HSD17B13 INHIBITORS AND USES THEREOF

Described herein are compounds that are HSD17B13 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with HSD17B13 activity.

FIELD OF THE INVENTION

Described herein are compounds that are hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with HSD17B13 activity.

BACKGROUND OF THE INVENTION

Hydroxysteroid dehydrogenase 17β13 (HSD17b13) is a member of the short-chain dehydrogenase/reductase enzymes highly expressed in the liver on lipid droplets. It has been shown to oxidize retinol, steroids such as estradiol, and bio-active lipids like leukotriene B4. Loss of HSD17b13 expression and enzymatic activity is associated with decreased incidence of liver disease. Inhibition of HSD17b13 enzymatic activity can be used for the treatment of liver diseases that result in hepatic inflammation, fibrosis, cirrhosis, and development of hepatocellular carcinoma.

SUMMARY OF THE INVENTION

In one aspect, described herein is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof:

wherein:J is

In another aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein:J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II′):

In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9). In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is H. In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is C1-6alkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III′):

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IV′):

In some embodiments is a compound of Formula (I′), (I), (III′), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is N. In some embodiments is a compound of Formula (I′), (I), (III′), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4. In some embodiments is a compound of Formula (I′), (I), (III′), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (I′), (I), (III′), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H, halogen, C1-6alkyl, or —N(R10)(R11). In some embodiments is a compound of Formula (I′), (I), (II′), (III′), or (IV′), a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N. In some embodiments is a compound of Formula (I′), (I), (II′), (III′), or (IV′), a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are CR3.

In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa′):

In some embodiments is a compound of Formula (I′), (I), or (III′), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa′):

In some embodiments is a compound of Formula (I′), (I), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa′):

In some embodiments is a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C6-10aryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is H. In some embodiments is a compound of Formula (I), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halogen.

In one aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

In another aspect, described herein is a method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the liver disease or condition is an alcoholic liver disease or condition. In some embodiments, the liver disease or condition is a nonalcoholic liver disease or condition. In some embodiments, the liver disease or condition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof.

In another aspect, described herein is a method of treating a disease or condition in a mammal that would benefit from hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) inhibition comprising administering a compound as described herein, or pharmaceutically acceptable salt or solvate thereof, to the mammal in need thereof. In some embodiments, the disease or condition in a mammal that would benefit from HSD17B13 inhibition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof. In some embodiments, the disease or condition in a mammal that would benefit from HSD17B13 inhibition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof.

In another aspect, described herein is a method of modulating hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) activity in a mammal, comprising administering to the mammal a compound of Formula (I′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, modulating comprises inhibiting HSD17B13 activity. In some embodiments of a method of modulating HSD17B13 activity in a mammal, the mammal has a liver disease or condition selected from liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, and combinations thereof. In some embodiments of a method of modulating HSD17B13 activity in a mammal, the mammal has a liver disease or condition selected from primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and combinations thereof.

In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.

In any of the embodiments disclosed herein, the mammal or subject is a human.

In some embodiments, compounds provided herein are administered to a human.

In some embodiments, compounds provided herein are orally administered.

Articles of manufacture, which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from HSD17B13 inhibition, are provided.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Hydroxysteroid dehydrogenase 17ß13 (HSD17b13) is a member of the short-chain dehydrogenase/reductase enzymes highly expressed in the liver on lipid droplets (Horiguchi et alBiochem Biophysl Res Comm,2008, 370, 235). It has been shown to oxidize retinol, steroids such as estradiol, and bio-active lipids like leukotriene B4 (Abul-Husn et al NEJM, 2018, 378, 1096 and Ma et al Hepatology, 2019, 69 1504). Exosome sequencing analysis of a large patient population identified a minor allele of HSD17b13 (rs72613567: TA) that was associated with reduced odds of developing liver disease (Abul-Husn et al NEJM, 2018, 378, 1096). Relative to subjects with the common HSD17b13 allele (rs72613567: T), subjects with the TA variant have lower serum ALT and AST and lower odds of alcoholic liver disease with or without cirrhosis, nonalcoholic liver disease with or without cirrhosis, and lower odds of hepatocellular carcinoma. Liver pathology analysis reveals that the subjects with the rs72613567: TA allele have decreased odds of having liver pathology analysis classified as NASH vs normal, NASH vs simple steatosis or NASH with fibrosis vs simple steatosis. Liver injury associated with the PNPLA3 rs738409 (p.I148M) is mitigated by the presence of the rs72613567: TA allele of HSD17b13. Additionally hepatic PNPLA3 mRNA expression is decreased in subjects with the rs72613567: TA allele. The rs72613567: TA allele was found to produce a truncated protein which is unable to metabolize substrates such as estradiol, suggesting the hepatic protective effects of the rs72613567: TA allele is due to loss of enzymatic activity.

Patients with NASH have shown elevated expression of hepatic of HSD17b13 mRNA relative to control subject. Further exploration of the role of HSD17b13 in NASH development identified a minor allele rs62305723 that encodes a P260S mutation of HSD17b13 that leads to loss of retinol metabolism and is associated with decreased hepatic ballooning and inflammation (Ma et al Hepatology, 2019, 69 1504).

HSD17b13 rs72613567: TA minor allele is associated with loss of HSD17b13 protein expression in the liver and protection from nonalcoholic steatohepatitis, ballooning degeneration, lobular inflammation and fibrosis. Transcription analysis shows changes in immune-responsive pathways in subjects with rs72613567: TA relative to the major allele (Pirolat et al JLR, 2019, 60, 176).

