HSD17B13 INHIBITORS AND USES THEREOF

Abstract

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.

Description

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

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y² is N(R⁹), O, S, or C(R⁴)₂;
  • Y³ is CR⁴ or N;
  • Y⁴ is C(O), C(R⁴)₂, N(R¹⁵), O, or S;
  • Y⁵ is C(O), C(R⁴)₂, or N(R¹⁵), wherein at least one of Y⁴ and Y³ is C(O);
  • Z¹, Z², Z³, and Z⁴ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴;
  • R⁹ is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), and —S(O)₂R¹³, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —N(R¹²)C(O)R¹⁶, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R¹⁵ is selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —S(O)R¹³, —S(O)₂R¹³, —C(O)OR¹⁰, —S(O)₂OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O) R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹), —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —N(R¹²)C(O)OR¹³, and —N(R¹²)C(O)N(R¹⁰)(R¹¹); and
  • each R¹⁶ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

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

• • wherein:
  • J is

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y² is N(R⁹), O, S, or C(R⁴)₂;
  • Y³ is CR⁴ or N;
  • Y⁴ is C(O), C(R⁴)₂, N(R¹⁵), O, or S;
  • Y⁵ is C(O), C(R⁴)₂, or N(R¹⁵), wherein at least one of Y⁴ and Y⁵ is C(O);
  • Z¹, Z², Z³, and Z⁴ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-4alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴;
  • R⁹ is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), and —S(O)₂R¹³, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-9alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰; and
  • R¹⁵ is selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —S(O)R¹³, —S(O)₂R¹³, —C(O)OR¹⁰, —S(O)₂OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O) R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹), —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —N(R¹²)C(O)OR¹³, and —N(R¹²)C(O)N(R¹⁰)(R¹¹).

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 Y² is N(R⁹). In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁹ is selected from H and C_1-6alkyl. In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁹ is H. In some embodiments is a compound of Formula (I′), (I), or (II′), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁹ is C_1-6alkyl.

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 Y³ is N. In some embodiments is a compound of Formula (I′), (I), (III′), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴. In some embodiments is a compound of Formula (I′), (I), (III′), or (IV′), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 R⁴ is H, halogen, C_1-6alkyl, 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 Y¹ is 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 X³ are 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 Z² is N. 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 Z² is CR⁵. 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 Z¹ and Z³ are CR⁵. 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 Z¹ is N; and Z³ are CR⁵. 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 Z³ is N; and Z¹ is CR⁵. 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 Z⁴ is N. 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 Z⁴ is CR⁵. 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 R⁵ is independently selected from H, halogen, —CN, C_1-6alkyl, 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 R⁵ is H. 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 L² is unsubstituted C_1-6alkylene. 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 L² is —CH₂—. 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 R⁸ is phenyl optionally substituted with one, two, or three R¹⁴. 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 R⁸ is unsubstituted phenyl. 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 R⁸ is C_1-9heteroaryl optionally substituted with one, two, or three R¹⁴. 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 R⁸ is unsubstituted C_1-9heteroaryl. 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 R⁸ is C_2-9heterocycloalkyl optionally substituted with one, two, or three R¹⁴. 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 R⁸ is unsubstituted C_2-9heterocycloalkyl. 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 R⁸ is C_3-6cycloalkyl optionally substituted with one, two, or three R¹⁴. 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 R⁸ is unsubstituted C_3-6cycloalkyl. 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 R⁸ is C_2-6alkyl optionally substituted with one, two, or three R¹⁴. 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 R⁸ is unsubstituted C_2-6alkyl. 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 L¹ is a bond. 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 L¹ is —N(R¹⁰)—. 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, and diazepanyl, wherein piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, and diazepanyl are 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 —R¹-L²-R⁸ is

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 R⁶ is independently selected from oxo, C_1-6alkyl, —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′), (I), (II′), (IIa′), (III′), (IIIa′), (IV′), or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

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 R¹ is C_3-8cycloalkyl 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 R¹ is C_6-10aryl 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 R¹ is C_1-9heteroaryl 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 R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, 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 R³ is independently selected from H, halogen, and C_1-6haloalkyl. In some embodiments is a compound of Formula (I), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is H. In some embodiments is a compound of Formula (I), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is halogen.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

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 al Biochem 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

Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are HSD17B13 inhibitors.

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

• • wherein:
  • J is

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y² is N(R⁹), O, S, or C(R⁴)₂;
  • Y³ is CR⁴ or N;
  • Y⁴ is C(O), C(R⁴)₂, N(R¹⁵), O, or S;
  • Y⁵ is C(O), C(R⁴)₂, or N(R¹⁵), wherein at least one of Y⁴ and Y⁵ is C(O);
  • Z¹, Z², Z³, and Z⁴ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—; L² is C_1-6alkylene optionally substituted with —OH; R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴; R⁹ is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), and —S(O)₂R¹³, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —N(R¹²)C(O)R¹⁶, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R¹⁵ is selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —S(O)R¹³, —S(O)₂R¹³, —C(O)OR¹⁰, —S(O)₂OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O) R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹), —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —N(R¹²)C(O)OR¹³, and —N(R¹²)C(O)N(R¹⁰)(R¹¹); and
  • each R¹⁶ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

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

• • wherein:
  • J is

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y² is N(R⁹), O, S, or C(R⁴)₂;
  • Y³ is CR⁴ or N;
  • Y⁴ is C(O), C(R⁴)₂, N(R¹⁵), O, or S;
  • Y⁵ is C(O), C(R⁴)₂, or N(R¹⁵), wherein at least one of Y⁴ and Y⁵ is C(O);
  • Z¹, Z², Z³, and Z⁴ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—; L² is C_1-6alkylene optionally substituted with —OH; R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴;
  • R⁹ is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), and —S(O)₂R¹³, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰; and
  • R¹⁵ is selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —S(O)R¹³, —S(O)₂R¹³, —C(O)OR¹⁰, —S(O)₂OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), —S(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹), —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —N(R¹²)C(O)OR¹³, and —N(R¹²)C(O)N(R¹⁰)(R¹¹).

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 Y² is N(R⁹). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹) and R⁹ is selected from H and C_1-6alkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹) and R⁹ is H. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹) and R⁹ is C_1-6alkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is C(R⁴)₂. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is C(R⁴)₂ and each R⁴ is independently selected from H, halogen, C_1-6alkyl, and —N(R¹⁰)(R¹¹). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is C(R⁴)₂ and each R⁴ is independently selected from H and C_1-6alkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y³ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, or —N(R¹⁰)(R¹¹).

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y¹ is CR⁴ and R⁴ is H, halogen, or C_1-6alkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are 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 X³ are each CR³ and each R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, 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 X³ are each CR³ and each R³ is independently selected from H, halogen, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are each CR³ and each R³ is independently selected from H, halogen, and C_1-6haloalkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(F), and X³ is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(Cl). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CH₃). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(Cl).

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is selected from H, halogen, C_1-6alkyl, C_1-6haloalkyl, and —OR¹⁰. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is H. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is halogen. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is F. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C₁. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C_1-6alkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C_1-6haloalkyl. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OR¹⁰. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OH. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OCH₃.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹, Z², and Z³ are CR⁵. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are CR⁵. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are CR⁵. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are CR⁵. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is CR⁵; and Z² and Z³ are N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is CR⁵, and Z¹ and Z³ are N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is CR⁵; and Z¹ and Z² are N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁵ is independently selected from H, halogen, —CN, C_1-6alkyl, and —OR¹⁰. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁵ is H. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹, Z², and Z³ are C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is C(H); and Z² and Z³ are N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is C(H); and Z¹ and Z³ are N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is C(H); and Z¹ and Z² are N. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CR⁵. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CR⁵ and R⁵ is selected H, halogen, —CN, C_1-6alkyl, and —OR¹⁰. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is C(H). In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is N.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is a bond. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —O—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(R¹⁰)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(H)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —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 L¹ is-CH₂N(H)—. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —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 L¹ is —N(H)CH₂—.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is selected from C_3-8cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-8cycloalkyl and C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl unsubstituted with R⁶. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C_2-9heterocycloalkyl 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 R¹ is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from C_1-6alkyl, —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 R¹ is

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

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

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

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

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

In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from —C(O)R¹³ and —S(O)₂R¹³. In some embodiments is a compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is

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

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

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

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

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

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

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

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl unsubstituted with R⁶.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is selected from C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl unsubstituted with R⁷. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C_1-9heteroaryl 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 R¹ is C_6-10aryl 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 R¹ is 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 R¹ is 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 R¹ is 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-R⁸ is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from oxo, C_1-6alkyl, —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-R⁸ is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is unsubstituted C_1-6alkylene. In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is —CH₂—.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is 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 R⁸ is unsubstituted phenyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_1-9heteroaryl 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 R⁸ is unsubstituted C_1-9heteroaryl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_3-6cycloalkyl 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 R⁸ is unsubstituted C_3-6cycloalkyl.

In some embodiments is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_2-6alkyl 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 R⁸ is unsubstituted C_2-6alkyl.

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

wherein:

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y² is N(R⁹), O, S, or C(R⁴)₂;
  • Z¹, Z², and Z³ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴,
  • R⁹ is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), and —S(O)₂R¹³, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —N(R¹²)C(O)R¹⁶, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰; and
  • each R¹⁶ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

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

wherein:

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y² is N(R⁹), O, S, or C(R⁴)₂;
  • Z¹, Z², and Z³ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴,
  • R⁹ is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —C(O)R¹³, —C(O)OR¹⁰, —C(O)N(R¹⁰)(R¹¹), and —S(O)₂R¹³, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl; and each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰.

In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹) and R⁹ is selected from H and C_1-6alkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹) and R⁹ is H. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is N(R⁹) and R⁹ is C_1-6alkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is C(R⁴)₂. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is C(R⁴)₂ and each R⁴ is independently selected from H, halogen, C_1-6alkyl, and —N(R¹⁰)(R¹¹). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y² is C(R⁴)₂ and each R⁴ is independently selected from H and C_1-6alkyl.

In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is N. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y¹ is CR⁴ and R⁴ is H, halogen, or C_1-6alkyl.

In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are 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 X³ are each CR³ and each R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, 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 X³ are each CR³ and each R³ is independently selected from H, halogen, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are each CR³ and each R³ is independently selected from H, halogen, and C_1-6haloalkyl. In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(F), and X³ is C(H). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(Cl). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CH₃). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (II′) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is 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 R⁹ is selected from H and C_1-6alkyl. In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁹ is C_1-6alkyl. In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁹ is —CH₃. In some embodiments is a compound of Formula (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁹ is H.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is selected from H, halogen, C_1-6alkyl, C_1-6haloalkyl, and —OR¹⁰. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is H. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is halogen. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is F. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C₁. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C_1-6alkyl. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C_1-6haloalkyl. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OR¹⁰. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OH. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —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 Z³ are CR⁵. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are CR⁵. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are CR⁵. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are CR⁵. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is CR⁵; and Z² and Z³ are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is CR⁵; and Z¹ and Z³ are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is CR⁵; and Z¹ and Z² are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁵ is independently selected from H, halogen, —CN, C_1-6alkyl, 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 R⁵ is 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 Z³ are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are C(H). In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is C(H); and Z² and Z³ are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is C(H); and Z¹ and Z³ are N. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is C(H); and Z¹ and Z² are N.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is a bond. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —O—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(R¹⁰)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(H)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —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 L¹ is —CH₂N(H)—. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —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 L¹ is —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 R¹ is selected from C_3-8cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-8cycloalkyl and C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from C_1-6alkyl, —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 R¹ is

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

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

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

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

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

In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from —C(O)R¹³ and —S(O)₂R¹³. In some embodiments is a compound of Formula (II′) or (IIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is

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

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

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

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

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

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

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

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is selected from C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_6-10aryl 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 R¹ is 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 R¹ is 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 R¹ is 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-R⁸ is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from oxo, C_1-6alkyl, —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-R⁸ is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is unsubstituted C_1-6alkylene. In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is —CH₂—.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is 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 R⁸ is unsubstituted phenyl.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_1-9heteroaryl 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 R⁸ is unsubstituted C_1-9heteroaryl.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_3-6cycloalkyl 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 R⁸ is unsubstituted C_3-6cycloalkyl.

In some embodiments is a compound of Formula (II′), (II), (IIa′) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_2-6alkyl 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 R⁸ is unsubstituted C_2-6alkyl.

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

wherein:

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y³ is CR⁴ or N;
  • Z¹, Z², and Z³ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹°)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴,
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —N(R¹²)C(O)R¹⁶, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³ and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰; and
  • each R¹⁶ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

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

wherein:

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y³ is CR⁴ or N;
  • Z¹, Z², and Z³ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • R² is selected from H, halogen, —CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-9alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴;
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl; and
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR 10, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰.

In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is N. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y¹ is CR⁴ and R⁴ is H, halogen, or C_1-6alkyl.

In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is N. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y³ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, 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 X³ are 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 X³ are each CR³ and each R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, 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 X³ are each CR³ and each R³ is independently selected from H, halogen, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are each CR³ and each R³ is independently selected from H, halogen, and C_1-6haloalkyl. In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(F), and X³ is C(H). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(Cl). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CH₃). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (III′) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is 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 R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, and —OR¹⁰. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R³ is independently selected from H, halogen, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R³ is independently selected from H, halogen, and C_1-6haloalkyl. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 R⁴ is H, halogen, C_1-6alkyl, or —N(R¹⁰)(R¹¹). In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is H. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is halogen. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is C_1-6alkyl. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is —CH₃. In some embodiments is a compound of Formula (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴ is —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 R² is selected from H, halogen, C_1-6alkyl, C_1-6haloalkyl, and —OR¹⁰. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is H. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is halogen. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is F. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C₁. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C_1-6alkyl. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is C_1-6haloalkyl. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OR¹⁰. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is —OH. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R² is-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 Z³ are CR⁵. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are CR⁵. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are CR⁵. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are CR⁵. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is CR⁵; and Z² and Z³ are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is CR⁵; and Z¹ and Z³ are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is CR⁵; and Z¹ and Z² are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁵ is independently selected from H, halogen, —CN, C_1-6alkyl, 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 R⁵ is 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 Z³ are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are C(H). In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is C(H); and Z² and Z³ are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is C(H); and Z¹ and Z³ are N. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is C(H); and Z¹ and Z² are N.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is a bond. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —O—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(R¹⁰)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(H)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —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 L¹ is —CH₂N(H)—. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is-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 L¹ is —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 R¹ is selected from C_3-8cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-8cycloalkyl and C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from C_1-6alkyl, —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 R¹ is

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

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

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

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

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

In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from —C(O)R¹³ and —S(O)₂R¹³. In some embodiments is a compound of Formula (III′) or (IIIa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is

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

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

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

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

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

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

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

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is selected from C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_6-10aryl 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 R¹ is 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 R¹ is 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 R¹ is 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-R⁸ is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from oxo, C_1-6alkyl, —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-R⁸ is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is unsubstituted C_1-6alkylene. In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is —CH₂—.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is 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 R⁸ is unsubstituted phenyl.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_1-9heteroaryl 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 R⁸ is unsubstituted C_1-9heteroaryl.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_3-6cycloalkyl 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 R⁸ is unsubstituted C_3-6cycloalkyl.

In some embodiments is a compound of Formula (III′), (III), (IIIa′) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_2-6alkyl 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 R⁸ is unsubstituted C_2-6alkyl.

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

wherein:

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y³ is CR⁴ or N;
  • Z¹, Z², Z³, and Z⁴ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴;
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —N(R¹²)C(O)R¹⁶, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹⁴ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰; and
  • each R¹⁶ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

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

wherein:

• • X¹, X², and X³ are each independently CR³ or N;
  • Y¹ is CR⁴ or N;
  • Y³ is CR⁴ or N;
  • Z¹, Z², Z³, and Z⁴ are each independently CR⁵ or N;
  • L¹ is selected from a bond, —O—, —N(R¹⁰)— —C(O)—, —S—, —S(O)—, —S(O)₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)C(O)—, —C(R¹⁰)(R¹¹) N(R¹⁰)—, and —N(R¹⁰)C(R¹⁰)(R¹¹)—;
  • L² is C_1-6alkylene optionally substituted with —OH;
  • R¹ is selected from:
    • a) C_3-10cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-10cycloalkyl and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R⁶; and
    • b) C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl are optionally substituted with one, two, or three R⁷;
  • each R³ and each R⁴ are each independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁵ is independently selected from H, halogen, hydroxy, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, and —N(R¹⁰)(R¹¹);
  • each R⁶ is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • each R⁷ are each independently selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰;
  • R⁸ is selected from C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_2-6alkyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R¹⁴;
  • each R¹⁰ is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl;
  • each R¹¹ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹² is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl;
  • each R¹³ is independently selected C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl; and each R 14 is independently selected from halogen, oxo, —CN, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)(R¹¹), —C(O)OR¹⁰, —OC(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)OR¹³, —N(R¹²)S(O)₂R¹³, —C(O)R¹³, —S(O)R¹³, —OC(O)R¹³, —C(O)N(R¹⁰)(R¹¹), —C(O)C(O)N(R¹⁰)(R¹¹), —N(R¹²)C(O)R¹³, —S(O)₂R¹³, —S(O)₂N(R¹⁰)(R¹¹)—, S(═O)(═NH)N(R¹⁰)(R¹¹), —CH₂C(O)N(R¹⁰)(R¹¹), —CH₂N(R¹²)C(O)R¹³, —CH₂S(O)₂R¹³, and —CH₂S(O)₂N(R¹⁰)(R¹¹), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, —OR¹⁰, —N(R¹⁰)(R¹¹), and —C(O)OR¹⁰.

