15-PGDH INHIBITORS

CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Application No. 63/299,756, filed on January 14, 2022, which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] In the United States, about 1 million people are affected with ulcerative colitis. Ulcerative colitis is a lifelong illness that has a profound emotional and social impact on the affected patients. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors have shown efficacy in animal models of ulcerative colitis and may provide a valuable treatment option.

SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein are compounds of Formula (I):

Formula (I); wherein:

X is C(R ₂ ) or N;

Y is C(R ₃ );

Z is C(R ₄ ) or N;

Li is -N(R ₅ )-, -O-, or -S-;

Ri is selected from Ce-Cioaryl and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 Rs;

R ₂ is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R ₃ is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy;

R ₄ is selected from hydrogen, -F, -Cl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

Rs is selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C ₃ -Cecycloalkyl, and C ₂ - Cgheterocycloalkyl, wherein Ci-Cealkyl, C ₃ -Cecycloalkyl, and C2-C9heterocycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy; each Re is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, - N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R ₉ , -S(=O) ₂ R ₉ , and - S(=O) ₂ N(R ₈ ) ₂ ; each R ₈ is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl, wherein Ci- Cealkyl is optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=0)N(RIO) ₂ ; each R ₉ is independently selected from Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=O)N(RW) ₂ ; and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0004] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:

Formula (la).

[0005] In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)-. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, Ci-Cealkyl, and Cs-Cecycloalkyl, wherein Ci-Cealkyl and Cs-Cecycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci- Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -O-. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl optionally substituted by 1, 2, 3, or 4 Rs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl optionally substituted by 1, 2, or 3 Rs, wherein each Rs is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , -N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , and - C(=O)N(R ₈ ) ₂ . In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ri is phenyl optionally substituted by 1 or 2 Rs, wherein each Re is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, and - ORs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl substituted by 1 Rs, wherein Rs is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, and -ORs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl substituted by 1 Rs, wherein Re is -CN. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 Rs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl are optionally substituted with 1, 2, or 3 Rs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl are optionally substituted with 1, 2, or 3 Rs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1, 2, or 3 Re. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1, 2, or 3 Re and each Rs is independently selected from halogen, - CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, -N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , and -C(=O)N(R ₈ ) ₂ . In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1 or 2 Rs and each Rs is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are substituted with 1 Re and Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , and -C(=O)OR ₈ .

[0006] In one aspect, provided herein are compounds of Formula (II):

Formula (II); wherein:

X is C(R ₂ ) or N;

Y is C(R ₃ );

Z is C(R ₄ ) or N;

L ₂ is -N(Rsa)-, -O-, -S-, or Ci-Cealkylene;

R ₂ is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R ₃ is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy;

R ₄ is selected from hydrogen, -F, -Cl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

Rsa is selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C ₃ -Cecycloalkyl, and C ₂ - Csiheterocycloalkyl, wherein Ci-Cealkyl, C ₃ -Cecycloalkyl, and C ₂ -C9heterocycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkoxy, and C ₃ -Cecycloalkyl; each R? is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, - Ci-C ₆ alkyl-OR ₈ , -N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R ₉ , - S(=O) ₂ R ₉ , and -S(=O) ₂ N(R ₈ ) ₂ ; or two R? are combined to form a 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl ring;

R? _a is selected from hydrogen and Ci-Cealkyl; each R ₈ is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl, wherein Ci- Cealkyl is optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=0)N(RIO) ₂ ; each R9 is independently selected from Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from -OR10, -N(RIO) ₂ , -C(=0)ORio, and -C(=0)N(Rio) ₂ ; each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl; n is 0 or 1; p is 0 or 1; and q is 0-4; or a pharmaceutically acceptable salt or solvate thereof.

[0007] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof:

Formula (Ila).

[0008] In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs _a )-. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs _a is selected from hydrogen, Ci-Cealkyl, and Cs-Cecycloalkyl, wherein Ci-Cealkyl and Cs-Cecycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci- Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs _a is hydrogen. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs _a is unsubstituted Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -O-. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is selected from hydrogen and Ci-Cealkyl. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is Ci-Cealkyl. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , -Ci-Cealkyl-ORs, -N(R ₈ )2, -C(=O)R9, - C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R9, -S(=O) ₂ R ₉ , and -S(=O) ₂ N(R ₈ ) ₂ . In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from halogen. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein two R7 are combined to form a 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl ring. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and p is 1. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 and p is 1. In some embodiments is a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 and p is 0.

[0009] In some embodiments is a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, -F, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.

[0010] In another aspect described herein is a pharmaceutical composition comprising a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0011] In another aspect described herein is a method of treating an inflammatory or fibrotic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II) or (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from ulcerative colitis and lung fibrosis.

INCORPORATION BY REFERENCE

[0012] 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.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0013] In the context of this disclosure, a number of terms shall be utilized. [0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0015] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0016] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0017] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4 ^th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

[0018] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification. [0019] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0020] As used herein, Ci-C _x includes C1-C2, C1-C3 . . . Ci-C _x . Ci-C _x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

[0021] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carboncarbon triple bond). The alkyl group may also be an “unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain.

[0022] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Ci-Cealkyl” or similar designations. By way of example only, “Ci- Cealkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0023] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.

[0024] The term “alkenyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms -C(R)=CR.2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. Non-limiting examples of an alkenyl group include -CH=CH2, - C(CH ₃ )=CH ₂ , -CH=CHCH ₃ , -CH=C(CH ₃ ) ₂ and -C(CH ₃ )=CHCH ₃ . The alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a “cycloalkenyl” group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group). [0025] The term “alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -C=C-R, wherein R refers to the remaining portions of the alkynyl group. Non-limiting examples of an alkynyl group include -C=CH, -C=CCH ₃ , -C=CCH ₂ CH ₃ and -C=CCH ₂ CH ₂ CH ₃ . The “R” portion of the alkynyl moiety may be branched, straight chain, or cyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0026] “Amino” refers to a -NH ₂ group.

[0027] The term “alkylamine” or “alkylamino” refers to the -N(alkyl) _x H _y group, where alkyl is as defined herein and x and y are selected from the group x=l, y=l and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl) ₂ group, where alkyl is as defined herein.

[0028] The term “aromatic” refers to a planar ring having a delocalized 7i-electron system containing 4n+2 % electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0029] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0030] “Carboxy” refers to -CO ₂ H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to, .

[0031] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0032] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An A-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0033] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0034] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0035] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include - CH ₂ C1, -CF ₃ , -CHF ₂ , -CH2CF3, -CF2CF3, and the like.

[0036] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF ₃ , -CHF ₂ , -CH ₂ F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH ₃ )3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH ₂ F, -OCH2CF3, -OCF2CF3, - OCF2CF2CF3, -OCF(CH ₃ ) ₂ , and the like.

[0037] The term “deuteroalkyl” refers to an alkyl group that is substituted with one or more deuteriums. [0038] The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, - CH2-CH2-NH-CH3, -CH ₂ -N(CH ₃ )-CH3, -CH2-CH2-NH-CH3, -CH ₂ -CH ₂ -N(CH3)-CH3, -CH ₂ -S- CH2-CH3, -CH ₂ -CH ₂ -S(O)-CH3, -CH ₂ -CH ₂ -S(O)2-CH3, -CH2-NH-OCH3, -CH ₂ -O-Si(CH ₃ )3, -CH ₂ - CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

[0039] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure.

[0040] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0041] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0042] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.

[0043] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-Cealkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. -NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituents may be L ^S R ^S , wherein each L ^s is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O) ₂ -, -NH-, -NHC(O)-, -C(O)NH-, S(=O) ₂ NH-, - NHS(=O) ₂ , -OC(O)NH-, -NHC(O)O-, -(Ci-C ₆ alkyl)-, or -(C2-C ₆ alkenyl)-; and each R ^s is independently selected from among H, (Ci-Cealkyl), (Cs-Cscycloalkyl), aryl, heteroaryl, heterocycloalkyl, and Ci-Ceheteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

[0044] As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. [0045] The term a “therapeutically effective amount” as used herein refers to the amount of a 15- PGDH inhibitor that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent conditions related to skin aging.

[0046] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0047] The term “modulate” encompasses either a decrease or an increase in activity or expression depending on the target molecule.

[0048] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

[0049] The term “patient” or “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0050] The term “soft-drug” as used herein, refers to drug substance and/or a chemical compound that is biologically active in the desired target tissue and that is metabolized, after exerting its effect in the target tissue, to a compound that is inactive against the biological target. In some embodiments, the soft-drug has no target biological activity in systemic circulation.

[0051] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.

[0052] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bi sulfates, sulfites, bi sulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0053] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, /f-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-m ethyl glucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0054] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. 15-PGDH Inhibition

[0055] Resolution of inflammation is now regarded as an active process towards the restoration of homeostasis, and failure of these anti-inflammatory mechanisms underpins development of many chronic inflammatory conditions. Specialized pro-resolving lipid mediators (SPMs) act as agonists of resolution and function through mechanisms including limiting neutrophil tissue accumulation, counter-regulating pro-inflammatory cytokines and promoting macrophage phagocytosis. The tight spatial and temporal regulation of SPMs may restrict their utility as exogenous pharmaceutical agents, but limiting their degradation may effectively promote resolution in a broad range of inflammatory diseases.

[0056] 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the critical enzyme for oxidation and inactivation of prostaglandins, and its broad specificity suggests a potential role in degrading other SPMs including lipoxins, resolvins and protectins. In some embodiments, inhibition of 15- PGDH shifts the balance of bioactive lipids in favor of a pro-resolving phenotype, with 15-PGDH inhibitors effective in animal models including ulcerative colitis and lung fibrosis.

Compounds

[0057] The compounds of Formula (I), (la), (II), and (Ila) described herein are 15-PGDH inhibitors. The compounds of Formula (I), (la), (II), and (Ila) described herein, and compositions comprising these compounds, are useful for the treatment of inflammatory and fibrotic disease. [0058] In some embodiments, the therapeutic agent(s) (e.g. compound of Formula (I), (la), (II) or (Ila)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any compound described above is suitable for any method or composition described herein.

[0059] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

Formula (I); wherein:

X is C(R ₂ ) or N;

Y is C(R ₃ );

Z is C(R ₄ ) or N;

Li is -N(R ₅ )-, -O-, or -S-; Ri is selected from Ce-Cioaryl and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 Re;

R2 is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R3 is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy;

R4 is selected from hydrogen, -F, -Cl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R5 is selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and C2- Cgheterocycloalkyl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, and C2-C9heterocycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy; each Rs is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, - N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R9, -S(=O) ₂ R ₉ , and - S(=O) ₂ N(R ₈ ) ₂ ; each R ₈ is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl, wherein Ci- Cealkyl is optionally substituted with 1, 2, or 3 groups selected from -OR10, -N(RIO)2, -C(=0)ORio, and -C(=0)N(RIO) ₂ ; each R9 is independently selected from Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from -OR10, -N(RIO)2, -C(=0)ORio, and -C(=O)N(Rw)2; and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl.

[0060] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is QR2). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is QR2) and R2 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is QR2) and R2 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0061] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is -F. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is -Cl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is Ci- Cehaloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R ₄ ) and R4 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

[0062] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci- Cehaloalkoxy.

[0063] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is selected from hydrogen, Ci-Cealkyl, and Cs-Cecycloalkyl, wherein Ci-Cealkyl and Cs-Cecycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is hydrogen.

[0064] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 hydroxy groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is CFF.

[0065] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is - N(Rs)- and Rs is unsubstituted cyclopropyl.

[0066] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted C2- Csiheterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted azetidinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted oxetanyl.

[0067] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -S-.

[0068] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl optionally substituted by 1, 2, 3, or 4 Rs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl optionally substituted by 1, 2, or 3 Rs, wherein each Re is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, -N(Rs)2, -C(=O)R9, - C(=O)ORs, and -C(=O)N(Rs)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ri is phenyl optionally substituted by 1 or 2 Rs, wherein each Re is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, and -ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl substituted by 1 Re, wherein Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, and -ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl substituted by 1 Re, wherein Re is -CN.

[0069] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 Rs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl are optionally substituted with 1, 2, or 3 Rs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl are optionally substituted with 1, 2, or 3 Rs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1, 2, or 3 Re. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1, 2, or 3 Re and each Rs is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, -N(Rs)2, -C(=O)R9, -C(=O)ORs, and -C(=O)N(RS)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1 or 2 Re and each Rs is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are substituted with 1 Rs and Rs is selected from halogen, -CN, Ci-Cealkyl, Ci- Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyridinyl substituted with 1 Rs and Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyrimidinyl substituted with 1 Rs and Rs is selected from halogen, -CN, Ci- Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyrazinyl substituted with 1 Re and Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyridazinyl substituted with 1 Re and Rs is selected from halogen, - CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is triazolopyridinone substituted with 1 Re and Rs is selected from halogen, -CN, Ci-Cealkyl, Ci- Cehaloalkyl, -ORs, and -C(=O)ORs.