Subjects with the rs72613567: TA allele of HSD17b13 are not only found to have lower histological evidence of fibrosis, but decreased hepatic expression of fibrotic genes like TGFb2 and Col3a1. In addition loss of HSD17b13 due to the rs72613567: TA allele has been shown to significantly change the expression of inflammatory gene ALOX5 and decreased plasma IL1b, IL6 and IL-10 (Luukkonen et al, JCI, 2020, 5 e132158). HSD17b13 rs72613567: TA carriers also show increased hepatic phospholipids PC (p16:0/16:0), PE (p16:0/18:1), PC (44: 5e), PC (36: 2e), PE (34:0), PE (36:3) and PC (34:3) possibly due to decreased phospholipid degradation from a decreased hepatic expression of PLD4.

The HSD17b13 rs72613567: TA allele, that has been shown to lack HSD17b13 enzymatic activity, is associated with decreased odds of developing severe fibrosis in patients with chronic HCV infection (About & Abel, NEJM, 2018, 379, 1875). Conversely the major allele rs72613567: T is associated with increasing the risk of development of fibrosis, cirrhosis and HCC in HCV infected patients with the PNPLA3 rs738409: G allele (De Benedittis et al. Gastroenterol Res Pract, 2020, 2020, 4216451).

The loss of function minor allele HSD17b13 rs72613567: TA reduces the risk of developing cirrhosis and hepatocellular carcinoma, is associated with a lower risk of liver-related mortality in the general population and further in patients with cirrhosis (Gellbert-Kristensen et al, Hepatology, 2020, 71, 56). Loss of HSD17b13 function also protects against development of HCC in subjects with alcoholic liver disease (Yang et al, Hepatology, 2019, 70, 231 and Stickel et al, Hepatology, 2020, 72, 88).

PNPLA3 rs738409: G is associated with increased fibrosis in patients with NAFLD. The minor HSD17b13 rs72613567: TA allele has been shown to counteract the PNPLA3 rs738409: G allele and decrease the prevalence of severe inflammation, ballooning and fibrosis (Seko et al, Liver Int, 2020, 40, 1686).

Loss of HSD17b13 enzymatic activity due to carrying the rs72613567: TA allele may delay the onset of autoimmune hepatitis (Mederacke et al, Aliment Pharmacol Ther, 2020, 00, 1).

HSD17b13 rs72613567: TA allele is associated with decreased fibrosis and cirrhosis in patents with copper induced liver injury from Wilson's disease (Ferenci et al, 2019, JHEP, 1, 2).

Compounds

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof:

wherein:J is

wherein:J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9) and R9is selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9) and R9is H. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9) and R9is C1-6alkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is C(R4)2. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is C(R4)2and each R4is independently selected from H, halogen, C1-6alkyl, and —N(R10)(R11). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is C(R4)2and each R4is independently selected from H and C1-6alkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4and R4is H, halogen, C1-6alkyl, or —N(R10)(R11).

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, or C1-6alkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, and C1-6haloalkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(F), and X3is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(Cl). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CH3). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(Cl).

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from H, halogen, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is H. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halogen. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is F. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-6alkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-6haloalkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OR10. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OH. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OCH3.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —O—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(R10)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —C(R10)(R11) N(R10)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is-CH2N(H)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(R10)C(R10)(R11)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)CH2—.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C3-8cycloalkyl and C2-9heterocycloalkyl, wherein C3-8cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl unsubstituted with R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl, wherein piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from C1-6alkyl, —OR10, —C(O)OR10, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from —C(O)R13and —S(O)2R13. In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl unsubstituted with R6.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R′ is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl unsubstituted with R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl are substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C6-10aryl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl substituted with one, two, or three R7. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl unsubstituted with R7.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from oxo, C1-6alkyl, —OR10, —C(O)OR10, —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is unsubstituted C1-6alkylene. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is —CH2—.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is phenyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted phenyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C1-9heteroaryl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C1-9heteroaryl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C3-6cycloalkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C3-6cycloalkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C2-6alkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C2-6alkyl.

In some embodiments is a compound of Formula (II′), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9) and R9is selected from H and C1-6alkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9) and R9is H. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is N(R9) and R9is C1-6alkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is C(R4)2. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is C(R4)2and each R4is independently selected from H, halogen, C1-6alkyl, and —N(R10)(R11). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2is C(R4)2and each R4is independently selected from H and C1-6alkyl.

In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, or C1-6alkyl.

In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, and C1-6haloalkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(F), and X3is C(H). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(Cl). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CH3). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(Cl).

In some embodiments is a compound of Formula (II′), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa′):

In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa):

In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is selected from H and C1-6alkyl. In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is C1-6alkyl. In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is —CH3. In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is H.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from H, halogen, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is H. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halogen. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is F. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-6alkyl. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-6haloalkyl. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OR10. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OH. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OCH3.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are CR5. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is N; and Z2and Z3are CR5. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is N; and Z1and Z3are CR5. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is N; and Z1and Z2are CR5. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is CR5; and Z2and Z3are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is CR5; and Z1and Z3are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is CR5; and Z1and Z2are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from H, halogen, —CN, C1-6alkyl, and —OR10. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is H. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is N; and Z2and Z3are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is N; and Z1and Z3are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is N; and Z1and Z2are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is C(H); and Z2and Z3are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is C(H); and Z1and Z3are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is C(H); and Z1and Z2are N.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —O—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(R10)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —C(R10)(R11) N(R10)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —CH2N(H)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(R10)C(R10)(R11)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)CH2—.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C3-8cycloalkyl and C2-9heterocycloalkyl, wherein C3-8cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl unsubstituted with R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl, wherein piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from C1-6alkyl, —OR10, —C(O)OR10, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from —C(O)R13and —S(O)2R13. In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl unsubstituted with R6.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl unsubstituted with R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl are substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C6-10aryl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl substituted with one, two, or three R7. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl unsubstituted with R7.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from oxo, C1-6alkyl, —OR10, —C(O)OR10, —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is unsubstituted C1-6alkylene. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is —CH2—.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is phenyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted phenyl.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C1-9heteroaryl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C1-9heteroaryl.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C3-6cycloalkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C3-6cycloalkyl.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C2-6alkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C2-6alkyl.