In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is N. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y³ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y³ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, or —N(R¹⁰)(R¹¹).

In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is N. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Y¹ is CR⁴ and R⁴ is H, halogen, C_1-6alkyl, C_1-6haloalkyl, —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 Y¹ is CR⁴ and R⁴ is H, halogen, or C_1-6alkyl.

In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are 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 X³ are each CR³ and each R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, 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 X³ are each CR³ and each R³ is independently selected from H, halogen, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹, X², and X³ are each CR³ and each R³ is independently selected from H, halogen, and C_1-6haloalkyl. In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(F), and X³ is C(H). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(Cl). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(F), X² is C(H), and X³ is C(CH₃). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(Cl), X² is C(H), and X³ is C(H). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(CF₃). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is C(F). In some embodiments is a compound of Formula (IV′) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X¹ is C(H), X² is C(H), and X³ is 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 R³ is independently selected from H, halogen, —CN, C_1-6alkyl, C_1-6haloalkyl, and —OR¹⁰. In some embodiments is a compound of Formula (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R³ is independently selected from H, halogen, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments is a compound of Formula (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R³ is independently selected from H, halogen, and C_1-6haloalkyl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹, Z², and Z³ are CR⁵. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are CR⁵. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are CR⁵. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are CR⁵. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is CR⁵; and Z² and Z³ are N. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is CR⁵; and Z′ and Z³ are N. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is CR⁵; and Z¹ and Z² are N. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁵ is independently selected from H, halogen, —CN, C_1-6alkyl, and —OR¹⁰. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁵ is H. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹, Z², and Z³ are C(H). In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is N; and Z² and Z³ are C(H). In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is N; and Z¹ and Z³ are C(H). In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is N; and Z¹ and Z² are C(H). In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z¹ is C(H); and Z² and Z³ are N. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z² is C(H); and Z¹ and Z³ are N. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z³ is C(H); and Z¹ and Z² are N. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CR⁵. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CR⁵ and R⁵ is selected H, halogen, —CN, C_1-6alkyl, and —OR¹⁰. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is C(H). In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is N.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is a bond. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —O—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(R¹⁰)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —N(H)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is —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 L¹ is —CH₂N(H)—. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L¹ is-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 L¹ is —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 R¹ is selected from C_3-8cycloalkyl and C_2-9heterocycloalkyl, wherein C_3-8cycloalkyl and C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is C_2-9heterocycloalkyl 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 R¹ is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from C_1-6alkyl, —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 R¹ is

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

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

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

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

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

In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from —C(O)R¹³ and —S(O)₂R¹³. In some embodiments is a compound of Formula (IV′) or (IVa′), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is

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

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

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

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

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

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

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

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is C_3-8cycloalkyl 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 R¹ is selected from C_6-10aryl and C_1-9heteroaryl, wherein C_6-10aryl and C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_1-9heteroaryl 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 R¹ is C_6-10aryl 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 R¹ is 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 R¹ is 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 R¹ is 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-R⁸ is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R⁶ is independently selected from oxo, C_1-6alkyl, —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-R⁸ is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein —R¹-L²-R⁸ is

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is unsubstituted C_1-6alkylene. In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein L² is —CH₂—.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is 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 R⁸ is unsubstituted phenyl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_1-9heteroaryl 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 R⁸ is unsubstituted C_1-9heteroaryl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_3-6cycloalkyl 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 R⁸ is unsubstituted C_3-6cycloalkyl.

In some embodiments is a compound of Formula (IV′), (IV), (IVa′) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is C_2-6alkyl 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 R⁸ is unsubstituted C_2-6alkyl.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

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

TABLE 1
Compound	Structure	Chemical Name
1		(R)-1-(4-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.01		(S)-1-(4-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.02		(S)-1-(4-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.03		(R)-1-(4-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.04		(S)-1-(4-(2-Benzylmorpholino)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.05		(R)-1-(4-(3-Benzylmorpholino)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.06		(R)-1-(4-(3-Benzylpyrrolidin-1-yl)phenyl)- 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.07		(S)-1-(4-(3-Benzylpyrrolidin-1-yl)phenyl)- 5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.08		1-(4-(4-Benzylpiperidin-1-yl)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.09		1-(4-(4-Benzylazepan-1-yl)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6-ol
1.10		1-(4-(4-Benzyl-4-methylpiperidin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3]triazol-6-ol
2		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.01		3-(5-(3-Benzylmorpholino)-3-methyl-1H- pyrazolo[3,4-c]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
2.02		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.03		(S)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.04		3-(5-(2-Benzylmorpholino)-3-methyl-1H- pyrazolo[3,4-c]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
2.05		3-(5-(2-Benzylmorpholino)-3-methyl-1H- pyrazolo[3,4-c]pyridin-1-yl)-2-fluoro-5- (trifluoromethyl)phenol
2.06		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-chloro- 1H-indazol-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
2.07		(R)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.08		(R)-1-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1H-indazol-3- yl)ethan-1-one
2.09		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
2.10		(S)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.11		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol
2.12		(R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H-indazol- 1-yl)-2,6-difluoro-5-(trifluoromethyl)phenol
2.13		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-indazol-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
2.14		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-indazol-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.15		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluorophenol
2.16		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-6-chloro-2- fluorophenol
2.17		(R)-2-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[3,4-c]pyridin-1-yl)-5-chloro-3- fluoropyridin-4-ol
2.18		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-chloro- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.19		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-c]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
2.20		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-chloro- 1H-pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.21		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro- 2-fluoro-5-(trifluoromethyl)phenol
2.22		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-chloro- 1H-pyrazolo[3,4-c]pyridin-1-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol
2.23		(R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-l)-1H- pyrazolo[3,4-c]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
2.24		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
2.25		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (dimethylamino)-1H-indazol-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.26		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-indazol-1-yl)-5-(trifluoromethyl)phenol
2.27		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-indazol-1-yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol
2.28		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-indazol-1-yl)-2-fluoro-5- (trifluoromethyl)phenol
2.29		(R)-2-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-indazol-1-yl)-6-(trifluoromethyl)pyridin- 4-ol
2.30		(R)-2-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 2H-indazol-2-yl)-6-(trifluoromethyl)pyridin- 4-ol
2.31		(R)-3-(5-(3-Benzylmorpholino)-3-methyl- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.32		(R)-3-(5-(2-Benzyl-4-ethylpiperazin-1-yl)-3- methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
2.33		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-6-fluoro-3- methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.34		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-6-chloro-3- methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
2.35		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyrimidin-1-yl)-5-chloro- 2,6-difluorophenol
2.36		(R)-5-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluoro-3- (trifluoromethyl)phenol
2.37		(R)-5-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-2H- pyrazolo[4,3-d]pyrimidin-2-yl)-2-fluoro-3- (trifluoromethyl)phenol
2.38		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol
2.39		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3-chloro- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro- 2-fluoro-5-(trifluoromethyl)phenol
2.40		(R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
2.41		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
3		(R)-3-(6-(3-Benzylmorpholino)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.01		2,6-Difluoro-3-(1-methyl-6-(2- phenethylpiperidin-1-yl)-1H-pyrazolo[4,3- c]pyridin-3-yl)-5-(trifluoromethyl)phenol
3.02		2,6-Difluoro-3-(1-methyl-6-(3- (morpholinomethyl)morpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol
3.03		2,6-Difluoro-3-(1-methyl-6-(3-((tetrahydro- 2H-pyrazin-4-yl)methyl)morpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol
3.04		2,6-Difluoro-3-(1-methyl-6-(3- ((tetrahydrofuran-3-yl)methyl)morpholino)- 1H-pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol
3.05		3-(6-(2-((1H-Pyrazol-1-yl)methyl)piperidin- 1-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
3.06		(S)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.07		(R)-3-(6-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.08		3-(6-(3-(Cyclopropylmethyl)morpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.09		3-(6-(3-(Cyclobutylmethyl)morpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.10		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-b]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.11		3-(6-(2-Benzylmorpholino)-1-methyl-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
3.12		(S)-3-(6-(2-Benzylpiperidin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.13		3-(6-(3-Benzylmorpholino)-1-methyl-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
3.14		(R)-3-(6-(3-Benzylmorpholino)-1-methyl- 1H-pyrazolo[3,4-b]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.15		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.16		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-b]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.17		(R)-3-(6-(3-Benzylmorpholino)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.18		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluorophenol
3.19		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-6-chloro-2- fluorophenol
3.20		(R)-3-(6-(2-Benzylpiperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.21		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-(oxetan-3- yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
3.22		3-(6-(2-Benzylpiperidin-1-yl)-1-methyl-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
3.23		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol
3.24		2,6-Difluoro-3-(6-(3-isobutylmorpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol
4		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
4.01		(R)-3-(6-(3-Benzylmorpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
4.02		(R)-6-(6-(3-Benzylmorpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-3-fluoro-4- (trifluoromethyl)benzene-1,2-diol
4.03		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
5		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.01		3-(6-(3-(Cyclopropylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
5.02		3-(6-(2-Benzylmorpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.03		3-(6-(3-Benzylmorpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.04		4-((1H-Pyrazol-1-yl)methyl)-1-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ol
5.05		1-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-4- (morpholinomethyl)piperidin-4-ol
5.06		(S)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.07		3-(6-(3-Benzyl-4-methylpiperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
5.08		(R)-3-(6-(3-Benzylmorpholino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.09		(S)-3-(6-(3-Benzylmorpholino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.10		3-(6-(3-(Cyclobutylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
5.11		2,6-Difluoro-3-(1-methyl-6-(2-(pyridin-2- ylmethyl)piperidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
5.12		3-(6-(2-Benzyl-4-methylpiperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
5.13		3-Benzyl-4-(3-(2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-2- one
5.14		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.15		(R)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.16		(S)-3-(6-(2-Benzylpiperidin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.17		(S)-3-(6-(2-Benzylpyrrolidin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.18		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.19		3-(6-(2-Benzylazetidin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.20		(R)-3-(6-(3-Benzylmorpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.21		(R)-2,6-Difluoro-3-(1-methyl-6-(3-(4- methylbenzyl)morpholino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
5.22		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.23		(R)-2,6-Difluoro-3-(6-(3-(4- fluorobenzyl)morpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
5.24		(R)-2,6-Difluoro-3-(6-(3-(3- fluorobenzyl)morpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
5.25		(R)-2,6-Difluoro-3-(6-(3-(2- fluorobenzyl)morpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
5.26		(R)-3-(6-(2-Benzyl-4-methylpiperazin-1-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
5.27		3-(6-((1-Benzylcyclobutyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.28		(R)-2,6-Difluoro-3-(6-(3-(4- methoxybenzyl)morpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
5.29		2,6-Difluoro-3-(1-methyl-6-(3-(pyrrolidin-1- ylmethyl)morpholino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
5.30		(R)-3-(6-(2-Benzylpyrrolidin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.31		(R)-3-(6-(2-Benzylpiperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.32		3-(6-(2-Benzylpiperidin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.33		3-(6-(3-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
5.34		3-(6-(2-((1H-1,2,4-Triazol-1- yl)methyl)piperidin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.35		2,6-Difluoro-3-(6-(3-isobutylmorpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 5-(trifluoromethyl)phenol
5.36		3-(6-((1-Benzylpiperidin-3- yl)(methyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
5.37		3-(6-(3-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
6		Methyl (R)-3-benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate
6.01		(R)-3-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-N,N- dimethylpiperazine-1-carboxamide
6.02		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one
6.03		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2-methoxyethan-1-one
6.04		(S)-1-(2-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one
6.05		(R)-1-(2-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one
6.06		(S)-2-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
6.07		(S)-2-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-N,N- dimethylpiperazine-1-carboxamide
6.08		Methyl (S)-2-benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate
6.09		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)propan-1-one
6.10		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)butan-1-one
6.11		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3-methoxypropan-1-one
6.12		(R)-3-(6-(2-Benzyl-4-((2- methoxyethyl)sulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
6.13		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one
6.14		(R)-3-(6-(2-Benzyl-4- (benzylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
6.15		(R)-3-(6-(2-Benzyl-4- (isopropylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
6.16		(R)-3-(6-(2-Benzyl-4- (cyclopropylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
6.17		(R)-3-(6-(2-Benzyl-4- (isobutylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
6.18		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3-(dimethylamino)propan- 1-one
6.19		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3-(methylamino)propan-1- one
6.20		(R)-N-(3-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3-oxopropyl)acetamide
6.21		(R)-3-(6-(2-Benzyl-4-((2- ethoxyethyl)sulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
6.22		(R)-3-(6-(2-Benzyl-4-(pyridin-3- ylsulfonyl)piperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
6.23		(R)-2-((3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)sulfonyl)acetic Acid
6.24		(R)-3-((3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)sulfonyl)propanoic Acid
6.25		(R)-4-((3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)sulfonyl)butanoic Acid
6.26		(R)-3-(6-(2-Benzyl-4-((2- hydroxyethyl)sulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
6.27		(R)-3-(6-(2-Benzyl-4-(pyridin-2- ylsulfonyl)piperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
6.28		(R)-3-(6-(2-Benzyl-4-((6-methoxypyridin-3- yl)sulfonyl)piperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
6.29		Ethyl (R)-3-benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate
6.30		Isopropyl (R)-3-benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate
7		(R)-3-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1- carboxamide
7.01		(S)-2-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1- carboxamide
8		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2-hydroxyethan-1-one
9		(R)-3-(3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3-oxopropanenitrile
10		(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
11		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro- 2-fluorophenol
11.01		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluorophenol
11.02		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro- 6-fluorophenol
11.03		(R)-5-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3- difluorophenol
11.04		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4,6- trifluorophenol
11.05		3-(6-((4-Benzyltetrahydro-2H-pyran-4- yl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
11.06		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro- 2-fluoro-5-(trifluoromethyl)phenol
11.07		3-(6-((4-Benzyltetrahydro-2H-pyran-4- yl)(methyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
11.08		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-methylphenol
11.09		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,5,6- trifluorophenol
11.10		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro- 2,5-difluorophenol
11.11		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol
11.12		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-chloro- 2,6-difluorophenol
11.13		3-(6-(2-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
11.14		1-(3-(Cyclopropylmethyl)-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1- yl)-2,2,2-trifluoroethan-1-one
11.15		(R)-6-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3- difluoro-4-hydroxybenzonitrile
11.16		2-(6-((R)-2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,5- difluoro-4-hydroxybenzonitrile
11.17		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- ethynyl-2,6-difluorophenol
11.18		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(prop-1-yn-1-yl)phenol
11.19		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro- 6-methyl-5-(trifluoromethyl)phenol
11.20		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,5- difluoro-6-methylphenol
11.21		3-(Cyclopropylmethyl)-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)- N,N-dimethylpiperazine-1-carboxamide
11.22		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-ethyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
11.23		Methyl (S)-4-(3-(2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholine- 3-carboxylate
11.24		(S)-4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-N- isopropylmorpholine-3-carboxamide
11.25		(S)-N-Cyclohexyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimdiin-6- yl)morpholine-3-carboxamide
11.26		(S)-(4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-3- yl)(piperidin-1-yl)methanone
11.27		3-(6-(2-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
11.28		3-(Cyclopropylmethyl)-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxamide
12		(S)-3-(6-(2-Benzylmorpholino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
12.01		(S)-2,6-Difluoro-3-(1-methyl-6-(2-(pyridin- 3-ylmethyl)morpholino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
12.02		(S)-4-((4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-2- yl)methyl)benoznitrile
12.03		(S)-3-((4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-2- yl)methyl)benzonitrile
12.04		(S)-4-((4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-2- yl)methyl)benzamide
12.05		(S)-3-((4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-2- yl)methyl)benzamide
12.06		(S)-3-((4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-2- yl)methyl)benzenesulfonamide
12.07		(S)-2,6-Difluoro-3-(1-methyl-6-(2-(3- methylbenzyl)morpholin)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
12.08		(S)-4-((4-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)morpholin-2- y)methyl)benzenesulfonamide
13		2,6-Difluoro-3-(6-((R)-2-((R)-hydroxy(p- tolyl)methyl)morpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
14		3-(6-(1-Benzylpiperidin-2-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol hydrochloride
14.01		3-(6-(1-Benzylpiperidin-3-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol hydrochloride
15		3-(6-(2-(Cyclohexylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
15.01		(S)-3-(6-(2-(Cyclohexylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
15.02		(R)-3-(6-(2-(Cyclohexylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
15.03		3-(6-(3-(Cyclohexylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
15.04		(R)-3-(6-(3-(Cyclohexylmethyl)morpholino)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
15.05		(S)-3-(6-(3-(Cyclohexylmethyl)morpholino)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
15.06		2,6-Difluoro-3-(1-methyl-6-(3-(pyridin-2- ylmethyl)morpholino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
15.07		2,6-Difluoro-3-(1-methyl-6-(3-(pyridin-3- ylmethyl)morpholino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
15.08		2,6-Difluoro-3-(1-methyl-6-(3-(pyridin-4- ylmethyl)morpholino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
15.09		(R)-5-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-2- one
15.10		(R)-3-(6-(2-Benzylazetidin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
15.11		(S)-3-(6-(2-Benzylazetidin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
15.12		(R)-3-(6-(3-Benzylmorpholino)-1-ethyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
15.13		(S)-2,6-Difluoro-3-(6-(3-(2-hydroxypropan- 2-yl)morpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
16		3-(6-((2R)-2-Benzyl-3- (methylsulfonyl)azetidin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
17		3-(6-((4-Benzyl-1-(methylsulfonyl)piperidin- 4-yl)(methyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
17.01		3-(6-((3-Benzyl-1-(methylsulfonyl)piperidin- 3-yl)(methyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
18		(R)-2,6-Difluoro-3-(1-methyl-6-(2-methyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
18.01		(R)-3-(6-(2-Ethyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
18.02		(R)-2,6-Difluoro-3-(1-methyl-6-(4- (methylsulfonyl)-2-propylpiperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
18.03		(S)-2,6-Difluoro-3-(6-(2-(methoxyemthyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
18.04		2,6-Difluoro-3-(6-(2-isobutyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
18.05		(S)-2,6-Difluoro-3-(6-(2-isobutyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
18.06		(R)-2,6-Difluoro-3-(6-(2-isobutyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
19		(S)-3-(6-(2-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
19.01		(R)-3-(6-(2-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
20		(S)-1-(3-(Cyclopropylmethyl)-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1- y)-2,2,2-trifluoroethan-1-one
20.01		(R)-1-(3-(Cyclopropylmethyl)-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1- yl)-2,2,2-trifluoroethan-1-one
21		(R)-5-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4- difluoro-3-hydroxybenzonitrile
21.01		3-(6-((R)-2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro- 2,4-difluorophenol
22		(R)-3-(6-(2-Benzyl-4-ethylpiperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride
22.01		(R)-3-(6-(2-Benzyl-4-propylpiperazin-1-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride
22.02		(R)-3-(6-(2-Benzyl-4-isopropylpiperazin-1- yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol
22.03		(S)-3-(6-(3-Benzylpiperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol hydrochloride
22.04		(S)-3-(6-(3-Benzyl-4-methylpiperazin-1-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
22.05		(S)-3-(6-(3-Benzyl-4-ethylpiperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
22.06		(S)-3-(6-(3-Benzyl-4-propylpiperazin-1-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2,6-difluoro-5-(trifluoromethyl)phenol
22.07		(S)-3-(6-(3-Benzyl-4-isopropylpiperazin-1- yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol
22.08		(R)-3-(6-(3-Benzylthiomorpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5-(trifluoromethyl)phenol
23		(R)-3-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6- yl)thiomorpholine 1,1-dioxide
23.01		(3R)-3-Benzyl-4-(3-(2,4-difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6- yl)thiomorpholine 1-oxide
24		(R)-Azetidin-1-yl(3-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1- yl)methanone
25		(S)-Azetidin-1-yl(2-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)piperazin-1- yl)methanone
26		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol
27		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1- yl)benzo[d]oxazol-2-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
27.01		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1- yl)benzo[d]oxazol-2-yl)-2,6-difluoro-5- (trifluoromethyl)phenol
27.02		(S)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1- yl)benzo[d]oxazol-2-yl)-2,6-difluoro-5- (trifluoromethyl)phenol