[0070] In some embodiments, provided herein is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:

Formula (la); wherein:

Li is -N(R ₅ )-, -O-, or -S-;

Ri is selected from Ce-Cioaryl and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 Rs;

R2 is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R3 is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy;

R4 is selected from hydrogen, -F, -Cl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R5 is selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and C2- Cgheterocycloalkyl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, and C2-C9heterocycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy; each Re is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, - N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R ₉ , -S(=O) ₂ R ₉ , and - S(=O) ₂ N(R ₈ ) ₂ ; each R ₈ is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl, wherein Ci- Cealkyl is optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=0)N(RIO) ₂ ; each R ₉ is independently selected from Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=O)N(RW) ₂ ; and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl.

[0071] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is halogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is Ci-Cehaloalkoxy.

[0072] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -F. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is - Cl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkoxy.

[0073] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cehaloalkoxy.

[0074] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -NfRs)-. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R.s)- and R5 is selected from hydrogen, Ci-Cealkyl, and Cs-Cecycloalkyl, wherein Ci-Cealkyl and Cs-Cecycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is hydrogen.

[0075] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 hydroxy groups. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(R5)- and R5 is CH3.

[0076] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is unsubstituted Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is - N(Rs)- and R5 is unsubstituted cyclopropyl.

[0077] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and R5 is unsubstituted C2- Csiheterocycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted azetidinyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -N(Rs)- and Rs is unsubstituted oxetanyl.

[0078] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -O-. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Li is -S-.

[0079] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl optionally substituted by 1, 2, 3, or 4 Rs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl optionally substituted by 1, 2, or 3 Rs, wherein each Re is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, -N(Rs)2, -C(=O)R9, - C(=O)ORs, and -C(=O)N(Rs)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ri is phenyl optionally substituted by 1 or 2 Rs, wherein each Re is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, and -ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl substituted by 1 Re, wherein Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, and -ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is phenyl substituted by 1 Rs, wherein Re is -CN.

[0080] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 Rs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl, wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl are optionally substituted with 1, 2, or 3 Rs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolopyridinone, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, and benzothiazolyl are optionally substituted with 1, 2, or 3 Rs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1, 2, or 3 Re. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1, 2, or 3 Re and each Rs is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, -N(Rs)2, -C(=O)R9, -C(=O)ORs, and -C(=O)N(RS)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are optionally substituted with 1 or 2 Re and each Rs is independently selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolopyridinone are substituted with 1 Rs and Rs is selected from halogen, -CN, Ci-Cealkyl, Ci- Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyridinyl substituted with 1 Rs and Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyrimidinyl substituted with 1 Rs and Rs is selected from halogen, -CN, Ci- Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyrazinyl substituted with 1 Re and Re is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is pyridazinyl substituted with 1 Re and Rs is selected from halogen, - CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORs, and -C(=O)ORs. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is triazolopyridinone substituted with 1 Re and Rs is selected from halogen, -CN, Ci-Cealkyl, Ci- Cehaloalkyl, -ORs, and -C(=O)ORs.

[0081] In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

Formula (II); wherein:

X is C(R ₂ ) or N;

Y is C(R ₃ );

Z is C(R ₄ ) or N;

L ₂ is -N(Rsa)-, -O-, -S-, or Ci-Cealkylene;

R ₂ is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R ₃ is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy;

R ₄ is selected from hydrogen, -F, -Cl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

Rsa is selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C ₃ -Cecycloalkyl, and C ₂ - C ₉ heterocycloalkyl, wherein Ci-Cealkyl, C ₃ -Cecycloalkyl, and C ₂ -C9heterocycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkoxy, and C ₃ -Cecycloalkyl; each R? is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , - Ci-C ₆ alkyl-OR ₈ , -N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R ₉ , - S(=O) ₂ R ₉ , and -S(=O) ₂ N(R ₈ ) ₂ ; or two R? are combined to form a 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl ring;

R? _a is selected from hydrogen and Ci-Cealkyl; each R ₈ is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl, wherein Ci- Cealkyl is optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=0)N(RIO) ₂ ; each R ₉ is independently selected from Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from -ORio, -N(RIO) ₂ , -C(=0)ORio, and -C(=O)N(Rw) ₂ ; each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl; n is 0 or 1; p is 0 or 1; and q is 0-4. [0082] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci- Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R ₂ ) and R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2) and R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0083] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is -F. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is -Cl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is Ci- Cehaloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4) and R4 is Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R ₄ ) and R4 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

[0084] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci- Cehaloalkoxy. [0085] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is selected from hydrogen, Ci-Cealkyl, and Cs-Cecycloalkyl, wherein Ci-Cealkyl and Cs-Cecycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is hydrogen.

[0086] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 hydroxy groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is CH3.

[0087] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is Cs-G.cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is - N(Rs)- and R5 is unsubstituted cyclopropyl.

[0088] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted C2- Csiheterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted azetidinyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is unsubstituted oxetanyl.

[0089] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -S-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is Ci-Cealkylene.

[0090] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1, 2, or 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , -Ci-Cealkyl-ORs, -N(R ₈ )2, -C(=O)R9, - C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R9, -S(=O) ₂ R ₉ , and -S(=O) ₂ N(R ₈ ) ₂ . In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from halogen, oxo, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , and -N(R ₈ )2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from halogen and Ci- Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein two R7 are combined to form a 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl ring.

[0091] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

[0092] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is hydrogen.

[0093] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and p is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 and p is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 and p is 0.

[0094] In some embodiments, provided herein is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof:

Formula (Ila); wherein:

L2 is -N(R _5a )-, -O-, -S-, or Ci-Cealkylene;

R2 is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

R3 is selected from hydrogen, halogen, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy;

R4 is selected from hydrogen, -F, -Cl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy;

Rsa is selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and C2- C ₉ heterocycloalkyl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, and C2-C9heterocycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkoxy, and Cs-Cecycloalkyl; each R7 is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , - Ci-C ₆ alkyl-OR ₈ , -N(R ₈ ) ₂ , -C(=O)R ₉ , -C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R ₉ , - S(=O) ₂ R ₉ , and -S(=O)2N(R ₈ )2; or two R7 are combined to form a 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl ring;

R? _a is selected from hydrogen and Ci-Cealkyl; each R ₈ is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl, wherein Ci- Cealkyl is optionally substituted with 1, 2, or 3 groups selected from -OR10, -N(RIO)2, -C(=0)ORio, and -C(=0)N(RIO) ₂ ; each R ₉ is independently selected from Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from -OR10, -N(RIO)2, -C(=0)ORio, and -C(=O)N(Rw)2; each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl; n is 0 or 1; p is 0 or 1; and q is 0-4. [0095] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkoxy.

[0096] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -F. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is - Cl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkoxy.

[0097] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cehaloalkoxy.

[0098] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)-. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is selected from hydrogen, Ci-Cealkyl, and Cs-Cecycloalkyl, wherein Ci-Cealkyl and Cs-Cecycloalkyl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is hydrogen. [0099] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 hydroxy groups. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from Ci-Cealkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(Rs)- and R5 is CH3.

[00100] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is Cs-G.cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted Cs-Cecycloalkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted cyclopropyl.

[00101] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cealkoxy, and Ci- Cehaloalkoxy. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted C2- Csiheterocycloalkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted azetidinyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -N(R5)- and R5 is unsubstituted oxetanyl.

[00102] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -O-. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is -S-. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is Ci-Cealkylene. [00103] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1, 2, or 3. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein each R? is independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , -Ci-Cealkyl-ORs, -N(R ₈ ) ₂ , -C(=O)R ₉ , - C(=O)OR ₈ , -C(=O)N(R ₈ ) ₂ , -NR ₈ C(=O)R ₉ , -NR ₈ S(=O) ₂ R ₉ , -S(=O) ₂ R ₉ , and -S(=O) ₂ N(R ₈ ) ₂ . In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein each R? is independently selected from halogen, oxo, Ci-Cealkyl, Ci-Cehaloalkyl, -OR ₈ , and -N(R ₈ ) ₂ . In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein each R? is independently selected from halogen and Ci- Cealkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein each R? is independently selected from halogen. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein two R? are combined to form a 3 - to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl ring.

[00104] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

[00105] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is Ci-Cealkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is -CFF. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R? _a is hydrogen.

[00106] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and p is 1. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 and p is 1. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 and p is 0.

[00107] In some embodiments, provided herein is a compound selected from:

pharmaceutically acceptable salt or solvate thereof.

[00108] In some embodiments, provided herein is a compound selected from:

pharmaceutically acceptable salt or solvate thereof.

[00109] In some embodiments, provided herein is a compound selected from:

pharmaceutically acceptable salt or solvate thereof.

[00110] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds. Further Forms of Compounds Disclosed Herein

Isomers

[00111] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (£), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.

Labeled compounds

[00112] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ C1, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., ³ H and carbon-14, z.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, z.e., ² H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

[00113] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

[00114] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[00115] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Solvates

[00116] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[00117] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Synthesis of Compounds

[00118] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[00119] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics.

[00120] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 ^th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3 ^rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.

Use of Protecting Groups

[00121] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[00122] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[00123] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[00124] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

[00125] Typically blocking/protecting groups may be selected from:

[00126] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).

Methods of Treatment and Prevention

[00127] In some embodiments is a method of treating an inflammatory or fibrotic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating a fibrotic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory or fibrotic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from ulcerative colitis and lung fibrosis. In some embodiments is a method of treating ulcerative colitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating lung fibrosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.

Pharmaceutical compositions and methods of administration

[00128] 15-PGDH inhibitors described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent diseases, disorders or conditions. Administration of 15-PGDH inhibitors as described herein can be in any pharmacological form including a therapeutically effective amount of a 15-PGDH inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[00129] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[00130] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[00131] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof.

[00132] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof.

[00133] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[00134] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.

[00135] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [00136] In some embodiments, 15-PGDH inhibitors described herein are administered to subjects in a biologically compatible form suitable for topical administration to treat or prevent dermal diseases, disorders or conditions. By “biologically compatible form suitable for topical administration” is meant a form of the 15-PGDH inhibitor to be administered in which any toxic effects are outweighed by the therapeutic effects of the inhibitor. Administration of 15-PGDH inhibitors as described herein can be in any pharmacological form including a therapeutically effective amount of a 15-PGDH inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[00137] Topical administration of a 15-PGDH inhibitor may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term “a semisolid composition” is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.

[00138] Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer such as DMSO to increase the absorption of the compounds. Patches can include those that control the rate of drug delivery to the skin. Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively. The reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water-resistant backing. Such a design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of skin. The monolithic design, for example, typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a water-proof backing. This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin. As the drug amount decreases in the patch to below the saturating level, the delivery rate falls.

[00139] In one embodiment, the topical composition may, for example, take the form of hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethyleneglycol (PEG) as the carrier, like the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, especially a microemulsion based on water-in-oil or oil-in-water, optionally with added liposomes. Suitable permeation accelerators (entraining agents) include sulphoxide derivatives such as dimethylsulfoxide (DMSO) or decylmethylsulfoxide (decyl-MSO) and transcutol (diethyleneglycolmonoethylether) or cyclodextrin; as well as pyrrolidones, for example 2- pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or the biodegradable N-(2- hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3 -diphenylurea; terpenes, for example D-limonene, menthone, a-terpinol, carvol, limonene oxide, or 1,8-cineol.

[00140] Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals. In general, such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00141] The carrier can also contain other pharmaceutically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation. The anti-skin aging compositions can also further comprise antioxidants, sun screens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.

[00142] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[00143] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00144] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[00145] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[00146] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [00147] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00148] Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[00149] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00150] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00151] The dose of the composition comprising at least one compound described herein differs, depending upon the patient's e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[00152] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00153] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

[00154] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[00155] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the 15- PGDH inhibitor and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Such calculations can be made without undue experimentation by one skilled in the art in light of the 15-PGDH inhibitor activities disclosed herein in assay preparations of target cells. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration.