In some embodiments is a compound of Formula (III′), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, or C1-6alkyl.

In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is N. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4and R4is H, halogen, C1-6alkyl, or —N(R10)(R11).

In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, and C1-6haloalkyl. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(F), and X3is C(H). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(Cl). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CH3). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(Cl).

In some embodiments is a compound of Formula (III′), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa′):

In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):

In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, and C1-6haloalkyl. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H, halogen, C1-6alkyl, or —N(R10)(R11). In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is H. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is halogen. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-6alkyl. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is —CH3. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is —N(H)CH3.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from H, halogen, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is H. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halogen. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is F. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-6alkyl. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-6haloalkyl. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OR10. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is —OH. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is-OCH3.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are CR5. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is N; and Z2and Z3are CR5. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is N; and Z1and Z3are CR5. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is N; and Z1and Z2are CR5. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is CR5; and Z2and Z3are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is CR5; and Z1and Z3are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is CR5; and Z1and Z2are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from H, halogen, —CN, C1-6alkyl, and —OR10. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is H. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is N; and Z2and Z3are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is N; and Z1and Z3are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is N; and Z1and Z2are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1is C(H); and Z2and Z3are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2is C(H); and Z1and Z3are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is C(H); and Z1and Z2are N.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —O—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(R10)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —C(R10)(R11) N(R10)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —CH2N(H)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is-N(R10)C(R10)(R11)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)CH2—.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C3-8cycloalkyl and C2-9heterocycloalkyl, wherein C3-8cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl unsubstituted with R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl, wherein piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from C1-6alkyl, —OR10, —C(O)OR10, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from —C(O)R13and —S(O)2R13. In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl unsubstituted with R6.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl unsubstituted with R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl are substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C6-10aryl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl substituted with one, two, or three R7. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl unsubstituted with R7.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from oxo, C1-6alkyl, —OR10, —C(O)OR10, —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is unsubstituted C1-6alkylene. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is —CH2—.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is phenyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted phenyl.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C1-9heteroaryl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C1-9heteroaryl.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C3-6cycloalkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C3-6cycloalkyl.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C2-6alkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C2-6alkyl.

In some embodiments is a compound of Formula (IV′), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is N. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y3is CR4and R4is H, halogen, C1-6alkyl, or —N(R10)(R11).

In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is CR4and R4is H, halogen, or C1-6alkyl.

In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3are each CR3and each R3is independently selected from H, halogen, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(F), and X3is C(H). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(Cl). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(F), X2is C(H), and X3is C(CH3). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(Cl), X2is C(H), and X3is C(H). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(CF3). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(F). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X1is C(H), X2is C(H), and X3is C(Cl).

In some embodiments is a compound of Formula (IV′), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa′):

In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa):

In some embodiments is a compound of Formula (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR10. In some embodiments is a compound of Formula (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from H, halogen, and C1-6haloalkyl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —O—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(R10)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —C(R10)(R11) N(R10)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —CH2N(H)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is-N(R10)C(R10)(R11)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is —N(H)CH2—.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C3-8cycloalkyl and C2-9heterocycloalkyl, wherein C3-8cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl unsubstituted with R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl, wherein piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, diazepanyl, 6-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 5,8-diazaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, or 2,6-diazaspiro[3.3]heptanyl are optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from C1-6alkyl, —OR10, —C(O)OR10, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)2R13, and —S(O)2N(R10)(R11)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from —C(O)R13and —S(O)2R13. In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl optionally substituted with one, two, or three R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl substituted with one, two, or three R6. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-8cycloalkyl unsubstituted with R6.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl unsubstituted with R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl are substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C6-10aryl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl optionally substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl substituted with one, two, or three R7. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is phenyl unsubstituted with R7.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from oxo, C1-6alkyl, —OR10, —C(O)OR10, —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —C(O)N(R10)(R11), —S(O)R13, and —S(O)2N(R10)(R11)—.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is unsubstituted C1-6alkylene. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is —CH2—.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is phenyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted phenyl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C1-9heteroaryl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C1-9heteroaryl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C3-6cycloalkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C3-6cycloalkyl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C2-6alkyl optionally substituted with one, two, or three R14. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is unsubstituted C2-6alkyl.

In some embodiments, compounds described herein include, but are not limited to, those described in Table 1.

In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.

In some embodiments, compounds described herein include, but are not limited to, those described in Table 2.

In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 2.

In another aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors,Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal fluids than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a “pharmaceutically acceptable base addition salt.”

In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl) methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound 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 compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.

In some embodiments, sites on the organic groups (e.g., alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic groups will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented 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 can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein is replaced with deuterium.

In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, 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/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. The prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. In some embodiments, a prodrug of the compound disclosed herein permits targeted delivery of the compound to a particular region of the gastrointestinal tract. Formation of a pharmacologically active metabolite by the colonic metabolism of drugs is a commonly used “prodrug” approach for the colon-specific drug delivery systems.