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.

TABLE 2
Structure Chemical Name
          (R)-3-(6-(2-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
          (S)-3-(6-(2-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
          (R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol
          (R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-2H- pyrazolo[4,3-d]pyrimidin-2-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
          (S)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-2H- pyrazolo[4,3-d]pyrimidin-2-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol
          (R)-2,6-Difluoro-3-(1-methyl-6-(4- (methylsulfonyl)-2-neopentylpiperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
          (S)-2,6-Difluoro-3-(1-methyl-6-(4- (methylsulfonyl)-2-neopentylpiperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol
          (S)-3-(6-(3-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol
          (R)-3-(6-(3-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol

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.

“Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

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, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a “pharmaceutically acceptable acid addition salt.” In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

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 as ³H and ¹⁴C 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, 6^th Edition, 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.

Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

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-C_x includes C₁-C₂, C₁-C₃ . . . C₁-C_x. 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-C₄ alkyl” 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-C₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C₁ alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C₂ alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C₂-C₄ alkylene). 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)_xH_y group, 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 “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

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 term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1 (2H)-onyl, 3,4-dihydroquinolin-2 (1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2 (3H)-onyl, 1H-benzo[d]imidazol-2 (3H)-onyl, benzo[d]thiazol-2 (3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (═O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

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

The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). In some other embodiments, optional substituents are individually and independently selected from D, halogen, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O) NH₂, —C(═O) NH(alkyl), —C(═O) N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, —CH₂CO₂H, —CH₂CO₂alkyl, —CH₂C(═O) NH₂, —CH₂C(═O) NH(alkyl), —CH₂C(═O) N(alkyl)₂, —CH₂S(═O)₂NH₂, —CH₂S(═O)₂NH(alkyl), —CH₂S(═O)₂N(alkyl)₂, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O) NH₂, —C(═O) NH(alkyl), —C(═O) N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂ (C₁-C₄alkyl), —C(═O) NH₂, —C(═O) NH(C₁-C₄alkyl), —C(═O) N(C₁-C₄alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and —S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents are independently selected from D, halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (═O).

The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

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 “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

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

The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

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 formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

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.

In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

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.

In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

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.

Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

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® L¹⁰⁰ and 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.

Additional pharmaceutical approaches to targeted delivery of therapeutics to particular regions of the gastrointestinal tract are known. Chourasia M K, Jain S K, Pharmaceutical approaches to colon targeted drug delivery systems, J Pharm Sci. 2003 January-April; 6 (1): 33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007; 24 (2): 147-202. Kumar P, Mishra B. Colon targeted drug delivery systems—an overview. Curr Drug Deliv. 2008 July; 5 (3): 186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 January; 3 (1): 111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 August; 16 (4): 731-741.

It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

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 the patient's condition does not improve, upon the doctor's discretion, the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's 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 LD₅₀ and the ED₅₀. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD₅₀ and 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 ED₅₀ with 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

The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

• • acac acetylacetone
  • ACN or MeCN acetonitrile
  • AcOH acetic acid
  • Ac acetyl
  • BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene
  • Bn benzyl
  • BOC or Boc tert-butyl carbamate
  • i-Bu iso-butyl
  • t-Bu tert-butyl
  • Cy cyclohexyl
  • CDI 1,1-carbonyldiimidazole
  • CPME cyclopentyl methyl ether
  • DAST (diethylamino) sulfur trifluoride
  • DBA or dba dibenzylideneacetone
  • DCE dichloroethane (ClCH₂CH₂Cl)
  • DCM dichloromethane (CH₂Cl₂)
  • DHP 3,4-dihydropyran
  • DIBAL-H diisobutylaluminum hydride
  • DIPEA or DIEA diisopropylethylamine
  • DMAP 4-(N,N-dimethylamino)pyridine
  • DME 1,2-dimethoxyethane
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • DMPU N,N′-dimethylpropyleneurea
  • DMSO dimethylsulfoxide
  • Dppf or dppf 1,1′-bis(diphenylphosphino) ferrocene
  • EDC or EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
  • EEDQ 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline eq equivalent(s)
  • Et ethyl
  • Et₂O diethyl ether
  • EtOH ethanol
  • EtOAc ethyl acetate
  • HATU 1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • HMPA hexamethylphosphoramide
  • HOBt 1-hydroxybenzotriazole
  • HPLC high performance liquid chromatography
  • IBX 2-iodoxybenzoic acid
  • KOAc potassium acetate
  • KHMDS potassium bis(trimethylsilyl) amide
  • NaHMDS sodium bis(trimethylsilyl) amide
  • LiHMDS lithium bis(trimethylsilyl) amide
  • LAH lithium aluminum anhydride
  • LCMS liquid chromatography mass spectrometry
  • 2-MeTHF 2-methyltetrahydrofuran
  • Me methyl
  • MeOH methanol
  • MOM methoxymethyl ether
  • MS mass spectroscopy
  • Ms mesyl
  • MTBE methyl tert-butyl ether
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • NIS N-iodosuccinimide
  • NMI 1-methylimidazole
  • NMM N-methyl-morpholine
  • NMP N-methyl-pyrrolidin-2-one
  • NMR nuclear magnetic resonance
  • OTf trifluoromethanesulfonate
  • PCC pyridinium chlorochromate
  • PE petroleum ether
  • PG protecting group
  • Ph phenyl
  • PPTS pyridium p-toluenesulfonate
  • iPr/i-Pr iso-propyl
  • RP-HPLC reverse-phase high-pressure liquid chromatography
  • rt room temperature
  • SEM 2-(trimethylsilyl) ethoxymethyl
  • TBS tert-butyldimethylsilyl
  • TBAF tetra-n-butylammonium fluoride
  • TBAI tetra-n-butylammonium iodide
  • TCFH chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • TMEDA N,N,N′,N′-tetramethylethylenediamine
  • TMS trimethylsilyl
  • TsOH/p-TsOH p-toluenesulfonic acid

Intermediate 1

6-(Benzyloxy)-1-(4-bromophenyl)-5,7-difluoro-1H-benzo[d][1,2,3]triazole

Step 1:3-(Benzyloxy)-2,4-difluoro-6-nitroaniline

Sodium hydride (3.12 g, 78.1 mmol, 60% in mineral oil) was added to a solution of 2,3,4-trifluoro-6-nitroaniline (5.00 g, 26.03 mmol) in THF (100 mL) at 0° C. under N₂. The mixture was stirred for 0.5 h. Benzyl alcohol (4.06 mL, 39.0 mmol) in THF (10 mL) was added dropwise at 0° C. The reaction mixture was stirred at rt for 1 h, poured into ice-water (100 mL) carefully, and then extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, filtered, concentrated, and then triturated with EtOH (20 mL) for 30 min to obtain 3-(benzyloxy)-2,4-difluoro-6-nitroaniline (5 g) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.78 (d, 1H), 7.45-7.36 (m, 5H), 7.29 (s, 2H), 5.35 (s, 2H).

Step 2:3-(Benzyloxy)-N-(4-bromophenyl)-2,4-difluoro-6-nitroaniline

Tris(dibenzylideneacetone)dipalladium(0) (1.63 g, 1.78 mmol) was added to a solution of 3-(benzyloxy)-2,4-difluoro-6-nitroaniline (5 g, crude), 1-bromo-4-iodobenzene (6.06 g, 21.4 mmol), XantPhos (2.06 g, 3.57 mmol), and 1-BuONa (3.43 g, 35.7 mmol) in toluene (80 mL) under N₂. The mixture was degassed and purged with N₂ 3 times, stirred at 100° C. overnight, allowed to cool to rt, poured into H₂O (80 mL), and then extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 1/1) to obtain 3-(benzyloxy)-N-(4-bromophenyl)-2,4-difluoro-6-nitroaniline (4.06 g, 35% over two steps; contains 3.2 g˜80% ¹H NMR purity and 3.0 g˜50% ¹H NMR purity) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.53 (s, 1H), 8.01 (d, 1H), 7.43-7.38 (m, 5H), 7.34 (d, 2H), 6.70 (d, 2H), 5.35 (s, 2H); LCMS: 435.0 [M+H]⁺.

Step 3:5-(Benzyloxy)-N1-(4-bromophenyl)-4,6-difluorobenzene-1,2-diamine

Iron powder (2.46 g, 44.12 mmol) was added to a solution of 3-(benzyloxy)-N-(4-bromophenyl)-2,4-difluoro-6-nitroaniline (3.20 g, 7.35 mmol), NH₄Cl (2.36 g, 44.12 mmol) in EtOH (40 mL), and H₂O (10 mL). The mixture was stirred at 80° C. for 1 h, allowed to cool to rt, and then filtered. The filtrate was concentrated under vacuum to obtain 5-(benzyloxy)-N1-(4-bromophenyl)-4,6-difluorobenzene-1,2-diamine (3 g) as a red oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.37-7.36 (m, 5H), 7.24-7.20 (m, 3H), 6.41-6.35 (m, 3H), 5.15 (s, 2H), 4.95 (s, 2H); LCMS: 405.0 [M+H]⁺.

Step 4:6-(Benzyloxy)-1-(4-bromophenyl)-5,7-difluoro-1H-benzo[d][1,2,3]triazole

Sulfuric acid (7.50 mL, 141 mmol) in H₂O (55 mL) and NaNO₂ (715 mg, 10.4 mmol) in H₂O (5 mL) were added to a solution of 5-(benzyloxy)-N1-(4-bromophenyl)-4,6-difluorobenzene-1,2-diamine (3 g, crude) in THF (30 mL) at 0° C. The mixture was stirred for 1 h, allowed to warm slowly to rt, poured into H₂O (20 mL), and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 5/1) to obtain 6-(benzyloxy)-1-(4-bromophenyl)-5,7-difluoro-1H-benzo[d][1,2,3]triazole (2.20 g, 89% over two steps) as a red solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.08 (d, 1H), 7.88 (d, 2H), 7.77 (d, 2H), 7.46-7.44 (m, 2H), 7.41-7.36 (m, 3H), 5.26 (s, 2H); LCMS: 416.0 [M+H]⁺.

Intermediate 2

(R)-3-Benzyl-1-(methylsulfonyl)piperazine TFA salt

Step 1: tert-Butyl(R)-2-benzyl-4-(methylsulfonyl)piperazine-1-carboxylate

Methanesulfonyl chloride (0.42 mL, 5.43 mmol) was added to a solution of tert-butyl(R)-2-benzylpiperazine-1-carboxylate (1.00 g, 3.62 mmol) and Et₃N (1.51 mL, 10.8 mmol) in CH₂Cl₂ (15 mL) at 0° C. The mixture was allowed to warm to rt, stirred overnight, poured into H₂O (20 mL) slowly, and then extracted with CH₂Cl₂ (3×30 mL). The combined organic layers were washed with brine (70 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate=20/1 to 3/1)) to give tert-butyl(R)-2-benzyl-4-(methylsulfonyl)piperazine-1-carboxylate (1.05 g, 82%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.30-7.26 (m, 2H), 7.22-7.18 (m, 3H), 4.30 (s, 1H), 3.96 (d, 1H), 3.53 (d, 1H), 3.40 (d, 1H), 3.17 (t, 1H), 2.88-2.66 (m, 7H), 1.24 (s, 9H); LCMS: 255.2 [(M-Boc)+H]⁺.

Step 2: (R)-3-Benzyl-1-(methylsulfonyl)piperazine TFA salt

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.

Int	Structure	Name	[M + H]+
2.011		(R)-3-Benzyl-1- (methylsulfonyl) piperazine HCl salt	255.2
2.02		(S)-3-Benzyl-1- (methylsulfonyl) piperazine TFA salt	255.2
2.031		(S)-3-Benzyl-1- (methylsulfonyl) piperazine HCl salt	255.2
2.041		(S)-2-Benzyl-1- (methylsulfonyl) piperazine HCl salt	255.1
2.051		(R)-2-Benzyl-1- (methylsulfonyl) piperazine HCl salt	255.1
Alternate conditions used: Step 1: 2 h-ON.
1Step 2: 4 M HCl in dioxane, dioxane or 1:1 dioxane/DCM, rt, 15-31 h.
2Prepared from Intermediate 2.01 by partitioning between DCM and sat. aq NaHCO3.