[00156] Toxicity and therapeutic efficacy of such 15-PGDH inhibitors can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 /ED50. 15-PGDH inhibitors that exhibit large therapeutic indices are preferred. While 15-PGDH inhibitors that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such inhibitors to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[00157] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such 15-PGDH inhibitors lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any 15 -PGDH inhibitor used in a method described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of 15-PGDH inhibitor that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to determine useful doses in humans more accurately. Levels in plasma may be measured, for example, by high performance liquid chromatography.

EXAMPLES

[00158] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[00159] Standard abbreviations and acronyms as defined in J. Org. Chem. 2007 72(1): 23A-24A are used herein. Other abbreviations and acronyms used herein are as follows:

Example 1: Synthesis of 4-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2- yl)amino)benzonitrile (Compound 1)

[00160] To a solution of 6-chloronicotinic acid (5.0 g, 31.7 mmol) in DMF (50 mL) was added DIEA (12.3 g, 95.2 mmol), HATU (12.6 g, 33.3 mmol) and 4,4-difluoropiperidine (4.2 g, 34.9 mmol) at 0°C. The reaction mixture was stirred for 2 hour at 25°C. The reaction mixture was extracted with EA (100 mL*3) and water (100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford compound A-1 (7.0 g, 85%). ESI-MS(EI ⁺ , m/z): 261.2.

[00161] To a solution of A-1 (150.0 mg, 0.58 mmol) in dioxane (5 mL) was added 4- aminobenzonitrile (102.6 mg, 0.87 mmol), Xantphos (67.0 mg, 0.12 mmol), Pd2(dba)3 (53.1 mg, 0.06 mmol) and CS2CO3 (378.2 mg, 1.16 mmol). The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 1 (120.0 mg, 61%). ESLMS (EI ⁺ , m/z): 342.2. 'H NMR (400 MHz, DMSO-tL) 8 9.92 (s, 1H), 8.36 (s, 1H), 7.92 (d, J= 92 Hz, 2H), 7.77 (d, J= 8.4 Hz, 1H), 7.72 (d, J= 8.8 Hz, 2H), 6.96 (d, J= 8.4 Hz, 1H), 3.61 (s, 4H), 2.07-1.97 (m, 4H).

Example 2: Synthesis of 6-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)isoquinolin-l(2H)-one (Compound 2) [00162] To a solution of 6-bromoisoquinolin-l(2H)-one (1.0 g, 4.5 mmol) in toluene (20 mL) was added cyclopropanamine (763.4 mg, 13.4 mmol), Pd2(dba)3 (817.0 mg, 0.9 mmol), (t-BuhP (2.0 mL, 1.8 mmol) and t-BuONa (857.1 mg, 8.9 mmol) at room temperature. The reaction mixture was stirred at 100°C overnight under nitrogen atmosphere. The solvent was removed in vacuo and the crude product was purified by column chromatography to afford compound B-l (130 mg, 15%). ESI-MS(EI ⁺ , m/z): 201.1.

[00163] To a solution of A-l (140.8 mg, 0.54 mmol) in 1,4-dioxane (10 mL) was added B-l (130.0 mg, 0.65 mmol), Pd2(dba)3 (99.6 mg, 0.11 mmol), XantPhos (125.2 mg, 0.22 mmol), and CS2CO3 (352.1 mg, 1.1 mmol) at room temperature. The reaction mixture was stirred at 100°C overnight under nitrogen atmosphere. The solvent was removed in vacuo and the crude product was purified by prep-HPLC to afford Compound 2 (6.6 mg, 3%). ESLMS (EI ⁺ , m/z): 425.2. 'H NMR (400 MHz, DMSO ) 6 8.66 (s, 1H), 8.06-7.96 (m, 3H), 7.70 (d, J= 8.0 Hz, 1H), 7.04 (s, 1H), 6.87 (d, J= 8.8 Hz, 1H), 6.79 (s, 1H), 6.57 (d, J= 7.6 Hz, 1H), 3.76-3.74 (m, 2H), 3.52 - 4.48 (m, 2H), 2.50 - 2.47 (m, 1H), 2.12 - 2.06 (m, 4H), 0.80 - 0.76 (m, 2H), 0.48 - 0.44 (m, 2H).

Example 3: Synthesis of 4-((5-(4,4-difluoropiperidine-l-carbonyl)-3-fluoropyridin-2- yl)amino)benzonitrile (Compound 3)

[00164] To a solution of 6-chloro-5-fluoronicotinic acid (500.0 mg, 2.8 mmol) in DMF (10 mL) was added DIEA (1.1 g, 8.5 mmol), HATU (1.1 g, 3.0 mmol) and 4,4-difluoropiperidine(517.3 mg, 4.3 mmol) at 0°C. The reaction mixture was stirred for 2 hour at 25°C. The reaction mixture was extracted with EA (30 mL*3) and water (30 mL). The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford compound C-1 (467.6 mg, 59%). ESI-MS(EI ⁺ , m/z): 279.2.

[00165] To a solution of C-1 (200.0 mg, 0.72 mmol) in dioxane (5 mL) was added 4- aminobenzonitrile (170.1 mg, 1.44 mmol), Xantphos (83.0 mg, 0.144 mmol), Pd2(dba)3 (73 mg, 0.08 mmol) and CS2CO3 (704.1 mg, 1.44 mmol). The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 3 (21.2 mg, 8%). ESLMS (EI ⁺ , m/z): 461.1. ^X H NMR (400 MHz, DMSO ) 8 9.70 (s, 1H), 8.20 (s, 1H), 8.04 (d, J= 8.8 Hz, 2H), 7.79 (d, J= 13.2 Hz, 1H), 7.75 (d, J= 8.8 Hz, 2H), 3.62 (s, 4H), 2.07 - 2.02 (m, 4H).

Example 4: Synthesis of 4-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyrimidi n-2- yl)amino)benzonitrile (Compound 4)

Compound 4

[00166] To a solution of ethyl 2-chloropyrimidine-5-carboxylate (1.30 g, 6.99 mmol) in toluene (30 mL) was added 4-(cyclopropylamino)benzonitrile (850 mg, 5.38 mmol), Pd2(dba)3 (986 mg, 1.08 mmol), Xantphos (625 mg, 1.08 mmol), and K2CO3 (1.5 g, 10.76 mmol) at room temperature. The reaction mixture was stirred at 80°C for 6h under N2. The solvent was removed in vacuo. The residue was purified by column chromatography to afford compound D-l (320 mg, 19%). ESI- MS(EI ⁺ , m/z): 309.3.

[00167] To a solution of D-l (320 mg, 0.73 mmol) in MeOH/JLO (v/v=2/l, 6 ml) was added LiOH (87 mg, 3.64 mmol). The reaction mixture was stirred at room temperature for Ih. The mixture was adjusted PH=5 with HC1 (IN) and was extracted with EA (30 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford compound D-2 (110 mg, 53.8%). ESI-MS(EI ⁺ , m/z): 281.2.

[00168] To a solution of D-2 (110 mg, 0.39 mmol) in DMF (3 mL) was added DIEA (201 mg, 1.56 mmol) and HATU (193 mg, 0.51 mmol) at 25° C. After stirring 10 min, 4,4-difluoropiperidine (57 mg, 0.47 mmol) was added. The mixture was stirred at room temperature for 2h. The reaction mixture was extracted with EA (2 mL*3) and water (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentracted in vacuo. The residue was purified by prep-HPLC to afford Compound 4 (67.4 mg, 45%). ESI-MS (EI ⁺ , m/z): 384.3. 'H NMR (400 MHz, DMSO ) 8 8.59 (s, 2H), 7.89 - 7.86 (m, 2H), 7.59 - 7.56 (m, 2H), 3.62 - 3.56 (m, 4H), 3.27 - 3.23 (m, IH), 2.11 - 2.01 (m, 4H), 1.01 - 0.97 (m, 2H), 0.52 - 0.48 (m, 2H).

Example 5: Synthesis of 5-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)picolinonitrile (Compound 5)

Compound 5

[00169] To a solution of 6-fluoronicotinic acid (5.0 g, 35.5 mmol) in DMF (50 mL) was added DIEA (12.3 g, 106.3 mmol), HATU (12.6 g, 37.3 mmol) and 4,4-difluoropiperidine (4.2 g, 39.1 mmol) at 0°C. The reaction mixture was stirred for 2h at 25°C. The reaction mixture was extracted with EA (100 mL*3) and water (100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford compound E-l (7.3 g, 85%). ESI-MS(EI ⁺ , m/z): 245.1.

[00170] A solution of E-l (1.0 g, 4.1 mmol) and cyclopropanamine (5 mL) in a sealed tube was heated at 100°C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford compound E-2 (1.1 g, 98%). ESI-MS(EI ⁺ , m/z): 282.2.

[00171] To a solution of E-2 (224.0 mg, 0.8 mmol) in dioxane (10 mL) was added 5- bromopicolinonitrile (218.3 mg, 1.2 mmol), Xantphos (92.5 mg, 0.16 mmol), Pd2(dba)3 (91.5 mg, 0.1 mmol) and CS2CO3 (781.9 mg, 2.4 mmol). The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 5 (117.5 mg, 38%). ESI-MS (EI ⁺ , m/z): 384.2. 'H NMR (400 MHz, DMSO ) 8 8.82 (s, 1H), 8.26 (s, 1H), 8.02 (s, 2H), 7.90 (d, J= 8.8 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 3.61 (s, 4H), 3.17 (s, 1H), 2.08-2.01 (m, 4H), 1.13 (d, J= 6.4 Hz, 2H), 0.60 (s, 2H).

Example 6: Synthesis of 4-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)(l- methylazetidin-3-yl)amino)benzonitrile (Compound 6) [00172] To a solution of 4-fluorobenzonitrile (1.0 g, 8.3 mmol) in DMF (10 mL) was added K2CO3 (2.3 g, 16.6 mmol) and tert-butyl 3 -aminoazetidine- 1 -carboxylate (1.7 g, 10.0 mmol). The reaction mixture was stirred at 100°C for 12h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford compound F- 1 (1.0 g, 45%). ESI-MS(EI ⁺ , m/z): 274.1.

[00173] A solution of F-l (1.0 g, 3.7 mmol) in DCM (8 mL) was cooled to 0 °C. TFA (2 mL) was slowly added dropwise and stirred at room temperature for Ih. The reaction mixture was concentrated in vacuo to afford compound F-2 (620.0 mg, 98 %) which was used in the next step without further purification. ESI-MS(EI ⁺ , m/z): 174.1.

[00174] To a solution of F-2 (620.0 mg, 3.6 mmol) in DCM (10 mL) and MeOH (10 mL) was added HCHO (215.6 mg, 7.2 mmol) and HOAc (one drop). The reaction mixture was stirred for 30 min at room temperature. NaBH(OAc)3 (1.5 g, 7.2 mmol) was added in the mixture. The reaction mixture was stirred for 2h at room temperature. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography to afford compound F-3 (600 mg, 90.0%). ESI-MS (EI ⁺ , m/z): 188.1.

[00175] To a solution of 6-bromonicotinic acid (1.0 g, 5.0 mmol) in DMF (10 mL) was added DIPEA (1.3 g, 10.0 mmol), HATU (2.0 g, 5.4 mmol) and 4,4-difluoropiperidine (726 mg, 6.0 mmol) at 0°C. The reaction mixture was stirred for 2h at 25°C. The reaction mixture was extracted with EA (50 mL*3) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to afford compound F-4 ( 1.0 g, 67%). ESI-MS(EI ⁺ , m/z): 305.1.

[00176] To a solution of F-4 (200.0 mg, 0.66 mmol) in 1,4-dioxane (6 mL) was added F-3 (147.6 mg, 0.79 mmol), Pd2(dba)3 (120.4 mg, 0.13 mmol), XantPhos (152.1 mg, 0.26 mmol), and CS2CO3 (427.6 mg, 1.3 mmol) and stirred at 100°C for 12h under N2. The reaction mixture was concentrated in vacuo and the crude product was purified by prep-HPLC to afford Compound 6 (4.0 mg, 2%). ESI-MS (EI ⁺ , m/z): 412.2. 'H NMR (400 MHz, DMSO ) 8 8.84 (s, IH), 8.20 (d, J = 8.8 Hz, IH), 8.13 (d, J= 8.0 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 7.31 (d, J= 92 Hz, IH), 5.46- 5.38 (m, IH), 5.29-5.22 (m, IH), 5.16-5.09 (m, IH), 3.77 - 3.51 (m, 4H), 3.26 - 3.16 (m, 2H), 2.53 - 2.51 (m, 3H), 2.24 - 2.06 (m, 4H).

