 and;L 3 -C(R a R a )-, then one R a is R Y2 Combined with W 2 and L 3 A double bond is formed between the remaining R a is selected from the group consisting of hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C3) haloalkyl, and (C3-C8) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (BV): [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 1 , B 2 , B 3 and B 4 Each of these is independently 1 and N; B 5A and B 5B each is independently selected from the group consisting of C and N; B 6A , B 6B and B 6C Each of these is independently O, S, CR 1 , N.R. N and N; (B-III) ----- are independently a single bond or a double bond; However, B 5A , B 5B , B 6A , B 6B and B 6C at least one of B is an independently selected heteroatom; 5A , B 5B , B 6A , B 6B and B 6C At least one of is C or CR 1 and B 5A , B 5B , B 6A , B 6B and B 6C A ring containing is a heteroaryl. [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 7 and B 8 are independently -O-, -NR N - and -C(R 1 )2- is selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 independently, CR 1 and N. selected from the group consisting of: Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl; (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl) and -C(O)NR 2 R 3 selected from the group consisting of: Each R 2 and R 3is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; R aa , R ab and R ac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 4 is a bond or -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; Z 1 and Z 2 are independently a bond, NH, N(C1-C6 alkyl), O, C(=O), or S(O) 0-2 and 1-2 R c C optionally substituted with 1-3 selected from the group consisting of alkylene; However, Z 1 and Z 2 is not a bond at the same time; Furthermore, however, Z 1 is NH, N(C1-C6 alkyl), -O- or -S-, Z 2 is a bond, C(=O), S(O) 1-2 or 1-2 R c C optionally substituted with 1-3 is alkylene; Z 2 is NH, N(C1-C6 alkyl), -O- or -S-, Z 1 is a bond, C(=O), S(O) 1-2 or 1 to 3 R c C optionally substituted with 1-3 is alkylene; Each R c are independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl, or a pair of R ctogether with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, and CN; b is an integer between 0 and 3 or a pharmaceutically acceptable salt or solvate thereof.

[0064] Additionally, Formula I: [ka] {In the formula, [ka] denotes a single or double bond, where permitted by valence; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 each independently represents C, CH, CR w and N, with the proviso that X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 at least two and at most four of are N; Each R wis independently selected from the group consisting of halogen; cyano; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) alkoxy; and (C1-C3) haloalkoxy; T 1 Ha-T 3 and -L a -(CR x R x ) q -T 3 selected from the group consisting of: T 3 teeth -N(R s )C(=O)R z ; -N(R s )C(=O)OR z ; -N(R s )C(=O)N(R s )R z ; -N(R s )S(O) 1-2 -R z ; -N(R s )S(=NR s )(=O)R z ; -S(O) 1-2 R z ; -P(=O)R z1 R z2 ; -C(=O)OH; -C(=O)N(R s )R z ; -S(O) 1-2 N(R s )R z ; -S(=NR s )(=O)N(R s )R z ; the below described: [ka] and 1 to 4 R which may optionally contain an endocyclic group selected from the group consisting of v5-10 membered heteroaryl optionally substituted with; the below described: [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R v (C1-C6)haloalkyl optionally further substituted with selected from the group consisting of: L a is a bond, -NH-, -N(C 1-3 alkyl)-, O or S(O) 0-2 and; q is 0, 1, 2 or 3, provided that when q is 0, L a is other than a bond; Each R s is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl; Each R x are independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; or A pair of R x together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or when q is 2 or 3, a pair of R on adjacent carbon atoms x together form double bonds between adjacent carbon atoms; R z , R z1 and R z2 are each independently hydrogen; 1 to 4 R v (C1-C6) alkyl optionally substituted with -R z3 ; and -L b -R z3 or R z1 and R z2each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R z1 and R z2 (in addition to the phosphorus bonded to) are heteroatoms each independently selected from O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected (C1-C6) alkyl; L b is 1 to 4 R v C optionally substituted with 1-3 is alkylene; R z3 is (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v optionally substituted with; R in each case v are independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, CN, -O(C1-C6) alkylene-O(C1-C6) alkyl, phenyl, -S(O) 0-2 -C1-C6 alkyl and halogen; T 2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R Tare independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is (C1-C3) alkylene optionally substituted with; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L each together with the atom to which it is attached forms a (C3-C6)cycloalkyl ring; Ring A is [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] [ka] [During the ceremony, W 2 is CR Y2 or N, L w is (C1-C3) alkylene. 1 to 4 R Y phenylene optionally substituted by; 1 to 3 R Y5-6 membered heteroarylene optionally substituted by 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with [ka] [During the ceremony, n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N] selected from the group consisting of: Here, mm is L 2 represents a point of attachment to L 3 represents the attachment point to; R in each case Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 When R Y1 and R Y2 The groups taken together form a (C1-C4) alkylene, wherein one of the CH2 units of said (C1-C4) alkylene is selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; L 3is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; R in each case a are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or A pair of R a together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; or [ka] and;W 2 is CR Y2 and;L 3 -C(R a R a )-, then one R a is R Y2 Combined with W 2 and L 3 A double bond is formed between the remaining R a is selected from the group consisting of hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C3) haloalkyl, and (C3-C8) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (BV): [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 1 , B 2 , B 3 and B 4 Each of these is independently 1 and N; B 5A and B 5B each is independently selected from the group consisting of C and N; B 6A , B 6B and B 6C Each of these is independently O, S, CR 1 , N.R. N and N; (B-III) ----- are independently a single bond or a double bond; However, B 5A , B 5B , B 6A , B 6B and B 6C at least one of B is an independently selected heteroatom; 5A , B 5B , B 6A , B 6B and B 6C At least one of is C or CR 1 and B 5A , B 5B , B 6A , B 6B and B 6C A ring containing is a heteroaryl. [ka] [During the ceremony, aa is L 3 represents the attachment point to; B 7 and B 8 are independently -O-, -NR N - and -C(R 1 )2- is selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 independently, CR 1 and N. selected from the group consisting of: Each R 1is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl; (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl) and -C(O)NR 2 R 3 selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; R aa , R ab and R ac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 4 is a bond or -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; Z 1 and Z 2 are independently a bond, NH, N(C1-C6 alkyl), O, C(=O), or S(O) 0-2 and 1-2 R c C optionally substituted with 1-3 selected from the group consisting of alkylene; However, Z 1 and Z 2 is not a bond at the same time; Furthermore, however, Z 1 is NH, N(C1-C6 alkyl), -O- or -S-, Z 2 is a bond, C(=O), S(O) 1-2 or 1-2 R c C optionally substituted with 1-3 is alkylene; Z 2 is NH, N(C1-C6 alkyl), -O- or -S-, Z 1is a bond, C(=O), S(O) 1-2 or 1 to 3 R c C optionally substituted with 1-3 is alkylene; Each R c are independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl, or a pair of R c together with the carbon atoms to which they are attached form a (C3-C8)cycloalkyl ring; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, and CN; b is an integer between 0 and 3 or a pharmaceutically acceptable salt or solvate thereof.

[0065] In certain embodiments of formula I, T 1 Ha-T 3 In certain embodiments of formula I, T 1 Ha-L a -(CR x R x ) q -T 3 is.

[0066] In certain embodiments of formula I, -L a is a bond. In certain embodiments of formula I, -L a -NH-, -N(C 1-3 As a non-limiting example of this embodiment, -L a can be -O-.

[0067] In some embodiments of formula I, q is 1. In some embodiments of formula I, q is 2 or 3.

[0068] In certain embodiments of formula I, each R x is hydrogen or (C1-C6) alkyl. As a non-limiting example of the above embodiment, each R x In some embodiments, a pair of R on the same carbon x are taken together with the carbon atoms to which they are attached to form a (C-C)cycloalkyl ring. As a non-limiting example of this embodiment, a pair of R on the same carbon x may be taken together with the carbon atom to which they are attached to form a cyclopropyl. x Each of is hydrogen.

[0069] In certain embodiments of formula I, T 1 Ha-(CR x R x )-T 3 In some embodiments, each R x is hydrogen. In some embodiments, a pair of R x together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl ring. For example, a pair of R x can be taken together with the carbon atom to which they are attached to form a cyclopropyl ring.

[0070] In certain embodiments of formula I, T 1 Ha-(CR x R x ) q -T 3 and q is 2 or 3. In certain embodiments, each R x is hydrogen.

[0071] In certain embodiments of formula I, T 1 -O-(CR x R x ) q -T 3and q is 1, 2, or 3. In some embodiments, q is 1. In some embodiments, q is 2 or 3. In some embodiments, each R x is hydrogen. In some embodiments, q is 1; x is hydrogen.

[0072] In certain embodiments of formula I, T 3 -N(R s )C(=O)R z , -N(R s )C(=O)OR z , -N(R s )C(=O)N(R s )R z , -N(R s )S(O) 1-2 -R z and -N(R s )S(=NR s )(=O)R z is selected from the group consisting of:

[0073] In certain embodiments of formula I, T 3 -N(R s )C(=O)R z In one embodiment, T 3 is -NHC(=O)R z is.

[0074] In certain embodiments of formula I, T 3 -N(R s )S(O) 1-2 -R z (e.g., -N(R s )S(O)2-R z In some embodiments, T 3 Ha-NHS(O)2R z is.

[0075] In certain embodiments of formula I, T 3 -N(R s )C(=O)N(R s )R z In one embodiment, T 3 -NHC(=O)NHRz is.

[0076] In certain embodiments of formula I, T 3 -N(R s )C(=O)OR z In one embodiment, T 3 -NHC(=O)OR z is.

[0077] In certain embodiments of formula I, T 3 -S(O) 1-2 R z In one embodiment, T 3 -S(O)2R z is.

[0078] In certain embodiments of formula I, T 3 is -C(=O)N(R s )R z , -S(O) 1-2 N(R s )R z and -S(=NR s )(=O)N(R s )R z is selected from the group consisting of:

[0079] In certain embodiments of formula I, T 3 is -C(=O)N(R s )R z In one embodiment, T 3 is -C(=O)NHR z is.

[0080] In certain embodiments of formula I, T 3 is -S(O)2N(R s )R z In one embodiment, T 3 -S(O)2NHR z is.

[0081] In certain embodiments of formula I, T 3 is -S(=NR s )(=O)N(R s )R zIn one embodiment, T 3 is -S(=NH)(=O)N(R s )R z For example, T 3 is -S(=NH)(=O)N(H)R z It could be.

[0082] In certain embodiments of formula I, R z is hydrogen.

[0083] In certain embodiments of formula I, R z is 1 to 4 R v is (C1-C6) alkyl optionally substituted with

[0084] In certain embodiments of formula I, R z is (C1-C3) alkyl. Non-limiting examples of the above embodiment include R z can be methyl, ethyl or isopropyl.

[0085] In certain embodiments of formula I, R z is 1 to 3 R v In some embodiments, R z is (C1-C3) alkyl substituted with 1 to 3 substituents each independently selected from the group consisting of halo and (C1-C3) alkoxy. For example, R z can be (C1-C3) alkyl substituted with 1 to 3 independently selected halo, e.g., —CH2CF3. As another non-limiting example, R z can be (C1-C3) alkyl substituted with (C1-C3) alkoxy, for example, -CH2CH2OMe.

[0086] In certain embodiments of formula I, R z Ha-R z3 or -L b -R z3 In some embodiments, R z Ha-R z3 or -CH2-R z3 In some embodiments, Rz3 is selected from the group consisting of (C-C)cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R v In some embodiments, R z3 is selected from the group consisting of (C-C)cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is selected from 1 to 2 R v Non-limiting examples of the above embodiment include R z3 is cyclopropyl, cyclobutyl, difluorocyclobutyl (e.g., [ka] ), cyclopentyl, oxetanyl (e.g., [ka] ), tetrahydropyranyl (e.g., [ka] ) or tetrahydro-2H-thiopyran 1,1-dioxide (e.g., [ka] ) can be.

[0087] In certain embodiments of formula I, R z3 (C6-C 10 aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 R v In some embodiments, R z3 is 1 to 2 R v For example, R z3 can be unsubstituted phenyl.

[0088] In certain embodiments of formula I, T 3 is -NHC(=O)R z or -NHS(O) 1-2 -Rz and;R z is 1 to 4 R v In some embodiments, R z is (C1-C3) alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R z is (C-C) alkyl substituted with (C-C) alkoxy (e.g., —CHCHOMe). In certain embodiments, R z is (C1-C3) alkyl substituted with 1 to 3 halo (e.g., —CH2CF3). In certain embodiments, T 3 is -NHC(=O)R z In one embodiment, T 3 Ha-NHS(O)2-R z is.

[0089] In certain embodiments of formula I, T 3 is -NHC(=O)R z or -NHS(O) 1-2 -R z and;R z Ha-R z3 or -CH2-R z3 In some embodiments, R z3 is selected from the group consisting of phenyl, (C-C)cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is selected from 1 to 2 R v Non-limiting examples include R z3 is phenyl, cyclopropyl, cyclobutyl, difluorocyclobutyl (e.g., [ka] ), cyclopentyl, oxetanyl (e.g., [ka] ), tetrahydropyranyl (e.g., [ka] ) or tetrahydro-2H-thiopyran 1,1-dioxide (e.g., [ka] In some embodiments, T 3 is -NHC(=O)R z In one embodiment, T 3 Ha-NHS(O)2-R z is.

[0090] In certain embodiments of formula I, T 3 -S(O)2R z and;R z is 1 to 4 R v In some embodiments, R z is (C1-C6) alkyl. For example, R z can be (C1-C3) alkyl.

[0091] In certain embodiments of formula I, T 3 is -C(=O)N(R s )R z , -S(O) 1-2 N(R s )R z and -S(=NR s )(=O)N(R s )R z R z is hydrogen or 1 to 4 R v In some embodiments, T 3 is -C(=O)N(R s )R z For example, T 3 is -C(=O)NHR z In some embodiments, T 3 is -S(O)2N(R s )R z For example, T 3 -S(O)2NHR z In one embodiment, T 3 is -S(=NRs )(=O)N(R s )R z For example, T 3 is -S(=NH)(=O)N(R s )R z (For example, -S(=NH)(=O)N(H)R z In some embodiments, R z is hydrogen. In some embodiments, R z is 1 to 4 R v For example, R z can be (C1-C6) alkyl, for example, methyl, ethyl, or isopropyl.

[0092] In certain embodiments of formula I, T 3 -N(R s )C(=O)N(R s )R z or -N(R s )C(=O)OR z and;R z is hydrogen or 1 to 4 R v In some embodiments, T 3 -NHC(=O)NHR z In one embodiment, T 3 -N(H)C(=O)OR z In some embodiments, R z is hydrogen. In some embodiments, R z is 1 to 4 R v For example, R z can be (C1-C6) alkyl, for example, methyl, ethyl, or isopropyl.

[0093] In certain embodiments of formula I, T 3 is -C(=O)OH.

[0094] In certain embodiments of formula I, T 3 is -P(=O)R z1 Rz2 In some embodiments, R z1 and R z2 are each independently selected (C-C) alkyl. For example, each R z1 may independently be methyl or ethyl.

[0095] In certain embodiments of formula I, T 3 teeth [ka] and 1 to 4 R which may optionally include an endocyclic group selected from the group consisting of v is a 5-10 membered heteroaryl optionally substituted with

[0096] In certain embodiments of formula I, T 3 is 1 to 4 R v In some embodiments, T 3 is a 5-membered heteroaryl having 2 to 4 ring heteroatoms selected from the group consisting of N, O, and S, wherein said heteroaryl is selected from the group consisting of 1 to 2 R v Non-limiting examples of such embodiments include T 3 teeth [ka] In some embodiments, the compound may be selected from the group consisting of: [ka] [ka] It could be.

[0097] In certain embodiments of formula I, T 3 teeth [ka] wherein the heteroaryl is a 5- to 6-membered heteroaryl containing an endocyclic group selected from the group consisting of 1 to 4 R v Non-limiting examples of such embodiments include T 3 teeth [ka] may be selected from the group consisting of:

[0098] In certain embodiments of formula I, T 3 teeth [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v In some embodiments, T 3 teeth [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v and optionally substituted 5-6 membered heterocycloalkyl.

[0099] In one embodiment, T 3 teeth [ka] and;Q 1 is C(=O) or S(O)2; Q 2 is O, NH, -CH2- or -CH2-CH2-; Q 3 is N or CH; --- is a single or double bond, provided that T 3 is non-aromatic. Non-limiting examples of such embodiments include T 3 teeth [ka] may be selected from the group consisting of:

[0100] In certain embodiments of formula I, T 3 is substituted with -OH, and optionally 1 to 2 R v In some embodiments, T is (C1-C6)haloalkyl, which may be further substituted with 3 is substituted with -OH, and optionally 1 to 2 R v In some embodiments, T is (C1-C6)haloalkyl, which may be further substituted with 3 is (C1-C6)haloalkyl substituted with -OH. 1 teeth [ka] It could be.

[0101] In certain embodiments of formula I, T 1 -N(R s )C(=O)R z or -N(R s )S(O) 1-2 -R z and;R z is 1 to 4 R v In some embodiments, R z is (C1-C3) alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R z is (C1-C3) alkyl substituted with 1 to 3 substituents each independently selected from the group consisting of halo and (C1-C3) alkoxy. For example, R z can be —CHCF or —CHCHOMe. In some embodiments, T 1 is -NHC(=O)R z In one embodiment, T 1 Ha-NHS(O)2-R z is.

[0102] In certain embodiments of formula I, T 1 -N(R s )C(=O)R z or -N(Rs )S(O) 1-2 -R z and;R z Ha-R z3 or -CH2-R z3 In one embodiment, R z3 is selected from the group consisting of phenyl, (C-C)cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is selected from 1 to 2 R v Non-limiting examples of the above embodiment include R z3 is phenyl, cyclopropyl, cyclobutyl, difluorocyclobutyl (e.g., [ka] ), cyclopentyl, oxetanyl (e.g., [ka] ), tetrahydropyranyl (e.g., [ka] ) or tetrahydro-2H-thiopyran 1,1-dioxide (e.g., [ka] In some embodiments, T 1 is -NHC(=O)R z In one embodiment, T 1 Ha-NHS(O)2-R z is.

[0103] In certain embodiments of formula I, T 1 Ha-(CR x R x ) q -S(O)2R z and q is 1, 2, or 3. In some embodiments, R z is 1 to 4 R v In some embodiments, R zis (C1-C3) alkyl. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, each R x is hydrogen.

[0104] In certain embodiments of formula I, T 1 is -C(=O)N(R s )R z , -S(O) 1-2 N(R s )R z and -S(=NR s )(=O)N(R s )R z In one embodiment, T 1 is -C(=O)N(R s )R z For example, T 1 is -C(=O)NHR z In some embodiments, T 1 is -S(O)2N(R s )R z For example, T 1 -S(O)2NHR z In some embodiments, T 1 is -S(=NR s )(=O)N(R s )R z For example, T 1 is -S(=NH)(=O)N(R s )R z (For example, -S(=NH)(=O)N(H)R z In some embodiments, R z is hydrogen or 1 to 4 R v In some embodiments, R z is hydrogen. In some embodiments, R z is 1 to 4 R v For example, R z can be (C1-C6) alkyl, for example, methyl, ethyl, or isopropyl.

[0105] In certain embodiments of formula I, T 1 -N(R s )C(=O)N(R s )R z or -N(R s )C(=O)OR z In one embodiment, T 1 -NHC(=O)NHR z In one embodiment, T 1 -N(H)C(=O)OR z In some embodiments, R z is hydrogen or 1 to 4 R v In some embodiments, R z is hydrogen. In some embodiments, R z is 1 to 4 R v For example, R z is (C1-C6) alkyl, for example, methyl, ethyl or isopropyl.

[0106] In certain embodiments of formula I, T 1 Ha-(CR x R x ) q -C(=O)OH; and q is 1, 2, or 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, each R x is hydrogen. In some embodiments (e.g., when q is 1), a pair of R x each together with the carbon atom to which it is attached forms a (C3-C8)cycloalkyl ring; if present, the remaining R x Each of R is hydrogen. As a non-limiting example of the above embodiment, a pair of R on the same carbon x may be taken together with the carbon atom to which they are attached to form a cyclopropyl ring. 1 teeth [ka] It could be.

[0107] In certain embodiments of formula I, T 1 is -C(=O)OH.

[0108] In certain embodiments of formula I, T 1 -O-(CR x R x ) q -C(=O)OH; and q is 1, 2, or 3. In some embodiments, q is 1. In some embodiments, each R x is hydrogen.

[0109] In certain embodiments of formula I, T 1 is -P(=O)R z1 R z2 In some embodiments, R z1 and R z2 are independently selected (C1-C3) alkyl. For example, R z1 and R z2 may independently be methyl or ethyl.

[0110] In certain embodiments of formula I, T 1 is a 5-membered heteroaryl having 2 to 4 ring heteroatoms selected from the group consisting of N, O, and S, wherein said heteroaryl is selected from the group consisting of 1 to 2 R v Non-limiting examples of such embodiments include T 1 teeth [ka] may be selected from the group consisting of:

[0111] In certain embodiments of formula I, T 1 teeth [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v and 5-6 membered heteroaryl, optionally further substituted with T.1 teeth [ka] may be selected from the group consisting of:

[0112] In one embodiment, T 1 teeth [ka] and;Q 1 is C(=O) or S(O)2; Q 2 is O, NH, -CH2- or -CH2-CH2-; Q 3 is N or CH; --- is a single or double bond, except that T 1 is non-aromatic. Non-limiting examples of such embodiments include T 1 teeth [ka] may be selected from the group consisting of:

[0113] In certain embodiments of formula I, T 1 is substituted with -OH, and optionally 1 to 2 R v In some embodiments, T is (C1-C6)haloalkyl, which may be further substituted with 1 is (C1-C6)haloalkyl substituted with -OH. 1 teeth [ka] It could be.