Intermediate 3

(R)-3-(4-Methoxybenzyl)morpholine Hydrochloride

Step 1: tert-Butyl (R,Z)-3-((2-tosylhydrazineylidene)methyl)morpholine-4-carboxylate

A mixture of tert-butyl(S)-3-formylmorpholine-4-carboxylate (950 mg, 4.41 mmol), 4-methylbenzenesulfonohydrazide (870 mg, 4.67 mmol), and methanol (20 mL) was stirred at rt overnight, concentrated, and then purified by silica gel chromatography (10-60% ethyl acetate in heptane) to give tert-butyl (R,Z)-3-((2-tosylhydrazineylidene)methyl)morpholine-4-carboxylate (1.62 g, 96%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.16 (s, 1H), 7.68 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.21 (br s, 1H), 4.39 (br s, 1H), 3.89 (br d, J=11.5 Hz, 1H), 3.65 (br d, J=11.0 Hz, 1H), 3.54-3.38 (m, 2H), 3.33-3.23 (m, 1H), 2.90-2.68 (m, 1H), 2.38 (s, 3H), 1.55-1.22 (m, 9H); LCMS: 284.3 [(M-Boc)+H]⁺.

Step 2: tert-Butyl(R)-3-(4-methoxybenzyl)morpholine-4-carboxylate

A mixture of tert-butyl (R,Z)-3-((2-tosylhydrazineylidene)methyl)morpholine-4-carboxylate (200 mg, 0.52 mmol), 4-methoxyphenylboronic acid (107 mg, 0.70 mmol), dioxane (1 mL), and potassium carbonate (208 mg, 1.51 mmol) was heated at 110° C. for 2 h, allowed to cool to rt, and then diluted with 20 mL EtOAc. The organic layer was washed with 15 mL water, washed with 15 mL brine, dried (Na₂SO₄), concentrated, and then purified by silica gel chromatography (0-20% ethyl acetate in heptanes) to give tert-butyl(R)-3-(4-methoxybenzyl)morpholine-4-carboxylate (65 mg, 40%).

Step 3: (R)-3-(4-Methoxybenzyl)morpholine Hydrochloride

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.

Int	Structure	Name	[M + H]+
3.011		(R)-3-(4-Fluorobenzyl) morpholine HCl salt	196.2
3.02		(R)-3-(3-Fluorobenzyl) morpholine HCl salt	196.3
3.03		(R)-3-(2-Fluorobenzyl) morpholine HCl salt	196.2
3.04		(R)-3-(4-Methylbenzyl) morpholine HCl salt	192.3
Alternate conditions used:
1Step 2: 80° C., 30 min then 110° C., 90 min. Step 2: 1-2 h. Step 3: 1-2 h.

Intermediate 4

2,6-Difluoro-3-iodo-5-(trifluoromethyl)phenol

Step 1: (2,6-Difluoro-3-(trifluoromethyl)phenyl)boronic Acid

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]⁻.

Step 2:2,6-Difluoro-3-(trifluoromethyl)phenol

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]⁻.

Step 3:2-(Benzyloxy)-1,3-difluoro-4-(trifluoromethyl)benzene

Benzyl bromide (43.2 mL, 363 mmol) was added to a mixture of 2,6-difluoro-3-(trifluoromethyl)phenol (60.3 g, 303 mmol), K₂CO₃ (126 g, 909 mmol), and DMF (600 mL) at rt. The mixture was stirred at 50° C. for 12 h, cooled to rt, poured into H₂O (500 mL) slowly, and then extracted with EtOAc (3×300 mL). The organic layers were combined, washed with brine (300 mL), dried (Na₂SO₄), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate=100:1 to 10:1) to give 2-(benzyloxy)-1,3-difluoro-4-(trifluoromethyl)benzene (54.5 g, 62%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.56-7.50 (m, 1H), 7.43-7.34 (m, 6H), 5.24 (s, 2H).

Step 4:3-(Benzyloxy)-2,4-difluoro-1-iodo-5-(trifluoromethyl)benzene

n-Butyllithium (2.5 M in hexanes, 104 mL, 260 mmol) was added dropwise to a mixture of 2-(benzyloxy)-1,3-difluoro-4-(trifluoromethyl)benzene (50.1 g, 173 mmol) in THF (300 mL) at −78° C. under N₂. The mixture was stirred for 1 h. Iodine (88.1 g, 347 mmol) in THF (200 mL) was added dropwise into the mixture at −78° C. The mixture was allowed to warm to rt, stirred for 12 h, diluted with sat. aq. Na₂SO₃ (500 mL), and then extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc=I/O) to give 3-(benzyloxy)-2,4-difluoro-1-iodo-5-(trifluoromethyl)benzene (64.3 g, 89%) as a yellow oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.93 (t, 1H), 7.44-7.35 (m, 5H), 5.25 (s, 2H).

Step 5:2,6-Difluoro-3-iodo-5-(trifluoromethyl)phenol

Boron tribromide (58.2 mL, 604 mmol) was added dropwise to a mixture of 3-(benzyloxy)-2,4-difluoro-1-iodo-5-(trifluoromethyl)benzene (50.2 g, 121 mmol) in CH₂Cl₂ (500 mL) at −78° C. under N₂. The mixture was stirred at rt for 4 h, quenched slowly with CH₃OH (˜200 mL) at 0° C., concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc=50:1 to 5:1) to give 2,6-difluoro-3-iodo-5-(trifluoromethyl)phenol (34.6 g, 86%) as a red solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.39 (s, 1H), 7.59 (t, 1H); LCMS: 322.9 [M−H]⁻.

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

Int	Structure	Name	[M − H]−
4.01		2-Chloro-6-fluoro-5-iodo-3- (trifluoromethyl)phenol	338.9

Alternate conditions used: Step 5: TFA, 70° C., 2 h.

Intermediate 5

3-Bromo-6-chloro-2-fluoro-5-(trifluoromethyl)phenol

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% CH₂Cl₂ in 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).

Intermediate 6

2-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1:2-(3-Bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (1.13 g, 1.71 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (0.46 g, 1.71 mmol), and bis(pinacolato) diboron (23.9 g, 94 mmol) was evacuated and refilled with nitrogen 3 times. Cyclopentyl methyl ether (90 mL) was added, and the mixture was evacuated and purged with nitrogen an additional 3 times. 4-Bromo-1,5-difluoro-2-(trifluoromethyl)benzene (22.3 g, 85 mmol) was added. The reaction was heated at 100° C. overnight, cooled to rt, concentrated under reduced pressure, and then purified by silica gel chromatography (0-20% EtOAc/heptane) to give 2-(3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (29.3 g, 84%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.32 (t, J=7.4 Hz, 1H), 1.32 (s, 12H).

Step 2:3-Bromo-2,6-difluoro-5-(trifluoromethyl)phenol

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 Na₂S₂O₃ solution 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).

Step 3:1-Bromo-2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene

Chloromethyl methyl ether (0.51 mL, 6.77 mmol) and DIEA (1.57 mL, 9.0 mmol) were added to a solution of 3-bromo-2,6-difluoro-5-(trifluoromethyl)phenol (1.25 g, 4.51 mmol) in CH₂Cl₂ (10 mL) at 0° C. The reaction was stirred at rt overnight, diluted with water, and then extracted with CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂. The combined organics were dried (MgSO₄), filtered, concentrated under reduced pressure, and then purified by silica gel chromatography (0-20% EtOAc/heptane) to give 1-bromo-2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (0.89 g, 58%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (t, J=7.0 Hz, 1H), 5.26 (s, 2H), 3.51 (s, 3H).

Step 4:2-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (0.47 g, 1.46 mmol), bis(pinacolato) diboron (558 mg, 2.2 mmol), and KOAc (287 mg, 2.92 mmol) in dioxane (5 mL) was evacuated and filled with nitrogen 3 times. Pd (dppf) Cl₂ (54 mg, 0.07 mmol) was added. The mixture was degassed and filled with nitrogen 3 more times, heated at 80° C. for 3 days, cooled to rt, concentrated under reduced pressure, and then purified by silica gel chromatography (0-20% EtOAc/heptanes) to give 2-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.36 g, 63%) as a colorless oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.62 (br t, J=6.7 Hz, 1H), 5.21 (s, 2H), 3.50 (s, 3H), 1.44-1.25 (m, 12H).

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

Int	Structure	Name	1H NMR
6.011		2-(4-Chloro-2-fluoro-3- (methoxymethoxy)-5- (trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane	1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 5.4 Hz, 1H), 5.24 (s, 2H), 3.66 (s, 3H), 1.37 (s, 12H)
6.022,3		2-Chloro-6-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-3-(trifluoromethyl)phenol	1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.40 (d, J = 5.0 Hz, 1H), 1.17 (s, 12H)
6.03		4,4,5,5-Tetramethyl-2-(2,4,5- trifluoro-3- (methoxymethoxy)phenyl)-1,3,2- dioxaborolane	1H NMR (400 MHz, DMSO-d6): δ 7.84 (dt, J = 7.0, 8.4 Hz, 1H), 5.24 (s, 2H), 3.50 (s, 3H), 1.17 (s, 12H)
6.04		2-(5-Chloro-2,4-difluoro-3- (methoxymethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolane	No data; made in situ
6.054		3-Bromo-5-chloro-2,6- difluorophenol	1H NMR (400 MHz, DMSO-d6): δ 11.28 (br s, 1H), 7.38 (t, J = 6.8 Hz, 1H)
Alternate conditions used:
Step 1: 16-22 h. Step 2: 5-49 h. Step 3: 1 h-ON. Step 4: 85° C., 0.5-1 h.
1Synthesized from Intermediate 5 following the procedure described for Intermediate 6, Steps 3-4.
2Isolated during the purification of Intermediate 6.01.
3Synthesized from Intermediate 4.01 following the procedure described for Intermediate 6, Step 4 (80° C. for 16 h in sealed reactor).
4Steps 1-2 only from 4-bromo-2-chloro-1,5-difluorobenzene.

Intermediate 7

2-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(1,5-Cyclooctadiene)(methoxy) iridium (I) dimer (92.1 mg, 0.139 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (37.2 mg, 0.139 mmol) were added to a solution of Intermediate 4, Step 3 (4.01 g, 13.88 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (2.93 g, 11.52 mmol) in THF (40 mL) under N₂. The mixture was stirred at 80° C. for 4 h, cooled to rt, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate=100/1 to 10/1) to give 2-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.3 g, 92%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.45 (t, 1H), 7.43-7.38 (m, 5H), 5.22 (s, 2H), 1.31 (s, 12H).

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.

Int	Structure	Name
6		2-(2,4-Difluoro-3- (methoxymethoxy)- 5- (trifluoromethyl) phenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane

Intermediate 7.01

2,4-Difluoro-3-methoxy-5-(tributylstannyl)benzonitrile

Step 1:2,4-Difluoro-3-methoxybenzonitrile

CuCN (460 mg, 5.13 mmol) was added to a solution of 1,3-difluoro-4-iodo-2-methoxy-benzene (0.99 g, 3.67 mmol) and DMF (15 mL). The mixture was stirred at 120° C. for 22 h, cooled to rt, diluted with H₂O (120 mL), and then extracted with EtOAc (120 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 99/1 to 82/18) to give 2,4-difluoro-3-methoxy-benzonitrile (293 mg, 47%) as a yellow solid. ¹H NMR (400 MHZ, CD₃OD): δ 7.40-7.60 (m, 1H), 7.10-7.26 (m, 1H), 4.00-4.10 (s, 3H).

Step 2:2,4-Difluoro-3-methoxy-5-(tributylstannyl)benzonitrile

n-BuLi (2 M in n-hexane, 950 μL) was added dropwise to a solution of i-Pr₂NH (293 μL, 2.07 mmol) and THF (4.9 mL) maintaining the temperature below −65° C. The reaction was stirred for 10 min and then a solution of 2,4-difluoro-3-methoxy-benzonitrile (292 mg, 1.73 mmol) and THF (10 mL) was added over 20 min at −65° C. The reaction was stirred at −65° C. for 30 min, and then tributyl(chloro) stannane (1.03 mL, 3.82 mmol) was added. The mixture was stirred at −65° C. for 1 h, warmed to rt, poured into sat. aq. KF (15 mL), and then extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: I/O to 97/3) to give 2,4-difluoro-3-methoxy-5-tributylstannyl-benzonitrile (522 mg, 66%) as a yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 7.10-7.22 (m, 1H), 3.92-3.98 (m, 3H), 1.39-1.51 (m, 6H), 1.21-1.28 (m, 6H), 1.01-1.12 (m, 6H), 0.80-0.84 ppm (m, 9H).

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.

Int	Structure	Name	1H NMR
7.02		(3-Benzyloxy- 4-chloro- 2,6- difluorophenyl) tributylstannane	1H NMR (400 MHz, DMSO- d6): δ 7.45-7.41 (m, 3H), 7.39-7.36 (m, 2H), 7.23-7.21 (m, 1H), 5.04-5.02 (m, 2H), 1.62-1.59 (m, 6H), 1.31-1.29 (m, 6H), 1.14-1.12 (m, 6H), 0.89-0.85 (m, 9H)

Intermediate 8

5-Chloro-3-methyl-1H-pyrazolo[4,3-d]pyrimidine

Step 1:5-Chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine

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]⁺.

Step 2:5-Chloro-3-methyl-1H-pyrazolo[4,3-d]pyrimidine

A mixture of 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (1.00 g, 3.57 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5.98 mL, 21.4 mmol, 50% w/w soln. in THF), Pd(dppf)Cl₂ (0.39 g, 0.53 mmol), K₃PO₄ (2.27 g, 10.7 mmol), and dioxane (6 mL) was degassed/backfilled with N₂ three times, heated in a microwave at 120° C. for 90 min, allowed to cool to rt, and then diluted with ethyl acetate. The organic layer was washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO₄), filtered, and then concentrated. The residue was dissolved in CH₂Cl₂ and 1 mL CH₃OH and purified via silica gel chromatography (0-50% ethyl acetate in heptane) to give 5-chloro-3-methyl-1H-pyrazolo[4,3-d]pyrimidine (0.16 g, 25%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.76 (br s, 1H), 9.24 (s, 1H), 2.52 (s, 3H); LCMS: 168.8 [M+H]⁺.

Intermediate 8.01

5-Bromo-6-fluoro-3-methyl-1H-pyrazolo[4,3-b]pyridine

Step 1:1-(3-Amino-5-fluoropyridin-2-yl) ethanone

Bromo(methyl) magnesium (14.1 mL, 3 M in THF) was added dropwise over 0.5 h to a solution of 3-amino-5-fluoropicolinonitrile (2.90 g, 21.2 mmol) and THF (30 mL) at −15° C. under N₂. The mixture was stirred at −15° C. for 0.5 h, stirred at rt for 5 h, poured into sat. aq. NH₄Cl (100 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 10/1 to 4/1) to give 1-(3-amino-5-fluoropyridin-2-yl) ethanone (2.10 g, 64%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.84 (d, 1H), 7.55-7.24 (m, 2H), 7.00 (d, 1H), 2.53 (s, 3H); LCMS: 155.2 [M+H]⁺.

Step 2:1-(3-Amino-6-bromo-5-fluoropyridin-2-yl) ethenone

NBS (2.54 g, 14.3 mmol) was added to a solution of 1-(3-amino-5-fluoropyridin-2-yl) ethanone (2.00 g, 13.0 mmol) and MeCN (40 mL). The mixture was stirred at rt for 3 h, poured into sat. aq. Na₂S₂O₃ (80 mL), and then extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to give 1-(3-amino-6-bromo-5-fluoropyridin-2-yl) ethanone (3.40 g) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.75-7.39 (m, 2H), 7.17 (d, 1H), 2.57 (s, 3H). LCMS: 233.0 [M+H]⁺.

Step 3:5-Bromo-6-fluoro-3-methyl-1H-pyrazolo[4,3-b]pyridine

A solution of NaNO₂ (1.07 g, 15.6 mmol) and H₂O (10 mL) was added dropwise over 0.5 h to a solution of 1-(3-amino-6-bromo-5-fluoropyridin-2-yl) ethanone (3.30 g, 14.2 mmol) and HCl (50 mL, 12 M) at 0° C. The mixture was stirred at 0° C. for 0.5 h, and then a solution of SnCl₂·2H₂O (7.35 g, 32.6 mmol) in HCl (20 mL, 12 M) was added dropwise. The reaction was stirred at 0° C. for 1 h, poured into sat. aq. NaHCO₃ (1 L) slowly, and then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to give 5-bromo-6-fluoro-3-methyl-1H-pyrazolo[4,3-b]pyridine (2.20 g) as a light yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 13.23 (s, 1H), 8.08 (d, 1H), 2.53-2.51 (m, 3H); LCMS: 230.0 [M+H]⁺.