Example 7: Synthesis of 7-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyi'idin-3(2H)-one (Compound 7)

[00177] To a solution of 7-bromo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 4.7 mmol) in DMF (15 mL) was added iodomethane (800.3 mg, 5.6 mmol) and K2CO3 (1.3 g, 9.4 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (50 mL), stirred for 30 min, and filtered. The solid was collected and dried at 50°C in vacuo to afford compound G-1 (800 mg, 75%). ESI-MS(EI ⁺ , m/z): 228.1.

[00178] To a solution of E-2 (200.0 mg, 0.72 mmol) in 1,4-di oxane (10 mL) was added G-1 (193.0 mg, 0.86 mmol), Pd2(dba)3 (130.2 mg, 0.14 mmol), XantPhos (164.6 mg, 0.28 mmol), and CS2CO3 (462.6 mg, 1.4 mmol) at room temperature. The reaction mixture was stirred at 100°C for 12h under N2. The reaction mixture was concentrated in vacuo and the crude product was purified by prep-HPLC to afford Compound 7 (160.2 mg, 53%). ESI-MS (EI ⁺ , m/z): 429.2. 'H NMR (400 MHz, DMSO ) 8 8.32 (s, 1H), 7.96 (d, J= 8.8 Hz, 1H), 7.83 (d, J= 7.6 Hz, 1H), 7.39 (d, J= 8.8 Hz, 1H), 7.13 (s, 1H), 6.63 (d, J= 7.2 Hz, 1H), 3.61-3.52 (m, 4H), 3.52 (s, 3H), 3.13 - 3.11 (m, 1H), 2.09 - 2.03 (m, 4H), 1.12 - 1.10 (m, 2H), 0.71 - 0.69 (m, 2H).

Example 8: Synthesis of 4-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)(l-

(hydroxymethyl)cyclopropyl)amino)benzonitrile (Compound 8)

[00179] To a solution of E-1 (600.0 mg, 2.5 mmol) in DMF (10 mL) was added K2CO3 (1.0 g, 7.4 mmol) and (l-aminocyclopropyl)methanol (641.8 mg, 7.4 mmol) and stirred for 12h at 100°C. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography to afford compound H-1 (130 mg, 17%). ESI-MS(EI ⁺ , m/z): 312.1.

[00180] To a solution of H-1 (130.0 mg, 0.42 mmol) in 1,4-di oxane (6 mL) was added 4- bromobenzonitrile (114.1 mg, 0.63 mmol), Pd2(dba)3 (114.7 mg, 0.13 mmol), XantPhos (96.6 mg, 0.17 mmol), and CS2CO3 (271.7 mg, 0.84 mmol). The reaction mixture was stirred for 12h at 100°C under N2. The reaction mixture was concentrated in vacuo. The crude product was purified by preo- HPLC to afford Compound 8 (2.2 mg, 1%). ESI-MS (EI ⁺ , m/z): 413.2. 'H NMR (400 MHz, DMSO-rL) 8 8.09 (s, 1H), 8.62 (d, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.30 (d, J= 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 4.34 (s, 2H), 3.80-3.24 (m, 4H), 2.06 - 2.86 (m, 4H), 0.97 - 0.95 (m, 2H), 0.86 - 0.84 (m, 2H).

Example 9: Synthesis of 7-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-(2-methoxyethyl)-[l,2,4]triazolo[4,3-a]pyi'idin- 3(2H)-one (Compound 9)

[00181] To a solution of 4-bromo-2-fluoropyridine (5.0 g, 28.6 mmol) in EtOH (200.0 mL) was added hydrazinium hydroxide solution (26.8 g, 428.7 mmol, 80%) at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue washed with water (100 mL) and filtered. The solid was collected and dried at 50°C in vacuo to afford compound 1-1 (5.0 g, 94%).

[00182] To a solution of 1-1 (4.0 g, 21.3 mmol) in THF (80.0 mL) was added CDI (6.89 g, 42.6 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with EA (80 mL*3) and H2O (100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue washed with DCM (40 mL) and filtered. The solid was collected and dried at 50°C in vacuo to afford compound 1-2 (3.5 g, 78%). ESI-MS(EI ⁺ , m/z): 214.1 and 216.1.

[00183] To a solution of 1-2 (1.0 g, 4.69 mmol) in DMF (15.0 mL) was added l-bromo-2- methoxyethane (971.8 mg, 7.0 mmol) and CS2CO3 (3.0 g, 9.38 mmol) at room temperature. The reaction mixture was stirred for 2h at 50°C. The mixture was poured into water (50 mL) and stirred for 30 min. The mixture was filtered and the solid was collected and dried at 50°C in vacuo to afford compound 1-3 (1.2 g, 94%). ESI-MS(EI ⁺ , m/z): 272.2.

[00184] To a solution of 1-3 (170.0 mg, 0.6 mmol) in dioxane (5.0 mL) was added (6- (cyclopropylamino)pyridin-3-yl)(4,4-difluoropiperidin-l-yl)m ethanone(147.0 mg, 0.5 mmol), Pd2(dba)3 (173 mg, 0.2 mmol), Xantphos (73.0 mg, 0.13 mmol) and CS2CO3 (616.0 mg, 1.9 mmol) at room temperature. The reaction mixture was stirred overnight at 100°C under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 9 (17.4 mg, 7%). ESI-MS (EI ⁺ , m/z): 473.2. 'H NMR (400 MHz, DMSO ) 6 8.31 (d, J= 2.4 Hz, 1H), 7.87 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.36 (d, J= 8.8 Hz, 1H), 7.02 (s, 1H), 6.62 (dd, J= 7.6 Hz, 2.0 Hz, 1H), 4.01 (t, J= 5.6 Hz, 2H), 3.69 (t, J= 5.2 Hz, 2H), 3.60 (s, 4H), 3.24 (s, 3H), 3.06 - 3.02 (m, 1H), 2.06-2.01 (m, 4H), 1.09 (d, J= 5.2 Hz, 2H), 0.67-0.63 (m, 2H).

Example 10: Synthesis of 5-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)picolinic acid (Compound 10)

[00185] To a solution of E-2 (300.0 mg, 1.07 mmol) in dioxane (8.0 mL) was added 5- bromopicolinic acid (257.3 mg, 1.28 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), Xantphos (249 mg, 0.43 mmol) and CS2CO3 (697 mg, 2.14 mmol) at room temperature. The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 10 (53.3 mg, 12%). ESI-MS (EI ⁺ , m/z): 403.2. 'H NMR (400 MHz, DMSO ) 6 12.95 (s, 1H), 8.79 - 8.54 (m, 1H), 8.33 - 8.11 (m, 1H), 8.10 - 7.70 (m, 3H), 7.46 - 7.19 (m, 1H), 3.59 (s, 4H), 3.15 (s, 1H), 2.03 (s, 4H), 1.24 - 0.87 (m, 2H), 0.57 - 0.49 (m, 2H).

Example 11: Synthesis of 5-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)pyrimidine-2-carbonitrile (Compound 11) , Compound 11

[00186] To a solution of E-2 (300.0 mg, 1.07 mmol) in dioxane (8.0 mL) was added 5- bromopyrimidine-2-carbonitrile (235.0 mg, 1.28 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), Xantphos (249 mg, 0.43 mmol) and CS2CO3 (697 mg, 2.14 mmol) at room temperature. The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 11 (23.9 mg, 6%). ESI-MS (EI ⁺ , m/z): 385.2. 'H NMR (400 MHz, DMSO-tL) 8 9.14 (s, 2H), 8.30 (d, J= 1.6 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.51 (d, J= 8.4 Hz, 1H), 3.62 (s, 4H), 3.25 - 3.13 (m, 1H), 2.14 - 1.98 (m, 4H), 1.31 - 1.12 (m, 2H), 0.74 - 0.60 (m, 2H).

Example 12: Synthesis of 7-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)(2- hydroxyethyl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyi'idin- 3(2H)-one (Compound 12)

[00187] E-l (300.0 mg, 1.2 mmol), 2-((tert-butyldimethylsilyl)oxy)ethan-l-amine (2 mL), and DIPEA (317.1 mg, 2.5 mmol) were heated in a sealed tube at 100°C overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford compound L-l (260.0 mg, 69%). ESI-MS(EI ⁺ , m/z): 314.2.

[00188] To a solution of L-l (260.0 mg, 0.65 mmol) in dioxane (5 mL) was added G-l (221.2 mg, 0.97 mmol), Xantphos (75.1 mg, 0.13 mmol), Pd2(dba)3 (60.0 mg, 0.06 mmol) and CS2CO3 (635.6 mg, 1.9 mmol). The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by column chromatography to afford compound L-2 (329.5 mg, 92%). ESI-MS(EI ⁺ , m/z): 547.3.

[00189] To a solution of L-2 (329.5 mg, 0.6 mmol) in THF (5 mL) was added TBAF (1.0 M in THF, 1.2 mL) at 0°C. The reaction mixture was stirred for Ih at room temperature. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 12 (139.4 mg, 54%). ESI-MS (EI ⁺ , m/z): 433.2. 'H NMR (400 MHz, DMSO ) 8 8.35 (d, J= 2.0 Hz, IH), 7.78 (d, J= 7.2 Hz, IH), 7.73 - 7.70 (m, IH), 7.11 (s, IH), 6.97 (d, J= 8.4 Hz, IH), 6.56 - 6.53 (m, IH), 4.93 (s, IH), 4.06 (t, J= 6.0 Hz, 2H), 3.63 (s, 6H), 3.51 (s, 3H), 2.13 - 1.98 (m, 4H).

Example 13: Synthesis of 6-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)pyridazine-3-carbonitrile (Compound 13)

[00190] To a solution of E-2 (300.0 mg, 1.07 mmol) in dioxane (5.0 mL) was added 6- chloropyridazine-3 -carbonitrile (179.0 mg, 1.28 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), Xantphos (249 mg, 0.43 mmol) and CS2CO3 (697 mg, 2.14 mmol) at room temperature. The reaction mixture was stirred at 100°C overnight under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 13 (17.9 mg, 4%). ESI-MS (EI ⁺ , m/z): 385.8. 'H NMR (400 MHz, DMSO-tL) 8 8.50 (d, J= 2.0 Hz, 1H), 8.12 (d, J= 9.6 Hz, 1H), 8.00 (dd, J= 8.4, 2.4 Hz, 1H), 7.82 (d, J= 9.6 Hz, 1H), 7.56 (d, J= 8.4 Hz, 1H), 3.62 (s, 4H), 3.26 - 3.15 (m, 1H), 2.16 - 2.01 (m, 4H), 1.12 - 1.11 (m, 2H), 0.65 - 0.58 (m, 2H).

Example 14: Synthesis of 7-(cyclohexyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2 - yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyi'idin-3(2H)-one (Compound 14)

[00191] E-l (300 mg, 1.23 mmol) and cyclohexanamine (5 mL) in a sealed tube were heated at 100°C for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography to afford compound N-l (317.0 mg, 80%). ESI-MS (EI ⁺ , m/z): 324.2.

[00192] To a solution of N-l (40 mg, 0.12 mmol) in dioxane (3 mL) was added G-l (32.6 mg, 0.14 mmol), CS2CO3 (81.5 mg, 0.25 mmol), Xantphos (27.7 mg, 0.05 mmol), and Pd2(dba)3 (23.0 mg, 0.025 mmol) at room temperature. The reaction mixture was stirred overnight at 100°C under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 14 (4.2 mg, 7%). ESI-MS (EI ⁺ , m/z): 471.4. 'H NMR (400 MHz, DMSO ) 6 8.33 (d, = 2.0 Hz, 1H), 7.93 (d, J= 7.2 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.10 (s,lH), 6.48 (d, J= 8.8 Hz, 1H), 6.33 (dd, J= 7.2, 1.6 Hz, 1H), 4.72 -4.64 (m, 1H), 3.62 (s, 4H), 3.57 (s, 3H), 2.13- 1.98 (m, 4H), 1.94-1.91 (m, 2H), 1.79-1.75 (m, 2H), 1.62-1.59 (m, 2H), 1.47 - 1.22 (m, 4H).

Example 15: Synthesis of 7-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)(oxeta n-3- yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyi’idin-3(2H)-on e (Compound 15)

[00193] E-l (500 mg, 2.05 mmol) and oxetan-3 -amine (5 mL) in a sealed tube were heated at 100°C for 2 h. The residue was purified by column chromatography to afford compound O-l (400.0 mg, 65.5%). ESI-MS (EI ⁺ , m/z): 298.1.