In some embodiments, a prodrug is formed by the formation of a covalent linkage between drug and a carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine. This approach involves the formation of a prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug. Formation of prodrugs has improved delivery properties over the parent drug molecule. The problem of stability of certain drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by prodrug formation, which is converted into the parent drug molecule once it reaches the colon. Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.

In some embodiments, covalent linkage of the drug with a carrier forms a conjugate. Such conjugates include, but are not limited to, azo bond conjugates, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates or amino-acid conjugates.

In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

In additional or further embodiments, the compounds are rapidly metabolized in plasma.

In additional or further embodiments, the compounds are rapidly metabolized by the intestines.

In additional or further embodiments, the compounds are rapidly metabolized by the liver.

Synthesis of Compounds

Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March's Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

In some embodiments, compounds are prepared as described in the Examples.

Certain Terminology

Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

As used herein, C1-Cxincludes C1-C2, C1-C3. . . C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1-C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers to a divalent alkyl group. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4alkylene). Typical alkylene groups include, but are not limited to, —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2CH2—, —CH2CH(CH3)—, —CH2C(CH3)2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, and the like.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula-C(R)═CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include-CH—CH2, —C(CH3)—CH2, —CH═CHCH3, —C(CH3)═CHCH3, and —CH2CH═CH2.

The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula —C≡C—R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include —C≡CH, —C≡CCH3—C≡CCH2CH3, —CH2C≡CH.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as defined herein.

The term “alkylamine” refers to the —N(alkyl)xHygroup, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic group, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fully saturated. In some embodiments, cycloalkyls are partially unsaturated. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like

The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., —NH—, —N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl.

The term “heteroalkylene” refers to a divalent heteroalkyl group.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, benzotriazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1˜4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1˜4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyls are spirocyclic or bridged compounds. In some embodiments, heterocycloalkyls are fully saturated. In some embodiments, heterocycloalkyls are partially unsaturated. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

The terms “kit” and “article of manufacture” are used as synonyms.

The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.

In some embodiments, a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g., such as the colon), include:(i) Coating with polymers: The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon.(ii) Coating with pH-sensitive polymers: The majority of enteric and colon targeted delivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. Most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100and S 100 are copolymers of methacrylic acid and methyl methacrylate. Additional pH-dependent coating polymers include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP) and cellulose acetate trimelliate.(iii) Coating with biodegradable polymers;(iv) Embedding in matrices;(v) Embedding in biodegradable matrices and hydrogels;(vi) Embedding in pH-sensitive matrices;(vii) Timed release systems;(viii) Redox-sensitive polymers;(ix) Bioadhesive systems;(x) Coating with microparticles;(xi) Osmotic controlled drug delivery.

Another approach towards colon-targeted drug delivery or controlled-release systems includes embedding the drug in polymer matrices to trap it and release it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of an HSD17B13 inhibitor. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

In some embodiments, described herein is a method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of Formula (I′), (I), (II′), (II), (IIa′), (IIa), (III′), (III), (IIIa′), (IIIa), (IV′), (IV), (IVa′), or (IVa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating or preventing an alcoholic or nonalcoholic liver disease or condition in a mammal, comprising administering to the mammal a compound of Formula (I′), (I), (II′), (II), (IIa′), (IIa), (III′), (III), (IIIa′), (IIIa), (IV′), (IV), (IVa′), or (IVa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the liver disease or condition is an alcoholic liver disease or condition. In some embodiments, the liver disease or condition is a nonalcoholic liver disease or condition. In some embodiments, the liver disease or condition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof. In some embodiments, the liver disease or condition is a chronic liver disease or condition.

In some embodiments, described herein is a method of modulating HSD17B13 activity in a mammal, comprising administering to the mammal a compound of Formula (I′), (I), (II′), (II), (IIa′), (IIa), (III′), (III), (IIIa′), (IIIa), (IV′), (IV), (IVa′), or (IVa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, modulating comprises inhibiting HSD17B13 activity. In some embodiments of a method of modulating HSD17B13 activity in a mammal, the mammal has a liver disease or condition selected from liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, and combinations thereof. In some embodiments of a method of modulating HSD17B13 activity in a mammal, the mammal has a liver disease or condition selected from primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and combinations thereof.

In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

In certain embodiments wherein a patient's status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder, or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

EXAMPLES

Trifluoroacetic acid (5.25 mL, 68.6 mmol) was added to a solution of tert-butyl(R)-2-benzyl-4-(methylsulfonyl)piperazine-1-carboxylate (1.05 g, 2.96 mmol) in CH2Cl2(15 mL) at rt. The mixture was stirred for 2 h and then concentrated to obtain (R)-3-benzyl-1-(methylsulfonyl)piperazine TFA salt (1.20 g) as a yellow oil. LCMS: 255.2 [M+H]+.

The Intermediates below were synthesized from the appropriate Boc-protected piperazine following the procedures described for Intermediate 2.

Hydrochloric acid (4 M in dioxane, 0.60 mL, 2.40 mmol) was added to a solution of tert-butyl(R)-3-(4-methoxybenzyl)morpholine-4-carboxylate (65 mg, 0.21 mmol) and CH2Cl2(1 mL) at rt. The mixture was stirred for 1.5 h, concentrated, and then dried on high vacuum overnight to give (R)-3-(4-methoxybenzyl)morpholine hydrochloride (45 mg) as an off-white solid. LCMS: 208.4 [M+H]+.