Intermediate 9

(R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidine

Step 1:5-Chloro-3-methyl-2-((2-(trimethylsilyl) ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidine

(2-(Chloromethoxy)ethyl) trimethylsilane (18.3 mL, 103 mmol) was added dropwise to a mixture of Intermediate 8 (11.6 g, 68.8 mmol) and Cs₂CO₃ (56.1 g, 172 mmol) in DMF (200 mL) at 0° C. The mixture was stirred at rt for 2 h, poured into H₂O (200 mL) slowly, and then filtered. The filtrate was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc=30:1 to 3:1) to give 5-chloro-3-methyl-2-((2-(trimethylsilyl) ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidine (5.32 g, 24%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 9.51 (s, 1H), 5.87 (s, 2H), 3.58 (t, 2H), 2.67 (s, 3H), 0.84 (s, 2H), −0.08 (s, 9H); LCMS: 299.0 [M+H]⁺.

Step 2: (R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidine

A mixture of 5-chloro-3-methyl-2-((2-(trimethylsilyl) ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidine (650 mg, 2.18 mmol), Intermediate 2.01 (696 mg, 2.39 mmol), potassium fluoride (379 mg, 6.53 mmol), and water (10 mL) was stirred at 100° C. overnight, allowed to cool to rt, and then diluted with EtOAc. The layers were separated, and the organic layer was dried (MgSO₄), filtered, and then concentrated. The residue was dissolved in CH₂Cl₂/TFA (2:1, 15 mL). The reaction was stirred at rt for 2 h and concentrated to give a mixture of (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidine and (R)-(5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)methanol. The mixture was dissolved in 10 mL CH₂Cl₂. Ethylenediamine (1 mL) was added, and the reaction was stirred over the weekend. Additional ethylendiamine (1 mL) was added. The reaction was stirred for 6 h and then diluted with water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, concentrated, and then purified by silica gel chromatography (0-100% EtOAc in heptane) to give (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidine (110 mg, 12%) as an off-white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 12.97 (s, 1H), 8.99 (s, 1H), 7.39-7.25 (m, 4H), 7.23-7.16 (m, 1H), 5.04-4.89 (m, 1H), 4.69 (br d, J=13.1 Hz, 1H), 3.70 (br d, J=10.6 Hz, 1H), 3.47 (br d, J=11.5 Hz, 1H), 3.30-3.20 (m, 1H), 3.07 (br t, J=11.2 Hz, 1H), 2.95-2.75 (m, 5H), 2.67 (br d, J=10.5 Hz, 1H), 2.46 (s, 3H); LCMS: 387.5 [M+H]⁺.

Intermediate 10

(R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-chloro-1H-pyrazolo[4,3-d]pyrimidine

Step 1:3,5-Dichloro-1H-pyrazolo[4,3-d]pyrimidine

N-Chlorosuccinimide (1.04 g, 7.76 mmol) was added to a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (1.00 g, 6.47 mmol) in DMF (20 mL). The reaction was stirred at rt for 18.5 h, diluted with ethyl acetate and water. The organic layer was dried (MgSO₄), filtered, concentrated, and then purified by silica gel chromatography (0-50% ethyl acetate in heptane) to give 3,5-dichloro-1H-pyrazolo[4,3-d]pyrimidine (1.01 g, 78%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 14.55-14.34 (m, 1H), 9.39 (s, 1H); LMCS: 189.2 [M+H]⁺.

Step 2:3,5-Dichloro-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine

Sodium hydride (158 mg, 4.11 mmol) was added slowly to a mixture of 3,5-dichloro-1H-pyrazolo[4,3-d]pyrimidine (432 mg, 2.29 mmol) and SEM-C₁ (0.73 mL, 4.11 mmol) in THF (6 mL) at 0° C. The reaction was stirred at rt for 30 min, quenched with water, and then extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried (MgSO₄), filtered, concentrated, and then purified by silica gel chromatography (0-50% ethyl acetate in heptane) to give 3,5-dichloro-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (328 mg, 45%) as an off-white semi-solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 9.63 (s, 1H), 5.86 (s, 2H), 3.55-3.50 (m, 2H), 0.84-0.80 (m, 2H), −0.08 (s, 9H); LMCS: 319.4 [M+H]⁺.

Step 3: (R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-chloro-1H-pyrazolo[4,3-d]pyrimidine

A mixture of 3,5-dichloro-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (100 mg, 0.313 mmol), Intermediate 2.01 (119 mg, 0.41 mmol), DIEA (0.21 mL, 1.25 mmol), and NMP (1 mL) was stirred at 140° C. overnight, allowed to cool to rt, and then diluted with EtOAc. The organic layer was washed with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, concentrated, and then purified by silica gel chromatography (0-100% EtOAc in heptane). The residue was dissolved in 2 mL CH₂Cl₂ and 1 mL TFA and then stirred at rt for 4 h. Additional trifluoroacetic acid (1 mL) was added. The reaction was stirred overnight, concentrated, dissolved in a mixture of EtOAc/heptane, and then concentrated to give crude (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-chloro-1H-pyrazolo[4,3-d]pyrimidine (17 mg, 13%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.73-11.49 (m, 1H), 9.08 (s, 1H), 7.41-7.32 (m, 2H), 7.32-7.24 (m, 2H), 7.22-7.14 (m, 1H), 4.97 (br d, J=4.4 Hz, 1H), 4.68 (br d, J=13.3 Hz, 1H), 3.71 (br d, J=9.8 Hz, 1H), 3.48 (br d, J=11.6 Hz, 1H), 3.33-3.25 (m, 1H), 3.12-3.01 (m, 1H), 2.89 (s, 3H), 2.88-2.80 (m, 2H), 2.76-2.68 (m, 1H); LCMS: 407.5 [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.

Int	Structure	Name	[M + H]+
10.011		(R)-5-(2- Benzyl-4- (methyl- sulfonyl) piperazin- 1-yl)-1H- pyrazolo [4,3-d] pyrimidine	373.5
Alternate conditions used:
1Step 3: DIEA, NMP, 130° C. for 3 h, 140° C. for ON, and then 150° C., 3 h; CH2Cl2/TFA (2:1), rt, overnight.

Intermediate 11

3-Benzyl-4-(3-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)morpholine

Step 1:5-Bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine

A suspension of 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine (5.14 g, 24.2 mmol), 2H-3,4-dihydropyran (6.6 mL, 72.7 mmol), p-toluenesulfonic acid (0.55 g, 2.91 mmol), and CH₂Cl₂ (50 mL) was stirred at rt for overnight. Additional 2H-3,4-dihydropyran (4.42 mL, 48.5 mmol) was added. The reaction was stirred at rt overnight and then diluted with NaHCO₃. The organic layer was dried (MgSO₄), filtered, concentrated, and then purified by silica gel chromatography (0-100% ethyl acetate in heptane) to give 5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (6 g, 83%) as an off-white semi-solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (d, J=1.1 Hz, 1H), 8.08 (d, J=1.1 Hz, 1H), 5.90 (dd, J=2.4, 9.7 Hz, 1H), 3.94-3.81 (m, 1H), 3.79-3.67 (m, 1H), 2.50 (s, 3H), 2.07-1.93 (m, 2H), 1.79-1.54 (m, 4H); LCMS: 298.1 [M+H]⁺.

Step 2:3-Benzyl-4-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)morpholine

A mixture of 5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (70 mg, 0.24 mmol), 3-benzylmorpholine (63 mg, 0.35 mmol), sodium tert-butoxide (68 mg, 0.71 mmol), Pd₂(dba)₃, and RuPhos (11 mg, 0.024 mmol) was degassed/backfilled with N₂ three times. Dioxane (2 mL) was added. The reaction was degassed/backfilled with N₂ for 3 min, stirred at 80° C. for 3 h, allowed to cool to rt, and then diluted with CH₂Cl₂ and water. The organic layer was dried (MgSO₄), filtered, concentrated, and then purified by silica gel chromatography (0-50% ethyl acetate in heptane) to give 3-benzyl-4-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)morpholine (56 mg, 60%) as a yellow oil. LCMS: 393.4 [M+H]⁺.

Step 3:3-Benzyl-4-(3-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)morpholine

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 CH₂Cl₂ and 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.

Int	Structure	Name	[M + H]+
11.01		(R)-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridine	386.5
11.02		(S)-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridine	386.3
11.03		2-Benzyl-4-(3-methyl-1H- pyrazolo[3,4-c]pyridin-5- yl)morpholine	309.4
11.04		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-indazole	405.4
11.05		(R)-5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridine	386.6
11.061		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (1,1-difluoroethyl)-1H-indazole	435.4
11.07		(S)-5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridine	386.4
11.08		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-indazole	385.5
11.09		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-pyrazolo[3,4-c]pyridine	406.5
11.102		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-c]pyridine	372.5
11.11		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-N,N- dimethyl-1H-indazol-3-amine	414.6
11.123		(R)-5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-6- fluoro-3-methyl-1H-pyrazolo[4,3- b]pyridine	404.2
Alternate conditions used:
Step 1: reaction time was 1-48 h. Step 2: reaction time was 3 h-overnight. Step 3: reaction time was 2 h-overnight. In some instances, additional t-BuONa, Pd2(dba)3, and RuPhos was needed.
1Synthesized from 3-acetyl-5-bromo-1H-indazole using the following sequence: Step 1, fluorination (DAST, CH2Cl2, 50° C., 3 days then rt, 10 days), Step 2, and then Step 3.
2Isolated as a by product of Intermediate 11.09 (Step 2) and then deprotected following the procedure for Step 3.
3Step 2: Xantphos, Xantphos Pd G4, Cs2CO3, toluene, 80° C., 2 h.

Intermediate 11.13

(R)-3-Benzyl-4-(3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)morpholine

(R)-3-Benzyl-4-(3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)morpholine was synthesized from Intermediate 8 (Step 1) using the following sequence: Intermediate 10 (Step 2), Intermediate 8 (Step 2), Buchwald coupling with (R)-3-benzylmorpholine (Pd(OAc)₂, BINAP, Cs₂CO₃, 100° C., 14 h), and then deprotection (2:1 CH₂Cl₂/TFA, rt, 2 h). ¹H NMR (400 MHZ, DMSO-d₆): δ 12.92 (s, 1H), 8.95 (s, 1H), 7.33-7.16 (m, 5H), 4.66-4.64 (m, 1H), 4.37 (d, 1H), 4.03-3.99 (m, 1H), 3.64 (d, 1H), 3.55-3.45 (m, 2H), 3.31-3.24 (m, 1H), 3.08-3.03 (m, 1H), 2.71 (dd, 1H), 2.45 (s, 3H); LCMS: 310.2 [M+H]⁺.

Intermediate 11.14

(R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-6-chloro-3-methyl-1H-pyrazolo[4,3-b]pyridine

(R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-6-chloro-3-methyl-1H-pyrazolo[4,3-b]pyridine was synthesized from 5-chloro-1H-pyrazolo[4,3-b]pyridine using the procedures described for Intermediate 8 (Step 1), Intermediate 11 (Step 1), Intermediate 8 (Step 2; 90° C., overnight), Intermediate 11 (Step 2), Intermediate 10 (Step 1; CH₃CN, 80° C., 2 h), and then Intermediate 11 (Step 3; 1:1 TFA/CH₂Cl₂). ¹H NMR (400 MHZ, DMSO-d₆): δ 12.86 (s, 1H), 8.09 (s, 1H), 7.26-7.14 (m, 5H), 4.03 (q, 3H), 3.59-3.45 (m, 2H), 3.22-3.06 (m, 2H), 2.97-2.91 (m, 4H), 2.86-2.80 (m, 1H), 1.99 (s, 3H); LCMS: 420.1 [M+H]⁺.

Intermediate 12

6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2.50 g, 8.91 mmol) was weighed into a 20 mL microwave vial. Tetrahydrofuran (5 mL), 2H-3,4-dihydropyran (1.47 mL, 16.1 mmol), and methanesulfonic acid (70 μL, 1.07 mmol) were added. The reaction was heated in a microwave at 90° C. for 1 h, allowed to cool to rt, diluted with 10 mL CH₂Cl₂, washed with saturated NaHCO₃, concentrated, and then purified by silica gel chromatography (0-50% EtOAc in hexanes to give 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (1.69 g, 87%) as an off-white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.65 (s, 1H), 8.00 (s, 1H), 5.90 (br d, J=8.1 Hz, 1H), 3.89 (br d, J=11.4 Hz, 1H), 3.81-3.70 (m, 1H), 2.37-2.26 (m, 1H), 2.04-1.94 (m, 2H), 1.76-1.64 (m, 1H), 1.64-1.53 (m, 2H); LCMS: 364.1 [M+H]⁺.

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

Int	Structure	Name	[M + H]+
12.011		6-Chloro-3-iodo-1- (tetrahydro-2H- pyran-2-yl)-1H- pyrazolo[3,4- d]pyrimidine	365.1
Alternate conditions used:
1DHP, p-toluenesulfonic acid monohydrate, CH2Cl2, rt, 15 h.

Intermediate 13

6-Chloro-3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Step 1:6-Chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Iodomethane (7.99 mL, 128 mmol) was added to a mixture of 6-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (20.1 g, 71.3 mmol) and K₂CO₃ (29.6 g, 214 mmol) in DMF (200 mL) at 0° C. The mixture was stirred at rt for 12 h, poured into H₂O (300 mL) slowly, and then extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate=30:1 to 3:1) to give 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (15.2 g, 72%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 9.01 (s, 1H), 4.00 (s, 3H); LCMS: 294.9 [M+H]⁺.

Step 2:6-Chloro-3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Pd(dppf)Cl₂·CH₂Cl₂ (2.77 g, 3.40 mmol) was added to a mixture of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (10.0 g, 34.0 mmol), Intermediate 6 (15.0 g, 40.8 mmol), Na₂CO₃ (2 M in H₂O, 42.5 mL, 84.9 mmol), and dioxane (120 mL) under N₂. The mixture was degassed and purged with N₂ 3 times, stirred at 80° C. for 1 h, allowed to cool to rt, diluted with H₂O (500 mL), and then extracted with EtOAc (2×300 mL). The combined organic layers were washed with brine (300 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc=30:1 to 3:1) to give 6-chloro-3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (13.8 g, 90%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 9.39 (d, 1H), 7.99 (t, 1H), 5.35 (s, 2H), 4.12 (s, 3H), 3.56 (s, 3H); LCMS: 409.0 [M+H]⁺.

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

Int	Structure	Name	[M + H]+
13.012		6-Chloro-3-(2,4-difluoro-3- (methoxymethoxy)-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[4,3-c]pyridine	408.0
13.021,5		6-Chloro-3-(2,4-difluoro-3- (methoxymethoxy)-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-b]pyridine	407.9
13.033		6-Chloro-3-(2,4-difluoro-3- (methoxymethoxy)-5- (trifluoromethyl)phenyl)-1-(oxetan-3- yl)-1H-pyrazolo[4,3-c]pyridine	450.2
13.044		6-Chloro-3-(2,4-difluoro-3- (methoxymethoxy)-5- (trifluoromethyl)phenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-d]pyrimidine	479.3
13.054		6-Chloro-3-(2,4-difluoro-3- (methoxymethoxy)-5- (trifluoromethyl)phenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[4,3-c]pyridine	478.1
13.06		3-(3-(Benzyloxy)-2,4-difluoro-5- (trifluoromethyl)phenyl)-6-chloro-1- methyl-1H-pyrazolo[3,4- d]pyrimidine	455.0
13.071,5		6-Chloro-3-(2,4-difluoro-3- methoxyphenyl)-1-methyl-1H- pyrazolo[4,3-c]pyridine	310.2
13.081,5		3-(3-(Benzyloxy)-4-chloro-2- fluorophenyl)-6-chloro-1-methyl-1H- pyrazolo[4,3-c]pyridine	402.3
13.091,6		2-Chloro-5-(6-chloro-1-methyl-1H- pyrazolo[4,3-c]pyridin-3-yl)-6- fluoro-3-(trifluoromethyl)phenol	380.3
13.105		3-(3-(Benzyloxy)-2,4-difluoro-5- (trifluoromethyl)phenyl)-6-chloro-1- ethyl-1H-pyrazolo[3,4-d]pyrimidine	did not ionize
Alternate conditions used:
1Step 1: THF instead of DMF, rt, 2-15 h.
2Step 1: CH3I, Cs2CO3, DMF, 50° C., 2 h.
3Step 1: 80° C., 15 h.
4Step 2 only.
5Step 2: Pd(dppf)Cl2, KF, dioxane, water, 90° C., 30-45 min.
6Step 2: Intermediate 6.02, Pd(dppf)Cl2, K2CO3, CH3CN, microwave, 90° C., 15 min.