[00194] To a solution of O-l (400.0 mg, 1.35 mmol) in dioxane (8 mL) was added G-l (610.0 mg, 2.7 mmol), t-BuONa (260.0 mg, 2.7 mmol), Xantphos (156.1 mg, 0.27 mmol), and Pd2(dba)3 (128.1 mg, 0.14 mmol) at room temperature. The reaction mixture was stirred overnight at 100°C under N2. The solvent was removed in vacuo. The residue was purified by prep-HPLC to afford Compound 15 (22.8 mg, 4%). ESI-MS (EI ⁺ , m/z): 445.2. 'H NMR (400 MHz, DMSO ) 6 8.72 (s, 1H), 8.19 (d, J= 10.0 Hz, 1H), 8.08 (d, J= 7.6 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J= 9.2 Hz, 1H), 6.78 (d, J= 7.6 Hz, 1H), 5.07 - 4.78 (m, 3H), , 3.73 - 3.63 (m, 6H), 3.59 (s, 3H), 2.17 - 2.05 (m, 4H).

Example 16: Synthesis of 7-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)(2,2,2 - trifluoroethyl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin -3(2H)-one (Compound 16)

[00195] To a solution of F-4 (500.0 mg, 1.64 mmol) and 2,2,2-trifluoroethan-l -amine (1.6 g, 16.4 mmol) in dioxane (10 mL) was added Pd2(dba)3 (302.0 mg, 0.33 mmol), t-Buxphos (280.0 mg, 0.66 mmol) and t-BuONa (315.0 mg, 3.28 mmol). The mixture was stirred at 100°C overnight under N2. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford compound 16 (450 mg, 85%). ESI-MS (EI ⁺ , m/z): 324.1.

[00196] To a solution of P-1 (100.0 mg, 0.31 mmol) and G-1 (84 mg, 0.37 mmol) in dioxane (5 mL) was added XantPhos (71.0 mg, 0.12 mmol), Pd2(dba)3 (56.0 mg, 0.061 mmol) and CS2CO3 (198.0 mg, 0.61 mmol). The mixture was stirred at 100°C overnight under N2. The reaction mixture was concentracted in vacuo. The residue was purified by prep-HPLC to afford Compound 16 (38.2 mg, 26%). ESI-MS (EI ⁺ , m/z): 471.1. 'H NMR (400 MHz, DMSO-tL) 8 8.40 (s, 1H), 7.89 (d, J=

7.6 Hz, 1H), 7.76 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (s, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.51 (dd, J= 7.6,

1.6 Hz, 1H), 5.00 - 4.94 (m, 2H), 3.61 (s, 4H), 3.53 (s, 3H), 2.11 - 2.00 (m, 4H).

Example 17: Synthesis of 7-(bicyclo[l.l.l]pentan-l-yl(5-(4,4-difluoropiperidine-l- carbonyl)pyridin-2-yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a] pyridin-3(2H)-one (Compound

[00197] To a solution of F-4 (500.0 mg, 1.64 mmol) and bicyclo[l. l.l]pentan-l -amine (816.0 mg, 9.84 mmol) in dioxane (10 mL) was added Pd2(dba)3 (302.0 mg, 0.33 mmol), t-Buxphos (280.0 mg, 0.66 mmol) and t-BuONa (315.0 mg, 3.28 mmol). The mixture was stirred at 100°C overnight under N2. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford compound Q-l (140 mg, 28%). ESI-MS (EI ⁺ , m/z): 308.2. [00198] To a solution of Q-l (100.0 mg, 0.33 mmol) and G-l (96.0 mg, 0.42 mmol) in dioxane (5 mL) was added XantPhos (75.0 mg, 0.13 mmol), Pd2(dba)3 (59.0 mg, 0.07 mmol) and CS2CO3 (63.0 mg, 0.65 mmol). The mixture was stirred at 100°C overnight under N2. The reaction mixture was concentracted in vacuo. The residue was purified by prep-HPLC to afford Compound 17 (21.6 mg, 14%). ESI-MS (EI ⁺ , m/z): 455.3. 'H NMR (400 MHz, DMSO ) 8 8.31 (s, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.71- 7.67 (m, 1H), 7.03 (s, 1H), 6.83 (d, J= 8.4 Hz, 1H), 6.32 - 6.29 (m, 1H), 3.65 - 3.59 (m, 4H), 3.53 (s, 3H), 2.51 (s, 1H), 2.32 - 2.15 (m, 6H), 2.07 - 1.98 (m, 4H).

Example 18: Synthesis of 4-((5-(4,4-difluoropiperidine-l-carbonyl)-3- (trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (Compound 18)

[00199] To a solution of 6-chloro-5-(trifluoromethyl)nicotinic acid (930 mg, 4.1 mmol, 1.0 eq.) in THF (5 mL) was added T3P (1.98 g, 6.20 mmol, 1.5 eq.) under 0°C over 30 minutes. DIEA (1.60 g, 12.40 mmol, 3.0 eq.) and 4,4-difluoropiperidine (500 mg, 4.13 mmol) were then added. The resulting mixture was stirred at room temperature for 3h. The reaction solution was concentrated in vacuo, diluted with water, filtered and concentrated in vacuo to afford compound R-l (703 mg, 90%) as a white solid.

[00200] To a solution of R-l (703 mg, 2.14 mmol) in DMF (10 mL) was added t-BuOK (721 mg, 6.42 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 6h. The reaction solution was filtered and concentrated in vacuo to afford Compound 18 (20 mg, 100%) as a white solid. ESI-MS (EI ⁺ , m/z): 412.1.

Example 19: Synthesis of 4-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)benzonitrile (Compound 19)

Compound 19 [00201] A-l (1.5 g, 5.77 mmol) and cyclopropanamine (4 mL) were heated at 110°C in a sealed tube overnight. The reaction mixture was purified by column chromatography to afford compound S-l (748 mg). ESI-MS (EI ⁺ , m/z): 282.2.

[00202] To a solution of S-l (400 mg, 1.423 mmol), 4-bromobenzonitrile (389 mg, 2.14 mmol), Pd2(dba)3 (130.3 mg, 0.142mmol), and XantPhos (165 mg, 0.285 mmol) in 1,4-dioxane (6 mL) was added CS2CO3 (927 mg, 2.846 mmol). The reaction mixture was stirred at 100°C overnight. The reaction was diluted with ethyl acetate and washed with water and brine. The crude mixture was purified by prep-HPLC to afford Compound 19 (100 mg). ESI-MS (EI ⁺ , m/z): 383.2.

Example 20: Synthesis of 4-((5-(4,4-difluoropiperidine-l-carbonyl)-3-methoxypyridin-2 - yl)amino)benzonitrile (Compound 20)

[00203] To a solution of 4,4-difluoropiperidine (293 mg, 2.42 mmol) in THF (10 mL), were added 6-chloro-5-methoxynicotinic acid (500 mg, 2.67 mmol), T3P (2.31 g, 3.63mmol), and DIEA (1.2 ml, 7.26 mmol). The mixture was stirred at RT for 2h. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure and purified by column chromatography to afford compound T-1 (200 mg). ESI-MS (EI ⁺ , m/z): 291.1.

[00204] To a solution of T-1 (100 mg, 0.345 mmol) in toluene (2 mL), were added 4- aminobenzonitrile (61.1 mg, 0.52 mmol), l. l'-binaphthyl-2.2'-diphemyl phosphine (53.7 mg, 0.086mmol), palladium (II) acetate (15.5 mg, 0.069 mmol), and cesium carbonate (224.8 mg, 0.69 mmol). The mixture was stirred at 80°C for 3h. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over TsfeSCL. The solvent was concentrated under reduced pressure and purified by prep-HPLC to afford Compound 20 (5 mg) as a white solid. ESI-MS (EI ⁺ , m/z): 373.2.

Example 21: Synthesis of (4,4-difluoropiperidin-l-yl)(6-((4-methoxy-3H-imidazo[4,5- c]pyridin-2-yl)amino)pyridin-3-yl)methanone (Compound 21) [00205] To a solution of 2-methoxypyridine-3,4-diamine (100 mg, 0.72 mmol) in EtOH (2 mL) and acetonitrile (2 mL) was added cyanic bromide (180 mg, 1.72 mmol). The reaction mixture was stirred at 45°C for 8h. The reaction mixture was concentrated under reduced pressure and purified by prep-TLC to afford the compound U-l (136 mg).

[00206] To a solution of U-l (30 mg, 0.180 mmol) in toluene (5 mL) was added F-4 (66 mg, 0.221 mmol), BINAP (23 mg, 0.037 mmol) and CS2CO3 (121 mg, 0.370 mmol) followed by Pd(OAc)2 (4.04 mg, 0.018 mmol). The reaction mixture was stirred at 100°C overnight. The reaction mixture was extracted with ethyl acetate (50 mL *3) and washed with H2O. The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated under reduced pressure and purified with prep-HPLC to afford Compound 21 (2 mg, 3%) as a white solid. ESI-MS (EI ⁺ , m/z): 389.2. 'H NMR (400 MHz, methanol-^) 8 8.50 (s, 1H), 7.86 (d, J= 8.7 Hz, 1H), 7.79 (d, J= 5.6 Hz, 1H), 7.17 - 7.12 (m, 2H), 4.08 (s, 3H), 3.78 (s, 4H), 2.09 (s, 4H).

Example 22: Synthesis of 7-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2- y

[00207] Methyl 6-fluoronicotinate (1.0 g, 6.4 mmol) and propan-2-amine (19.0 g, 322.5 mmol) were added to a sealed tube. The reaction mixture was capped and stirred at 100 °C for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (20% EtOAc/PE) to afford V-l (1.0 g, 80%). LCMS (ESI): m/z 195.2 [M+H] ⁺ .

[00208] To a solution of V-l (300.0 mg, 1.55 mmol) in PhMe (10 mL) was added 7-bromo-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (352 mg, 1.55 mmol), BINAP (290 mg, 0.46 mmol), Pd(OAc)2 (70 mg, 0.31 mmol), PhB(OH)2 (10 mg, 0.08 mmol) and NaOtBu (298 mg, 3.10 mmol). The reaction mixture was stirred at 90 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography to afford V-2 (150 mg, 28%). LCMS (ESI): m/z 342.3 [M+H] ⁺ .

[00209] To a solution of V-2 (100 mg, 0.15 mmol) in MeOH (4 mL) was added LiOHftO (19 mg, 0.45 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was triturated with EtOAc (15 mL). The filtrate was concentrated under reduced pressure to afford V-3 (45 mg, 46%). LCMS (ESI): m/z 328.3 [M+H] ⁺ .

[00210] To a solution of V-3 (50 mg, 0.09 mmol) in DMF (2 mL) was added DIPEA (36 mg, 0.28 mmol) and HATU (35 mg, 0.09 mmol). After 10 min, 4,4-difluoropiperidine (17 mg, 0.14 mmol) was added and the reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 22 (38 mg, 95%). LCMS (ESI): m/z 431.2 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-t/ ₆ ): 58.32 (d, J = 2.0 Hz, 1H), 7.90 (d, J= 7.2 Hz, 1H), 7.60 (dd, J= 8.8, 2.4 Hz, 1H), 7.08 (s, 1H), 6.50 (d, J= 8.8 Hz, 1H), 6.32 (dd, J= 7.6, 2.0 Hz, 1H), 5.14 - 4.83 (m, 1H), 3.60 (s, 4H), 3.55 (s, 3H), 2.02 (m, 4H), 1.19 (d, J= 6.8 Hz, 6H).

Example 23: Synthesis of 7-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)oxy)-2 - methyl-[l,2,4]triazolo[4,3-a]pyi"idin-3(2H)-one (Compound 23)

[00211] To a solution of 2-chloro-4-methoxypyridine (1.0 g, 6.99 mmol) in PhMe (20 mL) was added (diphenylmethylene)hydrazine (1.4 mg, 6.99 mmol), BINAP (871 mg, 1.40 mmol), Pd(OAc)2 (315 mg, 1.40 mmol), PhB(OH)2 (43 mg, 0.35 mmol) and NaOtBu (1.3 mg, 13.98 mmol). The reaction mixture was stirred at 90 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography (40% EtOAc/PE) to afford W-l (2.0 g, 94%). LCMS (ESI): m/z 304.2 [M+H] ⁺ .

[00212] To solution of W-l (1.0 g, 3.30 mmol) in cone. HC1 (10 mL) was stirred at 100°C overnight. The reaction mixture was basified (NH4OH), extracted with EtOAc (3 x 25 mL) and the combined organic layers were dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by flash chromatography (50% EtOAc/PE) to afford W-2 (200 mg, 43%). LCMS (ESI): m/z 140.2 [M+H] ⁺ .