[0114] In certain embodiments of formula I, X 2 is N;X 4 is N.

[0115] In certain embodiments of formula I, X 8 is C;X 5 is C.

[0116] In certain embodiments of formula I, X 3 is C.

[0117] In certain embodiments of formula I, X 2 is N;X 3 is C;X 4 is N;X 5 is C;X 8 is C.

[0118] In certain embodiments of formula I, X 1 , X 7 and X 6 each independently represents CH or CR w In one embodiment, X 2 is N;X 3 is C;X 4 is N;X 5 is C;X 8 is C.

[0119] In certain embodiments of formula I, X 1 , X 7 and X 6 Each of X is CH. 2 is N;X 3 is C;X 4 is N;X 5 is C;X 8 is C.

[0120] In certain embodiments of formula I, X 1 , X 7 and X 6 One of them is CR w and X 1 , X 7 and X 6 and each remaining X is CH. 2 is N;X 3 is C;X 4 is N;X 5 is C;X 8 is C.

[0121] In certain embodiments of formula I, X 6 is CR w and X 1 and X 7 is CH. As a non-limiting example of the above embodiment, X 6 can be CF. In some embodiments, X 2 is N;X 3 is C;X 4 is N;X 5 is C;X 8 is C.

[0122] In certain embodiments of formula I, X 1 , X 7 and X 6 One of the is N;X 1 , X 7 and X 6 Each of the remaining w In certain embodiments of formula I, X 1 is N;X 6 and X 7 is CH. In certain embodiments of formula I, X 6 is N;X 1 and X 7 is CH. In certain embodiments of formula I, X 7 is N;X 1 and X 6 is CH. In some embodiments, X 2 is N;X 3 is C;X 4 is N;X 5 is C;X 8 is C.

[0123] In some embodiments of Formula I, the moiety: [ka] teeth [ka] (for example, [ka] ) For example, the following part: [ka] teeth [ka] Another non-limiting example may be the moiety: [ka] teeth [ka] It could be.

[0124] In some embodiments of Formula I, the moiety: [ka] teeth [ka] For example, the following part: [ka] teeth [ka] Another non-limiting example may be the moiety: [ka] teeth [ka] Another non-limiting example may be the moiety: [ka] teeth [ka] It could be.

[0125] In certain embodiments of formula I, T 2 is (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, (C1-C6)alkyl substituted with 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T may be optionally substituted with

[0126] In certain embodiments of formula I, T 2 is (C1-C6)alkyl substituted with 3- to 6-membered heterocycloalkyl. In certain embodiments of formula I, T 2 is (C1-C6)alkyl substituted with 4- to 6-membered heterocycloalkyl. In certain embodiments of formula I, T 2 is (C1-C6) alkyl substituted with oxetanyl. 2 teeth [ka] For example, T 2 teeth [ka] where T 2 The stereocenter in has the (S) configuration.

[0127] In certain embodiments of formula I, L 1 is 1 to 3 R L Non-limiting examples of the above embodiment include (C1-C3) alkylene optionally substituted with 1 can be CH2.

[0128] In certain embodiments of formula I, L 1 is a bond.

[0129] In certain embodiments of formula I, L 2 is a bond.

[0130] In certain embodiments of formula I, L 1 is CH2;L 2 is a bond.

[0131] In certain embodiments of formula I, L 1 is a bond; L 2 is a bond. For the avoidance of doubt, L 1 is a bond;L 2 When is a bond, X 3 is directly bonded to ring A.

[0132] In certain embodiments of formula I, ring A is [ka] In one embodiment, W 1 is N. In some embodiments, W 2 is CR Y2 In some embodiments, R Y2 is hydrogen. For example, W 2 can be CH. In some embodiments, W 2 is N. In some embodiments, n1 is 0. In some embodiments, n1 is 1.

[0133] As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0134] In certain embodiments of formula I, ring A is [ka] In one embodiment, L w is CH2. In some embodiments, W 2is N. As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0135] In certain embodiments of formula I, ring A is 1 to 4 R Y partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocyclic ring optionally substituted with is selected from the group consisting of:

[0136] In certain embodiments of formula I, ring A is [ka] and;W 3 is N or CH; and n1 is 0, 1, or 2. In some embodiments, n1 is 0. In some embodiments, W 3 is N. In some embodiments, W 3 is CH. As a non-limiting example of the above embodiment, ring A is [ka] As a further non-limiting example of the above embodiment, ring A can be [ka] In certain embodiments of formula I, ring A can be [ka] In one embodiment, W 1 is N. In some embodiments, W 2 is CR Y2 In some embodiments, R Y2 is hydrogen. For example, W 2As a non-limiting example of this embodiment, ring A can be [ka] It could be.

[0137] In certain embodiments of formula I, L 2 is a bond; L 1 is CH2; Ring A is [ka] As a non-limiting example of the disclosure, ring A is [ka] It could be.

[0138] In certain embodiments of formula I, L 2 is a bond; L 1 is CH2; Ring A is [ka] is.

[0139] In certain embodiments of formula I, L 2 is a bond; L 1 is a bond; ring A is [ka] As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0140] In certain embodiments of formula I, L 3 is -O-.

[0141] In certain embodiments of formula I, B 4 is CR 1 (e.g., CH). In some embodiments of formula I, B 4is N.

[0142] In certain embodiments of formula I, B 1 is CR 1 (e.g., CH). In some embodiments of formula I, B 1 is N.

[0143] In certain embodiments of formula I, B 3 is CR 1 (e.g., CH). In some embodiments of formula I, B 3 is N.

[0144] In certain embodiments of formula I, B 2 is CR 1 (e.g., CH). In some embodiments of formula I, B 2 is N.

[0145] In certain embodiments of formula I, ring B is [ka] In one embodiment, B 2 is N. In some embodiments, B 4 is CR 1 (e.g., CH). In some embodiments, B 1 is CR 1 (e.g., CH). In some embodiments, B 3 is CR 1 (e.g., CH). In some embodiments, B 2 is N;B 1 , B 3 and B 4 independently, CR 1 For example, B 2 can be N;B 1 , B 3 and B 4 may each be CH.

[0146] In certain embodiments of formula I, ring B is [ka] As a non-limiting example of the above embodiment, ring B is [ka] It could be.

[0147] In certain embodiments of formula I, ring B is [ka] In one embodiment, B 9 is CR aa (e.g., CH or C(C1-C3 alkyl), such as CMe). In some embodiments, B 7 is —O—. In some embodiments, B 8 is —O—. In some embodiments, B 7 is -O-;B 8 is —O—. In some embodiments, nb is 1. In some embodiments, R ab is H. In some embodiments, R ac is H. In some embodiments, R aa , R ab and R ac are each H. In some embodiments, R aa is (C1-C3) alkyl; R ab and R ac is H. In some embodiments, nb is 0. In some embodiments, B 10 is CR 1 As a non-limiting example of the above embodiment, B 10 can be CH. In some embodiments, B 11 is CR 1 As a non-limiting example of the above embodiment, B 11 can be CH. In some embodiments, B 12 is CR 1 As a non-limiting example of the above embodiment, B 12 can be CH. In some embodiments, B 10 , B 11 and B 12are independently selected CRs 1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 are CH, respectively.

[0148] In certain embodiments of formula I, ring B is [ka] In one embodiment, B 7 is —O—. In some embodiments, B 8 is —O—. In some embodiments, B 7 is -O-;B 8 is —O—. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3) alkyl. Non-limiting examples of the above embodiment include R aa can be methyl. In some embodiments, R ab is H. In some embodiments, R ac is H. In some embodiments, R aa , R ab and R ac are each H. In some embodiments, R aa is (C1-C3) alkyl; R ab and R ac is H. In some embodiments, B 10 is CR 1 As a non-limiting example of the above embodiment, B 10 can be CH. In some embodiments, B 11 is CR 1 As a non-limiting example of the above embodiment, B 11 can be CH. In some embodiments, B 12 is CR 1 As a non-limiting example of the above embodiment, B 12 can be CH. In some embodiments, B 10 , B 11 and B 12 are independently selected CRs1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 Each is CH. In some embodiments, L 4 and R aa Both carbon atoms to which L is attached have the (R) configuration. 4 and R aa Both carbon atoms to which are attached have the (S) configuration.

[0149] In certain embodiments of formula I, ring B is [ka] In one embodiment, B 7 is —O—. In some embodiments, B 8 is —O—. In some embodiments, B 7 is -O-;B 8 is —O—. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3) alkyl. Non-limiting examples of the above embodiment include R aa can be methyl. In some embodiments, B 10 is CR 1 As a non-limiting example of the above embodiment, B 10 can be CH. In some embodiments, B 11 is CR 1 As a non-limiting example of the above embodiment, B 11 can be CH. In some embodiments, B 12 is CR 1 As a non-limiting example of the above embodiment, B 12 can be CH. In some embodiments, B 10 , B 11 and B 12 are independently selected CRs 1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12Each is CH. In some embodiments, L 4 and R aa Both carbon atoms to which L is attached have the (R) configuration. 4 and R aa Both carbon atoms to which are attached have the (S) configuration.

[0150] In certain embodiments of formula I, ring B is [ka] In one embodiment, B 9 is CR aa (e.g., CH or C(C1-C3 alkyl), such as CMe). In some embodiments, B 7 is —O—. In some embodiments, B 8 is —O—. In some embodiments, B 7 is -O-;B 8 In some embodiments, nb is 1. In some embodiments, R ab is H. In some embodiments, R ac is H. In some embodiments, R aa , R ab and R ac are each H. In some embodiments, R aa is (C1-C3) alkyl; R ab and R ac is H. In some embodiments, nb is 0. In some embodiments, B 10 is CR 1 As a non-limiting example of the above embodiment, B 10 can be CH. In some embodiments, B 11 is CR 1 As a non-limiting example of the above embodiment, B 11 can be CH. In some embodiments, B 12 is CR 1 As a non-limiting example of the above embodiment, B 12 can be CH. In some embodiments, B 10 , B 11and B 12 are independently selected CRs 1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 are CH, respectively.

[0151] In certain embodiments of formula I, ring B is [ka] In one embodiment, B 7 is —O—. In some embodiments, B 8 is —O—. In some embodiments, B 7 is -O-;B 8 is —O—. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3) alkyl. Non-limiting examples of the above embodiment include R aa can be methyl. In some embodiments, R ab is H. In some embodiments, R ac is H. In some embodiments, R aa , R ab and R ac are each H. In some embodiments, R aa is (C1-C3) alkyl; R ab and R ac is H. In some embodiments, B 10 is CR 1 As a non-limiting example of the above embodiment, B 10 can be CH. In some embodiments, B 11 is CR 1 As a non-limiting example of the above embodiment, B 11 can be CH. In some embodiments, B 12 is CR 1 As a non-limiting example of the above embodiment, B 12 can be CH. In some embodiments, B 10 , B 11 and B 12are independently selected CRs 1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 Each is CH. In some embodiments, L 4 and R aa Both carbon atoms to which L is attached have the (R) configuration. 4 and R aa Both carbon atoms to which are attached have the (S) configuration.

[0152] In certain embodiments of formula I, ring B is [ka] and;B 7 and B 8 is -O-;R aa is H or (C1-C3) alkyl. In some embodiments, B 10 , B 11 and B 12 are each independently selected CR 1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 can be CH. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3) alkyl (e.g., methyl). In some embodiments, R ab and R ac is H.

[0153] In certain embodiments of formula I, ring B is [ka] and;B 7 and B 8 is -O-;R aa is H or (C1-C3) alkyl. In some embodiments, B 10 , B 11 and B 12 are each independently selected CR1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 can be CH. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3) alkyl (e.g., methyl).

[0154] In certain embodiments of formula I, ring B is [ka] and;B 7 and B 8 is -O-;R aa is H or (C1-C3) alkyl. In some embodiments, B 10 , B 11 and B 12 are each independently selected CR 1 As a non-limiting example of the above embodiment, B 10 , B 11 and B 12 can be CH. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3) alkyl (e.g., methyl). In some embodiments, R ab and R ac is H.

[0155] As a non-limiting example, ring B is [ka] The carbon atom marked with ** has the (R) configuration.

[0156] As another non-limiting example, ring B is [ka] and the carbon atom marked with ** has the (S) configuration.

[0157] In certain embodiments of formula I, L 4 is a bond.

[0158] In some embodiments of formula I, ring B is (B-IV) or (BV); L 4 is a bond.

[0159] In certain embodiments of formula I, L 4 Ha-Z 1 -Z 2 -*, where the * represents the point of attachment to ring C.

[0160] In certain embodiments of formula I, Z 1 is —O—. In certain embodiments of formula I, Z 1 is a bond.

[0161] In certain embodiments of formula I, Z 2 is 1 to 2 R c Non-limiting examples of the above embodiment include -CH2-, optionally substituted with Z 2 can be -CH2-.

[0162] In one embodiment, L 4 is —O—CH—. In some embodiments, L 4 is -CH2-.

[0163] In certain embodiments of formula I, L 4 is a bond.

[0164] In certain embodiments of formula I, L 4 -OZ 2 -*, where * represents the point of attachment to ring C; Z 2 is 1 to 2 R c is —CH— optionally substituted with

[0165] In certain embodiments of formula I, L 3 is -O-; L is -CH2-.

[0166] In certain embodiments of Formula I, Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicycloheteroaryl. In certain embodiments, Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl. As a non-limiting example of such an embodiment, Ring C can be phenyl. As another non-limiting example, Ring C can be 6-membered heteroaryl (e.g., pyridyl).

[0167] In some embodiments of Formula I, b is 1 to 3. In some embodiments, b is 2. In some embodiments, b is 1. In some embodiments, b is 0.

[0168] In some embodiments of formula I, ring C is phenyl;

[0169] In some embodiments of formula I, ring C is phenyl;

[0170] In some embodiments of formula I, ring C is phenyl;

[0171] In some embodiments of formula I, ring C is a 6-membered heteroaryl (eg, pyridyl); and b is 1 or 2 (eg, 1).

[0172] In certain embodiments of Formula I, [ka] teeth [ka] In some embodiments, each occurrence of R b is independently selected from the group consisting of (C-C) alkyl, (C-C) haloalkyl, (C-C) alkoxy, (C-C) haloalkoxy, halogen, and CN. In certain embodiments, each occurrence of R b is independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0173] In certain embodiments of Formula I, [ka] teeth [ka] In some embodiments, R b is independently selected from the group consisting of (C-C) alkyl, (C-C) haloalkyl, (C-C) alkoxy, (C-C) haloalkoxy, halogen, and CN. In certain embodiments, R b is independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0174] In certain embodiments of Formula I, [ka] teeth [ka] In some embodiments, each occurrence of R b is independently selected from the group consisting of (C-C) alkyl, (C-C) haloalkyl, (C-C) alkoxy, (C-C) haloalkoxy, halogen, and CN. In certain embodiments, each occurrence of R b is independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0175] In certain embodiments, the compound of Formula I has the formula (I-A2): [ka] [During the ceremony, L 3 is -O-;-S-;-C(R a R a )-;-N(H)-;-N(C 1-3 alkyl)-; -C(=O)-; and -S(O) 1-2 - selected from the group consisting of; Z2 NH, N(C1-C6 alkyl), O, C(=O), S(O) 0-2 and -CR cA R cB - selected from the group consisting of where R cA and R cB are independently H and R c selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0176] In certain embodiments of Formula (I-A2), L 3 is -O-.

[0177] In certain embodiments of Formula (I-A2), Z 2 Ha-CR cA R cB As a non-limiting example of such an embodiment, Z 2 can be -CH2-.

[0178] In certain embodiments of Formula (I-A2), B 1 , B 2 , B 3 and B 4 The ring containing [ka] As a non-limiting example of the above embodiment, B 1 , B 2 , B 3 and B 4 The ring containing [ka] It could be.

[0179] In some embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0180] In some embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0181] In some embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0182] In some embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0183] In some embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0184] In certain embodiments of Formula (I-A2), T 1 Ha-NR s C(=O)R z or -NR s S(O) 1-2 -R z and;R z is 1 to 4 Rv In some embodiments, R z is (C1-C3) alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R z is (C-C) alkyl substituted with (C-C) alkoxy (e.g., —CHCHOMe). In certain embodiments, R z is (C1-C3) alkyl substituted with 1 to 3 independently selected halo (e.g., -CH2CF3).

[0185] In certain embodiments of Formula (I-A2), T 1 Ha-NR s C(=O)R z or -NR s S(O) 1-2 -R z and;R z Ha-R z3 or -CH2-R z3 In some embodiments, R z3 is selected from the group consisting of phenyl, (C-C)cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is selected from 1 to 2 R v For example, R z3 is phenyl, cyclopropyl, cyclobutyl, difluorocyclobutyl (e.g., [ka] ), cyclopentyl, oxetanyl (e.g., [ka] ), tetrahydropyranyl (e.g., [ka] ) or tetrahydro-2H-thiopyran 1,1-dioxide (e.g., [ka] In some embodiments, T 3 is -NHC(=O)R z In one embodiment, T 3 Ha-NHS(O)2-R z is.

[0186] In certain embodiments of Formula (I-A2), T 1 Ha-(CR x R x ) q -S(O)2R z and q is 1, 2, or 3. In some embodiments, R z is 1 to 4 R v In some embodiments of formula, R z is (C1-C3) alkyl. In some embodiments, q is 1. In some embodiments, q is 2 or 3. In some embodiments, each R x is hydrogen. In some embodiments, q is 1; x is hydrogen.

[0187] In certain embodiments of Formula (I-A2), T 1 is -C(=O)N(R s )R z , -S(O) 1-2 N(R s )R z and -S(=NR s )(=O)N(R s )R z In one embodiment, T 1 is -C(=O)N(R s )R z For example, T 1 is -C(=O)NHR z In some embodiments, T 1 is -S(O)2N(R s )R z For example, T 1 -S(O)2NHR z In some embodiments, T 1 is -S(=NR s)(=O)N(R s )R z For example, T 1 is -S(=NH)(=O)N(R s )R z (For example, -S(=NH)(=O)N(H)R z In some embodiments, R z is hydrogen or 1 to 4 R v In some embodiments, R z is hydrogen. In some embodiments, R z is 1 to 4 R v For example, R z can be (C1-C6) alkyl, for example, methyl, ethyl, or isopropyl.

[0188] In certain embodiments of Formula (I-A2), T 1 -N(R s )C(=O)N(R s )R z or -N(R s )C(=O)OR z In one embodiment, T 1 -NHC(=O)NHR z In one embodiment, T 1 -N(H)C(=O)OR z In some embodiments, R z is hydrogen or 1 to 4 R v In some embodiments, R z is hydrogen. In some embodiments, R z is 1 to 4 R v For example, R z can be (C1-C6) alkyl, for example, methyl, ethyl, or isopropyl.

[0189] In certain embodiments of Formula (I-A2), T 1 Ha-(CR x Rx ) q -C(=O)OH; and q is 1, 2, or 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, each R x is hydrogen. In some embodiments, a pair of R x each together with the carbon atom to which it is attached forms a (C3-C8)cycloalkyl ring; if present, the remaining R x is hydrogen. As a non-limiting example of the above embodiment, R x may be taken together with the carbon atoms to which they are attached to form a cyclopropyl ring. 1 teeth [ka] is.

[0190] In certain embodiments of Formula (I-A2), T 1 is C(=O)OH.

[0191] In certain embodiments of Formula (I-A2), T 1 -O-(CR x R x ) q -C(=O)OH; and q is 1, 2, or 3. In some embodiments, q is 1. In some embodiments, each R x is hydrogen.

[0192] In certain embodiments of Formula (I-A2), T 1 is -P(=O)R z1 R z2 In some embodiments, R z1 and R z2 is an independently selected (C1-C3) alkyl (e.g., methyl or ethyl).

[0193] In certain embodiments of Formula (I-A2), T 1is a 5-membered heteroaryl having 2 to 4 ring heteroatoms selected from the group consisting of N, O, and S, wherein said heteroaryl is selected from the group consisting of 1 to 2 R v Non-limiting examples of such embodiments include T 1 teeth [ka] may be selected from the group consisting of:

[0194] In certain embodiments of Formula (I-A2), T 1 teeth [ka] 1 to 4 R containing an endocyclic group selected from the group consisting of v and 5-6 membered heteroaryl, optionally further substituted with T. 1 teeth [ka] may be selected from the group consisting of:

[0195] In certain embodiments of Formula (I-A2), T 1 teeth [ka] and;Q 1 is C(=O) or S(O)2; Q 2 is O, NH, -CH2- or -CH2-CH2-; Q 3 is N or CH; --- is a single or double bond, except that T 1 is non-aromatic. Non-limiting examples of such embodiments include T 1 teeth [ka] may be selected from the group consisting of:

[0196] In certain embodiments of Formula (I-A2), T 1 is substituted with -OH, and optionally 1 to 2 R v In some embodiments, T is (C1-C6)haloalkyl, which may be further substituted with 1 is (C1-C6)haloalkyl substituted with -OH. 1 teeth [ka] It could be.

[0197] In certain embodiments of Formula (I-A2), T 2 is (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, (C1-C6)alkyl substituted with 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T may be optionally substituted with

[0198] In certain embodiments of Formula (I-A2), T 2 is a (C1-C3) alkyl substituted with a 4- to 6-membered heterocycloalkyl.