The Intermediates below were synthesized from Intermediate 3, Step 1 and the appropriate boronic acid following the procedures described for Intermediate 3, Steps 2-3.

n-Butyllithium (2.5 M in hexanes, 171 mL, 428 mmol) was added dropwise to a mixture of 2,4-difluoro-1-(trifluoromethyl)benzene (60.0 g, 329 mmol) in Et2O (˜400 mL) at −78° C. under N2. The reaction was stirred for 1 h. Trimethyl borate (44.7 mL, 395 mmol) in Et2O (200 mL) was added dropwise at −78° C. The reaction was stirred for 1 h, allowed to warm to rt, stirred for 10 h, and then quenched slowly with aq. HCl (1 M, 500 mL) under ice cooling. The organic layer was separated and washed with brine (300 mL) to give (2,6-difluoro-3-(trifluoromethyl)phenyl)boronic acid as a solution in Et2O (˜600 mL). LCMS: 225.1 [M−H]−.

Hydrogen peroxide (166 mL, 1.72 mol, 30% purity in H2O) was added to a solution of (2,6-difluoro-3-(trifluoromethyl)phenyl)boronic acid (74.4 g, 329 mmol) in Et2O (˜600 mL) at 0° C. The mixture was heated to 40° C., stirred for 4 h, and then allowed to cool to rt. The aqueous layer was separated. The organic layer was cooled to 0° C. and then quenched with aqueous Na2SO3(20% in H2O, ˜500 mL) keeping the temperature<20° C. The organic layer was separated. The aqueous layer was extracted with EtOAc (2×300 ml). The organic layers were combined, washed with water (2×300 ml), washed with brine (300 ml), dried (Na2SO4), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate=50:1 to 5:1) to give 2,6-difluoro-3-(trifluoromethyl)phenol (41.3 g, 63%) as a yellow oil.1H NMR (400 MHZ, DMSO-d6): δ 11.01 (s, 1H), 7.27-7.19 (m, 2H); LCMS: 196.9 [M−H]−.

The Intermediate below was synthesized from 2-chloro-4-fluoro-1-(trifluoromethyl)benzene following the procedures described for Intermediate 4.

1,3-Dichloro-5,5-dimethylhydantoin (5.52 g, 19.31 mmol) was added to the mixture of 3-bromo-2-fluoro-5-(trifluoromethyl)phenol (5.00 g, 19.3 mmol) and diisopropylamine HCl (0.03 g, 0.19 mmol) in toluene at 0° C. The yellow suspension was stirred at 0° C. in the absence of light for 2 h, diluted with water, and then extracted with ethyl acetate. The organic layer was dried (MgSO4), concentrated, and then purified by silica gel chromatography (0-50% CH2Cl2in heptane). The crude material was purified further by prep-HPLC (40-100% CH3CN in water with 0.1% TFA). The fractions were combined, concentrated, diluted with ethyl acetate, and then washed with NaHCO3. The aqueous layer was back extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered, and then concentrated to give 3-bromo-6-chloro-2-fluoro-5-(trifluoromethyl)phenol (3.3 g, 55%) as a white semi-solid.1H NMR (400 MHZ, DMSO-d6): δ 6.49-6.42 (m, 1H).

Hydrogen peroxide (30 w/w in H2O, 69 mL) was slowly added to a solution of 2-(3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.6 g, 61 mmol) in methanol (240 mL). The clear solution was stirred at rt for 5 h, quenched by the slow addition of saturated aqueous Na2S2O3solution over ˜1 h, stirred for 30 min, and then extracted twice with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure, and then purified by silica gel chromatography (0-20% EtOAc/heptane) to give 3-bromo-2,6-difluoro-5-(trifluoromethyl)phenol (16.9 g, 73%) as a semi-solid.1H NMR (400 MHZ, DMSO-d6): δ 11.62 (s, 1H), 7.56 (t, J=6.8 Hz, 1H).

The Intermediates below were synthesized from the appropriate Intermediate or starting material following the procedures described for Intermediate 6.

The Intermediate below was synthesized from 2,6-difluoro-3-(trifluoromethyl)phenol (Intermediate 4, Step 2) using the following sequence: Intermediate 6 (Step 3) and then Intermediate 7.

The Intermediate below was synthesized from 2-(benzyloxy)-1-chloro-3,5-difluorobenzene in a similar manner to that described in Intermediate 7.01, Step 2.

A mixture of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (8.83 g, 57.1 mmol), N-iodosuccinimide (3.86 g 17.1 mmol), and DMF (90 mL) was stirred at rt overnight. Additional N-iodosuccinimide (3.86 g 17.1 mmol) was added. The reaction was stirred overnight. Additional N-iodosuccinimide (3.86 g 17.1 mmol) was added. The reaction was stirred for 1.5 h. Water was added. The reaction was extracted with 10% CH3OH in CH2Cl2(×3). The combined organics were dried (MgSO4), filtered, and concentrated. Toluene was added, and then the solution was concentrated to remove DMF. Water (500 mL) was added. Solids formed. The mixture was filtered, and the filter cake was washed with water. The solids were dried on a lyophilizer to give 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (12.3 g, 73%) as a beige solid.1H NMR (400 MHZ, DMSO-d6): δ 14.57 (br s, 1H), 9.31 (s, 1H); LCMS: 280.7 [M+H]+.

The Intermediate below was synthesized from 5-chloro-1H-pyrazolo[4,3-d]pyrimidine following the procedure described for Intermediate 10, Step 2-3.

3-Benzyl-4-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)morpholine (56 mg, 0.24 mmol) was dissolved in 4 mL CH2Cl2and 2 mL TFA. The solution was stirred at rt overnight and then concentrated to give 3-benzyl-4-(3-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)morpholine (38 mg, 49%) as a yellow oil. LCMS: 309.3 [M+H]+.