[00213] To a solution of W-2 (150 mg, 1.08 mmol) in THF (8 mL) was added CDI (262.0 mg, 1.62 mmol). The reaction mixture was stirred at 40 °C overnight until LCMS. The solvent was removed in vacuo and the residue was purified by flash column chromatography (30% EtOAc/PE) to afford W-3 (150 mg, 84%). LCMS (ESI): m/z 166.2 [M+H] ⁺ . [00214] To a solution of W-3 (150 mg, 0.91 mmol) in DMF (8 mL) was added CS2CO3 (593.0 mg, 1.82 mmol). After 10 min, Mel (0.5 mL) was added and the reaction mixture was stirrred at RT under N2 atmosphere for 4 h. The mixture was quenched (aq. NaHCOs), extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried (ISfeSCh) and concentrated under reduced pressure. The residue was purified by flash chromatography to afford W-4 (100 mg, 61%). LCMS (ESI): m/z 180.2 [M+H] ⁺ .

[00215] To a solution of W-4 (100 mg, 0.56 mmol) in PhMe (5 mL) was added A1CL (233.0 mg, 1.68 mmol). The reaction mixture was stirred at 80 °C overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography to afford W-5 (50 mg, 54%). LCMS (ESI): m/z 166.1 [M+H] ⁺ .

[00216] To a solution of W-5 (50 mg, 0.30 mmol) in DMF (8 mL) was added (4,4- difluoropiperi din- l-yl)(6-fluoropyri din-3 -yl)m ethanone (74 mg, 0.30 mmol) and CS2CO3 (196.0 mg, 0.60 mmol). The reaction mixture was stirred at 100 °C overnight. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 23 (5 mg, 4%). LCMS (ESI): m/z 390.1 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/e): 8 8.34 (d, J= 1.6 Hz, 1H), 8.02 (dd, J= 8.4, 2.4 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.26 (d, J= 8.8 Hz, 1H), 7.03 (d, J= 1.4 Hz, 1H), 6.56 (dd, J= 7.6, 2.0 Hz, 1H), 3.60 (d, J= 78.4 Hz, 7H), 2.09-2.01 (m, 4H).

Example 24: Synthesis of (6-((lH-benzo[d][l,2,3]ti'iazol-5-yl)(cyclopropyl)amino)pyri din-3- yl)(4,4-difluoropiperidin-l-yl)methanone (Compound 24)

[00217] To a solution of 6-bromo-lH-benzo[d][l,2,3]triazole (500 mg, 2.54 mmol) in DMF (8 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (1.1 g, 6.33 mmol) and CS2CO3 (1.6 g, 5.08 mmol). The reaction mixture was stirred at 50 °C under N2 for 2 h. The solvent was removed in vacuo and the residue was purified by prep-TLC (10% MeOH/DCM) to afford W-l (490 mg, 59%). LCMS (ESI): m/z 328.0 [M+H] ⁺ .

[00218] To a solution of X-l (200 mg, 0.61 mmol) in PhMe (4 mL) was added (6-

(cy clopropylamino)pyri din-3 -yl)(4, 4-difluoropiperi din- l-yl)methanone (171 mg, 0.61 mmol), BINAP (76.1 mg, 0.12 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), PhB(OH)2 (15 mg, 0.12 mmol), and t-NaOtBu (117 mg, 1.20 mmol). The reaction mixture was stirred at 100 °C under N2 overnight.

The solvent was removed in vacuo and the residue was purified by prep-TLC (10% MeOH/DCM) to afford X-2 (240 mg, 74%). LCMS (ESI): m/z 529.3 [M+H] ⁺ . [00219] To a solution of X-2 (200 mg, 0.37 mmol) in THF (5 mL) was added 1 M HC1 (20 mL). The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Compound 24 (25 mg, 16%). LCMS (ESI): m/z 399.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d ₆ ): 6 8.16 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 7.2, 4.0 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8Hz, 1H), 3.59 (s, 4H), 3.20-3.12 (m, 1H), 2.05-1.99 (m, 4H), 0.94 (d, J = 5.2Hz, 2H), 0.55-0.56 (m, 2H).

Example 25: Synthesis of 7-((5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2- yl)(methyl)a 5)

Compound 25

[00220] A mixture of 6-fluoronicotinic acid (900 mg, 6.3 mmol) and methylamine (8 mL) was heated at 110 °C in a microwave reactor for 6 h. The solvent was removed in vacuo and the residue was purified by flash chromatography to afford Y-l (700 mg, 72%). LCMS (ESI): m/z 153.1 [M+H] ⁺ .

[00221] To a solution of Y-l (500 mg, 3.2 mmol) in dioxane (20 mL) was added 7-bromo-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (824.9 mg, 3.6 mmol), Xantphos (570 mg, 0.98 mmol), Pd2(dba)3 (301 mg, 0.32 mmol) and CS2CO3 (2.1 g, 6.5 mmol). The reaction mixture was stirred at 100 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-TLC to afford Y-2 (120 mg, 12%). LCMS (ESI): m/z 300.3 [M+H] ⁺ .

[00222] To a solution of Y-2 (120 mg, 0.40 mmol) in DMF (2.5 mL) was added DIPEA (155 mg, 1.2 mmol), HATU (160 mg, 0.42 mmol) and 4,4-difluoropiperidine (72 mg, 0.59 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The residue was purified by prep-HPLC to afford Compound 25 (59 mg, 37%). LCMS (ESI): m/z 403.3 [M+H] ⁺ . 'H NMR (400 MHz, CDCh): 8 8.41 (d, J= 2.0 Hz, 1H), 7.69 (t, J= 8.0 Hz, 2H), 6.93 (d, J= 8.8Hz, 1H), 6.71 (s, 1H), 6.45 (dd, J = 7.6, 1.6 Hz, 1H), 3.76 (s, 2H), 3.65 (s, 3H), 3.56 (s, 3H), 2.04 (s, 4H), 1.59 (s, 2H).

Example 26: Synthesis of 5-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-methylisoindoline-l, 3-dione (Compound 26)

[00223] To a solution of 5-bromoisobenzofuran-l, 3-dione (600 mg, 2.65 mmol) in HOAc (10 mL) was added NaOAc (435 mg, 5.30 mmol), and MeNTh in THF (1 mL). The reaction mixture was stirred at 100 °C under N2 for 12 h. The mixture was quenched with water and a precipitate collected by filtration. The filter cake was washed with water and then dried under vacuum to afford Z-l (400 mg, 63%). LCMS (ESI): m/z 240.1 [M+H] ⁺ .

[00224] To a solution of Z-l (200 mg, 0.84 mmol) in dioxane (10 mL) was added E-2 (236 mg, 0.84 mmol), Xantphos (146 mg, 0.25 mmol), Pd2(dba)3 (154 mg, 0.17 mmol) and CS2CO3 (548 mg, 1.68 mmol). The reaction mixture was stirred at 100 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 26 (93 mg, 25%). LCMS (ESI): m/z 441.2 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-de): 8 8.24 (d, J= 1.6 Hz, 1H), 7.88 - 7.80 (m, 3H), 7.72 (dd, J= 8.0, 2.0 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 3.60 (s, 4H), 3.21 - 3.16 (m, 1H), 3.03 (s, 3H), 2.09 - 1.99 (m, 4H), 1.10 - 1.06 (m, 2H), 0.59 - 0.55 (m, 2H).

Example 27: Synthesis of 7-(cyclopropyl(4-(4,4-difluoropiperidine-l-carbonyl)phenyl)a mino)- 2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 27)

[00225] To a solution of E-2 (170 mg, 0.61 mmol) in dioxane (10 mL) was added 7-bromo-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (G-l) (152 mg, 0.67 mmol), Xantphos (106 mg, 0.18 mmol), Pd2(dba)3 (112 mg, 0.12 mmol) and Cs2CO3 (398 mg, 1.22 mmol). The reaction mixture was stirred at 100°C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 27 (34 mg, 13%). LCMS (ESI): m/z 428.2 [M+H] ⁺ . 'H NMR (400 MHz, DMSO ): 6 7.65 (d, J= 7.6 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.27 (d, J= 8.4 Hz, 2H), 6.43 (d, J= 1.6 Hz, 1H), 6.16 (dd, J= 8.0, 2.4 Hz, 1H), 3.61 (s, 4H), 3.32 (s, 3H), 2.94-2.90 (m, 1H), 2.09-2.04 (m, 4H), 0.98- 0.93 (m, 2H), 0.62-0.58 (m, 2H).

Example 28: Synthesis of 7-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 28)

[00226] To a solution of E-2 (123 mg, 0.44 mmol) in dioxane (4 mL) was added 7-bromo-2-((2- (trimethylsilyl)ethoxy)methyl)-[l,2,4]triazolo[4,3-a]pyridin -3(2H)-one (150.0 mg, 0.44 mmol), CS2CO3 (285 mg, 0.88 mmol), Xantphos (76 mg, 0.13 mmol) and Pd2(dba)3 (80 mg, 0.09 mmol). The resulting mixture was stirred at 100°C overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried (ISfeSCh) and concentrated under reduced pressure. The residue was purified by flash chromatography to afford AA-1 (100 mg, 42%) as white solid. LCMS (ESI): m/z 282.1 [M+H] ⁺ .

[00227] To a solution of AA-1 (100 mg, 0.18 mmol) in DCM (5 mL) was added TFA (ImL). The resulting mixture was stirred at RT for 1 h. The reaction solution concentrated under reduced pressure and purified by prep-HPLC to afford Compound 28 (21 mg, 27%). LCMS (ESI): m/z 415.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d ₆ ): 8 12.25 (s, 1H), 8.30 (d, J= 2.0 Hz, 1H), 7.86 (dd, J= 8.8, 2.4 Hz, 1H), 7.71 (dd, = 7.6, 0.8 Hz, 1H), 7.35 (d, 9.2 Hz, 1H), 7.00 (d, J= 1.1 Hz,

1H), 6.56 (dd, J= 7.6, 2.0 Hz, 1H), 3.60 (s, 4H), 3.05 (ddd, J= 10.4, 6.8, 4.0 Hz, 1H), 2.10 - 2.00 (m, 4H), 1.11-1.05 (m, 2H), 0.66 (dd, J= 6.4, 4.0 Hz, 2H).

Example 29: Synthesis of 6-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-methylbenzo[d]isoxazol-3(2H)-one (Compound 29)

[00228] To a solution of 6-bromobenzo[d]isoxazol-3(2H)-one (400 mg, 1.88 mmol) in DMF (10 mL) was added CS2CO3 (1.23 g, 3.77 mmol), and Mel (276 mg, 2.26 mmol). The reaction mixture was stirred at 100°C under N2 for 12 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (50% EtOAc/PE) to afford AB-1 (400 mg, 94%). LCMS (ESI): m/z 228.1 [M+H] ⁺ .

[00229] To a solution of AB-1 (100.0 mg, 0.44 mmol) in dioxane (6 mL) was added E-2 (149 mg, 0.53 mmol), Xantphos (102 mg, 0.17 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and CS2CO3 (287 mg, 0.88 mmol). The reaction mixture was stirred at 100°C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 29 (10 mg, 5%). LCMS (ESI): m/z 429.2 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-d ₆ ): 6 8.24 (d, J= 2.0 Hz, 1H), 7.83 (dd, J= 8.8, 2.4 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 1.2 Hz, 1H), 7.27 (d, J= 8.4 Hz, 2H), 3.61 (s, 3H), 3.56 (s, 3H), 3.13-3.00 (m, 1H), 2.08-1.99 (m, 4H), 1.07-1.02 (m, 2H), 0.59- 0.55 (m, 2H).

Example 30: Synthesis of (6-(benzo[c][l,2,5]oxadiazol-5-yl(cyclopropyl)amino)pyridin- 3- yl)(4,4-difluoropiperidin-l-yl)methanone (Compound 30)

Compound 30

[00230] To a solution of 5-bromobenzo[c][l,2,5]oxadiazole (200 mg, 0.71 mmol) and E-2 (170 mg, 0.85 mmol) in dioxane (6 mL) was added Xantphos (164 mg, 0.28 mmol), Pd2(dba)3 (130 mg, 0.14 mmol) and CS2CO3 (461 mg, 1.42 mmol). The reaction mixture was stirred at 100°C under N2 overnight. The solvent was removed in vacuo. The residue was purified by flash column chromatography and then prep-HPLC to afford Compound 30 (75 mg, 27%). LCMS (ESI): m/z 400.2 [M+H] ⁺ .