[0199] In certain embodiments of Formula (I-A2), T 2 is (C1-C3) alkyl substituted with oxetanyl. 2 teeth [ka] where T 2 The stereocenter in has the (S) configuration.

[0200] In certain embodiments of Formula (I-A2), L 1 is CH2; Ring A is [ka] As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0201] In certain embodiments of Formula (I-A2), L 1 is a bond; ring A is [ka] As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0202] In certain embodiments of Formula (I-A2), L 1 is CH2; Ring A is [ka] and;W 3 is N or CH; and n1 is 0, 1, or 2. As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0203] In certain embodiments of formula (I-A2), ring C is selected from the group consisting of phenyl and 6-membered heteroaryl;

[0204] In certain embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0205] In certain embodiments of Formula (I-A2), [ka] teeth [ka] is.

[0206] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-A5), [ka] teeth [ka] is.

[0207] In certain embodiments of Formula (I-A2), at each occurrence of R b is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, and CN.

[0208] In certain embodiments of Formula (I-A2), at each occurrence of R b is independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0209] In certain embodiments, the compound of Formula I is selected from the group consisting of the compounds in Table C1 or Table C2, or a pharmaceutically acceptable salt or solvate thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 2-1 Table 2-2 Table 2-3 Table 2-4 [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15]

[0210] The compounds of formula I include pharmaceutically acceptable salts thereof. Additionally, the compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and may be useful as intermediate compounds for preparing and / or purifying the compounds of formula I and / or separating the enantiomers of the compounds of formula I. Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula I include trifluoroacetate salts.

[0211] Furthermore, the compounds of formula I or their salts may be isolated in the form of solvates, and it is therefore understood that all such solvates are included within the scope of the present invention. For example, the compounds of formula I and their salts can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0212] When used as a pharmaceutical, the compound of Formula I (including its pharmaceutically acceptable salts or solvates) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal), pulmonary (e.g., powder or aerosol inhalation or insufflation (including nebulizer); intratracheal or intranasal), oral, or parenteral. Oral administration can include preparations formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracerebral, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, fillers and the like may be required or desirable.

[0213] Also provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.In some embodiments, the composition is formulated for oral administration.In some embodiments, the composition is a solid oral formulation.In some embodiments, the composition is formulated as a tablet or capsule.

[0214] Further provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by intimately mixing the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0215] Suitable pharmaceutically acceptable carriers are well known in the art, and descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[0216] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0217] In some embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical preparations, such as Tween, poloxamer or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer, and wool fat. Cyclodextrins, e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives, e.g., hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilized derivatives, can also be used to enhance delivery of the compounds described herein. Compositions containing the chemical entities described herein in the range of 0.005% to 100%, with the balance being composed of non-toxic excipients, can be prepared. Contemplated compositions may contain the compounds provided herein in the range of 0.001% to 100%, in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such formulations are known or apparent to those skilled in the art, and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0218] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof may be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, intraintestinal, peridural, intrainterstitial, intraabdominal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intratracheal, intrathecal, intrasynovial, intratesticular, intraarachnoid, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[0219] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate (e.g., the compound of Formula (I-A2) or its pharmaceutically acceptable salt or solvate) or its pharmaceutical composition described herein can be formulated for parenteral administration, for example, for injection by intraarterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous or intraperitoneal route.For example, such compositions can be prepared as either an injectable liquid solution or suspension; a solid form suitable for preparing a solution or suspension by adding liquid before injection can also be prepared; and the preparation can also be emulsified.The preparation of such formulations is known to those skilled in the art in light of the present disclosure.In some embodiments, a device is used for parenteral administration.For example, such a device can include needle injectors, microneedle injectors, needleless injectors, and injection techniques.

[0220] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol solutions; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In some embodiments, the form must be sterile and fluid to the extent that it can be easily injected.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0221] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in dispersion, and by the use of surfactants. In some embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be achieved by using agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0222] In some embodiments, sterile injectable solutions are prepared by combining the required amount of a compound of Formula I or its pharmaceutically acceptable salt or solvate (e.g., a compound of Formula (I-A2) or its pharmaceutically acceptable salt or solvate) in a suitable solvent with various other ingredients listed above, and then optionally sterile filtering. In some embodiments, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other required ingredients listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze-drying technology, which obtains a powder of the active ingredient and additional desired ingredients from a previously sterile-filtered solution.

[0223] In some embodiments, pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxobenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl Any one or more of caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0224] In some embodiments, suppositories can be prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, that is solid at room temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0225] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition thereof described herein is formulated for local delivery to the gastrointestinal or GI tract by oral administration (e.g., a solid or liquid dosage form).

[0226] In some embodiments, the solid formulation for oral administration includes capsules, tablets, pills, powders, and granules.In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate (e.g., the compound of Formula (I-A2) or its pharmaceutically acceptable salt or solvate) is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acid, and sodium carbonate; e) solution retarders. The composition may be mixed with a soluble or non-soluble filler such as a soluble or non-soluble filler, ...

[0227] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a compound of Formula I provided herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) together with a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a separate solid formulation, powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (e.g., a gelatin or cellulose-based capsule). In some embodiments, unit formulations in which one or more compounds provided herein and pharmaceutical compositions or additional active agents are physically separated are also included, such as granules, capsules, and granules (or tablets in capsules); bilayer tablets; two-compartment gel capsules, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0228] In certain embodiments, other physiologically acceptable compounds may be included as wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0229] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral formulation excipients, such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0230] In some embodiments, the compound of Formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for ophthalmic administration. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloroisothiazolinone complex; Allergan, Inc.)).

[0231] In certain embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In certain embodiments, topical compositions may include ointments and creams. In certain embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In certain embodiments, creams containing selected active agents are typically viscous liquid or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, and the aqueous phase usually, although not necessarily, exceeds the volume of the oil phase and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0232] In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0233] In some embodiments, the dosage of the compound of Formula I or its pharmaceutically acceptable salt or solvate (e.g., the compound of Formula (I-A2) or its pharmaceutically acceptable salt or solvate) is determined based on many factors, including but not limited to, the type, age, weight, sex, medical condition, the severity of the patient's medical condition, the route of administration, and the activity of the compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dosage for a particular situation can be determined by those skilled in the pharmaceutical field.In some embodiments, the total daily dosage can be divided and administered in portions throughout the day, or administered by a method that provides sustained delivery.

[0234] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is administered at a dose of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In certain embodiments, the dose is a therapeutically effective amount.

[0235] In certain embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2), or a pharmaceutically acceptable salt or solvate thereof) is administered in an amount of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 100 mg / Kg). mg / Kg ~ approx. 10 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 5 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 1 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 0.5 mg / Kg; approx. 0.00 02mg / Kg ~ approx. 0.1mg / Kg; approx. 0.001mg / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001mg / Kg ~ approx. 10mg / Kg; approx. 0.00 1mg / Kg~about 5mg / Kg;about 0.001mg / Kg~about 1mg / Kg;about 0.001mg / Kg~about 0.5mg / Kg;about 0.001mg / Kg~about 0.1mg / Kg;about 0.01m g / Kg~about 50mg / Kg;about 0.01mg / Kg~about 25mg / Kg;about 0.01mg / Kg~about 10mg / Kg;about 0.01mg / Kg~about 5mg / Kg;about 0.01mg / Kg~about 1 In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) described herein is administered at a dose of about 100 mg / Kg.

[0236] In certain embodiments, the dose of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) can be administered on a daily basis (e.g., as a single dose or two or more divided doses) or off-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0237] In certain embodiments, the administration period of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof described herein (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of Formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient for a period of time, followed by a separation period during which administration of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is discontinued. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is administered for a first period of time, followed by a second period of time after the first period of time, during which administration is discontinued, followed by a third period of time during which administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is initiated, followed by a fourth period of time after the third period of time during which administration is discontinued.For example, a period of administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof), followed by a period during which administration is stopped, can be repeated for a predetermined or indefinite period. In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period of time for which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0238] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is orally administered to a patient one or more times daily (e.g., a once-daily, twice-daily, three times-daily, four times-daily, or once-daily dose).

[0239] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a patient one or more times daily (e.g., 1 to 4 times daily, twice daily, three times daily, four times daily, or once daily doses).

[0240] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a patient once a week.

[0241] Treatment method In some embodiments, the present disclosure features a method of treating a patient (e.g., a human) suffering from a disease, disorder, or condition in which modulation of GLP-1R (e.g., inhibited or impaired and / or increased or undesired GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include, or may further include, one or more conditions related to, coexisting with, or secondary to any one or more of the conditions described herein.

[0242] Provided herein is a method for treating a GLP-1-related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition.

[0243] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, recurrent thrombosis after angioplasty, and the like. Stenosis, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerular sclerosis, arthritis, osteoporosis, treatment of addiction These conditions include: cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0244] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinism, and the like. These conditions include: threonineemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0245] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, Syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0246] In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein result in one or more of the following: reduced blood glucose levels (e.g., reduced blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, increased insulin synthesis, activated insulin secretion, increased beta cell mass, regulated gastric acid secretion, regulated gastric emptying, reduced body mass index (BMI), and / or reduced glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided is a method for regulating glucose or insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition described herein.

[0247] In certain embodiments, provided herein are methods for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%), comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2) or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition described herein. In any of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D).

[0248] Indications Obesity In some embodiments, the disease, illness, or disorder is obesity and illness, illness, or disorder associated with or related to obesity.Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat accumulation).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-related type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0249] In some embodiments, the disease, disorder or disorder is related to obesity.Examples of such disease, disorder or disorder include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obesity-related diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity-hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

[0250] diabetes In some embodiments, the disease, disorder or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, more advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-related diabetes, autoimmune diabetes, and borderline diabetes.In some embodiments, the disease, disorder or disorder is type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, more advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0251] Provided herein are methods for treating diabetes in a patient, the method comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as disclosed herein (e.g., a compound of Formula (I-A2), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof).

[0252] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering a therapeutically effective amount of a compound of Formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition), to a patient identified or diagnosed as having type 2 diabetes.

[0253] Also provided is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula (I-A2), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof).

[0254] In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce non-fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce HbA1c levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce glucagon levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein increase insulin levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce BMI.

[0255] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less.

[0256] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less.

[0257] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 6.5% or less, about 6.0% or less, or about 5.0% or less.

[0258] In certain embodiments, a reduction in glucagon levels of about 5% to about 95% is shown with treatment of type 2 diabetes. A reduction in glucagon levels of about 15% to about 80% is shown with treatment of type 2 diabetes. A reduction in glucagon levels of about 25% to about 60% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 5% to about 95% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 15% to about 80% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 25% to about 60% is shown with treatment of type 2 diabetes.

[0259] In certain embodiments, a reduction in BMI of about 5% to about 95% is demonstrated with treatment of type 2 diabetes. A reduction in BMI of about 15% to about 80% is demonstrated with treatment of type 2 diabetes. A reduction in BMI of about 25% to about 60% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 40 or less, about 30 or less, or about 20 or less is demonstrated with treatment of type 2 diabetes.

[0260] In some embodiments, the disease, disorder or disorder is associated with diabetes (for example, diabetic complications).Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral arterial disease, cerebrovascular disease, hypertension, and risk factors related to uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fracture and cognitive dysfunction.

[0261] Other non-limiting examples of disorders related to diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-LDL cholesterolemia, postprandial dyslipidemia), metabolic syndrome (e.g., a metabolic disorder in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0262] In certain embodiments, the disease, condition, or disorder is diabetes and obesity. In certain embodiments, the compounds described herein are also useful for improving the therapeutic effectiveness of metformin.

[0263] Disorders of metabolically important tissues In certain embodiments, the disease, condition, or disorder is a disorder of a metabolically significant tissue. Non-limiting examples of metabolically significant tissue include liver, adipose tissue, pancreas, kidney, and intestine.

[0264] In some embodiments, the disease, condition, or disorder is fatty liver disease, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0265] Nonalcoholic fatty liver disease (NAFLD) refers to a group of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various diseases, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. This can cause liver disease in adults and children, ultimately resulting in cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, primarily isolated macrovesicular fatty liver (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient who is 21 years old or younger at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, including neonates (birth to 1 month old); infants (1 month to 2 years old); children (2 to 12 years old); and adolescents (12 to 21 years old (up to but not including their 22nd birthday)) (Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.).In certain embodiments, the pediatric patient is from birth to 28 days of age, from 29 days of age to 2 years of age, from 2 to 12 years of age, or from 12 to 21 years of age (up to but not including the 22nd birthday). In certain embodiments, the pediatric patient is from birth to 28 days of age, from 29 days of age to 1 year of age, from 1 month to 4 months of age, from 3 months to 7 months of age, from 6 months to 1 year of age, from 1 year to 2 years of age, from 2 years to 3 years of age, from 2 years to 7 years of age, from 3 years to 5 years of age, from 5 years to 10 years of age, from 6 years to 13 years of age, from 10 years to 15 years of age, or from 15 years to 22 years of age. In certain embodiments, the patient is an adult patient.

[0266] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); gallstones; gallbladder disease; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism, such as osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease and altered bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to improve post-surgical recovery and / or treat surgical trauma by preventing the catabolic response caused by surgical trauma.

[0267] Cardiovascular and vascular diseases In some embodiments, the disease, disorder, or disorder is a cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and prothrombotic conditions (e.g., elevated blood fibrinogen or plasminogen activator inhibitor levels).

[0268] In some embodiments, the disease, disorder, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[0269] Neurological disorders In certain embodiments, the disease, condition, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, U.S. Application No. 20060275288A1.

[0270] Non-limiting examples of psychiatric disorders include drug addiction / addiction (narcotics and amphetamines) and attention deficit hyperactivity disorder (ADHD).The compounds and pharmaceutical compositions described herein can be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing relapse of drug abuse, and alleviating the anxiety caused by the absence of certain addictive substances.See, for example, US Application No. 20120021979A1.

[0271] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, and for maintaining dopaminergic neuronal and motor function in Parkinson's disease (Morbus Parkinson's).

[0272] Insulin-related In certain embodiments, the disease, condition, or disorder is impaired fasting blood glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, abnormal paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides, and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0273] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of borderline impaired fasting blood glucose or fasting hyperglycemia to diabetes.

[0274] autoimmune disease In some embodiments, the disease, disorder or disorder is an autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disease associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease.See, for example, US Application No. 20120148586A1.

[0275] Gastrointestinal disorders In some embodiments, the disease, disorder, or disorder is a stomach or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogens), gastrointestinal disease, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy- and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0276] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the patient's weight gain may be due to excessive food intake or an unbalanced diet, or may be due to concomitant medication (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obese or may be weight gain in an obese patient. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain after smoking cessation.

[0277] In certain embodiments, the disease, condition, or disorder is an eating disorder, eg, overeating, binge eating, bulimia, or compulsive overeating.

[0278] Inflammatory diseases In some embodiments, the disease, illness or disorder is inflammatory disease.Non-limiting examples of inflammatory disease include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues (including liver, fat, pancreas, kidney and intestine), and pro-inflammatory condition (for example, elevated level of pro-inflammatory cytokines or inflammatory markers such as C-reactive protein in blood).

[0279] cancer In some embodiments, the disease, condition, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). gastrointestinal stromal tumor), colon cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, uterine cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), These include thyroid cancer, nasal cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0280] Hypothalamic-pituitary disorders In one embodiment, the disease, disorder, or condition is associated with the hypothalamic pituitary-gonadal axis. For example, the disease, disorder, or condition is associated with the hypothalamic pituitary-ovarian axis. In another example, the disease, disorder, or condition is associated with the hypothalamic pituitary-testicular axis. Disorders of the hypothalamic pituitary-gonadal axis include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0281] In certain embodiments, the diabetes-related disease, condition, or disorder is associated with the hypothalamic pituitary gonadal axis.

[0282] Pulmonary disease In certain embodiments, the disease, condition, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0283] In certain embodiments, the diabetes-related condition, disease, or disorder is a pulmonary disease.

[0284] Combination therapy In certain embodiments, the present disclosure includes both monotherapy and combination therapy regimens.

[0285] In certain embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the administration of the compounds described herein.

[0286] In certain embodiments, the methods described herein include administering a compound described herein in combination with one or more of dietary therapy (e.g., dietary monitoring for diabetes, dietary therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0287] In certain embodiments, the compounds of X described herein, or a pharmaceutically acceptable salt or solvate thereof, can be administered in combination with one or more additional therapeutic agents.

[0288] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapy agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidant agents, therapeutic agents for osteoporosis, vitamins, therapeutic agents for dementia, therapeutic agents for erectile dysfunction, therapeutic agents for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria, and antiemetic agents.

[0289] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., verneperit), cannabinoid receptor antagonists (e.g., cefotaxime), and the like. agonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β 3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearic acid-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium glucose transporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941), NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, WO 06 / 112549, WO 07 / 028135,compounds described in WO 08 / 047821, WO 08 / 050821, WO 08 / 136428, and WO 08 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-3 6, PYY3-36 derivatives, obineptide, TM-30339, TM-30335, oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human pre-islet peptide (human These include steroids (hyperlipidemic peptide) (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0290] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; fragments or derivatives of insulin (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., any of the glucagon analogs described in WO 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea drugs (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide). , thiazolidinedione drugs (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, GLP-1 / GIP receptor dual agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatidine, and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0291] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, and ileal bile acid transporter inhibitors. Inactive Insulin-binding protein (IBAT) inhibitors, glycyrrhizin, Schizosaccharomyces extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0292] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO 2004 / 039365), PKC inhibitors (e.g., Examples of such anti-inflammatory drugs include ruboxistaurin mesylate, AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase 1 (ASK-1) inhibitors.

[0293] In certain embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium salts, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO 97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl]piperidine-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0294] In certain embodiments, the one or more additional therapeutic agents include, for example, drugs useful as antihypertensives. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and β-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0295] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful as diuretics.Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazides (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone drugs (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0296] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as immunotherapeutics. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immune-enhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0297] In certain embodiments, the one or more additional therapeutic agents include, for example, drugs useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, WO 2002 / 06234, WO 2004 / 048363, WO 2005 / 030740, and compounds described in WO 2005 / 058823 and WO 2005 / 113504), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0298] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating osteoporosis.Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium.Suitable examples of vitamins include vitamin B1 and vitamin B12.Suitable examples of drugs for treating erectile dysfunction include apomorphine and sildenafil citrate.Suitable examples of drugs for treating urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride.Suitable examples of drugs for treating urinary disorders include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0299] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of persistent hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents used to treat complications associated with microangiopathy, antihyperlipidemic agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), cholesterol-lowering drugs, bile acid sequestrants (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid-binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, e.g., adrenoceptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin ), and mixed alpha / beta blockers (e.g., labetalol), adrenergic receptor agonists, e.g., alpha 2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers, e.g., dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., , eplerenone), centrally acting adrenergic drugs, such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activators)), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin)),Adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine amines, Serotonin transport modifiers, such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), the compounds described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639, and WO 2008 / 099794, GPR40 agonists (e.g., fasiglitanone, FAM or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO 2008 / 001931), SGLT-1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, anti-cachexia drugs for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, drugs for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M, metabolism-improving proteins or peptides, for example, glucokinase (GK), glucokinase regulatory protein (GKRP),Uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, hercoceride) (harkoseride), carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), local anesthetics (e.g., capsaicin), anxiolytics (e.g., benzothiazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies ( For example, T cell receptor and IL-2 receptor specific antibodies), B cell depleting therapeutic agents (for example, anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs that affect T cell migration (for example, anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysabri), drugs that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulatory agents (e.g., glatiramer), TNF-binding proteins (e.g., circulating TNF receptors), immunosuppressants (e.g., Mycophenolic acid, and metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide.

[0300] In some embodiments, the one or more additional therapeutic agents include, for example, therapeutic agents useful as antiemetics.As used herein, "antiemetic" agent refers to any agent that counters (e.g., reduces or eliminates) nausea or emesis (vomiting).Without being bound by theory, it is believed that administering one or more antiemetic agents in combination with the compound of formula (I) described herein may, for example, allow the patient to consume a normal diet, thereby allowing the compound of formula (I) to be administered at a higher dose, thereby allowing for a more rapid response to treatment.

[0301] Non-limiting examples of antiemetic agents include 5HT3-receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1-receptor antagonists (e.g., neurokinin substance 1 P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[0302] For example, the antiemetic may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3-receptor antagonists, NK1-receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0303] In certain embodiments, the antiemetic agent is a 5HT3-receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopiride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazapine. Non-limiting examples of other 5HT3-receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, quamosetron, ramosetron, licasetron, risperidone, ziprasidone, and zatosetron.

[0304] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopiride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazapine.

[0305] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0306] In certain embodiments, the 5HT-3-receptor antagonists are granisetron, dolasetron and ondansetron.

[0307] In certain embodiments, the 5HT-3-receptor antagonist is granisetron.

[0308] In certain embodiments, the 5HT-3-receptor antagonist is ondansetron.

[0309] In some embodiments, the antiemetic drug is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0310] In some embodiments, the antiemetic drug is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergics include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Dicypal (Norflex, orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Camadoline (procyclidine hydrochloride).

[0311] In some embodiments, the antiemetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0312] In some embodiments, the antiemetic agent is an NK1-receptor antagonist (e.g., a neurokinin substance 1 P receptor antagonist). Non-limiting examples of NK1-receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0313] Other non-limiting examples of NK1-receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR140333, CP-96,345, BIIF1149, NKP608C, NKP608A, CGP60829, SR140333 (norpitantium besylate / chloride), LY303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974j. Benserazide and carbidopak. This includes TAK-637 [(αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], PD154075, ([(2-benzofuran)-CHOCO]-(R)-α-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro4, D-Trp7,9,10, Phe11)SP4-11.