Intermediate 14

(R)-6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Intermediate 13, Step 1 (800 mg, 2.72 mmol) and Intermediate 2.01 (1.05 g, 4.13 mmol) were combined in a 20 mL microwave vial. 1-Methyl-2-pyrrolidinone (8 mL) and then DIEA (1.35 mL, 7.75 mmol) were added. The reaction was heated in a microwave at 150° C. for 1 h, allowed to cool to rt, and then diluted with 30 mL ethyl acetate. The organic layer was washed with 30 mL water, washed with 20 mL brine, dried (Na₂SO₄), filtered, and then concentrated. The residue was suspended in CH₂Cl₂: EtOAc (5:2, 10 mL), warmed with a heat gun, cooled to rt, and then filtered. The solids were washed with 10 mL EtOAc to give (R)-6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (664 mg, 48%) as a beige solid. The filtrate was purified by silica gel chromatography (0-15% EtOAc in hexanes). The fractions were concentrated and then suspended in CH₂Cl₂: EtOAc (5:2, 7 mL). The mixture was warmed with a heat gun, cooled to rt, and then filtered. The solids were washed with 5 mL EtOAc to give additional (R)-6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (212 mg, 15%). ¹H NMR (400 MHZ, DMSO-d₆): δ 8.62 (s, 1H), 7.36-7.24 (m, 4H), 7.22-7.13 (m, 1H), 5.14 (br s, 1H), 4.82 (br d, J=11.7 Hz, 1H), 3.87 (s, 3H), 3.70 (br d, J=10.6 Hz, 1H), 3.49 (br d, J=11.7 Hz, 1H), 3.41-3.34 (m, 1H), 3.10 (dd, J=9.4, 12.8 Hz, 1H), 2.92-2.89 (m, 3H), 2.88-2.75 (m, 3H); LCMS: 513.4 [M+H]⁺.

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

Int	Structure	Name	[M + H]+
14.01		N-(4-Benzyltetrahydro-2H-pyran-4- yl)-3-iodo-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-amine	450.5
14.021		N-(4-Benzyltetrahydro-2H-pyran-4- yl)-3-iodo-N, 1-dimethyl-1H- pyrazolo[3,4-d]pyrimidin-6-amine	464.5
14.03		tert-Butyl (R)-3-benzyl-4-(3-iodo-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 6-yl)piperazine-1-carboxylate	535.4
14.04		tert-Butyl (S)-2-benzyl-4-(3-iodo-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 6-yl)piperazine-1-carboxylate	535.3
14.052,3		(R)-6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- ethyl-3-iodo-1H-pyrazolo[3,4- d]pyrimidine	527.2
14.063		Methyl (S)-4-(3-iodo-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6- yl)morpholine-3-carboxylate	404.1
14.07		(R)-3-Benzyl-4-(3-iodo-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6- yl)thiomorpholine	452.1
Alternate conditions used: Reaction time was 1-5 h. Reaction temp was 120° C. or 150° C.
1Synthesized from Intermediate 14.01 by methylation: MeI, NaH, DMF, 0° C.-rt, 1-3 h.
2Used Intermediate 2.06 and Intermediate 13.10 (Step 1).
3KF, NMP, 100° C., overnight.

Intermediate 15

6-(2-(Cyclopropylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Step 1: tert-Butyl 3-(cyclopropylmethyl)-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate

Intermediate 13, Step 1 (150 mg, 0.509 mmol) and tert-butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate (147 mg, 0.611 mmol) were weighed into a 2 mL microwave vial. 1-Methyl-2-pyrrolidinone (1 mL) and N,N-diisopropylethylamine (275 μL, 1.58 mmol) were added. The reaction was heated in a microwave at 100° C. for 1.5 h, allowed to cool to rt, and then diluted with 10 mL EtOAc. The organic layer was washed with 10 mL water, washed with 10 mL brine, dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (0-20% EtOAc in hexanes) to give tert-butyl 3-(cyclopropylmethyl)-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (129 mg, 51%) as a white foam. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.49 (s, 1H), 4.91-4.73 (m, 1H), 4.46 (br dd, J=1.4, 13.9 Hz, 1H), 4.01 (br d, J=13.6 Hz, 1H), 3.95-3.86 (m, 1H), 3.72 (s, 3H), 3.00 (br d, J=9.0 Hz, 2H), 2.82-2.67 (m, 1H), 1.63-1.45 (m, 1H), 1.34 (s, 9H), 1.15 (br s, 1H), 0.65-0.48 (m, 1H), 0.39-0.23 (m, 2H), 0.00 (br s, 2H); LCMS: 499.5 [M+H]⁺.

Step 2:6-(2-(Cyclopropylmethyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

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.

Step 3:6-(2-(Cyclopropylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Triethylamine (100 μL, 0.717 mmol) was added to 6-(2-(cyclopropylmethyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (from the previous step) in CH₂Cl₂ (2 mL). The mixture was cooled in an ice/water bath. Methanesulfonyl chloride (22 μL, 0.28 mmol) was added at 0° C. The reaction was stirred at rt for 17 h, diluted with 10 mL CH₂Cl₂, washed with 10 mL water, dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (0-40% EtOAc in hexanes) to give 6-(2-(cyclopropylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (49 mg, 41%) as a white foam. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.61 (s, 1H), 5.12 (br s, 1H), 4.76 (br d, J=13.9 Hz, 1H), 3.83 (s, 3H), 3.71 (br d, J=11.6 Hz, 1H), 3.60 (br d, J=11.4 Hz, 1H), 3.17 (br t, J=11.4 Hz, 1H), 2.96-2.88 (m, 4H), 2.84-2.75 (m, 1H), 1.80-1.68 (m, 1H), 1.47-1.36 (m, 1H), 0.62 (br dd, J=1.5, 3.9 Hz, 1H), 0.42-0.27 (m, 2H), 0.20-0.00 (m, 2H); LCMS: 477.5 [M+H]⁺.

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

Int	Structure	Name	[M + H]+
15.01		1-(3-(Cyclopropylmethyl)-4-(3-iodo- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)piperazin-1-yl)- 2,2,2-trifluoroethan-1-one	495.7
15.02		6-(2-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-3- iodo-1-methyl-1H-pyrazolo[3,4- d]pyrimidine	491.5
15.032		3-(Cyclopropylmethyl)-4-(3-iodo-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 6-yl)-N,N-dimethylpiperazine-1- carboxamide	470.5
15.043		3-(Cyclopropylmethyl)-4-(3-iodo-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 6-yl)piperazine-1-carboxamide	442.5
Alternate conditions used:
Step 2: 2 h. Step 3: 0° C.-rt, 30 min.
1Isolated during the purification of Intermediate 15, Step 3.
2Synthesized from Intermediate 15 (Step 2) by acylation (dimethylcarbamyl chloride, TEA, CH2Cl2, 0° C.-rt, 1 h).
3Synthesized from Intermediate 15 (Step 2) by amine addition (isocyanatotrimethylsilane, TEA, THF, 0° C.-rt, overnight).

Intermediate 16

3-(Cyclohexylmethyl)morpholine

Step 1:2-Amino-3-cyclohexylpropan-1-ol

BH₃·Me₂S (10 M, 5.26 mL, 52.6 mmol) was added dropwise to a mixture of 2-amino-3-cyclohexylpropanoic acid (3.0 g, 17.5 mmol) and THF (50 mL) at 0° C. The mixture was heated at 50° C. overnight, allowed to cool to rt, poured into MeOH (50 mL) slowly, stirred for 0.5 h, and then concentrated to give 2-amino-3-cyclohexylpropan-1-ol (2.87 g) as a colorless oil.

Step 2:2-(2-Chloroacetamido)-3-cyclohexylpropyl 2-chloroacetate

2-Chloroacetyl chloride (4.12 g, 36.5 mmol) was added dropwise to a mixture of 2-amino-3-cyclohexylpropan-1-ol (2.87 g, 18.3 mmol), K₂CO₃ (5.04 g, 36.5 mmol), and MeCN (50 mL) at 0° C. The mixture was stirred at rt for 2 h, poured into H₂O (50 mL), and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to give 2-(2-chloroacetamido)-3-cyclohexylpropyl 2-chloroacetate (5.1 g) as a yellow oil.

Step 3:2-Chloro-N-(1-cyclohexyl-3-hydroxypropan-2-yl) acetamide

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]⁺.

Step 4:5-(Cyclohexylmethyl) morpholin-3-one

t-BuOK (9.00 g, 80.2 mmol) was added to a solution of 2-chloro-N-(1-cyclohexyl-3-hydroxypropan-2-yl) acetamide (3.75 g, 16.0 mmol) and i-PrOH (50 mL). The mixture was stirred at rt for 1 h, heated at 40° C. overnight, allowed to cool to rt, adjusted to pH=2 with 1 M HCl, and then concentrated. The residue was diluted with H₂O (50 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to give 5-(cyclohexylmethyl)morpholin-3-one (1.9 g) as a yellow oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.04 (s, 1H), 3.93-3.92 (d, 2H), 3.79-3.76 (m, 1H), 3.43-3.38 (m, 2H), 1.65-1.62 (d, 6H), 1.36-1.33 (m, 2H), 1.24-1.15 (m, 3H), 0.85-0.80 (m, 2H); LCMS: 198.2 [M+H]⁺.

Step 5:3-(Cyclohexylmethyl)morpholine

BH₃·Me₂S (10 M, 2.40 mL, 24.0 mmol) was added dropwise to a mixture of 5-(cyclohexylmethyl)morpholin-3-one (1.58 g, 8.01 mmol) and THF (20 mL) at 0° C. The mixture was stirred at rt overnight, poured into MeOH (50 mL) slowly, stirred for 0.5 h, and then concentrated to give 3-(cyclohexylmethyl)morpholine (1.4 g) as a colorless oil.

The Intermediates below were synthesized from the appropriate 2-amino-3-(pyridinyl) propanoic acid using the following sequence: Intermediate 16 (Step 1: rt, overnight; Step 2: THF/water as solvent to provide free OH directly), cyclization (NaH, THF, 0° C., 0.5 h), amide reduction (2.4 M LiAlH₄ in THF, THF, rt, overnight).

Int	Structure	Name	[M + H]+
16.011		3-(Pyridin-2- ylmethyl) morpholine bis- hydrochloride	179.2
16.02		3-(3- Pyridylmethyl) morpholine	179.2
16.032		3-(Pyridin-4- ylmethyl) morpholine	179.1
1After amide reduction: Boc protection (Boc2O, CH2Cl2, TEA, rt, 2 h), silica gel purification, Boc deprotection (4 M HCl in EtOAc, rt, 1 h);
2Step 1: 2.4 M LiAH4 in THF, THF, 0° C.-rt, overnight.

Intermediate 17

3-(Cyclohexylmethyl)-1-(methylsulfonyl)piperazine

Step 1: Ethyl 2-(benzylamino)-3-cyclohexylpropanoate

NaBH(OAc)₃ (4.17 g, 19.67 mmol) was added to a mixture of ethyl 2-amino-3-cyclohexylpropanoate (1.96 g, 9.83 mmol), benzaldehyde (0.90 mL, 8.85 mmol), and DCE (30 mL) at 0° C. The mixture was stirred at rt for 2 h, poured into H₂O (30 mL), adjusted to pH=8 with sat. aq. NaHCO₃, and then extracted with DCM (20 mL×3). The organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 50/1 to 5/1) to give ethyl 2-(benzylamino)-3-cyclohexylpropanoate (1.76 g, 22%) as a yellow oil. LCMS: 290.2 [M+H]⁺.

Step 2: Ethyl 2-(benzyl (2-((tert-butoxycarbonyl)amino) ethyl)amino)-3-cyclohexylpropanoate

NaBH(OAc)₃ (2.81 g, 13.3 mmol) was added to a mixture of ethyl 2-(benzylamino)-3-cyclohexylpropanoate (1.92 g, 6.63 mmol), tert-butyl (2-oxoethyl) carbamate (950 mg, 5.97 mmol), and DCE (20 mL) at 0° C. The mixture was stirred at rt for 2 h, poured into H₂O (20 mL), adjusted to pH=8 with sat. aq. NaHCO₃, and then extracted with DCM (10 mL×3). The organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 50/1 to 5/1) to give ethyl 2-(benzyl (2-((tert-butoxycarbonyl)amino) ethyl)amino)-3-cyclohexylpropanoate (2.17 g, 76%) as a yellow oil. LCMS: 433.3 [M+H]⁺.

Step 3: Ethyl 2-((2-aminoethyl) (benzyl)amino)-3-cyclohexylpropanoate hydrochloride

A mixture of ethyl 2-(benzyl (2-((tert-butoxycarbonyl)amino) ethyl)amino)-3-cyclohexylpropanoate (2.04 g, 4.72 mmol) and HCl/EtOAc (4M, 30 mL) was stirred at rt for 0.5 h and then concentrated to give ethyl 2-((2-aminoethyl) (benzyl)amino)-3-cyclohexylpropanoate hydrochloride (1.6 g) as a yellow solid: LCMS: 333.3 [M+H]⁺.

Step 4:4-Benzyl-3-(cyclohexylmethyl)piperazin-2-one

Sodium methoxide (1.15 g, 21.3 mmol) was added to a solution of ethyl 2-((2-aminoethyl) (benzyl)amino)-3-cyclohexylpropanoate hydrochloride (1.57 g, 4.26 mmol) and MeOH (20 mL). The mixture was stirred at rt for 2 h, poured into H₂O (20 mL), and then filtered. The filter cake was washed with H₂O (50 mL) and then dried under vacuum to give 4-benzyl-3-(cyclohexylmethyl)piperazin-2-one (1.4 g) as a white solid. ¹H NMR (400 MHZ, CDCl₃): δ 7.34-7.28 (m, 5H), 5.94 (s, 1H), 3.89-3.86 (m, 1H), 3.60-3.57 (m, 1H), 3.52-3.48 (m, 1H), 3.28-3.24 (m, 1H), 3.19-3.16 (m, 1H), 3.12-3.06 (m, 1H), 2.63-2.59 (m, 1H), 1.72-1.48 (m, 8H), 1.28-1.13 (m, 3H), 0.96-0.82 (m, 2H); LCMS: 287.3 [M+H]⁺.

Step 5:1-Benzyl-2-(cyclohexylmethyl)piperazine

LiAlH₄ (726 mg, 19.1 mmol) was added in 2 portions to a mixture of 4-benzyl-3-(cyclohexylmethyl)piperazin-2-one (1.37 g, 4.78 mmol) in THF (30 mL) at 0° C. under N₂. The mixture was heated at 65° C. for 2 h, allowed to cool to rt, poured into sat. aq. NaK tartrate (30 mL), and then extracted with EtOAc (20 mL×3). The organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to give 1-benzyl-2-(cyclohexylmethyl)piperazine (1.32 g) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.34-7.21 (m, 5H), 4.02 (d, 1H), 3.17 (d, 1H), 3.04-3.00 (m, 1H), 2.84-2.75 (m, 2H), 2.71-2.60 (m, 2H), 2.45-2.36 (m, 1H), 2.18-2.09 (m, 1H), 1.78-1.58 (m, 8H), 1.33-1.24 (m, 4H), 0.98-0.85 (m, 2H); LCMS: 273.2 [M+H]⁺.

Step 6:1-Benzyl-2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazine

MsCl (1.16 mL, 15.0 mmol) was added to a solution of 1-benzyl-2-(cyclohexylmethyl)piperazine (1.26 g, 4.63 mmol), Et₃N (3.22 mL, 23.1 mmol), and DCM (20 mL) at 0° C. The mixture was stirred at rt for 2 h, poured into water (20 mL), and then extracted with DCM (10 mL×3). The organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 20/1 to 2/1) to give 1-benzyl-2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazine (1.24 g, 82% over 4 steps) as a yellow solid. ¹H NMR (400 MHZ, CDCl₃): δ 7.32-7.24 (m, 5H), 3.90 (d, 1H), 3.37-3.30 (m, 2H), 3.22-3.10 (m, 2H), 3.02-2.99 (m, 1H), 2.83-2.79 (m, 1H), 2.77 (s, 3H), 2.71-2.67 (m, 1H), 2.40-2.34 (m, 1H), 1.70-1.53 (m, 6H), 1.40-1.20 (m, 5H), 1.00-0.85 (m, 2H); LCMS: 351.2 [M+H]⁺.

Step 7:3-(Cyclohexylmethyl)-1-(methylsulfonyl)piperazine

1-Benzyl-2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazine (553 mg, 1.58 mmol) and AcOH (0.24 mL, 3.94 mmol) were added to a mixture of 20% Pd(OH)₂/C (50% water, 700 mg) and THF (20 mL) under N₂. The mixture was degassed with 3 vacuum/H₂ cycles, stirred under H₂ (15 Psi) at rt for 2 h, and then filtered through Celite with MeOH (600 mL) washing. The filtrate was concentrated to give 3-(cyclohexylmethyl)-1-(methylsulfonyl)piperazine (530 mg) as a yellow oil. LCMS: 261.2 [M+H]⁺.