Example 31: Synthesis of 5-(cyclopropyl(5-(4,4-difluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-methylisoindolin-l-one (Compound 31)

Compound 31

[00231] To a solution of E-2 (300 mg, 1.33 mmol) in dioxane (20 mL) was added 5-bromo-2- methylisoindolin-l-one (240 mg, 1.07 mmol), CS2CO3 (1.74 g, 5.35 mmol), Xantphos (185 mg, 0.32 mmol) and Pd2(dba)3 (192 mg, 0.21 mmol). The resulting mixture was stirred at 100 °C under N2 for 5 h and then diluted with water. The reaction mixture was extracted with DCM and the combined organic layers dried (TsfeSCL) and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Compound 31 (11 mg, 2%). LCMS (ESI): m/z 427.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-de): 8 8.18 (d, J= 2.4 Hz, 1H), 7.76 (dd, J= 8.8, 2.4 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.48 (s, 1H), 7.35 (dd, J= 8.0, 1.4 Hz, 1H), 7.12 (d, J= 8.8 Hz, 1H), 4.46 (s, 2H), 3.59 (s, 4H), 3.12-3.09 (m, 1H), 3.07 (s, 3H), 2.06-2.00 (m, 4H), 0.97 (t, J= 6.0 Hz, 2H), 0.53 (dd, J= 6.8, 3.6 Hz, 2H). Example 32: Synthesis of 7-(cyclopropyl(5-(piperidine-l-carbonyl)pyridin-2-yl)amino)- 2- methyl-[l,2,

[00232] To a solution of 6-fluoronicotinic acid (500 mg, 3.55 mmol) in DMF (10 mL) was added DIPEA (1.37 g, 10.65 mmol) and HATU (1.4 g, 3.73 mmol). After 20 min, piperidine (362 mg, 4.25 mmol) was added and the reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by flash chromatography to afford AC-1 (630 mg, 85%). LCMS (ESI): m/z 209.1 [M+H] ⁺ .

[00233] A mixture of AC-1 (400 mg, 1.92 mmol) and cyclopropanamine (5 mL) was stirred at 80 °C for 8 h in a sealed tube. The solvent was removed in vacuo and the residue was purified by flash chromatography to afford the compound AC-2 (400 mg, 85%). LCMS (ESI): m/z 426.2 [M+H] ⁺ .

[00234] To a solution of AC-2 (300 mg, 1.22 mmol) and 7-bromo-2-methyl-[l,2,4]triazolo[4,3- a]pyri din-3 (2H)-one (G-l) (279 mg, 1.22 mmol) in dioxane (10 mL) was added Pd2(dba)3 (223 mg, 0.24 mmol) Xantphos (282 mg, 0.48 mmol) and CS2CO3 (793 mg, 2.44 mmol). The reaction mixture was stirred at 100 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 32 (104 mg, 22%). LCMS (ESI): m/z 393.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-d ₆ ): 8 8.24 (d, J= 2.0 Hz, 1H), 7.80 (dd, J= 8.4, 2.4 Hz, 1H), 7.73 (dd, J= 7.6, 0.8 Hz, 1H), 7.40 - 7.29 (m, 1H), 7.03 - 6.93 (m, 1H), 6.61 (dd, J= 7.6, 2.0 Hz, 1H), 3.46 (s, 4H), 3.32 (s, 3H), 3.10-2.99 (m, 1H), 1.61 (d, J= 4.4 Hz, 2H), 1.52 (s, 4H), 1.18-1.00 (m, 2H), 0.73-0.57 (m, 2H).

Example 33: Synthesis of 7-(cyclopropyl(5-(4-fluoropiperidine-l-carbonyl)pyridin-2- yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyi'idin-3(2H)-one (Compound 33)

[00235] A mixture of 6-fluoronicotinic acid (4.5 g, 31.91 mmol) and cyclopropanamine (22.5 mL) was stirred at 100 °C in a sealed tube overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (50% EtOAc/PE) to afford AD-1 (2.9 g, 51%). LCMS (ESI): m/z 179.1 [M+H] ⁺ .

[00236] To a solution of AD-1 (2.9 g, 16.29 mmol) in PhMe (50 mL) was added 7-bromo-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.88 g, 19.54 mmol), Xantphos (1.89 g, 3.29 mmol), Pd2(dba)3 (2.98 g, 3.29 mmol) and CS2CO3 (15.92 g, 48.86 mmol). The reaction mixture was stirred at 100 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography to afford AD-2 (1.2 g, 23%). LCMS (ESI): m/z 326.1 [M+H] ⁺ . [00237] To a solution of AD-2 (100 mg, 0.31 mmol) in DMF (2 mL) was added DIPEA (119.25 mg, 0.92 mmol), HATU (120 mg, 0.37 mmol) and 4-fhioropiperidine (38 mg, 0.38 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 33 (20 mg, 16%). LCMS (ESI): m/z 411.3 [M+H] ⁺ . 'H NMR (400 MHz, MeOD v) 8 8.31 (d, J= 2.0 Hz, 1H), 7.86 (dd, J= 8.8, 2.4 Hz, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.45 (d, J= 8.8 Hz, 1H), 7.00 (d, J= 1.2 Hz, 1H), 6.72 (dd, J= 7.6, 2.0 Hz, 1H), 4.12-3.37 (m, 8H), 3.03 (d, J= 3.6 Hz, 1H), 1.89 (s, 4H), 1.14 (dd, J= 6.8, 1.6 Hz, 2H), 0.74 (dd, J = 3.6, 2.0 Hz, 2H).

Example 34: Synthesis of 7-(cyclopropyl(5-(pyrrolidine-l-carbonyl)pyridin-2-yl)amino) -2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 34)

[00238] To a solution of pyrrolidine (100.0 mg, 0.31 mmol) in DMF (5 mL) was added DIPEA (120.0 mg, 0.93 mmol) and HATU (130.0 mg, 0.34 mmol). After 10 min, pyrrolidine (22.0 mg, 0.31 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 34 (8 mg, 7%). LCMS (ESI): m/z 379.2 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/ ₆ ): 6 8.39 (d, J= 2.0 Hz, 1 H), 7.95 (dd, J = 8.8, 2.4 Hz, 1 H), 7.73 (d, J= 7.6 Hz, 1 H), 7.34 (d, J= 8.8 Hz, 1 H), 6.99 (d, J= 1.2 Hz, 1 H), 6.60 (dd, J= 7.6, 2.0 Hz, 1 H), 3.50 (s, 3H), 3.50-3.40 (m, 4 H), 3.11-2.98 (m, 1 H), 1.84 (s, 4H), 1.08 (q, J= 6.8 Hz, 2H), 0.72-0.55 (m, 2H).

Example 35: Synthesis of 7-(cyclopropyl(5-(3,3-difluoropyrrolidine-l-carbonyl)pyridin -2- yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 35)

[00239] To a solution of AD-2 (100 mg, 0.31 mmol) in DMF (5 mL) was added DIPEA (120 mg, 0.93 mmol) and HATU (130 mg, 0.34 mmol). After 10 min, 3,3-difluoropyrrolidine (33 mg, 0.31 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was removed in vacuo andthe crude residue was purified by prep-HPLC to afford Compound 35 (21 mg, 16%). LCMS (ESI): m/z 415.1 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/ ₆ ): 8 8.41 (d, J= 2.0 Hz, 1H), 7.97 (dd, J= 8.8, 2.0 Hz, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 7.03 (d, J= 1.2 Hz, 1H), 6.62 (dd, J= 7.6, 1.6 Hz, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 3.51 (s, 3H), 3.11 - 3.00 (m, 1H), 2.48 - 2.39 (m, 2H), 1.09 (q, J= 6.8 Hz, 2H), 0.69-0.56 (m, 2H).

Example 36: Synthesis of 7-((5-(azetidine-l-carbonyl)pyridin-2-yl)(cyclopropyl)amino) -2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 36)

AD-2 Compound 36

[00240] To a solution of AD-2 (70 mg, 0.22 mmol) in DMF (2 mL) was added DIPEA (83 mg, 0.65 mmol), HATU (84 mg, 0.26 mmol) and azetidine (15 mg, 0.26 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to afford Compound 36 (2 mg, 3%). LCMS (ESI): m/z 365.2 [M+H] ⁺ . 'H NMR (400 MHz, MeOD v): 6 8.48 (d, J= 2.0 Hz, 1H), 8.03 (dd, J= 8.8, 2.4 Hz, 1H), 7.70 (dd, J = 7.6, 0.7 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 7.03 (d, J= 1.2 Hz, 1H), 6.72 (dd, J= 7.6, 2.0 Hz, 1H), 4.46 (t, J= 7.6 Hz, 2H), 4.20 (t, J= 7.6 Hz, 2H), 3.61 (s, 3H), 3.08-3.01 (m, 1H), 2.46-2.31 (m, 2H), 1.22 -1.07 (m, 2H), 0.80 - 0.66 (m, 2H).

Example 37: Synthesis of (S)-7-(cyclopropyl(5-(3-fluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 37)

^AD-2 Compound 37

[00241] To a solution of AD-2 (70 mg, 0.22 mmol) in DMF (2 mL) was added DIPEA (83 mg, 0.65 mmol), HATU (84 mg, 0.26 mmol) and (S)-3 -fluoropiperidine (27 mg, 0.26 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to afford Compound 37 (3 mg, 3%). LCMS (ESI): m/z 411.3 [M+H] ⁺ . 'H NMR (400 MHz, MeOD-d ₄ ) 6 8.29 (d, J= 2.0 Hz, 1H), 7.85 (dd, J= 8.8, 2.4 Hz, 1H), 7.69 (dd, J= 7.6, 0.4 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.00 (d, J= 1.2 Hz, 1H), 6.72 (dd, J= 7.6, 2.0 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.35 - 4.20 (m, 2H), 3.61 (s, 3H), 3.58 - 3.48 (m, 1H), 3.09 - 3.01 (m, 1H), 2.03 - 1.88 (m, 3H), 1.64 (s, 1H), 1.21 - 1.09 (m, 2H), 0.81 - 0.66 (m, 2H).

Example 38: Synthesis of 7-((5-(3-azabicyclo[3.1.1]heptane-3-carbonyl)pyridin-2- yl)(cyclopropyl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridi n-3(2H)-one (Compound 38)

AD-2 Compound 38

[00242] To a solution of AD-2 (80 mg, 0.25 mmol) in DMF (2 mL) was added DIPEA (95 mg, 0.74 mmol) and HATU (96 mg, 0.30 mmol). After 10 min, 3-azabicyclo[3.1.1]heptane (29 mg, 0.30 mmol) was added and the reaction mixture was stirred for RT for 2 h. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 38 (30 mg, 30%). LCMS (ESI): m/z 405.3 [M+H] ⁺ . ^X H NMR (400 MHz, DMSO-d ₆ ): 8 8.34 (dd, J= 2.4, 0.8 Hz, 1H), 7.91 (dd, J= 8.8, 2.4 Hz, 1H), 7.72 (dd, J= 7.6, 0.8Hz, 1H), 7.35 (dd, J= 8.8, 0.8 Hz, 1H), 6.97 (dd, J= 2.0, 0.8 Hz, 1H), 6.59 (dd, J= 7.6, 2.0 Hz, 1H), 3.74 (d, J= 2.8 Hz, 2H), 3.65 (t, J= 6.0 Hz, 2H), 3.50 (s, 3H), 3.30 (s, 2H), 3.11-2.95 (m, 1H), 2.37 (dt, J= 6.8, 3.5 Hz, 1H), 2.11 (ddd, J= 9.2, 6.6, 2.4 Hz, 2H), 1.49-1.25 (m, 2H), 1.11-0.95 (m, 2H), 0.76-0.56 (m, 2H).

Example 39: Synthesis of 7-(cyclopropyl(5-(3,3-difluoroazetidine-l-carbonyl)pyridin-2 - yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 39) [00243] To a solution of AD-2 (80 mg, 0.25 mmol) in DMF (2 mL) was added DIPEA (97 mg, 0.75 mmol) and HATU (99 mg, 0.26 mmol). After 10 min, 3,3-difluoroazetidine (35 mg, 0.38 mmol) was added and the reaction mixture wasstirred at RT for 1 h. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to afford Compound 39 (3 mg, 3%). LCMS (ESI): m/z 401.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/ ₆ ): 6 8.48 (d, J= 2.4 Hz, 1H), 8.04 (dd, J= 8.8, 2.4 Hz, 1H), 7.78 (dd, J= 7.6, 1.2 Hz, 1H), 7.34 (d, J= 8.8 Hz, 1H), 7.07 (dd, J= 2.0, 1.2 Hz, 1H), 6.61 (dd, J= 7.6, 2.0 Hz, 1H), 4.99-5.00 (m, 4H), 3.51 (s, 3H), 3.20-2.96 (m, 1H), 1.14 -1.02 (m, 2H), 0.69-0.58 (m, 2H).