[0314] In some embodiments, the antiemetic drug is an antidopamine agonist / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0315] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), a cannabinoid agonist such as WIN55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0316] Other exemplary antiemetics include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0317] Still other exemplary antiemetic agents include those disclosed in U.S. Patent Application No. 20120101089A1; U.S. Patent No. 10,071,088B2; U.S. Patent No. 6,673,792B1; U.S. Patent No. 6,197,329B1; U.S. Patent No. 10,828,297B1; U.S. Patent No. 10,322,106B2; U.S. Patent No. 10,525,033B2; WO 2009080351A1; WO 2019203753A2; WO 2002020001A2; U.S. Patent No. 8,119,697B2; U.S. Patent No. 5,039,528; U.S. Patent Application No. 20090305964A1; and WO 2006 / 111169, which are incorporated by reference in their entireties.

[0318] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact or administration of the compound and pharmaceutical composition (e.g., about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month).

[0319] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and pharmaceutical composition. In one example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are administered to the patient simultaneously in the same formulation. In another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are administered to the patient simultaneously in separate formulations.

[0320] Patient Selection In certain embodiments, the methods described herein further include identifying a patient (e.g., subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0321] In certain embodiments, the methods described herein further include identifying a subject (e.g., a patient) suffering from a disease, disorder, or condition provided herein (e.g., a GLP-1-related disease, disorder, or condition).

[0322] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) suffering from type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or higher. In certain embodiments, the HbA1c level is about 8.0% or higher. In certain embodiments, the HbA1c level is about 10.0% or higher. In certain embodiments, the HbA1c level is about 12.0% or higher. In certain embodiments, the HbA1c level is about 14.0% or higher. In certain embodiments, the HbA1c level is about 16.0% or higher. In some embodiments, the HbA1c level is about 18.0% or higher. In some embodiments, the HbA1c level is about 20.0% or higher. In some embodiments, the HbA1c level is about 22.0% or higher. In some embodiments, the HbA1c level is about 24.0% or higher.

[0323] In some embodiments, the fasting blood glucose level is from about 120 mg / dL or more to about 750 mg / dL or more. In some embodiments, the fasting blood glucose level is from about 200 mg / dL or more to about 500 mg / dL or more. In some embodiments, the fasting blood glucose level is from about 300 mg / dL or more to about 700 mg / dL or more.

[0324] In some embodiments, the non-fasting blood glucose level is from about 190 mg / dL or more to about 750 mg / dL or more. In some embodiments, the non-fasting blood glucose level is from about 250 mg / dL or more to about 450 mg / dL or more. In some embodiments, the non-fasting blood glucose level is from about 400 mg / dL or more to about 700 mg / dL or more.

[0325] In certain embodiments, determining whether a patient has type 2 diabetes further comprises determining the patient's BMI. In certain embodiments, the patient's BMI is about 22 kg / m 2 or more to about 100 kg / m 2 In certain embodiments, the patient's BMI is about 30 kg / m or greater. 2 or more to about 90 kg / m 2 In certain embodiments, the patient's BMI is about 40 kg / m or greater. 2 or more to about 80 kg / m 2 In certain embodiments, the patient's BMI is about 50 kg / m or greater. 2 or more to about 70 kg / m 2 Or even more.

[0326] In certain embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In certain embodiments, the patient is about 10 years old or older. In certain embodiments, the patient is about 15 years old or older. In certain embodiments, the patient is about 20 years old or older. In certain embodiments, the patient is about 25 years old or older. In certain embodiments, the patient is about 30 years old or older. In certain embodiments, the patient is about 35 years old or older. In certain embodiments, the patient is about 40 years old or older. In certain embodiments, the patient is about 42 years old or older. In certain embodiments, the patient is about 44 years old or older. In certain embodiments, the patient is about 46 years old or older. In certain embodiments, the patient is about 48 years old or older. In certain embodiments, the patient is about 50 years old or older. In certain embodiments, the patient is about 52 years old or older. In some embodiments, the patient is about 54 years of age or older. In some embodiments, the patient is about 56 years of age or older. In some embodiments, the patient is about 58 years of age or older. In some embodiments, the patient is about 60 years of age or older. In some embodiments, the patient is about 62 years of age or older. In some embodiments, the patient is about 64 years of age or older. In some embodiments, the patient is about 66 years of age or older. In some embodiments, the patient is about 68 years of age or older. In some embodiments, the patient is about 70 years of age or older. In some embodiments, the patient is about 72 years of age or older. In some embodiments, the patient is about 74 years of age or older. In some embodiments, the patient is about 76 years of age or older. In some embodiments, the patient is about 78 years of age or older.In some embodiments, the patient is about 80 years of age or older. In some embodiments, the patient is about 85 years of age or older. In some embodiments, the patient is about 90 years of age or older. In some embodiments, the patient is about 95 years of age or older. In some embodiments, the patient's ethnicity may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander. [Example]

[0327] The present invention is further described in the following examples, which do not limit the scope of the invention as claimed.

[0328] General information: All evaporations were performed using a rotary evaporator under reduced pressure. Analytical samples were dried under reduced pressure (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems are reported as mixtures (by volume). NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained using a SHIMADZU LC20-MS2020 or Agilent 1260 Series 6125B mass spectrometer or Agilent 1200 Series 6110 or 6120 mass spectrometer with electrospray ionization, unless otherwise indicated.

[0329] Example 1: N-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-5-methylpyridine-3-carboxamide (Compound 101a) [ka] Step A: tert-butyl (S)-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate To a solution of tert-butyl (S)-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate (5.32 g, 15.15 mmol) in DMF (40 mL) were added KCO (6.27 g, 45.45 mmol) and 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (4.6 g, 15.15 mmol). The resulting mixture was stirred at 50 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (DCM:MeOH=80:1) to give tert-butyl (S)-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate as a brown oil (2.33 g, yield: 78%). MS calculated: 618.3; MS found: 619.3 [M+H] + .

[0330] Step B: (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine To a solution of tert-butyl (S)-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate (1.64 g, 2.65 mmol) in DCM (15 mL) was added TFA (3 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine as a brown oil (1.04 g). MS calculated: 518.2; MS found: 519.2 [M+H] + .

[0331] Step C: N-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-5-methylpyridine-3-carboxamide (Compound 101a) [ka] To a solution of 5-methylnicotinic acid (64 mg, 0.47 mmol) in DMF (2 ml), DIEA (151 mg, 1.17 mmol), HATU (194 mg, 0.51 mmol), and (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine (200 mg, 0.39 mmol) were added. The resulting mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction mixture was directly purified by preparative HPLC to give compound 101a as a white solid (7.68 mg, yield: 78%). MS calculated: 637.3; MS found: 638.3 [M+H]+. 1H NMR (400MHz, DMSO-d6): 10.36(s, 1H), 8.93(d, J=2.0Hz, 1H), 8.60(d, J=1.2Hz, 1H), 8.41(d, J=5.6Hz, 1H) , 8.12-8.15(m, 1H), 8.04(d, J=1.6Hz, 1H), 7.53-7.61(m, 2H), 7.31-7.36(m, 4H), 6.73(d, J=6.0Hz, 1H), 4. 98-5.12(m, 2H), 4.66-4.71(m, 1H), 4.47-4.58(m, 2H), 4.35-4.40(m, 1H), 4.08(s, 2H), 3.89(d, J=13.6Hz , 1H), 3.77(d, J=13.6Hz, 1H), 2.65-2.79(m, 3H), 2.30-2.47(m, 6H), 1.88-1.96(m, 2H), 1.58-1.67(m, 2H).

[0332] Example 2: N-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)pyridine-3-carboxamide (Compound 102a) [ka] The synthesis of 102a was similar to that of compound 101a, except that nicotinic acid was used instead of 5-methylnicotinic acid. Compound 102a was obtained as a white solid (5.75 mg, yield: 78%). MS calculated: 623.2; MS found: 624.3 [M+H] + . 1H NMR (400MHz, DMSO-d6): 10.61(s, 1H), 8.76(d, J=4.4Hz, 1H), 8.41(d, J=6.0Hz, 1H), 8.18-8.20(m, 2H), 8 .06-8.10(m, 1H), 7.67-7.72(m, 2H), 7.59(d, J=8.8Hz, 1H), 7.32-7.37(m, 4H), 6.74(d, J=5.6Hz, 1H), 4.9 9-5.13(m, 2H), 4.66-4.72(m, 1H), 4.47-4.59(m, 2H), 4.36-4.41(m, 1H), 4.09(s, 2H), 3.90(d, J=13.6Hz, 1H), 3.78(d, J=13.6Hz, 1H), 2.66-2.80(m, 3H), 2.30-2.52(m, 3H), 1.89-1.96(m, 2H), 1.58-1.78(m, 2H).

[0333] Example 3: N-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-2-methylpyridine-3-carboxamide (Compound 103a) [ka] The synthesis of 103a was similar to that of compound 101a, except that 2-methylnicotinic acid was used instead of 5-methylnicotinic acid. Compound 103a was obtained as a white solid (10.14 mg, yield: 78%). 1H NMR (400MHz, DMSO-d6): 10.38 (s, 1H), 8.55 (dd, J=4.8Hz, 1.6Hz, 1H), 8.41 (d, J=6.0Hz, 1H), 8.03 (d, J=1.6Hz, 1H), 7. 88(dd, J=7.6Hz, 1.6Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.50(dd, J=8.8Hz, 1.6Hz, 1H), 7.31-7.40(m, 5H), 6.73(d, J=5.6H) z, 1H), 4.95-5.12(m, 2H), 4.63-4.72(m, 1H), 4.46-4.60(m, 2H), 4.33-4.38(m, 1H), 4.08(s, 2H), 3.88(d, J=13.6Hz, 1 H), 3.77(d, J=13.2Hz, 1H), 2.64-2.80(m, 3H), 2.58(s, 3H), 2.30-2.45(m, 3H), 1.89-1.98(m, 2H), 1.55-1.70(m, 2H).

[0334] Example 4: N-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-methylpyridine-3-carboxamide (Compound 104a) [ka] The synthesis of 104a was similar to that of compound 101a, except that 6-methylnicotinic acid was used instead of 5-methylnicotinic acid. Compound 104a was obtained as a white solid (13.26 mg, yield: 78%). MS calculated: 637.3; MS found: 638.3 [M+H] + . 1H NMR (400MHz, DMSO-d6): 10.44(s, 1H), 8.57(s, 1H), 8.54(d, J=4.8Hz, 1H), 8.41(d, J=5.6Hz, 1H), 8.03 (s, 1H), 7.59(d, J=7.2Hz, 1H), 7.46-7.52(m, 2H), 7.30-7.37(m, 4H), 6.73(d, J=5.6Hz, 1H), 4.97-5.1 2(m, 2H), 4.65-4.71(m, 1H), 4.45-4.58(m, 2H), 4.33-4.39(m, 1H), 4.09(s, 2H), 3.88(d, J=13.2Hz, 1H ), 3.78(d, J=13.6Hz, 1H), 2.67-2.78(m, 3H), 2.30-2.45(m, 6H), 1.89-1.98(m, 2H), 1.56-1.70(m, 2H).

[0335] Example 5: N-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-4-methylpyridine-3-carboxamide (Compound 105a) [ka] The synthesis of 105a was similar to that of compound 101a, except that 4-methylnicotinic acid was used instead of 5-methylnicotinic acid. Compound 105a was obtained as a white solid (12.70 mg, yield: 8.6%). MS calculated: 637.3; MS found: 638.3 [M+H] + . 1H NMR (400MHz, DMSO-d6): 10.42(s, 1H), 8.65(s, 1H), 8.53(d, J=4.8Hz, 1H), 8.41(d, J=6.0Hz, 1H), 8.04(d, J= 2.0Hz, 1H), 7.57-7.60(m, 1H), 7.49-7.53(m, 1H), 7.31-7.40(m, 5H), 6.73(d, J=5.6Hz, 1H), 4.80-5.12(m, 2H) ), 4.62-4.70(m, 1H), 4.46-4.59(m, 2H), 4.33-4.40(m, 1H), 4.08(s, 2H), 3.88(d, J=13.2Hz, 1H), 3.77(d, J= 13.2Hz, 1H), 2.64-2.80(m, 3H), 2.40-2.45(m, 4H), 2.30-2.39(m, 2H), 1.85-1.98(m, 2H), 1.55-1.69(m, 2H).

[0336] Example 6: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-1,3-benzodiazole (Compound 106a) [ka] Step A: (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile At 0°C, (S)-oxetan-2-ylmethanamine (3.04 g, 16.61 mmol) and DIEA (5.84 g, 45.3 mmol) were added successively to a solution of 4-fluoro-3-nitrobenzonitrile (2.5 g, 15.1 mmol) in THF (25 mL). The reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with HO and extracted with EA (30 mL x 3). The organic layers were combined, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile as a yellow solid (2.4 g, 80% yield). MS calculated: 233.1; MS found: 234.0 [M+H] +.

[0337] Step B: (S)-3-amino-4-((oxetan-2-ylmethyl)amino)benzonitrile To a solution of (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile (2.4 g, 10.3 mmol) and Zn (6.7 g, 103 mmol) in MeOH (24 mL) was added AcOH (1.85 g) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction was filtered and the solid was washed with NaHCO (aq). The filtrate was quenched with HO and extracted with EA (20 mL × 3). The organic layers were combined, dried over NaSO, and concentrated to give (S)-3-amino-4-((oxetan-2-ylmethyl)amino)benzonitrile as a yellow solid (1.4 g, 58.3% yield). MS calculated: 203.1; MS found: 204.1 [M+H] + .

[0338] Step C: (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide To a solution of (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile (1 g, 4.9 mmol) in THF (10 mL) was added 2-chloroacetic anhydride (1 g, 5.9 mmol). The reaction was stirred at 30 °C for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide as a yellow solid (230 mg, 23% yield). MS calculated: 279.1; MS found: 280.1 [M+H] + .

[0339] Step D: (S)-2-(4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide A mixture of 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (216 mg, 0.72 mmol) and K2CO3 (298 mg, 2.16 mmol) in DMF (2 ml) was added to (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide (200 mg, 0.72 mmol). The reaction was stirred at 60 °C for 3 h. After completion of the reaction, the reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give (S)-2-(4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide as a yellow solid (250 mg, yield 60%). MS calculated: 546.2; MS found: 547.5 [M+H] +

[0340] Step E: (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile To a solution of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)-N-(5-cyano-4-fluoro-2-((((S)-oxetan-2-yl)methyl)amino)phenyl)acetamide (250 mg, 0.46 mmol) in toluene (3 ml) was added AcOH (1 mL). The reaction was stirred at 110° C. for 2 h. After completion of the reaction, the reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over Na2SO4 and concentrated to give (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile as a yellow oil (130 mg, yield: 78%). MS calculated: 528.2; MS found: 529.2 [M+H] + .

[0341] Step F: (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbimidic acid To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile (250 mg, 0.47 mmol) in EtOH (4 mL) were added NH2OH HCl (197 mg, 2.84 mmol) and TEA (475 mg, 4.7 mmol) successively. The reaction was stirred at 90 °C for 2 h. After completion of the reaction, the reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated. The reaction mixture was purified by HPLC to give (S,E)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbimidic acid as a colorless oil (130 mg, yield: 78%). MS calculated: 562.2; MS found: 281.7 [M / 2+H] + .

[0342] Step G: (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbimidic acid (130 mg, 0.23 mmol) in THF (3 mL) gave TFAA (194 mg, 0.93 mmol). The reaction was stirred at 30 °C for 2 h. After completion of the reaction, the reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over Na2SO4 and concentrated to give (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole as a colorless oil (180 mg, yield: 78%). MS calculated: 639.2; MS found: 640.8 [M+H] +

[0343] Step H: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-1,3-benzodiazole (Compound 106a) To a solution of (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (180 mg, 0.28 mmol) in DMF (2 mL) was added N2H4·HO (42.3 mg, 0.85 mmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was purified by preparative HPLC to give compound 106a as a white solid (25.47 mg, 14% yield). MS calculated: 638.2; MS found: 639.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6):δ 8.42(d, J=5.2Hz, 1H), 8.29(brs, 1H), 7.82-7.96(m, 2H), 7.31-7.36(m, 4H), 6.7 4(d, J=5.6Hz, 1H), 5.01-5.13(m, 2H), 4.74-4.81(m, 1H), 4.60-4.67(m, 1H), 4.48 -4.53(m, 1H), 4.37-4.42(m, 1H), 4.09(s, 2H), 3.90-4.01(m, 1H), 3.79-3.90(m, 1H), 2.67-2.83(m, 3H), 2.32-2.50(m, 3H), 1.87-2.10(m, 2H), 1.55-1.75(s, 2H).

[0344] Example 7: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-(1H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazole (Compound 107a) [ka] To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-5-isocyano-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (150 mg, 0.28 mmol) in dioxane (2 mL) was added TMSN3 (153.9 mg, 1.35 mmol) and n-BuSnO (133.5 mg, 0.54 mmol). The resulting mixture was stirred at 110 °C for 3 hours. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give compound 107a as a white solid (23.15 mg, yield: 78%). MS calculated: 571.2; MS found: 572.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 8.41 (d, J=5.6Hz, 1H), 8.22 (d, J=0.8Hz, 1H), 7.92 (dd, J=8.8Hz, 0.8Hz, 1H) , 7.78(d, J=8.4Hz, 1H), 7.31-7.36(m, 4H), 6.73(d, J=5.6Hz, 1H), 4.98-5.14(m, 2H), 4.72-4.78(m, 1H), 4.58-4.63(m, 1H), 4.47-4.53(m, 1H), 4.36-4.42(m, 1H), 4.08(s, 2H), 3.94(d, J=13.6Hz, 1H), 3.81(d, J=13.6Hz, 1H), 2.67-2.82(m, 3H), 2.32-2.46(m, 3H), 1.88-1.97(m, 2H), 1.58-1.67(m, 2H).

[0345] Example 8: 3-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 108a) [ka] To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide (170 mg, 0.3 mmol) in THF / DMF (4 mL / 4 mL) was added TEA (90 mg, 0.9 mmol) and CDI (102.86 mg, 1.86 mmol). The resulting mixture was stirred at 100°C for 3 hours. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give compound 108a as a white solid (16.66 mg, yield: 9.36%). MS calculated: 587.2; MS found: 588.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 8.41(d, J=6.0Hz, 1H), 8.04(d, J=0.8Hz, 1H), 7.80(d, J=8.4Hz, 1H), 7.69(d d, J=8.4Hz, 1.2Hz, 1H), 7.30-7.38(m, 4H), 6.73(d, J=6.0Hz, 1H), 4.98-5.13(m, 2H), 4.72-4.79(m, 1H), 4.58-4.64(m, 1H), 4.46-4.52(m, 1H), 4.35-4.41(m, 1H), 4.08(s, 2H), 3.93(d, J=13.6Hz, 1H), 3.80(d, J=13.6Hz, 1H), 2.66-2.80(m, 3H), 2.32-2.46(m, 3H), 1.88-1.98(m, 2H), 1.55-1.69(m, 2H).

[0346] Example 9: 3-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 109a) [ka] Step A: (S)-2-(4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)-N-(5-isocyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide To a solution of 2-(4-chloro-2-fluorobenzyl)-6-(piperidin-4-yloxy)pyridine (640 mg, 2.0 mmol) in DMF (5 mL) was added KCO (828 mg, 6.0 mmol) and (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide (558 mg, 2.0 mmol). The resulting mixture was stirred at 50° C. for 2 hours. The reaction was filtered and concentrated to give (S)-2-(4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)-N-(5-isocyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide as a brown oil (470 mg, crude). MS calculated: 563.2; MS found: 564.2 [M+H] + .

[0347] Step B: (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-isocyano-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole To a solution of (S)-2-(4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)-N-(5-isocyano-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide (540 mg, 0.96 mmol) in toluene (6 mL) was added AcOH (1 mL). The resulting mixture was stirred at 110° C. for 3 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to give (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-isocyano-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole as a purple solid (330 mg, yield: 78%). MS calculated: 545.2; MS found: 546.2 [M+H] + .

[0348] Step C: (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide To a solution of (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-isocyano-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (195 mg, 0.36 mmol) in EtOH (7 mL) was added TEA (144 mg, 4.12 mmol) and NHOH·HCl (149 mg, 2.16 mmol). The resulting mixture was stirred at 90 °C for 12 h. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide as a yellow solid (370 mg, crude). MS calculated: 578.2; MS found: 579.3 [M+H] + .

[0349] Step D: 3-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 109a) To a solution of (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide (220 mg, 0.38 mmol) in THF / DMF (1.5 mL / 1.5 mL) was added TEA (114 mg, 1.14 mmol) and CDI (92 mg, 0.57 mmol). The resulting mixture was stirred at 50°C for 3 hours. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give compound 109a as a white solid (26.48 mg, yield: 78%). MS calculated: 604.2; MS found: 605.3 [M+H] + . 1H NMR (400MHz, DMSO-d6): 8.04 (d, J=1.6Hz, 1H), 7.80 (d, J=8.8Hz, 1H), 7.69 (dd, J=8.4Hz, 1.6Hz, 1H), 7.58-7.65 (m, 1 H), 7.34-7.39(m, 2H), 7.23(dd, J=8.4Hz, 2.0Hz, 1H), 6.82(d, J=7.2Hz, 1H), 6.58(d, J=8.4Hz, 1H), 5.06-5.14(m, 1H) , 4.72-4.84(m, 2H), 4.57-4.63(m, 1H), 4.46-4.52(m, 1H), 4.35-4.41(m, 1H), 4.01(s, 2H), 3.92(d, J=13.2Hz, 1H), 3. 78(d, J=13.6Hz, 1H), 2.65-2.80(m, 3H), 2.37-2.46(m, 1H), 2.20-2.35(m, 2H), 1.80-1.89(m, 2H), 1.47-1.58(m, 2H).