Intermediate 18

tert-Butyl 4-amino-4-benzylpiperidine-1-carboxylate

Step 1:4-Benzyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic (isobutyl carbonic) anhydride

Isobutyl carbonochloridate (1.54 mL, 11.7 mmol) was added dropwise to a solution of 4-benzyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.50 g, 7.83 mmol), 4-methylmorpholine (1.2 mL, 10.9 mmol), and THF (50 mL) at −15° C. under N₂. The reaction was stirred at −15° C. for 2 h to give 4-benzyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic (isobutyl carbonic) anhydride as a colorless solution. LCMS: 442.3 [M+Na]⁺.

Step 2: tert-Butyl 4-(azidocarbonyl)-4-benzylpiperidine-1-carboxylate

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.

Step 3: tert-Butyl 4-amino-4-benzylpiperidine-1-carboxylate

The solution of tert-butyl 4-(azidocarbonyl)-4-benzylpiperidine-1-carboxylate (˜4.65 mmol; estimated by TLC purity) in toluene (90 mL) was added dropwise over ˜10 min to refluxing toluene (30 mL). The reaction was refluxed for 2 h, allowed to cool to rt, concentrated, and then diluted with THF (25 mL) and water (25 mL). A solution of KOH (1.06 g, 18.9 mmol) and water (5 mL) was added dropwise at 0° C. The reaction was allowed to warm to rt, stirred overnight, concentrated to remove THF, diluted with water (25 mL), adjusted to pH˜9 with aq. HCl (6M, ˜3 mL), and then extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 3/1) to give tert-butyl 4-amino-4-benzylpiperidine-1-carboxylate (900 mg, 40% over 3 steps) as a colorless oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.32-7.16 (m, 5H), 3.66-3.51 (m, 2H), 3.20-3.05 (m, 2H), 2.64-2.57 (m, 2H), 1.43-1.28 (m, 13H), 1.25-1.11 (m, 2H); LCMS: 291.3 [M+H]⁺.

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

Int	Structure	Name	[M + H]+
18.01		tert-Butyl 3-amino-3- benzylpiperidine- 1-carboxylate	291.2

Intermediate 19

Step 1: (R)-4-Benzylazetidin-2-one

MsCl (0.24 mL, 2.76 mmol) was added to a mixture of (R)-3-amino-4-phenylbutanoic acid (451 mg, 2.52 mmol), NaHCO₃ (1.27 g, 15.1 mmol), and MeCN (15 mL) at 80° C. The reaction was stirred at 80° C. for 2 h, allowed to cool to rt, filtered, and then concentrated to give (R)-4-benzylazetidin-2-one (621 mg; 5 batches combined during filtration) as white solid.

Step 2: (R)-4-Benzyl-1-(tert-butyldimethylsilyl) azetidin-2-one

A mixture of (R)-4-benzylazetidin-2-one (621 mg, 3.85 mmol), tert-butylchlorodimethylsilane (638 mg, 4.24 mmol), DIEA (1.0 mL, 5.78 mmol), and DCM (8 mL) was stirred at rt for 2 h under N₂, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1 to 0/1) to give (R)-4-benzyl-1-(tert-butyldimethylsilyl) azetidin-2-one (623 mg, 58%) as a yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 7.40-7.28 (m, 3H), 7.16 (d, 2H), 3.79-3.70 (m, 1H), 3.28-3.23 (m, 1H), 3.04-2.98 (m, 1H), 2.73-2.68 (m, 1H), 2.63-2.57 (m, 1H), 1.02 (s, 9H), 0.32 (s, 3H), 0.29 (s, 3H); LCMS: 276.2 [M+H]⁺.

Step 3: (3R,4R)-4-Benzyl-1-(tert-butyldimethylsilyl)-3-(methylthio) azetidin-2-one

LDA (2 M in THF, 0.85 mL) was added dropwise to a solution of (R)-4-benzyl-1-(tert-butyldimethylsilyl) azetidin-2-one (391 mg, 1.42 mmol) and THF (15 mL) at −78° C. The reaction was stirred for 15 min, and then a solution of 1,2-dimethyldisulfane (69.2 mg, 0.732 mmol) in THF (0.5 mL) was added dropwise at −78° C. The reaction was stirred at −78° C. for 10 min, poured (while still cold) into water (30 mL), and then extracted with ethyl acetate (25 mL×3). The combined organic phase was washed with brine (70 mL), dried with anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1 to 0/1) to give (3R,4R)-4-benzyl-1-(tert-butyldimethylsilyl)-3-(methylthio) azetidin-2-one (301 mg, 65%) as a yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 7.41-7.35 (m, 3H), 7.25-7.16 (m, 2H), 3.78-3.74 (m, 1H), 3.71-3.63 (m, 1H), 3.34-3.26 (m, 1H), 2.73-2.62 (m, 1H), 1.86-1.79 (m, 3H), 1.03 (s, 9H), 0.34 (s, 3H), 0.31 (s, 3H); LCMS: 322.2 [M+H]⁺.

Step 4: (2R,3S)-2-Benzyl-3-(methylthio) azetidine

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]⁺.

Intermediate 20

(R)-3-Benzyl-1-ethylpiperazine

Step 1: (R)-tert-Butyl 2-benzyl-4-ethylpiperazine-1-carboxylate

A mixture of (R)-tert-butyl 2-benzylpiperazine-1-carboxylate (1.0 g, 3.62 mmol), iodoethane (0.43 mL, 5.43 mmol), DIEA (1.89 mL, 10.85 mmol), and MeCN (10 mL) was stirred at rt for 2 h under N₂, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 5/1-2/1) to give (R)-tert-butyl 2-benzyl-4-ethylpiperazine-1-carboxylate (3.85 g, 87%) as a yellow oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.33-7.24 (m, 2H), 7.23-7.11 (m, 3H), 4.11 (s, 1H), 3.77 (d, 1H), 3.09 (t, 1H), 2.98-2.76 (m, 3H), 2.68 (d, 1H), 2.43-2.28 (m, 1H), 2.27-2.15 (m, 1H), 1.82 (td, 2H), 1.41-1.11 (m, 9H), 0.99 (t, 3H); LCMS: 305.3 [M+H]⁺

Step 2: (R)-3-Benzyl-1-ethylpiperazine hydrochloride

A mixture of (R)-tert-butyl 2-benzyl-4-ethylpiperazine-1-carboxylate (3.85 g, 12.65 mmol) and HCl/EtOAc (4 M, 3.16 mL) was stirred at rt for 2 h and then concentrated to give (R)-3-benzyl-1-ethylpiperazine hydrochloride (3.0 g) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 12.11-11.75 (m, 1H), 10.67-10.30 (m, 1H), 10.04-9.67 (m, 1H), 7.48-7.14 (m, 5H), 3.99-3.83 (m, 1H), 3.80-3.62 (m, 1H), 3.60-3.37 (m, 5H), 3.35-3.03 (m, 2H), 2.93 (dd, 1H), 1.29-1.11 (m, 3H); LCMS: 205.2 [M+H]⁺.

Step 3: (R)-3-Benzyl-1-ethylpiperazine

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.

Intermediate 21

tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1 (2H)-carboxylate

Step 1: tert-Butyl 6-((diphenoxyphosphoryl)oxy)-3,4-dihydropyridine-1 (2H)-carboxylate

LiHMDS (37.6 mL, 1 M in THF) was added to a solution of tert-butyl 2-oxopiperidine-1-carboxylate (7.40 g, 27.6 mmol) in THF (50 mL) at −78° C. The reaction was stirred at −78° C. for 1 h, and then a solution of diphenyl phosphorochloridate (5.0 g, 25.1 mmol) and THF (50 mL) was added at −78° C. The mixture was allowed to warm to rt, stirred for 1 h, quenched with H₂O (100 mL), and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1 to 5/1) to give tert-butyl 6-((diphenoxyphosphoryl)oxy)-3,4-dihydropyridine-1 (2H)-carboxylate (9.62 g, 88%) as a yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 8.56-7.96 (m, 1H), 7.30-7.20 (m, 4H), 7.20-7.15 (m, 2H), 7.12 (t, 4H), 3.58 (t, 1H), 3.54-3.47 (m, 1H), 2.50-2.38 (m, 1H), 2.16-2.03 (m, 1H), 1.79-1.71 (m, 2H), 1.50-1.41 (m, 6H), 1.36 (s, 3H); LCMS: 432.2 [M+H]⁺.

Step 2: tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1 (2H)-carboxylate

Pd(PPh₃)₂Cl₂ (292.9 mg, 0.417 mmol) was added to a mixture of tert-butyl 6-((diphenoxyphosphoryl)oxy)-3,4-dihydropyridine-1 (2H)-carboxylate (6.0 g, 13.9 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.30 g, 20.8 mmol), PPh₃ (219 mg, 0.83 mmol), K₂CO₃ (2.88 g, 20.9 mmol), and dioxane (500 mL). The mixture was degassed with 3 vacuum/N₂ cycles, heated at 90° C. for 7 h, allowed to cool to rt, quenched with H₂O (100 mL), and then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate: I/O to 8/1) to give tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1 (2H)-carboxylate (562 mg, 13%) as a colorless oil. ¹H NMR (400 MHZ, CDCl₃): δ 5.21 (d, 1H), 3.48-3.39 (m, 2H), 2.09-1.99 (m, 2H), 1.77 (d, 2H), 1.58-1.47 (m, 9H), 1.30-1.27 (m, 12H); LCMS: 310.3 [M+H]⁺.

Intermediate 22

(R)-5-(2-Benzyl-4-ethylpiperazin-1-yl)-3-methyl-2H-pyrazolo[4,3-d]pyrimidine

(R)-5-(2-Benzyl-4-ethylpiperazin-1-yl)-3-methyl-2H-pyrazolo[4,3-d]pyrimidine was synthesized from Intermediate 9 (Step 1) and Intermediate 20 following the procedures described for Intermediate 10 (Step 3; KF instead of DIEA) and then Intermediate 11 (Step 3). ¹H NMR (400 MHZ, DMSO-d₆): δ 9.57 (s, 1H), 9.27 (s, 1H), 7.71-7.43 (m, 5H), 5.22-4.99 (m, 1H), 4.80 (d, 1H), 2.86-2.81 (m, 9H), 2.77 (s, 3H), 1.36 (t, 3H); LCMS: 337.3 [M+H]⁺.

Intermediate 23

(R)-3-Benzylthiomorpholine

Step 1: (R)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl methanesulfonate

MsCl (1.39 mL, 17.9 mmol) was added to a mixture of tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl) carbamate (3.01 g, 12.0 mmol), Et₃N (2.50 mL, 17.9 mmol), and DCM (30 mL) at 0° C. The reaction was stirred at 25° C. for 1 h, diluted with DCM (30 mL), washed with 1 M HCl (30 mL), washed with sat. aq. NaHCO₃ (30 mL), washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated to give (R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropyl methanesulfonate (3.55 g) as a white solid. ¹H NMR (400 MHZ, CDCl₃): δ 7.36-7.25 (m, 5H), 5.34 (s, 1H), 4.83-4.81 (m, 1H), 4.18-4.16 (m, 2H), 3.06 (s, 3H), 2.98-2.96 (m, 2H), 1.46 (s, 9H); LCMS: 274.1 [(M-tBu+H)+H]⁺.

Step 2: (R)-Methyl 2-((2-((tert-butoxycarbonyl)amino)-3-phenylpropyl)thio) acetate

Methyl 2-sulfanylacetate (1.51 mL, 16.7 mmol) was added to a mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropyl methanesulfonate (2.5 g, 7.59 mmol), K₂CO₃ (2.1 g, 15.2 mmol), and MeCN (30 mL). The mixture was stirred at 80° C. for 1 h, cooled to rt, concentrated, diluted with EtOAc (50 mL), washed with 1 M HCl (20 mL), washed with sat. aq. NaHCO₃ (20 mL), washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated to give crude (R)-methyl 2-((2-((tert-butoxycarbonyl)amino)-3-phenylpropyl)thio) acetate (2.55 g) as a yellow oil. LCMS: 240.1 [(M-Boc+H)+H)]⁺.

Step 3: (R)-5-Benzylthiomorpholin-3-one

A mixture of (R)-methyl 2-((2-((tert-butoxycarbonyl)amino)-3-phenylpropyl)thio) acetate (2.55 g, 7.51 mmol) and HCl/EtOAc (4 M, 1 mL) was stirred at rt for 1 h and then concentrated. A mixture of this residue, MeOH (1 mL), and Et₃N (3.1 mL, 22.5 mmol) was stirred at 25° C. for 24 h, concentrated, diluted with EtOAc (30 mL), washed with 1 M HCl (10 mL), washed with sat. aq. NaHCO₃ (10 mL), washed with brine (10 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc: 20/1 to 2/1) to give (R)-5-benzylthiomorpholin-3-one (925 mg, 59%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 7.80 (s, 1H), 7.34-7.22 (m, 5H), 4.34-4.21 (m, 1H), 3.25-3.21 (m, 1H), 3.10-3.06 (m, 1H), 2.83-2.82 (m, 1H), 2.80-2.76 (m, 2H), 2.50-2.49 (m, 1H); LCMS: 208.1 [M+H]⁺.

Step 4: (R)-3-Benzylthiomorpholine

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]⁺.

Compound 1

(R)-1-(4-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)phenyl)-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-ol

Step 1: (R)-1-(4-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)phenyl)-6-(benzyloxy)-5,7-difluoro-1H-benzo[d][1,2,3]triazole

Tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.07 mmol) was added to a solution of Intermediate 1 (300 mg, 0.72 mmol), Intermediate 2 (319 mg, 0.86 mmol), RuPhos (67.2 mg, 0.14 mmol), and 1-BuONa (346 mg, 3.60 mmol) in dioxane (6 mL) under N₂. The mixture was degassed and purged with N₂ 3 times, stirred at 100° C. for 3 h, allowed to cool to rt, poured into H₂O (10 mL), and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 2/1) to obtain (R)-1-(4-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)phenyl)-6-(benzyloxy)-5,7-difluoro-1H-benzo[d][1,2,3]triazole (205 mg, 48%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.03 (d, 1H), 7.64-7.62 (m, 2H), 7.46-7.44 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.21 (m, 7H), 5.25 (s, 2H), 4.31 (d, 1H), 3.76-3.67 (m, 2H), 3.45 (d, 1H), 3.06 (d, 1H), 3.00-2.89 (m, 6H), 2.59 (d, 1H); LCMS: 590.2 [M+H]⁺

Step 2: (R)-1-(4-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)phenyl)-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-ol

A mixture of (R)-1-(4-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)phenyl)-6-(benzyloxy)-5,7-difluoro-1H-benzo[d][1,2,3]triazole (195 mg, 0.33 mmol) and TFA (3.0 mL, 40.5 mmol) was stirred at 50° C. for 3 h, allowed to cool to rt, quenched with sat. aq. NaHCO₃until pH=˜ 8, and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by prep-HPLC [water (FA)-CH₃CN] to obtain (R)-1-(4-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)phenyl)-5,7-difluoro-1H-benzo[d][1,2,3]triazol-6-ol (75 mg, 45%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 10.96 (s, 1H), 7.90 (d, 1H), 7.63-7.60 (m, 2H), 7.32-7.19 (m, 7H), 4.30 (d, 1H), 3.71 (d, 2H), 3.44 (d, 1H), 3.25 (t, 1H), 3.05 (d, 1H), 2.99-2.88 (m, 5H), 2.57 (d, 1H); LCMS: 500.0 [M+H]⁺

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

Cmpd	Structure	Name	[M + H]+
1.01		(S)-1-(4-(2-Benzyl-4- (methylsulfonyl)piperazin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3]triazol-6-ol	500.1
1.021		(S)-1-(4-(3-Benzyl-4- (methylsulfonyl)piperazin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3 ]triazol-6-ol	500.1
1.031		(R)-1-(4-(3-Benzyl-4- (methylsulfonyl)piperazin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3]triazol-6-ol	500.1
1.041		(S)-1-(4-(2- Benzylmorpholino)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3 ]triazol-6- ol	423.1
1.051		(R)-1-(4-(3- Benzylmorpholino)phenyl)-5,7- difluoro-1H-benzo[d][1,2,3]triazol-6- ol	423.1
1.061		(R)-1-(4-(3-Benzylpyrrolidin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3 ]triazol-6-ol	407.2
1.071		(S)-1-(4-(3-Benzylpyrrolidin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3 ]triazol-6-ol	407.1
1.081		1-(4-(4-Benzylpiperidin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3 ]triazol-6-ol	421.1
1.091		1-(4-(4-Benzylazepan-1-yl)phenyl)- 5,7-difluoro-1H- benzo[d][1,2,3]triazol-6-ol	435.2
1.101		1-(4-(4-Benzyl-4-methylpiperidin-1- yl)phenyl)-5,7-difluoro-1H- benzo[d][1,2,3]triazol-6-ol	435.3
Alternate conditions used:
1Step 1 only: 100° C., ON (benzyl was cleaved during Buchwald reaction).