Example 40: Synthesis of 7-(cyclopropyl(5-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolid ine-l- carbonyl)pyridin-2-yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a] pyridin-3(2H)-one (Compound 40)

[00244] To a solution of AD-2 (80 mg, 0.25 mmol) in DMF (2 mL) was added DIPEA (97 mg, 0.75 mmol) and HATU (99 mg, 0.26 mmol). After 10 min, ((25,45)-4-fluoropyrrolidin-2- yl)methanol (45 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to afford Compound 40 (7 mg, 6%). LCMS (ESI): m/z 427.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/ ₆ ): 8 8.37 (d, J= 2.0 Hz, 1H), 7.94 (dd, J= 8.4, 2.4 Hz, 1H), 7.73 (dd, J= 7.6, 1.2 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.00 (d, J= 1.2 Hz, 1H), 6.61 (dd, J= 7.6, 2.0 Hz, 1H), 5.31 (d, J= 56.0 Hz, 1H), 4.89 (t, = 5.6 Hz, 1H), 4.49-4.01 (m, 1H), 4.00-3.61 (m, 3H), 3.50 (s, 3H), 3.33-3.26 (m, 1H), 3.11- 3.00 (m, 1H), 2.39-2.05 (m, 2H), 1.12-1.05 (m, 2H), 0.78-0.57 (m, 2H).

Example 41: Synthesis of (R)-7-(cyclopropyl(5-(3-fluoropiperidine-l-carbonyl)pyridin- 2- yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 41)

AD-2 Compound 41

[00245] To a solution of AD-2 (80 mg, 0.25 mmol) in DMF (2 mL) was added DIPEA (97 mg, 0.75 mmol) and HATU (98.86 mg, 0.26 mmol). After 10 min, R)-3 -fluoropiperidine (39 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to afford Compound 41 (61 mg, 60%). LCMS (ESI): m/z 411.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/ ₆ ): 6 8.23 (d, J= 2.0 Hz, 1H), 7.80 (dd, J= 8.4, 2.4 Hz, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.36 (d, J= 8.6 Hz, 1H), 7.00 (d, J= 1.2 Hz, 1H), 6.61 (dd, J= 7.6, 2.0 Hz, 1H), 4.77 (d, J= 44.0 Hz, 1H), 3.39 -3.61(m, 2H), 3.58 -3.52 (m, 1H), 3.50 (s, 3H), 3.27-3.08 (m, 1H), 3.08-3.01 (m, 1H), 1.96-1.78 (m, 2H), 1.75-1.65 (m, 1H), 1.61-1.55 (m, 1H), 1.12-1.04 (m, 2H), 0.69-0.56 (m, 2H).

Example 42: Synthesis 7-((5-(5-azaspiro[2.5]octane-5-carbonyl)pyridin-2- yl)(cyclopropyl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridi n-3(2H)-one (Compound 42)

[00246] To a solution of AD-2 (80 mg, 0.25 mmol) in DMF (2 mL) was added DIPEA (97 mg, 0.75 mmol) and HATU (99 mg, 0.26 mmol). After 10 min, 5-azaspiro[2.5]octane (42 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to afford Compound 42 (35 mg, 33%). LCMS (ESI): m/z 419.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-t/ ₆ ): 6 8.21 (s, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.73 (dd, J= 7.6, 0.8 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 6.99 (dd, J= 2.0, 0.8 Hz, 1H), 6.61 (dd, J= 7.6, 2.0 Hz, 1H), 6.34-6.41 (m, 5H), 3.31-3.15 (m, 2H), 3.10-2.99 (m, 1H), 1.65-1.55 (m, 2H), 1.51-1.42 (m, 2H), 1.19-1.01 (m, 2H), 0.72-0.53 (m, 2H), 0.48-0.05 (m, 4H).

Example 43: Synthesis 7-((cyclopropylmethyl)(5-(4,4-difluoropiperidine-l-carbonyl) pyridin- 2-yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 43)

[00247] A mixture of methyl 6-fluoronicotinate (900 mg, 5.8 mmol) and cyclopropylmethanamine (6 mL) was heated to 100°C in a sealed tube overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography to afford AE-1 (700 mg, 58%). LCMS (ESI): m/z 207.1 [M+H] ⁺ .

[00248] To a solution of AE-1 (300 mg, 3.2 mmol) in PhMe (20 mL) was added 7-bromo-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (G-l) (365 mg, 1.6 mmol), Xantphos (252 mg, 0.43 mmol), Pd2(dba)3 (133 mg, 0.14 mmol) and CS2CO3 (947 mg, 2.9 mmol). The reaction mixture was stirred at 100 °C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-TLC to afford AE-2 (200.0 mg, 38%). LCMS (ESI): m/z 354.2 [M+H] ⁺ .

[00249] To a solution of AE-2 (200 mg, 0.56 mmol) in MeOH (5 mL) was added LiOH (118 mg, 2.8 mmol). The reaction mixture was stirred at 50 °C for 2 h and then acidified to pH 3 with HC1. The mixture was filtrated and the filtrate concentrated to afford AE-3 (120 mg, 62%). LCMS (ESI): m/z 340.2 [M+H] ⁺ .

[00250] To a solution of AE-3 (100 mg, 0.29 mmol) in DMF (2 mL) was added DIPEA (114 mg, 0.88 mmol), HATU (117 mg, 0.31 mmol) and 4,4-difluoropiperidine (53 mg, 0.43 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The crude residue was purified by prep-HPLC to afford Compound 43 (78 mg, 60%). LCMS (ESI): m/z 443.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO-de) 6 8.36 (d, J= 2.0 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.70 (dd, J= 8.8, 2.4 Hz, 1H), 7.03 (d, J= 1.2 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.50 (dd, J= 7.6, 2.0 Hz, 1H), 3.92 (d, J= 6.8 Hz, 2H), 3.61 (s, 3H), 3.51 (s, 3H), 3.30 (s, 1H), 2.04 (dt, J= 19.6, 6.8 Hz, 4H), 1.22-1.12 (m, 1H),

0.45-0.39 (m, 2H), 0.22 (d, J= 4.8 Hz, 2H).

Example 44: Synthesis 7-(l-(5-(4,4-difluoropiperidine-l-carbonyl)pyridin-2-yl)ethy l)-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (Compound 44)

[00251] To a solution of methyl 6-acetylnicotinate (500 mg, 2.94 mmol) in THF (20 mL) was added l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methan esulfonamide (1.57 g, 4.41 mmol) and LiHMDS (983 mg, 5.88 mmol) at -78 °C under N2. The reaction mixture was then warmed slowly to RT overnight. The reaction mixture was quenched with water and extracted with EtOAc, then the combined organic layers were dried (NazSC ) and concentrated under reduced pressure. The residue was purified by flash chromatography to afford AF-1 as a white solid (275 mg, 30%).

[00252] To a solution of AF-1 (275 mg, 0.88 mmol) in dioxane (15 mL) was added (2-methyl-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridin-7-yl)boronic acid (239 mg, 1.05 mmol), NazCOs (186 mg, 1.76 mmol) and Pd(dppf)C12 (129 mg, 0.18 mmol). The resulting mixture was stirred at 100 °C under N2 for 12 h. The reaction solution was diluted with water and extracted with EtOAc. The combined organic layers were dried (ISfeSCU) and concentrated under reduced pressure. The residue was purified by flash chromatography to afford AF-2 (130 mg, 47%) as a white solid. [00253] To a solution of AF-2 (50 mg, 0.16 mmol) in EtOAc (10 mL) was added Pd/C (5 mg) at RT. The mixture was degassed and backfilled with H2. The reaction mixture was stirred at 0 °C for 1 h. The reaction solution was diluted with water and extracted with DCM. The combined organic layers dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep- HPLC to afford AF-3 (40 mg, 80%) as a white solid.

[00254] To a solution of AF-3 (40 mg, 0.13 mmol) in MeOH (10 mL) was added LiOH (22 mg, 0.52 mmol). The resulting mixture was stirred at RT for 1 h. The reaction solution was diluted with water and extracted with EtOAc. The combined organic layers dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the compound AF-4 (30 mg, 78%) as a white solid.

[00255] To a solution of AF-4 (30 mg, 0.10 mmol) in DMF (5 mL) was added 4,4- difluoropiperidine (23.8 mg, 0.20 mmol), DIPEA (26 mg, 0.20 mmol) and HATU (38 mg, 0.10 mmol). The resulting mixture was stirred at RT for 2 h until TLC and LCMS showed the reaction was complete. The crude reaction mixture was purified directly by prep-HPLC to afford Compound 44 (1 mg, 5%) as a white solid. LCMS (ESI): m/z 402.3 [M+H] ⁺ . 'H NMR (400 MHz, MeOD-tL): 8 8.62 (d, J= 1.6 Hz), 7.87 (dd, J= 8.0, 2.0 Hz), 7.70 (dd, J= 7.2, 0.8 Hz), 7.48 (d, J= 8.0 Hz), 7.10 (s), 6.60 (dd, J= 7.2, 1.2 Hz), 4.31 (q, J= 7.2 Hz), 3.94-3.50 (m), 2.06 (s), 1.69 (d, J = 7.2 Hz).

Example 45: Synthesis 7-((6-(4,4-difluoropiperidine-l-carbonyl)-2-methoxypyridin-3 - yl)amino)-2-methyl-[l,2,4]triazolo[4,3-a]pyi'idin-3(2H)-one (Compound 45)

AG-2 Compound 45 [00256] To a solution of 6-methoxy-5-nitropicolinic acid (400 mg, 2.02 mmol) in DMF (10 mL) was added DIPEA (782 mg, 6.06 mmol) and HATU (844.0 mg, 2.22 mmol) at 20 °C. After 10 min, 4,4-difluoropiperidine (293 mg, 2.42 mmol) was added and the reaction mixture stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography to afford AG-1 (415 mg, 68%). LCMS (ESI): m/z 302.1 [M+H] ⁺ .

[00257] To a solution of AG-1 (400 mg, 1.33 mmol) in MeOH (10 mL) was added Pd/C (80.0 mg). The reaction mixture was stirred at RT under EE (15 psi) overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford AG-2 (350 mg, 97%). LCMS (ESI): m/z 272.2 [M+H] ⁺ ,

[00258] To a solution of AG-2 (350 mg, 1.29 mmol) in dioxane (10 mL) was added 7-bromo-2- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (293.0 mg, 1.29 mmol), Xantphos (299 mg, 0.52 mmol), Pd2(dba)3 (236 mg, 0.26 mmol) and CS2CO3 (1.3 g, 3.87 mmol). The reaction mixture was stirred at 100°C under N2 overnight. The solvent was removed in vacuo and the residue was purified by prep-HPLC to afford Compound 45 (54 mg, 10%). LCMS (ESI): m/z 419.2 [M+H] ¹⁺ . 'H NMR (400 MHz, DMSO ): 8 8.57 (s, 1H), 7.79 (dd, J= 11.6, 7.6 Hz, 2H), 7.34 (d, J= 7.6 Hz, 1H), 6.62 (dd, J= 7.6, 2.0 Hz, 1H), 6.36 (d, J= 1.2 Hz, 1H), 3.95 (s, 3H), 3.76 (t, 1.4 Hz, 4H), 3.43 (s, 3H), 2.09 (s, 4H).

Example 46: 15-PGDH Biochemical Assay

[00259] The biochemical assay was performed using the 15-PGDH Inhibitor Screening Kit supplied by PromoKine (Cat. number PK-CA577-K503).

[00260] 15-PG was oxidized by 15-PDGH generating 15-Keto metabolites and oxidizing NAD. NADH reduces a Fluorometric probe and thus, generating an enhanced and stable fluorescence signal which was measured kinetically at 25 °C during 1 hour (Ex: 530/25; Em: 590/35). Initial velocity was observed during the first 20 minutes of the assay for which the slope was determined by dividing the net ARFU values by the time At. Enzymatic inhibition of the test compounds was evaluated by measuring the enzyme activity in the presence of the test compound at a concentration range between 10,000 and 2.4 nM. The % Relative Activity is calculated to the enzyme control condition (in the absence of inhibitor) which is defined as 100 % activity. The concentration for 50% inhibition from the concentration-response curves of the test compounds is represented as the IC50 value and shown in Table 1. Table 1

[00261] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.