[0350] Example 10: 2-{[4-({6-[(4-chloro-2-fluorophenyl)methyl]pyridin-2-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-(1H-1,2,3,4-tetrazol-5-yl)-1H-1,3-benzodiazole (Compound 110a) [ka] To a solution of (S)-2-((4-((6-(4-chloro-2-fluorobenzyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-isocyano-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (200 mg, 0.37 mmol) in dioxane (3 mL) was added TMSN3 (211 mg, 1.84 mmol) and n-BuSnO (184 mg, 0.74 mmol). The resulting mixture was stirred at 110 °C for 3 hours. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give compound 110a as a white solid (23.15 mg, yield: 78%). MS calculated: 588.2; MS found: 589.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): 8.27(s, 1H), 7.94(dd, J=8.4Hz, 1.6Hz, 1H), 7.85(d, J=8.4Hz, 1H), 7.60(t, J=7.6 Hz, 1H), 7.35-7.41(m, 2H), 7.24(dd, J=8.4Hz, 2.0Hz, 1H), 6.82(d, J=7.2Hz, 1H), 6.58(d, J=8.4Hz, 1H), 5. 05-5.14(m, 1H), 4.72-4.87(m, 2H), 4.60-4.67(m, 1H), 4.48-4.53(m, 1H), 4.37-4.42(m, 1H), 3.95-4.03(m , 3H), 3.86(d, J=13.6Hz, 1H), 2.67-2.87(m, 3H), 2.30-2.49(m, 3H), 1.84-1.94(m, 2H), 1.51-1.63(m, 2H).

[0351] Example 11: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)pyridine-3-carboxamide (Compound 111a) [ka] Step A: tert-butyl (4-fluoro-3-nitrophenyl)carbamate A mixture of 4-fluoro-3-nitroaniline (30 g, 192 mmol), (Boc)2O (50.3 g, 231 mmol), DMAP (2.3 g, 18.85 mmol), and TEA (79.4 mL, 570 mmol) in THF (500 mL) was stirred at 50 °C for 3 hours. After the reaction was complete, the mixture was filtered and concentrated in vacuo to give the crude product. The residue was purified by column chromatography (PE:EA = 5:1) to give tert-butyl (4-fluoro-3-nitrophenyl)carbamate as a yellow solid (41.2 mg, yield: 78%). MS calculated: 256.09; MS observed: 255.1 [MH] - .

[0352] Step B: tert-butyl (S)-(3-nitro-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate A mixture of (S)-oxetan-2-ylmethanamine (12 g, 65.4 mmol), DIEA (21.17 g, 164.07 mmol), and tert-butyl (4-fluoro-3-nitrophenyl)carbamate (14 g, 54.69 mmol) in DMSO (200 mL) was stirred at 70 °C for 16 h. After completion of the reaction, the reaction was quenched with 500 mL of HO. The mixture was then extracted with ethyl acetate (600 mL × 3). The organic layers were combined and dried over NaSO. The mixture was then filtered and concentrated in vacuo to give the crude product. The residue was purified by column chromatography (PE:EA = 3:1) to give tert-butyl (S)-(3-nitro-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate as a red solid (11.8 g, yield: 78%).

[0353] Step C: tert-butyl (S)-(3-amino-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate A mixture of tert-butyl (S)-(3-nitro-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate (11.8 mg, 36.53 mmol) and Pd / C (10% w / w, 1.1 g) in MeOH (120 mL) was stirred at room temperature for 16 hours under H2. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl (S)-(3-amino-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate as a purple solid (14.3 mg, crude). MS calculated: 293.2; MS found: 294.2 [M+H] + .

[0354] Step D: tert-butyl (S)-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate A solution of tert-butyl (S)-(3-amino-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate (13.3 g) and 2-chloroacetic anhydride (7.76 g, 45.37 mmol) in THF (130 mL) was stirred at room temperature for 5 hours. The reaction mixture was then stirred at 60° C. for 12 hours. After completion of the reaction, the mixture was concentrated, and the residue was purified by column chromatography (PE:EA=1:2) to give tert-butyl (S)-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate as a purple oil (14.2 mg, 83% yield). MS calculated: 351.1; MS found: 352.1 [M+H] + .

[0355] Step E: tert-butyl (S)-(2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate To a solution of tert-butyl (S)-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate (518 mg, 1.47 mmol) in DMF (10 mL) was added KCO (608 mg, 4.41 mmol) and 2-(4-chloro-2-fluorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (640 mg). The resulting mixture was stirred at 50° C. for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give tert-butyl (S)-(2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate as a yellow solid (790 mg, yield: 78%). MS calculated: 636.3; MS found: 637.1 [M+H] + .

[0356] Step F: (S)-2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine To a solution of tert-butyl (S)-(2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate (790 mg, 1.24 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give (S)-2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine as a yellow solid (50 mg, crude). MS calculated: 536.2; MS found: 537.2 [M+H] + .

[0357] Step G: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)pyridine-3-carboxamide (Compound 111a) To a solution of (S)-2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine (80 mg, 0.15 mmol) in DMF (2 mL) was added nicotinic acid (27 mg, 0.22 mmol), DIEA (58 mg, 0.45 mmol), and HATU (74 mg, 0.19 mmol). The resulting mixture was stirred at room temperature for 1 hour, and LC-MS showed the reaction was complete. The residue was purified by preparative HPLC to give compound 111a as a white solid (10.99 mg, yield: 78%). MS calculated: 641.2; MS found: 642.5 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 10.41(s, 1H), 9.14(s, 1H), 8.76(d, J=4.0Hz, 1H), 8.40(d, J=6.0Hz, 1H), 8.32(d, J=8.0Hz, 1H), 8.05(s, 1H), 7 .50-7.61(m, 3H), 7.35-7.42(m, 2H), 7.24-7.28(m, 1H), 6.73(d, J=6.0Hz, 1H), 5.06-5.12(m, 1H), 4.84-4.92( m, 1H), 4.64-4.71(m, 1H), 4.47-4.59(m, 2H), 4.32-4.41(m, 1H), 4.15(s, 2H), 3.88(d, J=13.2Hz, 1H), 3.75(d, J=13.6Hz, 1H), 2.65-2.80(m, 3H), 2.38-2.50(m, 1H), 2.20-2.29(m, 2H), 1.85-1.93(m, 2H), 1.54-1.64(m, 2H).

[0358] Example 12: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-methoxypyridine-3-carboxamide (Compound 112a) [ka] The synthesis of 112a was similar to that of compound 111a, except that 6-methoxypyridine-3-carboxylic acid was used instead of pyridine-3-carboxylic acid. Compound 112a was obtained as a white solid (39.39 mg, yield: 78%). MS calculated: 671.2; MS found: 672.3 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 10.21(s, 1H), 8.81(d, J=2.4Hz, 1H), 8.40(d, J=6.0Hz, 1H), 8.26(dd, J=8.8Hz, 2.4Hz, 1H), 8.02(d, J=2.0Hz, 1H), 7.51-7.5 9(m, 2H), 7.37-7.42(m, 2H), 7.25(dd, J=8.0Hz, 2.0Hz, 1H), 6.96(d, J=8.8Hz, 1H), 6.73(d, J=6.0Hz, 1H), 5.05-5.12(m, 1H) , 4.85-4.93(m, 1H), 4.63-4.71(m, 1H), 4.47-4.57(m, 2H), 4.34-4.40(m, 1H), 4.15(s, 2H), 3.94(s, 3H), 3.87(d, J=13.6Hz, 1H), 3.74(d, J=13.6Hz, 1H), 2.65-2.79(m, 3H), 2.37-2.48(m, 1H), 2.20-2.29(m, 2H), 1.84-1.94(m, 2H), 1.54-1.63(m, 2H).

[0359] Example 13: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-methylpyridine-3-carboxamide (Compound 113a) [ka] The synthesis of 113a was similar to that of compound 111a, except that 6-methylpyridine-3-carboxylic acid was used instead of pyridine-3-carboxylic acid. Compound 113a was obtained as a white solid (41.13 mg, yield: 78%). MS calculated: 655.3; MS found: 656.3 [M+H] + . 1H NMR (400MHz, DMSO-d6): 10.32(s, 1H), 9.03(d, J=2.0Hz, 1H), 8.41(d, J=5.6Hz, 1H), 8.23(dd, J=8.4Hz, 2.4Hz, 1H), 8.05( s, 1H), 7.52-7.61(m, 2H), 7.38-7.44(m, 3H), 7.26(dd, J=8.4Hz, 2.0Hz, 1H), 6.74(d, J=5.6Hz, 1H), 5.07-5.13(m, 1H), 4.8 6-4.94(m, 1H), 4.66-4.72(m, 1H), 4.48-4.58(m, 2H), 4.36-4.41(m, 1H), 4.16(s, 2H), 3.89(d, J=13.2Hz, 1H), 3.75(d, J= 13.6Hz, 1H), 2.68-2.80(m, 3H), 2.57(s, 3H), 2.38-2.48(m, 1H), 2.20-2.35(m, 2H), 1.85-1.93(m, 2H), 1.53-1.68(m, 2H).

[0360] Example 14: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-ethylpyridine-3-carboxamide (Compound 114a) [ka] The synthesis of 114a was similar to that of compound 111a, except that 6-ethylpyridine-3-carboxylic acid was used instead of pyridine-3-carboxylic acid. Compound 114a was obtained as a white solid (21.7 mg, yield: 34.8%). MS calculated: 669.3; MS found: 670.4 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 10.32(s, 1H), 9.04(d, J=2.0Hz, 1H), 8.40(d, J=5.6Hz, 1H), 8.23(dd, J=8.4Hz, 2.4Hz, 1H), 8.04(d, J=1.6Hz, 1H), 7.51-7.61( m, 2H), 7.37-7.44(m, 3H), 7.25(dd, J=8.4Hz, 2.0Hz, 1H), 6.73(d, J=5.6Hz, 1H), 5.06-5.12(m, 1H), 4.85-4.91(m, 1H), 4.65-4 .71(m, 1H), 4.47-4.58(m, 2H), 4.34-4.40(m, 1H), 4.15(s, 2H), 3.87(d, J=13.2Hz, 1H), 3.75(d, J=13.6Hz, 1H), 2.84(q, J=7.6 Hz, 2H), 2.64-2.78(m, 3H), 2.39-2.46(m, 1H), 2.20-2.31(m, 2H), 1.85-1.92(m, 2H), 1.52-1.64(m, 2H), 1.27(t, J=7.6Hz, 3H).

[0361] Example 15: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-(2-methoxyethoxy)pyridine-3-carboxamide (Compound 115a) [ka] The synthesis of 115a was similar to that of 111a, except that 6-(2-methoxyethoxy)nicotinic acid was used instead of pyridine-3-carboxylic acid. Compound 115a was finally obtained as a white solid (22.5 mg, yield: 28.1%). MS calculated: 715.3; MS found: 716.5 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 10.21(s, 1H), 8.79(d, J=2.4Hz, 1H), 8.41(d, J=6.0Hz, 1H), 8.26(dd, J=8.8Hz, 2.8Hz, 1H), 8.02(d, J=1.6Hz, 1H), 7.51-7.60(m, 2H), 7.37-7.42(m, 2H), 7.25(dd, J=8.0Hz, 2.0Hz, 1H), 6.96(d, J=8.8Hz, 1H), 6.73(d, J=5.6Hz, 1H), 5.05-5.11(m, 1H), 4.85-4. 91(m, 1H), 4.65-4.70(m, 1H), 4.46-4.57(m, 4H), 4.34-4.40(m, 1H), 4.15(s, 2H), 3.88(d, J=13.6Hz, 1H), 3.75(d, J=13.2Hz, 1H) , 3.68-3.70(m, 2H), 3.31(s, 3H), 2.64-2.78(m, 3H), 2.39-2.49(m, 1H), 2.21-2.31(m, 2H), 1.85-1.92(m, 2H), 1.52-1.63(m, 2H).

[0362] Example 16: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-(propan-2-yl)pyridine-3-carboxamide (Compound 116a) [ka] The synthesis of 116a was similar to that of compound 111a, except that 6-isopropylnicotinic acid was used instead of pyridine-3-carboxylic acid. Compound 116a was finally obtained as a white solid (15.69 mg, yield: 78%). MS calculated: 683.3; MS found: 684.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): 10.32(s, 1H), 9.04(d, J=2.0Hz, 1H), 8.41(d, J=6.0Hz, 1H), 8.23(dd, J=8.4Hz, 2.4Hz, 1H), 8.04(d, J=1.6H) z, 1H), 7.53-7.60(m, 2H), 7.37-7.46, m, 3H), 7.25(dd, J=8.4Hz, 2.0Hz, 1H), 6.73(d, J=5.6Hz, 1H), 5.05-5.133(m, 1H), 4.85-4.93( m, 1H), 4.63-4.72(m, 1H), 4.45-4.59(m, 2H), 4.34-4.40(m, 1H), 4.15(s, 2H), 3.87(d, J=13.6Hz, 1H), 3.75(d, J=13.6Hz, 1H), 3.08- 3.16(m, 1H), 2.64-2.78(m, 3H), 2.39-2.49(m, 1H), 2.21-2.30(m, 2H), 1.87-1.91(m, 2H), 1.52-1.63(m, 2H), 1.28(d, J=6.8Hz, 6H).

[0363] Example 17: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-cyclopropylpyridine-3-carboxamide (Compound 117a) [ka] The synthesis of 117a was similar to that of compound 111a, except that 6-cyclopropylnicotinic acid was used instead of pyridine-3-carboxylic acid. Compound 117a was finally obtained as a white solid (39.34 mg, yield: 78%). MS calculated: 681.3; MS found: 682.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): 10.26(s, 1H), 8.95(d, J=1.6Hz, 1H), 8.40(d, J=6.0Hz, 1H), 8.17(dd, J=8.4Hz, 2.4Hz, 1H), 8.03(s , 1H), 7.50-7.59(m, 2H), 7.37-7.48(m, 3H), 7.25(dd, J=8.0Hz, 1.6Hz, 1H), 6.73(d, J=6.0Hz, 1H), 5.05-5.11(m, 1H), 4.83- 4.93(m, 1H), 4.62-4.71(m, 1H), 4.45-4.59(m, 2H), 4.32-4.39(m, 1H), 4.15(s, 2H), 3.88(d, J=13.6Hz, 1H), 3.74(d, J=14.0 Hz, 1H), 2.66-2.81(m, 3H), 2.35-2.49(m, 1H), 2.18-2.32(m, 3H), 1.84-1.92(m, 2H), 1.52-1.64(m, 2H), 1.00-1.07(m, 4H).

[0364] Example 18: 2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-[(1E)-2-(pyridin-3-yl)ethenyl]-1H-1,3-benzodiazole (Compound 118a) [ka] Step A: (S)-4-iodo-2-nitro-N-(oxetan-2-ylmethyl)aniline To a solution of 1-fluoro-4-iodo-2-nitrobenzene (1 g, 3.75 mmol) and (S)-oxetan-2-ylmethanamine MsOH salt (820 mg, 4.48 mmol) in DMSO (10 mL) was added DIEA (1.44 g, 11.2 mmol) at room temperature. The reaction was stirred at 70 °C for 3 hours. After completion of the reaction, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give (S)-4-iodo-2-nitro-N-(oxetan-2-ylmethyl)aniline as a yellow solid (1.3 g, 96% yield). MS calculated: 334.0; MS found: 334.9 [M+H] + .

[0365] Step B: (S)-4-iodo-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine NiCl (543 mg, 4.20 mmol) was added to a solution of (S)-4-iodo-2-nitro-N-(oxetan-2-ylmethyl)aniline (700 mg, 2.10 mmol) in MeOH (10 mL) at 0 °C. Then, NaBH (238 mg, 6.3 mmol) was added slowly. After the reaction was completed, it was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give (S)-4-iodo-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine as a yellow solid (540 mg, 85% yield). MS calculated: 304.0; MS found: 305.0 [M+H] + .

[0366] Step C: (S)-2-(chloromethyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole To a solution of (S)-4-iodo-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (440 mg, 1.45 mmol) in THF (5 mL) was added 2-chloroacetic anhydride (270 mg, 1.59 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS, which showed that the starting material was consumed. The reaction was then stirred at 60°C for 16 hours. After the reaction was complete, the reaction was filtered and concentrated to give the crude product, which was purified by column chromatography to give (S)-2-(chloromethyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole as a yellow oil (530 mg, crude, 80% purity). MS calculated: 362.0; MS found: 362.8 [M+H] + .

[0367] Step D: (S)-2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole A mixture of 2-(4-chloro-2-fluorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (115 mg), (S)-2-(chloromethyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (106 mg, 0.292 mmol), and K2CO3 (121 mg, 0.876 mmol) in DMSO (4.0 mL) was stirred at 60 °C for 3 h. After cooling, the mixture was diluted with HO (50 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with brine (25 mL × 1), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to give (S)-2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole as a white solid (90 mg, yield: 47.6%). MS calculated: 647.1; MS found: 648.5 [M+H] + .

[0368] Step E: 2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-[(1E)-2-(pyridin-3-yl)ethenyl]-1H-1,3-benzodiazole (Compound 118a) A solution of (E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyridine (48 mg, 0.209 mmol), Pd(dppf)Cl (5.0 mg, 0.007 mmol), KCO (29 mg, 0.209 mmol), HO (1.0 mL), and (S)-2-((4-((2-(4-chloro-2-fluorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (45 mg, 0.070 mmol) in dioxane (4.0 mL) was stirred at 100° C. for 18 h under an Ar atmosphere. After cooling, the solid was filtered and washed with EA. The filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give compound 118a as a white solid (8.3 mg). MS calculated: 624.2; MS found: 625.2 [M+H] + . 1 H NMR (400MHz, MeOD):δ 9.01(s, 1H), 8.79(d, J=8.4Hz, 1H), 8.66(d, J=5.2Hz, 1H), 8.44(d, J=6.0Hz, 1H), 8.0 2-7.98(m, 2H), 7.81-7.70(m, 3H), 7.42-7.32(m, 2H), 7.22-7.15(m, 2H), 6.80(d, J=6 .0Hz, 1H), 5.31-5.19(m, 2H), 4.79(s, 2H), 4.76-4.60(m, 3H), 4.47-4.40(m, 1H), 4.2 1(s, 2H), 3.62-3.45(m, 4H), 2.84-2.75(m, 1H), 2.56-2.47(m, 1H), 2.23-2.03(m, 4H).

[0369] Example 19: N-(2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl)-6-phenylpyridine-3-carboxamide (Compound 119a) [ka] The synthesis of 119a was similar to that of compound 111a, except that 6-phenylnicotinic acid was used instead of pyridine-3-carboxylic acid. Compound 119a was obtained as a white solid (30.47 mg, yield: 78%). MS calculated: 717.3; MS found: 718.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 10.43(s, 1H), 9.22(d, J=2.0Hz, 1H), 8.40-8.44(m, 2H), 8.13-8.21(m, 3H), 8.08(s, 1H), 7 .50-7.62(m, 5H), 7.38-7.43(m, 2H), 7.25(dd, J=8.0Hz, 1.6Hz, 1H), 6.74(d, J=5.6Hz, 1H), 5.06-5.13(m, 1H), 4.85 -4.93(m, 1H), 4.64-4.72(m, 1H), 4.47-4.59(m, 2H), 4.33-4.41(m, 1H), 4.15(s, 2H), 3.89(d, J=13.6Hz, 1H), 3.75 (d, J=13.2Hz, 1H), 2.65-2.83(m, 3H), 2.38-2.49(m, 1H), 2.20-2.32(m, 2H), 1.83-1.94(m, 2H), 1.53-1.66(m, 2H).

[0370] Example 20: 2-[(4-chlorophenyl)methyl]-4-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyrimidine (Compound 120a) [ka] Step A: 6-hydroxy-5-nitronicotinamide To a solution of 6-hydroxy-5-nitronicotinic acid (5 g, 27.2 mmol) in DMF (25 mL) was added CDI (4.85 g, 29.9 mmol) at room temperature. The reaction was stirred at 50 °C for 2 h. Ammonia (35 mL, 25%-28% w / w aqueous solution) was then added, and the reaction was stirred at room temperature for 1 h. The reaction mixture was filtered and washed with water. The solid was dried to give 6-hydroxy-5-nitronicotinamide as a yellow solid (4.2 g, crude, 86% yield).

[0371] Step B: 6-chloro-5-nitronicotinonitrile 6-Hydroxy-5-nitronicotinamide (4.2 g, 23.0 mmol) was dissolved in POCl3 (40 mL). The reaction was stirred at 120 °C for 8 hours. The reaction was concentrated under reduced pressure to give the crude product. The crude product was dissolved in ethyl acetate (100 mL) and washed with NaHCO3 solution. The organic layer was washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to give 6-chloro-5-nitronicotinonitrile as a yellow solid (2.7 g, 64% yield).