The Intermediates below were synthesized from the appropriate Intermediate or starting material following the procedures described for Intermediate 11.

The Intermediate below was synthesized from 6-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine following the procedure described for Intermediate 12.

The Intermediates below were synthesized from the appropriate Intermediate and the appropriate starting material following the procedures described for Intermediate 13.

The Intermediates below were synthesized from the appropriate Intermediate and the appropriate amine following the procedure described for Intermediate 14.

tert-Butyl 3-(cyclopropylmethyl)-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (125 mg, 0.251 mmol) was weighed into an 8 mL vial. Dichloromethane (1 mL) and TFA (200 μL) were added. The reaction was stirred at rt for 5 h, concentrated, diluted with CH2Cl2(1 mL), concentrated, diluted with CH2Cl2(1 mL), and then concentrated to give 6-(2-(cyclopropylmethyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine, which was used in the next step without purification.

The Intermediate below was isolated during the purification of Intermediate 15, Step 3.

LiOH·H2O (3.45 g, 82.2 mmol) was added to a mixture of 2-(2-chloroacetamido)-3-cyclohexylpropyl 2-chloroacetate (5.1 g, 16.4 mmol) and THF (50 mL). The reaction was stirred at rt for 2 h, diluted with H2O (30 mL), and then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give 2-chloro-N-(1-cyclohexyl-3-hydroxypropan-2-yl) acetamide (3.75 g) as a yellow oil. LCMS: 234.2 [M+H]+.

A solution of NaN3(1.55 g, 23.8 mmol) an water (5 mL) was added dropwise to the solution of 4-benzyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic (isobutyl carbonic) anhydride (˜5.96 mmol; estimated by LCMS purity) in THF (50 mL) at −15° C. under N2. The reaction mixture was allowed to warm to rt, stirred overnight, poured into ice/water (100 mL), and extracted with toluene (30 mL×3). The combined organic layers were dried over Na2SO4, filtered, and then concentrated to ˜90 mL to give a yellow solution of tert-butyl 4-(azidocarbonyl)-4-benzylpiperidine-1-carboxylate in toluene.

The Intermediate below was synthesized from 3-benzyl-1-(tert-butoxycarbonyl) piperidine-3-carboxylic acid following the procedures described for Intermediate 18.

BH3·THF (1 M in THF, 3.74 mL) was added to a solution of (3R,4R)-4-benzyl-1-(tert-butyldimethylsilyl)-3-(methylthio) azetidin-2-one (301 mg, 0.936 mmol) and THF (10 mL) at 0° C. The reaction was stirred at rt for 12 h, and then MeOH (10 mL) was added. The reaction was heated at 75° C. for 2 h, allowed to cool to rt, and then concentrated to give (2R,3S)-2-benzyl-3-(methylthio) azetidine (165 mg) as colorless oil. LCMS: 194.2 [M+H]+.

A mixture of (R)-3-benzyl-1-ethylpiperazine hydrochloride (3.0 g, 12.46 mmol), Ambersep 900 OH anion exchange resin (250 mg), and MeOH (20 mL) was stirred at rt for 30 min. The reaction was filtered, and the filtrate was concentrated to give (R)-3-benzyl-1-ethylpiperazine (2.1 g) as a white solid.

BH3·THF (1 M in THF, 7.4 mL) was slowly added to a mixture of (R)-5-benzylthiomorpholin-3-one (0.51 g, 2.46 mmol) and THF (2 mL) at 25° C. The reaction was stirred at 70° C. for 2 h, cooled to rt, quenched with MeOH (˜50 mL), and then concentrated. The residue, EtOAc (10 mL), and 1 M NaOH (20 mL) was stirred for 0.5 h and then extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated to give (R)-3-benzylthiomorpholine (402 mg) as a yellow oil. LCMS: 194.1 [M+H]+.

The Compounds below were synthesized from Intermediate 1 and the appropriate amine following the procedures described for Compound 1.

The Compounds below were synthesized from the appropriate Intermediate and the appropriate aryl halide following the procedure described for Compound 2.

The Compounds below were synthesized from the appropriate Intermediate and the appropriate amine following the procedure described for Compound 3.

The Compounds below were synthesized from Intermediate 13.05 and the appropriate amine following the procedure described for Compound 4.

The Compounds below were synthesized from the appropriate Intermediate and the appropriate amine following the procedure described for Compound 5.

A mixture of (R)-tert-butyl 3-benzyl-4-(3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (677 mg, 0.975 mmol) and 4 M HCl in EtOAc (20 mL, 80 mmol) was stirred at rt for 2 h. The reaction mixture was concentrated to dryness to give (R)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (702 mg) as a yellow solid which was used directly in the next step without further purification. LCMS: 595.1 [M+H]+.

(R)-3-Benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methylpiperazine-1-carboxamide was synthesized from (R)-3-(6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride and methylcarbamic chloride following the procedure described for Compound 6, Step 3. LCMS: 562.1 [M+H]+.

The Compounds below were synthesized from the appropriate Intermediate and the appropriate boronic ester or boronic acid following the procedure described for Compound 11.

The Compounds below were synthesized from Compound 12, Step 3 and the appropriate boronic acid following the procedure described for Compound 12, Steps 4-5.

The Compound below was synthesized from Intermediate 13.06 and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate following the procedures described for Compound 14, Steps 1-3 and then reductive amination (benzaldehyde, NaBH(OAc) 3, CH2Cl2, rt, 2 h).

The Compounds below were synthesized from Intermediate 13.06 or Intermediate 13.10 and the appropriate Intermediate or starting material following the procedures described for Compound 15.