[0372] Step C: (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinonitrile To a solution of 6-chloro-5-nitronicotinonitrile (1 g, 5.5 mmol) and (S)-oxetan-2-ylmethanamine MsOH salt (1.2 g, 6.5 mmol) in DMSO (10 mL) was added DIEA (2.11 g, 16.5 mmol) at room temperature. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 3:1) to give (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile as an orange solid (1.4 g, crude). MS calculated: 234.1; MS found: 235.1 [M+H] + .

[0373] Step D: (S)-N'-hydroxy-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinimidamide To a solution of (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile (1.4 g, 6.0 mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (2.06 g, 30.0 mmol) and TEA (3.6 g, 36.0 mmol). The reaction was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give (S)-N'-hydroxy-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinimidamide as a yellow solid (1.1 g, 69% yield). MS calculated: 267.1; MS found: 268.1 [M+H] + .

[0374] Step E: (S)-3-nitro-N-(oxetan-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine To a solution of (S)-N'-hydroxy-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinimidamide (1.0 g, 3.7 mmol) in THF (10 mL) was added TFAA (3.14 g, 14.8 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with NaHCO3 solution (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 5:1) to give (S)-3-nitro-N-(oxetan-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine as a yellow solid (1.0 g, 76% yield). MS calculated: 345.1; MS found: 346.1 [M+H] + .

[0375] Step F: (S)—N2-(oxetan-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridine-2,3-diamine To a solution of (S)-3-nitro-N-(oxetan-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (950 mg, 2.75 mmol) in THF / HO (10 mL / 1 mL) was added Zn (1.8 g, 27.5 mmol), NHCl (2.9 g, 55.0 mmol), and CHCOOH (0.5 mL). The reaction was stirred at 70 °C for 2 hours. After completion of the reaction, the reaction was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=1:1) to give (S)-N-(oxetan-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridine-2,3-diamine as a yellow solid (600 mg, 69% yield). MS calculated: 315.1; MS found: 316.1 [M+H] + .

[0376] Step G: (S)-3-(2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of (S)-N2-(oxetan-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridine-2,3-diamine (600 mg, 1.9 mmol) in THF (6 mL) was added 2-chloroacetic anhydride (356 mg, 2.1 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. Then, the reaction was stirred at 60° C. for 16 hours. After the reaction was complete, the reaction was concentrated in vacuo. The residue was purified by column chromatography (PE:EA=2:1) ​​to give (S)-3-(2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole as a yellow solid (440 mg, 62% yield). MS calculated: 373.1; MS found: 374.0 [M+H] + .

[0377] Step H: (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (145 mg) in DMF (2 mL) was added K2CO3 (111 mg, 0.804 mmol). After several minutes, (S)-3-(2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (100 mg, 0.268 mmol) was added. The resulting mixture was heated at 60 °C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column eluting with DCM:MeOH=20:1 to give (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole as a white solid (100 mg, 58.5% yield). MS calculated: 640.2; MS found: 641.3 [M+H] + .

[0378] Step I: 2-[(4-chlorophenyl)methyl]-4-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyrimidine (Compound 120a) To a solution of (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (100 mg, 0.156 mmol) in DMF (2 mL) was added hydrazine hydrate (0.1 mL, 85 wt%). The solution was heated at 60° C. for 30 minutes. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to give compound 120a as a white solid (18.6 mg, yield: 18.6%). MS calculated: 639.2; MS found: 640.3 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 15.42(brs, 1H), 9.00(d, J=2.0Hz, 1H), 8.61(d, J=1.6Hz, 1H), 8.42(d, J=6.0Hz, 1H), 7. 31-7.36(m, 4H), 6.73(d, J=6.0Hz, 1H), 5.14-5.21(m, 1H), 5.01-5.10(m, 1H), 4.80-4.8 8(m, 1H), 4.68-4.74(m, 1H), 4.47-4.53(m, 1H), 4.32-4.39(m, 1H), 4.08(s, 2H), 3.92-4 .06(m, 2H), 2.66-2.88(m, 3H), 2.34-2.55(m, 3H), 1.91-2.01(m, 2H), 1.61-1.74(m, 2H).

[0379] Example 21: 2-[(4-chlorophenyl)methyl]-5-fluoro-4-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyrimidine (Compound 121a) [ka] 2-(4-chlorobenzyl)-5-fluoro-4-(piperidin-4-yloxy)pyrimidine (223 mg), (S)-3-(2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (160 mg, 0.429 mmol), and KCO 3(1 A solution of a mixture of 121a (77.6 mg, 1.287 mmol) in DMF (3 mL) was heated at 60° C. for 2 hours. Then, hydrazine hydrate (0.1 mL, 85 wt %) was added. The reaction mixture was stirred at 60° C. for 30 minutes. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to give compound 121a as a white solid (32.33 mg, yield: 11.4%). MS calculated: 657.2; MS found: 658.3 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 8.97(d, J=2.0Hz, 1H), 8.50(d, J=2.8Hz, 1H), 8.41(d, J=1.6Hz, 1H), 7.31-7.3 7(m, 4H), 5.07-5.20(m, 2H), 4.76-4.81(m, 1H), 4.63-4.71(m, 1H), 4.45-4.53 (m, 1H), 4.34-4.40(m, 1H), 4.09(s, 2H), 3.88-3.96(m, 2H), 2.65-2.82(m, 3H) , 2.47-2.54(m, 1H), 2.38-2.45(m, 2H), 1.93-2.02(m, 2H), 1.65-1.77(m, 2H).

[0380] Example 22: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-6-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-1,3-benzodiazole (Compound 122a) [ka] Step A: (S)-2-Fluoro-5-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile At 0°C, (S)-oxetan-2-ylmethanamine MsOH salt (2.69 g, 14.7 mmol) and DIEA (6 g, 49 mmol) were added successively to a solution of 2,4-difluoro-5-nitrobenzonitrile (3 g, 6.3 mmol) in THF (30 mL). The reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give (S)-2-fluoro-5-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile as a yellow solid (2.1 g, 70% yield). MS calculated: 251.1; MS found: 251.9 [M+H] + .

[0381] Step B: (S)-5-amino-2-fluoro-4-((oxetan-2-ylmethyl)amino)benzonitrile To a solution of (S)-2-fluoro-5-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile (2.1 g, 8.4 mmol) and Zn (5.5 g) in MeOH (21 mL) was added AcOH (1.51 g) at room temperature. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction mixture was filtered and washed with solid NaHCO (aq). The filtrate was quenched with HO and extracted with EA (20 mL × 3). The organic layers were combined, dried over NaSO, and concentrated to give (S)-5-amino-2-fluoro-4-((oxetan-2-ylmethyl)amino)benzonitrile as a yellow solid (1.8 g, 85.7% yield). MS calculated: 221.1; MS found: 222.1 [M+H] + .

[0382] Step C: (S)-2-chloro-N-(5-cyano-4-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide To a solution of (S)-5-amino-2-fluoro-4-((oxetan-2-ylmethyl)amino)benzonitrile (1.8 g, 8.14 mmol) in THF (18 mL) was added 2-chloroacetic anhydride (1.7 g, 9.77 mmol). The reaction was stirred at 30° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give (S)-2-chloro-N-(5-cyano-4-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide as a yellow oil (610 mg, 30% yield). MS calculated: 297.1; MS found: 298.1 [M+H] + .

[0383] Step D: (S)-2-(4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-N-(5-cyano-4-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide To a mixture of 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (1.2 g, 3.83 mmol) in DMF (20 mL) was added KCO (1.6 g, 11.49 mmol), (S)-2-chloro-N-(5-cyano-4-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide (910 mg, 3.06 mmol), and the mixture was heated at 50° C. for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM / MeOH=30 / 1) to give (S)-2-(4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-N-(5-cyano-4-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide as a yellow solid (1.42 g, yield: 78%). MS calculated: 564.2; MS found: 565.2 [M+H] + .

[0384] Step E: Synthesis of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile To a solution of (S)-2-(4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-N-(5-cyano-4-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)acetamide (1.3 g, 2.3 mmol) in MeOH (20 mL) was added 2 M NaOH (4.6 mL) and the mixture was stirred at 50° C. for 3 h. The reaction was quenched with water and extracted with DCM / MeOH (20 / 1), the organic layers were combined, dried over NaSO, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM / MeOH=30 / 1) to give (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile as a yellow solid (810 mg, yield: 78%). MS calculated: 546.2; MS found: 547.2 [M+H] + .

[0385] Step F: (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile (760 mg, 1.4 mmol) in EtOH (10 mL) was added NHOH (50% in HO) (230 mg, 7.0 mmol), and the resulting mixture was stirred at 70 °C for 5 h. The reaction was quenched with water and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated to give (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide as a white solid (810 mg). The crude product was used in the next step without further purification. MS calculated: 579.2; MS found: 580.2 [M+H] + .

[0386] Step G: (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboximidamide (400 mg) in THF (8.0 mL) was added TFAA (435 mg, 2.07 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with DCM / MeOH (20 / 1). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM / MeOH=30 / 1) to give (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole as a white solid (400 mg, yield: 78%). MS calculated: 657.2; MS found: 658.2 [M+H] + .

[0387] Step H: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-6-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-1,3-benzodiazole (Compound 122a) To a solution of (S)-3-(2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (170 mg, 0.26 mmol) in DMF (3 mL) was added NH2NH2·HO (26 mg, 0.52 mmol), and the resulting mixture was stirred at 40 °C for 2 h. The mixture was purified by preparative HPLC to give 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-6-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-1,3-benzodiazole as a white solid (37.37 mg, yield: 78%). MS calculated: 656.2; MS found: 657.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 8.41 (d, J=5.6Hz, 1H), 8.08 (d, J=6.4Hz, 1H), 7.66 (d, J=7.2Hz, 1H) , 7.30-7.37(m, 4H), 6.73(d, J=6.0Hz, 1H), 5.07-5.13(m, 1H), 4.98-5.07(m, 1H), 4.69-4.76 (m, 1H), 4.48-4.60(m, 2H), 4.39-4.44(m, 1H), 4.08(s, 2H), 3.91(d, J=14.0Hz, 1H), 3.77(d, J=13.6Hz, 1H), 2.66-2.81(m, 3H), 2.30-2.49(m, 3H), 1.89-1.97(m, 2H), 1.58-1.70(m, 2H).

[0388] Example 23: 2-[(4-chlorophenyl)methyl]-4-[(1-{[3-(2-ethoxyethyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl}piperidin-4-yl)oxy]pyrimidine (Compound 123) [ka] Step A: 6-((2-ethoxyethyl)amino)-5-nitronicotinonitrile To a solution of 6-chloro-5-nitronicotinonitrile (1.0 g, 5.45 mmol) and 2-ethoxyethan-1-amine (514 mg, 5.78 mmol) in DMSO (15 mL) was added DIEA (2.1 g, 16.38 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give 6-((2-ethoxyethyl)amino)-5-nitronicotinonitrile as a yellow solid (1.1 g, 73% yield). MS calculated: 236.1; MS found: 237.1 [M+H] + .

[0389] Step B: 6-((2-ethoxyethyl)amino)-N'-hydroxy-5-nitronicotine imidamide To a solution of 6-((2-ethoxyethyl)amino)-5-nitronicotinonitrile (1 g, 4.2 mmol) and NHOH·HCl (1.75 g, 25.2 mmol) in EtOH (10 mL) was added TEA (4.2 g, 42 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. After the reaction was complete, the reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over NaSO, and concentrated to give 6-((2-ethoxyethyl)amino)-N'-hydroxy-5-nitronicotinimidamide as a yellow solid (1 g, 88% yield). MS calculated: 269.1; MS found: 270.1 [M+H] + .

[0390] Step C: N-(2-ethoxyethyl)-3-nitro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine A solution of 6-((2-ethoxyethyl)amino)-N'-hydroxy-5-nitronicotinimidamide (1 g, 3.7 mmol) and TFAA (3.9 g, 18.6 mmol) in THF (10 mL) was stirred at room temperature for 30 minutes. After the reaction was completed, the residue was quenched with HO and extracted with EA (20 mL × 3). The organic layers were combined, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give N-(2-ethoxyethyl)-3-nitro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine as a yellow solid (1.3 g, 95% yield). MS calculated: 347.1; MS found: 348.1 [M+H] + .

[0391] Step D: N2-(2-ethoxyethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridine-2,3-diamine To a mixture of N-(2-ethoxyethyl)-3-nitro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (1.2 g, 3.46 mmol) and Zn (1.12 g, 17.3 mmol) in THF (12 mL) was added NH4Cl (1.85 g, 34.6 mmol) and 6 drops of AcOH. The reaction was stirred at 60 °C for 2 h. After the reaction was complete, the reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated to give N2-(2-ethoxyethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridine-2,3-diamine as a brown solid (1 g, 83% yield). MS calculated: 317.1; MS found: 318.1 [M+H] +

[0392] Step E: 3-(2-(chloromethyl)-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N2-(2-ethoxyethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridine-2,3-diamine (500 mg) in dioxane (5 mL) was added 2-chloroacetic anhydride (323 mg, 1.89 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was stirred at 60° C. for 12 hours. The reaction was quenched with HO and extracted with EA (5 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give 3-(2-(chloromethyl)-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole as a yellow oil (630 mg, yield: 78%). MS calculated: 375.1; MS found: 376.1 [M+H] +。

[0393] Step F: 2-[(4-chlorophenyl)methyl]-4-[(1-{[3-(2-ethoxyethyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl}piperidin-4-yl)oxy]pyrimidine (Compound 123) To a solution of 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (320 mg, 1.06 mmol) and K2CO3 (220 mg, 1.59 mmol) in DMF (2 mL) was added 3-(2-(chloromethyl)-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (200 mg, 0.53 mmol). The reaction was stirred at 60 °C for 2 h. NH2NH2·HO (80 mg, 1.59 mmol) was added, and the mixture was stirred at 60 °C for 0.5 h. The reaction mixture was purified by preparative HPLC to give compound 123 as a white solid (7.85 mg, yield: 78%). MS calculated: 641.2; MS found: 642.4 [M+H] +。 1H NMR (400MHz, DMSO-d6):δ 8.99(d, J=2.0Hz, 1H), 8.57(d, J=2.0Hz, 1H), 8.41(d, J=6.0Hz, 1H), 7.31-7.36 (m, 4H), 6.73(d, J=5.6Hz, 1H), 4.98-5.06(m, 1H), 4.63(t, J=5.6Hz, 2H), 4.08(s , 2H), 3.92(s, 2H), 3.81(t, J=5.6Hz, 2H), 3.40-3.47(m, 2H), 2.70-2.79(m, 2H), 2.30-2.43(m, 2H), 1.91-1.98(m, 2H), 1.60-1.70(m, 2H), 1.04(t, J=6.8Hz, 3H).

[0394] Example 24: 3-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 144a) [ka] Step A: (S)-5-amino-6-((oxetan-2-ylmethyl)amino)nicotinonitrile A mixture of (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinonitrile (3.0 g, 12.8 mmol), Fe (3.6 g, 64.1 mmol), and NHCl (6.9 g, 128.2 mmol) in EtOH (60 mL) and water (20 mL) was stirred at 80 °C for 1 h. The mixture was poured into cold water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated to give (S)-5-amino-6-((oxetan-2-ylmethyl)amino)nicotinonitrile as a white solid (2.4 g, 78% yield). MS calculated: 204.1; MS found: 205.3 [M+H]. + .

[0395] Step B: (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile To a solution of (S)-5-amino-6-((oxetan-2-ylmethyl)amino)nicotinonitrile (2.4 g) in THF (20 mL) was added 2-chloroacetic anhydride (2.0 g, 11.7 mmol). The mixture was stirred at room temperature for 2 h. The mixture was then stirred at 60 °C for 16 h. Additional 2-chloroacetic anhydride was then added, and the mixture was stirred at 60 °C for another 16 h. The mixture was poured into aqueous sodium bicarbonate (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was purified by column chromatography on silica gel to give (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile as a yellow oil (1.1 g, yield: 78%). MS calculated: 262.1; MS found: 263.1 [M+H] + .

[0396] Step C: (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile To a solution of 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (526 mg, 1.7 mmol) in DMF (5 mL) were added TEA (345 mg, 3.4 mmol) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (150 mg, 0.57 mmol). The resulting mixture was stirred at 50 °C for 2 h. After the reaction was complete, the mixture was diluted with EA (50 mL) and washed with HO (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=1 / 50) to give (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile as a yellow oil. MS calculated: 529.2; MS found: 530.2 [M+H] + .

[0397] Step D: (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (150 mg, 0.3 mmol) in EtOH (4 mL) was added TEA (114 mg, 1.1 mmol) and NH2OH HCl (116.76 mg, 1.68 mmol). The resulting mixture was stirred at 90 °C for 1 h. After the reaction was complete, the mixture was diluted with EA (30 mL) and washed with HO (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The reaction mixture was concentrated to give (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide as a yellow solid (130 mg, crude). MS calculated: 562.2; MS found: 563.1 [M+H] + .

[0398] Step E: 3-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one To a solution of (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide (100 mg, 0.18 mmol) in THF (2 mL) was added TEA (54 mg, 0.54 mmol) and CDI (43.24 mg, 0.27 mmol). The resulting mixture was stirred at 70 °C for 3 h. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give 3-(2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one Compound 144a as a white solid (29 mg, yield: 78%). MS calculated: 588.2; MS found: 589.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6):δ 8.77(d, J=1.6Hz, 1H), 8.41(d, J=6.0Hz, 1H), 8.35(d, J=2.0Hz, 1H), 7.30-7.37(m , 4H), 6.73(d, J=5.6Hz, 1H), 5.12-5.20(m, 1H), 4.97-5.10(m, 1H), 4.77-4.85(m, 1 H), 4.65-4.73(m, 1H), 4.45-4.52(m, 1H), 4.31-4.38(m, 1H), 4.08(s, 2H), 3.95(s , 2H), 2.62-2.80(m, 3H), 2.33-2.51(m, 3H), 1.90-1.98(m, 2H), 1.60-1.60(m, 2H).

[0399] Example 25: 2-[(4-chlorophenyl)methyl]-6-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyridine (Compound 143a) [ka] Starting from 2-(4-chlorobenzyl)-6-(piperidin-4-yloxy)pyridine and using a method similar to that for compound 120a, 2-[(4-chlorophenyl)methyl]-6-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyridine Compound 143a was obtained as a white solid (37 mg). MS calculated: 638.2; MS found: 639.4 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 8.99(d, J=2.0Hz, 1H), 8.56(d, J=2.0Hz, 1H), 7.59(dd, J=8.4, 7.6Hz, 1H), 7.29-7.38(m, 4H), 6.8 2(d, J=7.2Hz, 1H), 6.58(d, J=8.0Hz, 1H), 5.15-5.21(m, 1H), 4.92-5.00(m, 1H), 4.81-4.86(m, 1H) ), 4.68-4.75(m, 1H), 4.47-4.53(m, 1H), 4.34-4.40(m, 1H), 3.90-4.00(m, 4H), 2.72-2.83(m, 2H) , 2.65-2.72(m, 1H), 2.45-2.54(m, 1H), 2.34-2.43(m, 2H), 1.90-1.97(m, 2H), 1.55-1.70(m, 2H). 19 F-NMR(377MHz):-62.99.

[0400] Example 26: 2-[(4-chloro-2-fluorophenyl)methyl]-4-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyrimidine (Compound 142a) [ka] Starting from 2-(4-chloro-2-fluorobenzyl)-4-(piperidin-4-yloxy)pyrimidine hydrochloride, a similar method to that for compound 120a was used to obtain 2-[(4-chloro-2-fluorophenyl)methyl]-4-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyrimidine compound 142a as a white solid (9 mg). MS calculated: 657.2; MS found: 658.7 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 15.41(brs, 1H), 8.99(d, J=1.6Hz, 1H), 8.59(d, J=1.6Hz, 1H), 8.41(d, J=6.0Hz, 1H), 7.35-7 .42(m, 2H), 7.21-7.26(m, 1H), 6.73(d, J=5.6Hz, 1H), 5.14-5.21(m, 1H), 4.79-4.92(m, 2H), 4.68-4.73(m, 1H), 4.46-4.52(m, 1H), 4.32-4.40(m, 1H), 4.15(s, 2H), 3.90-4.00(m, 2H), 2. 65-2.81(m, 3H), 2.42-2.54(m, 1H), 2.27-2.37(m, 2H), 1.85-1.93(m, 2H), 1.55-1.70(m, 2H). 19 F-NMR (377MHz): -63.64, -114.06.

[0401] Example 27: 2-[(4-chloro-2-fluorophenyl)methyl]-6-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyridine (Compound 141a) [ka] Starting from 2-(4-chloro-2-fluorobenzyl)-6-(piperidin-4-yloxy)pyridine hydrochloride, a similar method to that for compound 120a was used to obtain 2-[(4-chloro-2-fluorophenyl)methyl]-6-({1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}oxy)pyridine Compound 141a as a white solid (20 mg). MS calculated: 656.2; MS found: 657.4 [M+H] + . 1H NMR (400MHz, DMSO-d6):δ 15.38(brs, 1H), 8.99(d, J=1.6Hz, 1H), 8.60(d, J=2.0Hz, 1H), 7.60(t, J=8.4Hz, 1H), 7.34-7.40(m, 2 H), 7.23(dd, J=8.4Hz, 2.0Hz, 1H), 6.82(d, J=7.2Hz, 1H), 6.58(d, J=8.0Hz, 1H), 5.14-5.22(m, 1H), 4. 80-4.88(m, 2H), 4.68-4.75(m, 1H), 4.47-4.53(m, 1H), 4.33-4.40(m, 1H), 4.01(s, 2H), 3.90-4.00(m , 2H), 2.65-2.82(m, 3H), 2.43-2.55(m, 1H), 2.27-2.36(m, 2H), 1.83-1.92(m, 2H), 1.50-1.64(m, 2H). 19 F-NMR (377MHz): -63.65, -114.57.