A solution of tert-butyl 4-benzyl-4-((3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)(methyl)amino)piperidine-1-carboxylate (105 mg, 0.145 mmol) and HCl/EtOAc (4 M, 23 mL) was stirred at rt for 1 h and then concentrated to give 3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N-(4-benzylpiperidin-4-yl)-N, 1-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (90 mg) as a yellow oil.

The Compound below was synthesized from Intermediate 13.06 and Intermediate 18.01 following the procedures described for Compound 17.

The Compounds below were synthesized from Intermediate 13.06 and the appropriate piperazine starting material following the procedures described for Compound 17 (Steps 1,3-4) and then deprotection (TFA, 50° C. or 70° C., 2 h).

The Compound below was the first eluting enantiomer from the SFC separation of Compound 19.

The Compound below was synthesized from Intermediate 14 and Intermediate 7.02 following the procedures described for Compound 21 (Step 1) and then Compound 6 (Step 4).

The Compounds below were synthesized from the appropriate Intermediates following the procedures described for Compound 22.

The Compounds below were synthesized in a similar manner to the procedures described herein and in PCT/US2021/052679.

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s), optional buffer(s), and taste masking excipients) to provide a 20 mg/mL solution.

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed into size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

Example A-5: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Materials

Compounds

Inhibitor compounds were serially diluted in DMSO and then further diluted in assay buffer to a 10× concentration consisting of 1% DMSO.

Procedure

HSD17b13 enzyme was diluted in 1× assay buffer to the desired enzyme concentration based on the specific activity of the enzyme lot. 20 μL of diluted enzyme was added to each well along with 2.5 μL of 10× inhibitor solution. Assay plate was incubated at RT for 20 minutes, and then 2.5 μL of a 10× substrate/cofactor mix was added to each well for a final concentration of 50 μM estradiol and 1 mM NAD+. Assay plate was incubated at 37° C. for 3 hours. NAD (P) H-Glo™ Detection System reagents were prepared according to manufacturer's specifications, and 25 μL was added to each well. After incubating for 1 hour at RT, luminescence was measured.

Representative data for exemplary compounds disclosed herein is presented in Table 3.

Materials

Compounds

Inhibitor compounds were serially diluted in DMSO and then further diluted in assay buffer to a 10× concentration consisting of 1% DMSO.

Procedure

HSD17b1 enzyme was diluted in 1× assay buffer to the desired enzyme concentration based on the specific activity of the enzyme lot. 20 μL of diluted enzyme was added to each well along with 2.5 μL of the 10× inhibitor solution. Assay plate was incubated at RT for 20 minutes, and then 2.5 μL of a 10× substrate/cofactor mix was added to each well for a final concentration of 55 μM testosterone and 1 mM NADP. Assay plate was incubated at 37° C. for 1 hour. NAD (P) H-Glo™ Detection System reagents were prepared according to manufacturer's specifications, and 25 μL was added to each well. After incubating for 1 hour at RT, luminescence was measured.

Materials and Setup

Compounds

Inhibitor compounds were serially diluted in DMSO and then further diluted in assay buffer to a 10× concentration consisting of 1% DMSO.

Procedure

HSD17b2 enzyme was diluted in 1× assay buffer to the desired enzyme concentration based on the specific activity of the enzyme lot. 20 μL of diluted enzyme was added to each well along with 2.5 μL of 10× inhibitor solution. Assay plate was incubated at RT for 20 minutes, and then 2.5 μL of 10× substrate/cofactor mix was added to each well for a final assay concentration of 1 μM estradiol and 500 μM NAD+. Assay plate was incubated at RT for 1 hour. NAD (P) H-Glo™ Detection System reagents were prepared according to manufacturer's specifications and 25 μL was added to each well. After incubating for 1 hour at RT, luminescence was measured.

Example B-4: In Vitro HSD17b13 Cell Based Assay

Seeding

Transfection and Plate

After the 18 h incubation, media was replaced with 15 mL of fresh media: EMEM without Phenol Red (Quality Biological Cat #112-212-101), 10% CSS (Sigma Cat #F6765) and GlutaMax (Gibco Cat #35050-061). In a polypropylene tube, 20 μg pCMV6 HSD17B13 (Origene Cat #RC213132) was diluted in OptiMEM (Life Technologies, Cat #31985-062) to 2 mL. 60 μL of transfection reagent (X-tremeGENE HP Roche, Cat #06 366 236 001) was added, and the tube was vortexed and incubated at room temperature for 20 minutes. The transfection reagent/DNA mixture was added to the cells in the T75 flask, and the cells were incubated at 37° C. in 5% CO2for 18 hours. The next day, the cells were resuspended in EMEM media with 10% CSS and plated in a 96 well plate at 80,000 cells/well, 100 μL/well. Cells were incubated at 37° C. in 5% CO2for 18 hours.

Test Compounds

Compounds were serially diluted in DMSO (1000× final concentration) and then further diluted in EMEM media with 10% CSS to a 20× final concentration. 10 μL of the 20× compound mix was added to each well of transfected cells, and the cells were incubated at 37° C. in 5% CO2for 30 minutes. 100 μL of EMEM media with 100 μM estradiol (Sigma cat #E8875) was added to each well, and the cells were incubated for 4 hours at 37° C. in 5% CO2. The cell media was collected and examined for estradiol and estrone concentrations by LCMS.

Example B-5: In Vitro HSD17b11 Cell Based Assay

Seeding

Transfection and Plate

After the 18 h incubation, the media was replaced with 15 mL of fresh media: EMEM without Phenol Red (Quality Biological Cat #112-212-101), 10% CSS (Sigma Cat #F6765) and GlutaMax (Gibco Cat #35050-061). In a polypropylene tube, 20 μg pCMV6 HSD17B11 (Origene Cat #RC205941) was diluted in OptiMEM (Life Technologies, Cat #31985-062) to 2 mL. 60 μL of transfection reagent (X-tremeGENE HP Roche, Cat #06 366 236 001) was added, and the tube was vortexed and incubated at room temperature for 20 minutes. The transfection reagent/DNA mixture was added to the cells in the T75 flask, and the cells were incubated at 37° C. in 5% CO2for 18 hours. The next day, the transfected cells were resuspended in EMEM media with 10% CSS and plated in a 96 well plate at 80,000 cells/well, 100 μL/well. Cells were incubated at 37° C. in 5% CO2for 18 hours.

Test Compounds

Compounds were serially diluted in DMSO (1000× final concentration) and then further diluted in EMEM media with 10% CSS to a 20× final concentration. 10 μL of the 20× compound mix was added to each well of the transfected cells, and the cells were incubated at 37° C. in 5% CO2for 30 minutes. 100 μL of EMEM media with 60 μM of estradiol (Sigma cat #E8875) was added, and the cells were incubated for 4 hours at 37° C. in 5% CO2. The cell media was examined for estradiol and estrone concentrations by LCMS.

NASH is induced in male C57BL/6 mice by diet-induction with AMLN diet (DIO-NASH) (D09100301, Research Diet, USA) (40% fat (18% trans-fat), 40% carbohydrates (20% fructose) and 2% cholesterol). The animals are kept on the diet for 29 weeks. After 26 weeks of diet induction, liver biopsies are performed for base line histological assessment of disease progression (hepatosteatosis and fibrosis), stratified and randomized into treatment groups according to liver fibrosis stage, steatosis score, and body weight. Three weeks after biopsy the mice are stratified into treatment groups and dosed daily by oral gavage with an HSD17B13 inhibitor for 8 weeks. At the end of the study liver biopsies are performed to assess hepatic steatosis and fibrosis by examining tissue sections stained with H&E and Sirius Red, respectively. Total collagen content in the liver is measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. Triglycerides and total cholesterol content in liver homogenates are measured in single determinations using autoanalyzer Cobas C-111 with commercial kit (Roche Diagnostics, Germany) according to manufacturer's instructions.

Fibrosis is induced in C57BL/6 male mice by bi-weekly oral administration of CCl4. CCl4is formulated 1:4 in oil and is oral dosed at a final concentration of 0.5 ul/g mouse. After 2-4 weeks of fibrosis induction the compounds is administered daily by oral gavage for 2-8 weeks of treatment while continuing CCl4administration. At study termination livers are formalin fixed and stained with H&E or Sirius Red stain for histopathological evaluation of inflammation and fibrosis. Total collagen content is measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. Collagen gene induction is measured by qPCR analysis of Col1a1 and Col3a1 mRNA. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are measured by a clinical chemistry analyzer.

Example B-8: Mouse PK Study

The plasma pharmacokinetics of any one of the compounds disclosed herein as a test article is measured following a single bolus intravenous and oral administration to mice (CD-1, C57BL, and diet induced obesity mice). Test article is formulated for intravenous administration in a vehicle solution of DMSO, PEG400, hydroxypropyl-β-cyclodextrin (HPBCD) and is administered (for example at a dose volume of 3 mL/kg) at selected dose levels. An oral dosing formulation is prepared in appropriate oral dosing vehicles (vegetable oils, PEG400, Solutol, citrate buffer, or carboxymethyl cellulose) and is administered at a dose volume of 5˜10 mL/kg at selected dose levels. Blood samples (approximately 0.15 mL) are collected by cheek pouch method at pre-determined time intervals post intravenous or oral doses into tubes containing EDTA. Plasma is isolated by centrifugation of blood at 10,000 g for 5 minutes, and aliquots are transferred into a 96-well plate and stored at −60° C. or below until analysis.

Calibration standards of test article are prepared by diluting DMSO stock solution with DMSO in a concentration range. Aliquots of calibration standards in DMSO are combined with plasma from naïve mouse so that the final concentrations of calibration standards in plasma are 10-fold lower than the calibration standards in DMSO. PK plasma samples are combined with blank DMSO to match the matrix. The calibration standards and PK samples are combined with ice-cold acetonitrile containing an analytical internal standard and centrifuged at 1850 g for 30 minutes at 4° C. The supernatant fractions are analyzed by LC/MS/MS and quantitated against the calibration curve. Pharmacokinetic parameters (area under the curve (AUC), Cmax, Tmax, elimination half-life (T1/2), clearance (CL), steady state volume of distribution (Vass), and mean residence time (MRT)) are calculated via non-compartmental analysis using Microsoft Excel (version 2013).

Example B-9: Mouse CDA-HFD NASH Model

A NASH phenotype with mild fibrosis can be induced in C57BL/6 mice by feeding a choline-deficient diet with 0.1% methionine and 60% kcal fat (Research Diet A06071302) for 4-12 weeks. After 4-6 weeks of diet induction compounds can be administered daily by oral gavage for 4-8 weeks of treatment while continuing CDA-HFD feeding. At study termination livers can be formalin fixed and stained with H&E and Sirius Red stain histopathological evaluation of steatosis, inflammation, and fibrosis. Total collagen content can be measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. Collagen gene induction can be measured by qPCR analysis of Col1a1 or Col3a1. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) can be measured by a clinical chemistry analyzer.