[0402] Example 28: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-5-(3-methyl-1H-pyrazol-5-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole (Compound 131a) [ka] Step A: (S)-4-Bromo-2-nitro-N-(oxetan-2-ylmethyl)aniline A mixture of 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.4 mmol), (S)-oxetan-2-ylmethanamine methanesulfonic acid (14.1 g, 77.0 mmol), and DIEA (17.5 g, 136.3 mmol) in DMSO (100 mL) was stirred at 70 °C for 5 h. After the reaction was complete, the mixture was diluted with EA (50 mL × 3) and washed with HO (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 5 / 1) to give (S)-4-bromo-2-nitro-N-(oxetan-2-ylmethyl)aniline as a red solid (11.5 g, 98% yield). MS calculated: 286.0; MS found: 287.0 [M+H]. + .

[0403] Step B: (S)-4-Bromo-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine To a solution of (S)-4-bromo-2-nitro-N-(oxetan-2-ylmethyl)aniline (5.0 g, 17.5 mmol) in MeOH (100 mL) was added NiCl (4.5 g, 34.9 mmol), and the resulting mixture was stirred at 0 °C for 20 min, followed by the addition of NaBH (2.0 g, 52.4 mmol). The resulting mixture was stirred at 0 °C for 30 min, quenched with water (200 mL), and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over NaSO. The residue was purified by column chromatography on silica gel (PE / EA = 3 / 1) to give (S)-4-bromo-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine as a yellow solid (3.0 g, 67% yield). MS calculated: 256.0; MS found: 257.0 [M+H].

[0404] Step C: (S)-5-Bromo-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole A solution of (S)-4-bromo-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (3.0 g, 11.7 mmol) and 2-chloroacetic anhydride (2.4 g, 14.1 mmol) in dioxane (30 mL) was stirred at room temperature for 3 hours, then at 60 °C for 16 hours. The reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (70 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column silica gel chromatography (PE / EA = 3 / 1) to give (S)-5-bromo-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole as a yellow solid (2.8 g, 71% yield). MS calculated: 314.0; MS found: 315.0 [M+H]. + .

[0405] Step D: (S)-5-bromo-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole To a mixture of (S)-5-bromo-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (500 mg, 1.6 mmol) in DMF (10 mL) was added K2CO3 (2.1 g, 15.9 mmol) and 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (1.0 g, 3.3 mmol). The resulting mixture was heated at 60 °C for 5 h. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (70 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA=1 / 1) to give (S)-5-bromo-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole as a yellow oil (1.0 g, 95% yield). MS calculated: 581.2; MS found: 582.1 M+H. + .

[0406] Step E: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-5-(3-methyl-1H-pyrazol-5-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole A solution of (S)-5-bromo-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (50 mg, 0.085 mmol), Pd(dppf)Cl·DCM (7 mg, 0.008 mmol), KOAc (25 mg, 0.26 mmol), DPPF (1.3 mg, 0.004 mmol), and (3-methyl-1H-pyrazol-5-yl)boronic acid (21 mg, 0.17 mmol) in DMF (2 mL) was stirred at 80 °C for 4 h under N2. After the reaction was completed, the reaction mixture was directly purified by preparative HPLC to give 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-5-(3-methyl-1H-pyrazol-5-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole Compound 131a as a white solid (3.0 mg, yield 5%). MS calculated: 583.2; MS found: 584.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6):δ 8.41(d, J=5.6Hz, 1H), 7.92(s, 1H), 7.59-7.65(m, 2H), 7.30-7.38(m, 4H), 6.73(d, J=6.0Hz, 1 H), 6.43(s, 1H), 4.98-5.12(m, 2H), 4.66-4.72(m, 1H), 4.53-4.60(m, 1H), 4.46-4.53(m, 1H), 4 .35-4.41(m, 1H), 4.08(s, 2H), 3.90(d, J=13.6Hz, 1H), 3.76(d, J=13.2Hz, 1H), 2.65-2.80(m, 3H), 2.40-2.50(m, 1H), 2.30-2.40(m, 2H), 2.25(s, 3H), 1.88-1.97(m, 2H), 1.55-1.69(m, 2H).

[0407] Example 29: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-5-carboxylic acid (Compound 134a) [ka] Step A: Methyl (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzoate To a solution of methyl 4-fluoro-3-nitrobenzoate (500 mg, 2.5 mmol) and (S)-oxetan-2-ylmethanamine MsOH salt (460 mg, 2.5 mmol) in ACN (10 mL) was added CsCO (2.45 g, 7.5 mmol) at room temperature. The reaction was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give methyl (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzoate as an orange solid (500 mg, 72% yield). MS calculated: 266.1; MS found: 267.3 [M+H] + .

[0408] Step B: Methyl (S)-3-amino-4-((oxetan-2-ylmethyl)amino)benzoate To a solution of methyl (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzoate (100 mg, 0.14 mmol) in MeOH (2 mL) was added Pd / C (20 mg, 50 wt%). The reaction vessel was purged with H2 three times, and the reaction was stirred under H2 (15 psi) at room temperature for 1 h. After completion of the reaction, the reaction was filtered and concentrated under reduced pressure to give methyl (S)-3-amino-4-((oxetan-2-ylmethyl)amino)benzoate as a colorless oil (100 mg, crude). MS calculated: 236.1; MS found: 237.0 [M+H] + .

[0409] Step C: Methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate To a solution of methyl (S)-3-amino-4-((oxetan-2-ylmethyl)amino)benzoate (100 mg, crude) in THF (3 mL) was added 2-chloroacetic anhydride (79.7 mg, 0.47 mmol). The reaction was stirred at room temperature for 1 hour and then at 80° C. for 72 hours. After completion of the reaction, the reaction was concentrated and purified by column chromatography to give methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate as a gray solid (50 mg, 40% yield, 2 steps). MS calculated: 294.1; MS found: 295.1 [M+H] + .

[0410] Step D: Methyl (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate To a solution of 2-(4-chlorobenzyl)-4-(piperidin-4-yloxy)pyrimidine (409 mg) in DMF (2 mL) was added DIEA (133 mg, 1.02 mmol) and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (100 mg, 0.340 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours, quenched with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (10 mL × 5), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH=10 / 1) to give methyl (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate as a yellow oil (80 mg, 42.1% yield). MS calculated: 561.2. MS found: 562.2 [M+H] + .

[0411] Step E: 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-5-carboxylic acid (Compound 134a) To a solution of methyl (S)-2-((4-((2-(4-chlorobenzyl)pyrimidin-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (60 mg, 0.107 mmol) in MeOH (1 mL) and HO (0.1 mL) was added NaOH (5 mg, 0.125 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was directly purified by preparative HPLC to give 2-{[4-({2-[(4-chlorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-5-carboxylic acid, compound 134a, as a white solid (6.54 mg, 11.2% yield). MS calculated: 547.2; MS found: 548.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6):δ 8.40(d, J=6.0Hz, 1H), 8.04(s, 1H), 7.77(dd, J=8.4Hz, J=1.6Hz, 1H), 7.40(d, J=8.40Hz, 1H) , 7.31-7.38(m, 4H), 6.73(d, J=6.0Hz, 1H), 4.95-5.13(m, 2H), 4.68-4.73(m, 1H), 4.45-4.60 (m, 2H), 4.34-4.40(m, 1H), 4.08(s, 2H), 3.89(d, J=13.2Hz, 1H), 3.75(d, J=13.6Hz, 1H), 2.6 4-2.80(m, 3H), 2.38-2.53(m, 1H), 2.28-2.38(m, 2H), 1.87-1.97(m, 2H), 1.55-1.70(m, 2H).

[0412] Example 30: 2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-5-carboxylic acid (Compound 135a) [ka] Using a similar method to compound 134a, 2-{[4-({2-[(4-chloro-2-fluorophenyl)methyl]pyrimidin-4-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-5-carboxylic acid, compound 135a, was obtained as a white solid (83 mg). MS calculated: 565.2; MS found: 566.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6):δ 8.48(d, J=6.0Hz, 1H), 8.39(d, J=0.8Hz, 1H), 7.91(dd, J=8.4Hz, J=1.6Hz, 1H), 7.79-7.83(m, 1H), 7 .37-7.45(m, 2H), 7.25(dd, J=8.0Hz, J=1.6Hz, 1H), 6.81(d, J=6.0Hz, 1H), 5.12-5.23(m, 1H), 5.00- 5.07(m, 1H), 4.78-4.94(m, 3H), 4.64-4.71(m, 1H), 4.46-4.53(m, 1H), 4.30-4.38(m, 1H), 4.17(s, 2) H), 3.35-3.65(m, 4H), 2.66-2.78(m, 1H), 2.27-2.38(m, 1H), 2.13-2.24(m, 2H), 1.95-2.10(m, 2H). 19 F-NMR(377MHz):-114.01.

[0413] Example 31: 2-{[4-({6-[(4-chloro-2-fluorophenyl)methyl]pyridin-2-yl}oxy)piperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-1,3-benzodiazole (Compound 137a) [ka] Step A: (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile To a solution of 4-fluoro-3-nitrobenzonitrile (5 g, 30.1 mmol) and (S)-oxetan-2-ylmethanamine MsOH salt (6.1 g, 33.1 mmol) in DMSO (60 mL) was added DIEA (11.6 g, 90.3 mmol) at room temperature. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (200 mL × 3). The organic layers were combined, washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 3:1) to give (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzonitrile as an orange solid (4.9 g, 70%). MS calculated: 233.1; MS found: 234.1 [M+H] + .

[0414] Step B: (S)-N'-hydroxy-3-nitro-4-((oxetan-2-ylmethyl)amino)benzimidamide To a solution of (S)-3-nitro-4-((oxetan...

Claims

1. Formula I: 【Chemistry 1】 {During the ceremony, 【Chemistry 2】 represents a single or double bond, where permitted by valence; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ and X ８ each independently represents C, CH, CR ｗ and N, where X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ and X ８ at least two and at most four of are N; Each R ｗ are independently halogen; cyano; １ -C ６ ) alkyl; (C １ -C ６ ) haloalkyl; １ -C ６ ) alkoxy; and (C １ -C ３ ) haloalkoxy; T １ Ha-T ３ and -L ａ - (CR ｘ R ｘ ) ｑ -T ３ selected from the group consisting of: T ３ teeth -N(R ｓ )C(=O)R ｚ ; -N(R ｓ )C(=O)OR ｚ ; -N(R ｓ )C(=O)N(R ｓ )R ｚ ; -N(R ｓ )S(O) １－２ -R ｚ ; -N(R ｓ )S(=NR ｓ )(=O)R ｚ ; -S(O) １－２ R ｚ ; -P(=O)R ｚ１ R ｚ２ ; -C(=O)OH; -C(=O)N(R ｓ )R ｚ ; -S(O) １－２ N(R ｓ )R ｚ ; -S(=NR ｓ )(=O)N(R ｓ )R ｚ ; the below described: 【Chemistry 3】 and 1 to 4 R which may optionally include an endocyclic group selected from the group consisting of ｖ 5-10 membered heteroaryl optionally substituted with 【Chemistry 4】 One to four R ｖ 5-10 membered heterocycloalkyl optionally substituted with -OH and optionally 1 to 2 R ｖ (C １ -C ６ )Haloalkyl selected from the group consisting of: L ａ is a bond, -NH-, -N(C １－３ alkyl)-, O or S(O) ０－２ and q is 0, 1, 2 or 3, provided that when q is 0, L ａ is other than a bond; Each R ｓ are independently hydrogen, (C １ -C ６ ) alkyl and (C ３ -C ８ ) cycloalkyl; Each R ｘ are independently hydrogen, halogen, (C １ -C ６ ) alkyl and (C １ -C ３ ) haloalkyl ； or A pair of R ｘ Each of them, together with the carbon atom to which it is bonded, is represented by (C ３ -C ８ ) forming a cycloalkyl ring; or when q is 2 or 3, a pair of R ｘ together form a double bond between adjacent carbon atoms; R ｚ , R ｚ１ and R ｚ２ are each independently hydrogen; 1 to 4 R ｖ (C １ -C ６ ) alkyl; -R ｚ３ and -L ｂ -R ｚ３ or R ｚ１ and R ｚ２ each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R ｚ１ and R ｚ２ In addition to the phosphorus bonded to １ -C ６ ) optionally substituted with alkyl; L ｂ is 1 to 4 R ｖ C optionally substituted with １－３ is alkylene; R ｚ３ (C ３ -C ６ ) cycloalkyl, 3- to 6-membered heterocycloalkyl, (C ６ -C １０ aryl and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1 to 4 R ｖ optionally substituted with; R in each case ｖ are independent, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkoxy, CN, -O(C １ -C ６ ) alkylene-O(C １ -C ６ ) alkyl, phenyl, -S(O) ０－２ -C １ -C ６ selected from the group consisting of alkyl and halogen; T ２ is hydrogen, or (C １ -C ６ ) alkoxy, (C １ -C ６ ) thioalkoxy, (C １ -C ６ )Haloalkoxy, S(O) ２ (C １ -C ６ alkyl), (C ３ -C ６ ) optionally substituted with cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl (C １ -C ６ ) alkyl, wherein said (C ３ -C ６ ) each of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from 1 to 4 R Ｔ optionally substituted with; Each R Ｔ are independently OH, SH, CN, NO ２ , halogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) cyanoalkyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkoxy, (C ３ -C ６ ) cycloalkyl, amino, (C １ -C ６ ) alkylamino and di(C １ -C ６ ) alkylamino; L １ is a bond or 1 to 3 R Ｌ (C １ -C ３ ) alkylene; L ２ is a bond, -O-, -S(O) ０－２ - or -NH-; Each R Ｌ are independently halogen, (C １ -C ３ ) alkyl and (C １ -C ３ ) haloalkyl; or a pair of R Ｌ Each of them, together with the atom to which it is bonded, is expressed as (C ３ -C ６ ) forming a cycloalkyl ring; Ring A is 【Chemistry 5】 [During the ceremony, n1 is 0, 1 or 2; W １ is CR Ｙ１ or N; W ２ is CR Ｙ２ or N. 【Chemistry 6】 [During the ceremony, W ２ is CR Ｙ２ or N, L ｗ (C １ -C ３ ) alkylene. 1 to 4 R Ｙ phenylene optionally substituted with 1 to 3 R Ｙ optionally substituted 5-6 membered heteroarylene; 1 to 4 R Ｙ Partially unsaturated monocyclic ring optionally substituted with ５ -C ８ ) cycloalkylene; and 1 to 4 R Ｙ partially unsaturated monocyclic 5-8 membered heterocycloalkylene optionally substituted with 【Chemistry 7】 [During the ceremony, n1 is 0, 1 or 2; W １ is CR Ｙ１ or N; W ２ is CR Ｙ２ or N. selected from the group consisting of: Here, mm is L ２ represents a point of attachment to L ３ represents a point of attachment to R in each case Ｙ are independently halogen, CN, -OH, oxo, (C １ -C ６ ) alkyl, (C １ -C ３ ) haloalkyl, (C １ -C ３ ) alkoxy and (C １ -C ３ ) haloalkoxy; R Ｙ１ and R Ｙ２ are each independently hydrogen, halogen, CN, -OH, (C １ -C ６ ) alkyl, (C １ -C ３ ) haloalkyl, (C １ -C ３ ) alkoxy and (C １ -C ３ ) haloalkoxy; or W １ is CR Ｙ１ And W ２ is CR Ｙ２ When R Ｙ１ and R Ｙ２ The group is united, (C １ -C ４ ) alkylene, wherein (C １ -C ４ ) Alkylene CH ２ One of the units is O, S, NH and N(C １－３ ) alkyl, optionally substituted with a heteroatom selected from the group consisting of: L ３ -O-; -S-; -C(R ａ R ａ )-;-N(H)-;-N(C １－３ -C(=O)-; and -S(O) １－２ - selected from the group consisting of; R in each case ａ are independently hydrogen, halogen, CN, -OH, (C １ -C ６ ) alkyl, (C １ -C ３ ) haloalkyl, (C ３ -C ８ ) cycloalkyl, (C １ -C ３ ) alkoxy and (C １ -C ３ ) haloalkoxy; or A pair of R ａ Each of them, together with the carbon atom to which it is bonded, is represented by (C ３ -C ８ ) forming a cycloalkyl ring; or Ring A is 【Chemistry 8】 and W ２ is CR Ｙ２ and L ３ -C(R ａ R ａ )-, one R ａ is R Ｙ２ Combined with W ２ and L ３ A double bond is formed between the remaining R ａ are hydrogen, halogen, CN, (C １ -C ６ ) alkyl, (C １ -C ３ ) haloalkyl and (C ３ -C ８ ) cycloalkyl; Ring B is (BI), (B-II), (B-III), (B-IV) and (B-V): 【Chemistry 9】 [During the ceremony, aa is L ３ represents a point of attachment to B １ , B ２ , B ３ and B ４ Each of the groups independently represents CR １ and N; B ５Ａ and B ５Ｂ each is independently selected from the group consisting of C and N; B ６Ａ , B ６Ｂ and B ６Ｃ each independently represents O, S, CR １ , N.R. Ｎ and N; Each ------ in (B-III) is independently a single bond or a double bond; However, B ５Ａ , B ５Ｂ , B ６Ａ , B ６Ｂ and B ６Ｃ at least one of B is an independently selected heteroatom; ５Ａ , B ５Ｂ , B ６Ａ , B ６Ｂ and B ６Ｃ At least one of is C or CR １ And B ５Ａ , B ５Ｂ , B ６Ａ , B ６Ｂ and B ６Ｃ A ring containing the formula: is heteroaryl. 【Chemistry 10】 [During the ceremony, aa is L ３ represents a point of attachment to B ７ and B ８ are independently -O-, -NR Ｎ - and -C(R １ ) ２ - selected from the group consisting of; B ９ is N or CR ａａ and nb is 0 or 1; B １０ , B １１ and B １２ is independent, CR １ and N. selected from the group consisting of: Each R １ are hydrogen, halogen, CN, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl; １ -C ３ ) Alkyl(C ３ -C ６ ) cycloalkyl, (C １ -C ３ ) alkyl(3-5 membered heterocycloalkyl) and -C(O)NR ２ R ３ selected from the group consisting of: Each R ２ and R ３ are independently H and (C １ -C ６ ) alkyl; Each R Ｎ is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, C(=O)(C １ -C ６ ) alkyl, S(O) ２ (C １ -C ６ ) alkyl and C(=O)O(C １ -C ６ ) alkyl; R ａａ , R ａｂ and R ａｃ are each independently H, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; L ４ is a bond or -Z １ -Z ２ -*, where the * represents the point of attachment to Ring C; Z １ and Z ２ are independently a bond, NH, N(C １ -C ６ Alkyl), O, C(=O), S(O) ０－２ and 1 to 2 R ｃ C optionally substituted with １－３ alkylene; However, Z １ and Z ２ is not a bond at the same time; Furthermore, however, Z １ NH, N(C １ -C ６ alkyl), -O- or -S-, when Z ２ is a bond, C(=O), S(O) １－２ Or 1-2 R ｃ C optionally substituted with １－３ is alkylene; Z ２ NH, N(C １ -C ６ alkyl), -O- or -S-, when Z １ is a bond, C(=O), S(O) １－２ Or 1 to 3 R ｃ C optionally substituted with １－３ is alkylene; Each R ｃ are independently halogen, (C １ -C ６ ) alkyl and (C １ -C ３ ) haloalkyl, or a pair of R ｃ Each of them, together with the carbon atom to which it is bonded, is represented by (C ３ -C ８ ) forming a cycloalkyl ring; Ring C is phenyl, 5- to 6-membered heteroaryl, (C ３ -C ６ ) cycloalkyl, (C ５ -C １０ ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R ｂ are independent, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkoxy, halogen, (C ３ -C ６ ) selected from the group consisting of cycloalkyl and CN; b is an integer from 0 to 3. or a pharma- ceutically acceptable salt or solvate thereof.

2. The following a to n: a. T 1 is -T 3 ; or b. T 1 is -L a -(CR x R x ) q -T 3 ; or c. -L a is a bond; or d. -L a is -NH-, -N(C 1-3 alkyl)-, -O- or -S-; or e. -L a is -O-; or f. q is 1; or g. q is 2 or 3; or h. each R x is hydrogen or (C 1 -C 6 )alkyl; or i. each R x is hydrogen; or j. a pair of R x on the same carbon, taken together with the carbon atom to which they are each attached, form a (C 3 -C 8 )cycloalkyl ring; or k. a pair of R x on the same carbon, taken together with the carbon atom to which they are attached, form a cyclopropyl; or l. T 1 is -(CR x R x )-T 3 , where optionally each R x is hydrogen or a pair of R x together with the carbon atom to which they are each attached form a (C 3 -C 8 )cycloalkyl ring; or m. T 1 is -(CR x R x ) q -T 3 , where q is 2 or 3 and optionally each R x is hydrogen; or n. T 1 is -O-(CR x R x ) q -T 3 , where q is 1, 2 or 3, optionally q is 1, and / or each R x is hydrogen; 2. The compound of claim 1 ,

3. The following a to jj: T 3 is selected from the group consisting of -N(R s )C(═O)R z , -N(R s )C(═O)OR z , -N(R s )C(═O)N(R s )R z , -N(R s )S(O) 1-2 -R z and -N(R s )S(═NR s )(═O)R z ; or b. T 3 is —N(R s )C(═O)R z ; or c. T 3 is -NHC(=O)R z ; or d. T 3 is —N(R s )S(O) 1-2 —R z ; or e. T 3 is -NHS(O) 2 R z ; or f. T 3 is —S(O) 1-2 R z ; or g. T 3 is -S(O) 2 R z ; or h. R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; or i. R z is (C 1 -C 3 )alkyl optionally substituted with 1 to 4 R v ; or j. R z is (C 1 -C 3 ) alkyl; or k. R z is methyl, ethyl, or isopropyl; or l. R z is (C 1 -C 3 )alkyl substituted with 1 to 3 R v ; or m. R z is (C 1 -C 3 )alkyl substituted with 1 to 3 substituents each independently selected from halo and (C 1 -C 3 )alkoxy, e.g., R z is -CH 2 CF 3 or -CH 2 CH 2 OMe; or n. R z is -R z3 or -L b -R z3 ; or R z is -R z3 or -CH 2 -R z3 ; or p. R z3 is selected from the group consisting of (C 3 -C 6 )cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1-4 R v ; or q. R z3 is selected from the group consisting of (C 3 -C 6 )cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1-2 R v ; or r. R z3 is cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, oxetanyl, tetrahydropyranyl, or tetrahydro-2H-thiopyran 1,1-dioxide; or s. R z3 is selected from the group consisting of (C 6 -C 10 )aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-4 R v ; optionally R z is (C 1 -C 3 )alkyl optionally substituted with (C 1 -C 3 )alkoxy; or R z is (C 1 -C 3 )alkyl substituted with 1 to 3 halo; or t. R z3 is phenyl optionally substituted with 1-2 R v ; or T 3 is -NHC(=O)R z or -NHS(O) 1-2 -R z ; R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; optionally R z3 is selected from the group consisting of phenyl, (C 3 -C 6 )cycloalkyl and 3 to 6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 2 R v , for example, R z3 is phenyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, oxetanyl, tetrahydropyranyl or tetrahydro-2H-thiopyran 1,1-dioxide; or v. T 3 is —NHC(═O)R z or —NHS(O) 1-2 —R z ; R z is —R z3 or —CH 2 —R z3 ; or w. T 3 is —S(O) 2 R z ; R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; or x. T 3 is -C(=O)OH; or y. T 3 is -P(═O)R z1 R z2 ; or z. R z1 and R z2 are each independently selected (C 1 -C 3 )alkyl; or aa. T 3 is a 5-10 membered heteroaryl optionally substituted with 1-4 R v , wherein said heteroaryl is: 【Chemistry 11】 which may optionally include an endocyclic group selected from the group consisting of bb. T 3 is a 5-6 membered heteroaryl optionally substituted with 1-4 R v ; cc. T 3 is a 5-membered heteroaryl having 2-4 ring heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl is optionally substituted with 1-2 R v . dd. T3 is 【Chemistry 12】 Selected from the group consisting of ee. T3 【Chemistry 13】 and R v is an optionally substituted 5-6 membered heteroaryl optionally containing an endocyclic group selected from the group consisting of: ff. T3 is 【Chemistry 14】 Selected from the group consisting of gg. T 3 is a 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl is 【Chemistry 15】 wherein said heterocycloalkyl is optionally substituted with 1 to 4 R v . hh. T3 【Chemistry 16】 wherein said heterocycloalkyl is optionally substituted with 1 to 4 R v ; ii. T3 is 【Chemistry 17】 Q 1 is C(═O) or S(O) 2 ; Q 2 is O, NH, —CH 2 — or —CH 2 —CH 2 —; Q 3 is N or CH; --- is a single or double bond with the proviso that T 3 is non-aromatic; or jj. T3 【Chemistry 18】 Selected from the group consisting of:

3. The compound according to claim 1 or 2,

4. The following a to aa: a. T 1 is -N(R s )C(═O)R z or -N(R s )S(O) 1-2 -R z ; R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; optionally R z is (C 1 -C 3 )alkyl; or R z is (C 1 -C 3 )alkyl substituted with 1 to 3 substituents each independently selected from halo and (C 1 -C 3 )alkoxy, for example, R z is -CH 2 CF 3 or -CH 2 CH 2 OMe; or b. T 1 is —N(R s )C(═O)R z or —N(R s )S(O) 1-2 —R z ; R z is —R z3 or —CH 2 —R z3 ; optionally R z3 is selected from the group consisting of phenyl, (C 3 -C 6 )cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1-2 R v , e.g., R z3 is phenyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, oxetanyl, tetrahydropyranyl, or tetrahydro-2H-thiopyran 1,1-dioxide; or c. T 1 is -NHC(=O)R z ; or d. T 1 is -NHS(O) 2 -R z ; or e. T 1 is -(CR x R x ) q -S(O) 2 R z ; q is 1, 2 or 3; In some cases, i. R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; and / or ii. R z is (C 1 -C 3 ) alkyl; and / or iii. q is 1; and / or iv. each R x is hydrogen; or f. T 1 is -(CR x R x ) q -C(═O)OH or -C(═O)OH; q is 1, 2 or 3; In some cases, i. q is 1; or ii. q is 2; or iii. each R x is hydrogen, A pair of R x on the same carbon, together with the carbon atom to which each is attached, forms a (C 3 -C 8 )cycloalkyl ring; when present, each remaining R x is hydrogen, and optionally a pair of R x on the same carbon, taken together with the carbon atom to which they are attached, form a cyclopropyl ring; or g. T 1 is C(═O)OH; 【Chemistry 19】 is ； or h. T 1 is -O-(CR x R x ) q -C(═O)OH; optionally q is 1; or each R x is hydrogen; or i. T 1 is -P(═O)R z1 R z2 ; optionally R z1 and R z2 are independently selected (C 1 -C 3 )alkyl; or j. T 1 is a 5-membered heteroaryl having 2-4 ring heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl is optionally substituted with 1-2 R v ; or k. T 1 is 【Chemistry 20】 Selected from the group consisting of: or l. T 1 is 【Chemistry 21】 wherein said heteroaryl is optionally further substituted with 1 to 4 R v ; or m. T 1 is 【Chemical 22】 Selected from the group consisting of: or n. T 1 is 【Chemistry 23】 Q 1 is C(═O) or S(O) 2 ; Q 2 is O, NH, —CH 2 — or —CH 2 —CH 2 —; Q 3 is N or CH; --- is a single or double bond with the proviso that T 3 is non-aromatic; or o. T 1 【Chemistry 24】 or p. X 2 is N; X 4 is N; or q. X 8 is C; X 5 is C; or r. X 3 is C; or s. X 2 is N; X 3 is C; X 4 is N; X 5 is C; X 8 is C; or t. each of X 1 , X 7 and X 6 is independently CH or CR w ; or u. each of X 1 , X 7 and X 6 is CH; or v. one of X 1 , X 7 and X 6 is CR w ; and the remaining each of X 1 , X 7 and X 6 is CH; or w. X 6 is CR w ; X 1 and X 7 are CH; optionally X 6 is C—F; or x. one of X 1 , X 7 and X 6 is N; and the remaining each of X 1 , X 7 and X 6 is CH or CR w ; or y. X 1 is N; X 6 and X 7 are CH; or z. X 6 is N; X 1 and X 7 are CH; or aa. X 7 is N; X 1 and X 6 are CH; 2. The compound of claim 1 ,

5. The following part 【Chemistry 25】 but 【Chemistry 26】 The compound according to any one of claims 1 to 3,

6. The following a to b: a. T2 is i. (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, (C 1 -C 6 )haloalkoxy, S(O) 2 (C 1 -C 6 alkyl), (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl substituted with 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 R T ; or ii. (C 1 -C 6 )alkyl substituted with a 3- to 6-membered heterocycloalkyl; or iii. (C 1 -C 3 )alkyl substituted with a 4- to 6-membered heterocycloalkyl; or iv. (C 1 -C 3 )alkyl substituted with oxetanyl; or v. The following structure: 【change】 The In some cases, 【Chemical 27】 has the (S) configuration; or b. L 1 is i. (C 1 -C 3 )alkylene optionally substituted with 1 to 3 R L ; or ii. CH2; or iii. is a bond; or iv. is a bond; or v. CH 2 ; L 2 is a bond; or vi. L 1 is a bond; L 2 is a bond; The compound according to any one of claims 1 to 5,

7. The following a to d: a. Ring A is 【Chemistry 28】 and optionally here i. W 1 is N; and / or ii. W 2 is CR Y2 , optionally CR Y2 is hydrogen or W 1 is N; and / or iii. n1 is 0 or n1 is 1; or b. Ring A is 【Chemical 29】 or c. Ring A is 【Chemistry 30】 where, optionally, L w is CH 2 ; or W2 is N; d. Ring A is 【Chemistry 31】 is The compound according to any one of claims 1 to 6,

8. The following a to d: a. Ring A is partially unsaturated monocyclic (C 5 -C 8 )cycloalkylene optionally substituted with 1 to 4 R Y ; and Partially unsaturated monocyclic 5-8 membered heterocycloalkylene optionally substituted with 1-4 R Y . or b. Ring A is 【Chemistry 32】 W 3 is N or CH; n1 is 0, 1 or 2; Here, depending on the case, i. n1 is 0 ii. W 3 is N or c. Ring A is 【Chemical Formula 33】 or d. Ring A is 【Chemical 34】 is The compound according to any one of claims 1 to 6,

9. The following a to c: a. L2 is: i. is a bond; L 1 is CH 2 ; Ring A is 【Chemistry 35】 and wherein optionally, ring A is 【Chemical 36】 is ； or ii. is a bond; L 1 is a bond; ring A is 【Chemical 37】 is; or iii. is a bond; L 1 is a bond; ring A is 【Chemical Formula 38】 and wherein optionally, ring A is 【Chemical Formula 39】 is b. L 3 is —O—; —S—; —C(R a R a )—; —N(H)—; —N(C 1-3 alkyl)-; —C(═O)—; or —S(O) 1-2 —; and / or c. L 3 is —O— The compound according to any one of claims 1 to 5,

10. The following a to c: a. Ring B is 【Chemistry 40】 where, optionally, i. B 4 is CR 1 ; or ii. B4 is CH; or iii. B 1 is CR 1 ; or iv. B 1 is CH; or v. B 3 is CR 1 ; or vi. B3 is CH; or vii. B2 is N; or b. Ring B is 【Chemistry 41】 or c. Ring B is 【Chemistry 42】 The compound according to any one of claims 1 to 9, wherein

11. The following a to n: a. The following i to v: i. Ring B is 【Chemistry 43】 is ； or ii. Ring B is 【Chemistry 44】 is; or iii. Ring B is 【Chemistry 45】 is; or iv. Ring B is 【Chemistry 46】 is; or v. Ring B is 【Chemistry 47】 is; and / or b. B 7 is —O—; and / or c. B 8 is —O—; and / or d. B 7 is —O—; and / or e. The following i to iii: i. The following (A) to (C) (A) R aa is H; or R aa is (C 1 -C 3 )alkyl; or R aa is methyl; and / or (B) R ac is H; or (C) R ac is H; or ii. R aa , R ab and R ac are each H; or iii. R aa is (C 1 -C 3 )alkyl; R ab and R ac are H; and / or f. B 10 is CR 1 ; and / or g. B 10 is CH; and / or h. B 11 is CR 1 ; and / or i. B 11 is CH; and / or j. B 12 is CR 1 ; and / or k. B 12 is CH; and / or l. The following i to iii: i. Ring B is 【Chemistry 48】 B 7 and B 8 are -O-; R aa is H or (C 1 -C 3 )alkyl; or ii. Ring B is 【Chemistry 49】 B 7 and B 8 are -O-; R aa is H or (C 1 -C 3 )alkyl; or iii. Ring B is 【Chemistry 50】 B 7 and B 8 are -O-; R aa is H or (C 1 -C 3 )alkyl, optionally selected from the following (A) to (D): (A) R aa is H; or R aa is (C 1 -C 3 )alkyl; and / or (B) R ab and R ac are H; and / or (C) B 10 , B 11 and B 12 are each independently selected from CR 1 ; and / or (D) B 10 , B 11 and B 12 are CH or m. the carbon atom to which both L 4 and R aa are attached has the (R) configuration; or the carbon atom to which both L 4 and R aa are attached has the (S) configuration; or n. Ring B is 【Chemistry 51】 and the carbon atom marked with an ** has the (R) configuration; or Ring B is 【Chemistry 52】 and the carbon atom marked with ** has the (S) configuration. The compound according to any one of claims 1 to 10, wherein

12. The following a to j: a. L4 is a bond; or b. L 4 is -Z 1 -Z 2 -*, where the * represents the point of attachment to Ring C; or c. Z 1 is -O-; or d. Z 1 is a bond; or e. Z 2 is -CH 2 - optionally substituted with 1-2 R c ; or f. Z 2 is —CH 2 —; or g. L 4 is —O—CH 2 —*, where the * represents the point of attachment to Ring C; or h. L 4 is -CH 2 -; or i. L 4 is -O-Z 2 -*, where the * represents the point of attachment to Ring C; Z 2 is -CH 2 - optionally substituted with 1 to 2 R c , for example, Z 2 is -CH 2 -; or j. L 3 is -O-; L 4 is -CH 2 - The compound according to any one of claims 1 to 11, wherein

13. The following a to j: a. Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicycloheteroaryl; or b. Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl; or c. Ring C is phenyl; or d. b is 1 to 3; or e. b is 2; or f. b is 1; or g. b is 0; or h. Ring C is phenyl; and b is 2; or i. 【Chemistry 53】 but 【Chemical 54】 is ； or j. Ring C is phenyl; b is 1; or k) The following structure: 【Chemistry 55】 but 【Chemistry 56】 is; or l. Ring C is phenyl; b is 0; or m. R b at each occurrence is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, and CN; or n. R b at each occurrence is independently selected from the group consisting of -F, -Cl, CF 3 and CN; The compound according to any one of claims 1 to 12, wherein 14. The compound of claim 1, wherein the compound has the formula (I-A2): 【Chemistry 57】 [During the ceremony, L 3 is selected from the group consisting of -O-; -S-; -C(R a R a )-; -N(H)-; -N(C 1-3 alkyl)-; -C(═O)-; and -S(O) 1-2 -; Z 2 is selected from the group consisting of NH, N(C 1 -C 6 alkyl), O, C(═O), S(O) 0-2 and —CR cA R cB —; wherein R cA and R cB are independently selected from the group consisting of H and R c ; Wherein, optionally, the following a to k: a. L 3 is —O—; or b. Z 2 is -CR cA R cB -; or c) Z 2 is —CH 2 —; or d. The ring containing B 1 , B 2 , B 3 and B 4 is 【Chemistry 58】 is; or e. The ring containing B 1 , B 2 , B 3 and B 4 is 【Chemical Formula 59】 is; or f. X 3 is C; X 2 and X 4 are N; X 5 and X 8 are C. g. Next part 【Chemistry 60】 but 【Chemistry 61】 is; or h. Next part 【Chemistry 62】 but 【Chemistry 63】 is; or i. The next part 【Chemistry 64】 but 【Chemistry 65】 is; or j. Next part 【Chemistry 66】 but 【Chemistry 67】 is; or k. Next part 【Chemistry 68】 but 【Chemistry 69】 is It is of the or a pharma- ceutically acceptable salt thereof.

15. The following a to j: a. T 1 is -NR s C(═O)R z or -NR s S(O) 1-2 -R z ; R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; and optionally R z is (C 1 -C 3 )alkyl; or R z is (C 1 -C 3 )alkyl substituted with (C 1 -C 3 )alkoxy; or R z is (C 1 -C 3 )alkyl substituted with 1 to 3 independently selected halo; or b. T 1 is —NR s C(═O)R z or —NR s S(O) 1-2 —R z ; R z is —R z3 or —CH 2 —R z3 ; optionally, R z3 is selected from the group consisting of phenyl, (C 3 -C 6 )cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1-2 R v , e.g., R z3 is phenyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, oxetanyl, tetrahydropyranyl, or tetrahydro-2H-thiopyran 1,1-dioxide; or c. T 1 is -NHC(=O)R z ; or d. T 1 is -NHS(O) 2 -R z ; or e. T 1 is -(CR x R x ) q -S(O) 2 R z ; q is 1, 2 or 3; Wherein, optionally, the following i to iv: i. R z is (C 1 -C 6 )alkyl optionally substituted with 1 to 4 R v ; or ii. R z is (C 1 -C 3 ) alkyl; or iii. q is 1; or iv. each R x is hydrogen or f. T 1 is —O—(CR x R x ) q —C(═O)OH; q is 1, 2 or 3; Wherein, optionally, the following i to ii: i. q is 1; or q is 2; and / or ii. each R x is hydrogen; or A pair of R x on the same carbon, together with the carbon atom to which each is attached, forms a (C 3 -C 8 )cycloalkyl ring; when present, each remaining R x is hydrogen. is; wherein optionally a pair of R x on the same carbon together with the carbon atom to which each is attached forms a cyclopropyl ring; or g. T 1 is 【Chemistry 70】 is ； or h. T 1 is -O-(CR x R x ) q -C(=O)OH; q is 1, 2 or 3; where optionally q is 1; and / or Each R x is hydrogen or i. T 1 is -P(=O)R z1 R z2 , where optionally R z1 and R z2 are independently selected (C 1 -C 3 )alkyl; or j. T 1 is a 5-membered heteroaryl having 2-4 ring heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl is optionally substituted with 1-2 R v ; or k. T 1 is 【Chemistry 71】 Selected from the group consisting of: or l. T 1 is 【Chemical 72】 wherein said heteroaryl is optionally further substituted with 1 to 4 R v ; or m. T 1 is 【Chemical 73】 Selected from the group consisting of: or n. T 1 is 【Chemical Formula 74】 Q 1 is C(═O) or S(O) 2 ; Q 2 is O, NH, —CH 2 — or —CH 2 —CH 2 —; Q 3 is N or CH; --- is a single or double bond with the proviso that T 3 is non-aromatic; or o. T 1 【Chemistry 75】 Selected from the group consisting of 15. The compound of claim 14,

16. The following a to d: T 2 is (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, (C 1 -C 6 )haloalkoxy, S(O) 2 (C 1 -C 6 alkyl), (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl substituted with 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each of said (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R T ; or b. T 2 is (C 1 -C 3 )alkyl substituted with a 4- to 6-membered heterocycloalkyl; or c. T 2 is (C 1 -C 3 )alkyl substituted with oxetanyl; or d. T2 is 【Chemical Formula 76】 and optionally the stereocenter in T 2 is in the (S) configuration.

16. The compound according to claim 14 or 15,

17. The following a to g: a. L 1 is CH 2 ; Ring A is 【Chemical 77】 is ； or b. Ring A is 【Chemical 78】 is; or c. L 1 is a bond; ring A is 【Chemical Formula 79】 is; or d. Ring A is 【Chemistry 80】 is; or e. L 1 is CH 2 ; Ring A is 【Chemistry 81】 W 3 is N or CH; n1 is 0, 1 or 2; or f. Ring A is 【Chemistry 82】 is; or g. Ring A is 【Chemistry 83】 is The compound according to any one of claims 14 to 16, which is of the formula:

18. The following a to f: a. Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl; b is 1 or 2; or b. The following structure: 【Chemistry 84】 but 【Chemistry 85】 is ； or c. The following structure: 【Chemistry 86】 but 【Chemistry 87】 is; or d. The following structure 【Chemistry 88】 but 【Chemistry 89】 is; or e. R b at each occurrence is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, and CN; or f. R b at each occurrence is independently selected from the group consisting of -F, -Cl, CF 3 and CN; The compound according to any one of claims 14 to 17,

19. A compound according to any one of claims 1 to 18, selected from the group consisting of the compounds in Table C1 or Table C2 below. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】 【Table 2-15】 20. A pharmaceutical comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

21. The pharmaceutical composition of claim 20 for use in a method for treating type 2 diabetes in a patient.

22. The pharmaceutical composition described in claim 20, which is administered orally.

23. The pharmaceutical composition of claim 21 or 22, administered together with a further therapy or therapeutic agent, optionally comprising one of the following: a. the additional therapy or treatment is selected from the group consisting of an antidiabetic drug, an antiobesity drug, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) treatment, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof, optionally comprising one of the following i-iv: i. the antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic peptide (GIP), insulin or an insulin analog, an α-glucosidase inhibitor, a sodium-dependent glucose transporter 1 (SGLT1) inhibitor, or any combination thereof, where optionally the biguanide is metformin; or ii. the anti-obesity agent is selected from the group consisting of neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human proislet peptide (HIP), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, or any combination thereof; or iii. The GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. iv. the NASH treating agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof; or b. The additional therapeutic agents are administered in separate dosage amounts sequentially in any order A medicine that is

24. The following a to c: a. a method of regulating insulin levels in a patient, optionally wherein said regulation results in increased insulin levels; or b. a method of regulating glucose levels in a patient, optionally wherein said regulation results in a decrease in glucose levels; or c. Methods of Treating a GLP-1 Related Disease, Disorder, or Condition in a Patient A medicament according to claim 20 for use in In some cases, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes mellitus of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, lipid disorders, and the like. Adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hypertension selected from lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof; In some cases, the conditions may include type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance ... selected from phosphorus tolerance, hepatic insulin resistance, alcohol intake disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof; Wherein optionally the disease, disorder or condition is selected from, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers or any combination thereof.

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