Compound 2

(R)-3-(5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

A mixture of Intermediate 9 (88 mg, 0.23 mmol), Intermediate 4 (111 mg, 0.342 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (28.7 μL, 0.182 mmol), CuI (17 mg, 0.091 mmol), potassium phosphate (193 mg, 0.911 mmol), and DMSO (3 mL) were degassed/backfilled with N₂, stirred at 100° C. overnight, allowed to cool to rt, diluted with methanol, and then purified by prep-HPLC (20-100% CH₃CN in water with 0.1% TFA) to give (R)-3-(5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,6-difluoro-5-(trifluoromethyl)phenol (68 mg, 49%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.84-11.58 (m, 1H), 9.01 (d, J=2.3 Hz, 1H), 7.50 (t, J=7.0 Hz, 1H), 7.41-7.23 (m, 4H), 7.22-7.13 (m, 1H), 5.07-4.97 (m, 1H), 4.72 (br d, J=13.1 Hz, 1H), 3.72 (br d, J=11.2 Hz, 1H), 3.49 (br d, J=11.9 Hz, 1H), 3.39-3.26 (m, 1H), 3.14-3.03 (m, 1H), 2.94-2.88 (m, 3H), 2.88-2.79 (m, 2H), 2.73 (br dd, J=3.4, 12.7 Hz, 1H), 2.60-2.52 (m, 3H); LCMS: 583.5 [M+H]⁺.

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

Cmpd	Structure	Name	[M + H]+
2.01		3-(5-(3-Benzylmorpholino)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.4
2.02		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.4
2.03		(S)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.5
2.04		3-(5-(2-Benzylmorpholino)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.5
2.051		3-(5-(2-Benzylmorpholino)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2-fluoro-5- (trifluoromethyl)phenol	487.5
2.06		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-indazol-1-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol	601.5
2.07		(R)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.4
2.082		(R)-1-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- (2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1H-indazol- 3-yl)ethan-1-one	609.5
2.09		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	569.5
2.10		(S)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.5
2.111		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol	598.4
2.123		(R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- indazol-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.5
2.13		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-indazol-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	581.6
2.143		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-indazol-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	596.5
2.151		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluorophenol	514.6
2.161		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-6-chloro-2-fluorophenol	530.6
2.171		(R)-2-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[3,4-c]pyridin-1- yl)-5-chloro-3-fluoropyridin-4-ol	531.6
2.18		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-pyrazolo[4,3-d]pyrimidin- 1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	603.6
2.19		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	568.7
2.20		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-pyrazolo[3,4-c]pyridin-1- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	602.5
2.211		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[4,3-d]pyrimidin- 1-yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol	599.6
2.221		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-pyrazolo[3,4-c]pyridin-1- yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol	620.5
2.233		(R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[3,4-c]pyridin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	583.6
2.244		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-pyrazolo[3,4- c]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	597.7
2.25		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (dimethylamino)-1/-indazol-1-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	610.6
2.261		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-indazol-1-yl)-5- (trifluoromethyl)phenol	545.7
2.271		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-indazol-1-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol	597.6
2.285		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-indazol-1-yl)-2-fluoro-5- (trifluoromethyl)phenol	563.6
2.29		(R)-2-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-indazol-1-yl)-6- (trifluoromethyl)pyridin-4-ol	546.7
2.306		(R)-2-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-2H-indazol-2-yl)-6- (trifluoromethyl)pyridin-4-ol	546.7
2.317		(R)-3-(5-(3-Benzylmorpholino)-3- methyl-1H-pyrazolo[4,3-d]pyrimidin- 1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	506.1
2.327		(R)-3-(5-(2-Benzyl-4-ethylpiperazin- 1-yl)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	533.2
2.337		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-6- fluoro-3-methyl-1H-pyrazolo[4,3- b]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	600.2
2.34		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-6- chloro-3-methyl-1H-pyrazolo[4,3- b]pyridin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	616.1
2.35		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- methyl-1H-pyrazolo[4,3-d]pyrimidin- 1-yl)-5-chloro-2,6-difluorophenol	549.3
2.36		(R)-5-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-2- fluoro-3-(trifluoromethyl)phenol	551.3
2.378		(R)-5-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-2H- pyrazolo[4,3-d]pyrimidin-2-yl)-2- fluoro-3-(trifluoromethyl)phenol	551.2
2.38		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-6- chloro-2-fluoro-5- (trifluoromethyl)phenol	585.5
2.39		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- chloro-1H-pyrazolo[4,3-d]pyrimidin- 1-yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol	621.3
2.403		(R)-3-(3-Amino-5-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	584.5
2.413		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-3- (methylamino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	598.4
Alternate conditions used:
Reaction time varied: 2-48 h. Reaction temp varied: 100-110° C. In some instances, additional aryl iodide, bromide or chloride, CuI, trans-N,N′-dimethylcyclohexane-1,2-diamine, and K3PO4 were needed for full conversion to desired product.
1Aryl bromide or chloride was used;
2From Intermediate 11.06 (difluoro hydrolysis to ketone during coupling);
3Synthesized from Compound 2.06 or 2.22 or 2.18: 0.4 M ammonia solution in dioxane or methylamine HCl, AdBrettPhos, AdBrettPhos Palladacycle Gen. 3, NaOtBu, dioxane, 80° C., 2 h-overnight.
4Synthesized from Compound 2.22: methylamine HCl, AdBrettPhos, AdBrettPhos Palladacycle Gen. 3, NaOtBu, dioxane, 80° C., 4.5 h, additional NaOtBu, AdBrettPhos, AdBrettPhos Palladacycle Gen 3 added, 80° C., ON, and then 2 M methylamine in THF, AdBrettPhos, AdBrettPhos Palladacycle Gen. 3, NaOtBu, 80° C., 45 min.
5Isolated in the synthesis of Compound 2.27.
6Isolated in the synthesis of Compound 2.29.
7Bis[(tetrabutylammonium iodide)copper(I) iodide] instead of Cul and 110° C. instead of 100° C.
8Isolated in the synthesis of Compound 2.36.

Compound 3

(R)-3-(6-(3-Benzylmorpholino)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

A mixture of Intermediate 13.01 (75 mg, 0.18 mmol), (R)-3-benzyl-morpholine (63 mg, 0.36 mmol), Pd₂(dba)₃ (19 mg, 0.021 mmol), RuPhos (20 mg, 0.043 mmol), NaO^tBu (40 mg, 0.42 mmol), and dioxane (2 mL) was purged with nitrogen for 5 min, heated in a microwave at 90° C. for 90 min, allowed to cool to rt, and then diluted with 20 mL EtOAc. The organic layer was washed with 15 mL saturated NH₄Cl, washed with 15 mL brine, dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (0-30% EtOAc in heptane) [Note: no purification was needed prior to deprotection for some compounds in the table below]. The residue was dissolved in CH₂Cl₂ (2 mL) and TFA (1 mL), stirred at rt for 15 min, concentrated, and then purified by prep-HPLC to give (R)-3-(6-(3-benzylmorpholino)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol (38 mg, 41%) as an off-white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.38 (br s, 1H), 8.81 (d, J=3.1 Hz, 1H), 7.54 (t, J=7.0 Hz, 1H), 7.35-7.26 (m, 4H), 7.24-7.15 (m, 1H), 6.81 (s, 1H), 4.63 (br d, J=9.2 Hz, 1H), 4.10-3.99 (m, 4H), 3.86 (br d, J=12.5 Hz, 1H), 3.71-3.65 (m, 1H), 3.64-3.55 (m, 1H), 3.52 (br d, J=10.3 Hz, 1H), 3.30 (dt, J=2.5, 12.4 Hz, 1H), 3.06 (br t, J=11.7 Hz, 1H), 2.63 (br dd, J=3.7, 12.5 Hz, 1H); LCMS 505.5 [M+H]⁺.

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

Cmpd	Structure	Name	[M + H]+
3.01		2,6-Difluoro-3-(1-methyl-6-(2- phenethylpiperidin-1-yl)-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol	517.5
3.02		2,6-Difluoro-3-(1-methyl-6-(3- (morpholinomethyl)morpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol	514.5
3.03		2,6-Difluoro-3-(1-methyl-6-(3- ((tetrahydro-2H-pyran-4- yl)methyl)morpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol	513.4
3.04		2,6-Difluoro-3-(1-methyl-6-(3- ((tetrahydrofuran-3- yl)methyl)morpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol	499.4
3.05		3-(6-(2-((1H-Pyrazol-1- yl)methyl)piperidin-1-yl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	493.4
3.06		(S)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.5
3.07		(R)-3-(6-(2-benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.5
3.08		3-(6-(3- (Cyclopropylmethyl)morpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	469.4
3.09		3-(6-(3- (Cyclobutylmethyl)morpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	483.5
3.10		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.6
3.11		3-(6-(2-Benzylmorpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.5
3.12		(S)-3-(6-(2-Benzylpiperidin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	503.5
3.13		3-(6-(3-Benzylmorpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.4
3.14		(R)-3-(6-(3-Benzylmorpholino)-1- methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.5
3.15		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.7
3.16		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-b]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	582.6
3.17		(R)-3-(6-(3-Benzylmorpholino)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.5
3.181		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluorophenol	514.5
3.192		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-6-chloro-2-fluorophenol	530.4
3.203		(R)-3-(6-(2-Benzylpiperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	504.6
3.21		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- (oxetan-3-yl)-1H-pyrazolo[4,3- c]pyridin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	624.5
3.22		3-(6-(2-Benzylpiperidin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-2,6-difluoro-5- (trifluoromethyl)phenol	509.7
3.23		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[4,3-c]pyridin-3- yl)-6-chloro-2-fluoro-5- (trifluoromethyl)phenol	598.6
3.24		2,6-Difluoro-3-(6-(3- isobutylmorpholino)-1-methyl-1H- pyrazolo[4,3-c]pyridin-3-yl)-5- (trifluoromethyl)phenol	471.4
Alternate condition used:
Reaction times varied: 60-90 min.
1Demethylation: 1 M boron tribromide in CH2Cl2, CH2Cl2, 0° C.-rt, 3 h.
2Debenzylation: Palladium hydroxide on carbon, THF, H2, rt, 15 h.
3Boc protected amine was used.

Compound 4

(R)-3-(6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

A mixture of Intermediate 13.05 (75 mg, 0.16 mmol), Intermediate 2.01 (59 mg, 0.20 mmol), tris(dibenzylideneacetone) dipalladium (0) (7.19 mg, 0.01 mmol), RuPhos (7.32 mg, 0.02 mmol), and sodium tert-butoxide (45 mg, 0.47 mmol) in dioxane (3 mL) was purged with nitrogen for 5 minutes, heated in a microwave at 90° C. for 75 min, and then partitioned between CH₂Cl₂ and saturated sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with CH₂Cl₂. The combined organics were washed with saturated sodium hydrogen carbonate solution, dried (Na₂SO₄), and then concentrated under reduced pressure. The residue was taken up in CH₃OH. Hydrogen chloride solution (4.0 M in dioxane, 0.20 mL, 0.78 mmol) was added. The reaction was stirred at rt for 15 h and then concentrated under reduced pressure. The residue was taken up in CH₂Cl₂ (5 mL): TFA (2 mL), stirred at rt for 1 h, concentrated under reduced pressure, and then purified by prep-HPLC (5-95% CH₃CN: H₂O) to give the desired product (R)-3-(6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol as a white powder (12 mg, 13%). ¹H NMR (400 MHZ, DMSO-d₆): δ 13.40 (br s, 1H), 11.83-11.00 (m, 1H), 8.86 (d, J=3.2 Hz, 1H), 7.57 (t, J=7.1 Hz, 1H), 7.30 (d, J=4.3 Hz, 4H), 7.24-7.17 (m, 1H), 6.74 (s, 1H), 4.87-4.77 (m, 1H), 4.16 (br d, J=13.0 Hz, 1H), 3.71 (br d, J=11.2, 1H), 3.48 (br d, J=11.6 Hz, 1H), 3.28 (dt, J=3.4, 12.4 Hz, 1H), 3.06 (dd, J=10.3, 12.9 Hz, 1H), 2.97-2.82 (m, 5H), 2.60 (dd, J=3.4, 12.7 Hz, 1H); LCMS: 568.5 [M+H]⁺.

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

Cmpd	Structure	Name	[M + H]+
4.011		(R)-3-(6-(3-Benzylmorpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	491.4
4.022		(R)-6-(6-(3-Benzylmorpholino)-1H- pyrazolo[4,3-c]pyridin-3-yl)-3- fluoro-4-(trifluoromethyl)benzene- 1,2-diol	489.7
4.033		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	568.5
Alternate conditions used:
1THP/MOM deprotection: 1.25 M HCl in CH3OH, rt, 50 min then TFA/CH2Cl2 (1:2), rt, overnight.
2Isolated during the purification of Compound 4.01.
3MOM deprotection: 4 M HCl in dioxane, CH3OH, 17 h, concentrated, then THP deprotection: TFA/CH2Cl2 (1:5), rt, 2 h, 40° C., 1 h, concentrated, purified, and then 4 M HCl in dioxane, CH3OH, 50° C., 24 h

Compound 5

(R)-3-(6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

A mixture of Intermediate 13 (100 mg, 0.24 mmol), Intermediate 2.01 (93 mg, 0.32 mmol), DIEA (0.21 mL, 1.22 mmol) and NMP (1 mL) was heated in a microwave reactor at 140° C. for 15 h and then partitioned between saturated NaHCO₃ and EtOAc. The aqueous layer was extracted with EtOAc. The combined organics were dried (Na₂SO₄) and concentrated (note: aqueous work up was omitted for some compounds in the table below). The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) and further purified by prep-HPLC (CH₃CN: water with 0.1% TFA) to give (R)-3-(6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol (11 mg, 8%) as a white powder. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.43 (br s, 1H), 9.00 (d, J=2.7 Hz, 1H), 7.59 (t, J=7.1 Hz, 1H), 7.40-7.32 (m, 2H), 7.29 (br t, J=7.3 Hz, 2H), 7.22-7.14 (m, 1H), 5.22-5.10 (m, 1H), 4.90-4.82 (m, 1H), 3.97 (s, 3H), 3.72 (br d, J=11.5 Hz, 1H), 3.51 (br d, J=11.9 Hz, 1H), 3.43-3.33 (m, 1H), 3.12 (br dd, J=9.2, 12.9 Hz, 1H), 2.93-2.79 (m, 6H); LCMS: 583.5 [M+H]⁺.

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

Cmpd	Structure	Name	[M + H]+
5.011		3-(6-(3- (Cyclopropylmethyl)morpholino)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	470.7
5.021		3-(6-(2-Benzylmorpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	506.7
5.031		3-(6-(3-Benzylmorpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	506.6
5.041		4-((1H-Pyrazol-1-yl)methyl)-1-(3- (2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperidin-4-ol	510.4
5.051		1-(3-(2,4-Difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)- 4-(morpholinomethyl)piperidin-4- ol	529.4
5.061		(S)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	583.5
5.071		3-(6-(3-Benzyl-4-methylpiperazin- 1-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	519.4
5.081		(R)-3-(6-(3-Benzylmorpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	506.4
5.091		(S)-3-(6-(3-Benzylmorpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	506.4
5.101		3-(6-(3- (Cyclobutylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	484.4
5.11		2,6-Difluoro-3-(1-methyl-6-(2- (pyridin-2-ylmethyl)piperidin-1- yl)-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-5-(trifluoromethyl)phenol	505.4
5.121		3-(6-(2-Benzyl-4-methylpiperazin- 1-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	519.4
5.13		3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-2-one	519.4
5.144		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	583.5
5.15		(R)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	583.5
5.16		(S)-3-(6-(2-Benzylpiperidin-1-yl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	504.5
5.17		(S)-3-(6-(2-Benzylpyrrolidin-1-yl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	490.7
5.182		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	569.5
5.19		3-(6-(2-Benzylazetidin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	476.4
5.202		(R)-3-(6-(3-Benzylmorpholino)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	492.5
5.21		(R)-2,6-Difluoro-3-(1-methyl-6-(3- (4-methylbenzyl)morpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	520.6
5.223		(S)-3-(6-(3-Benzyl-4- (methylsulfonyl)piperazin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	569.6
5.23		(R)-2,6-Difluoro-3-(6-(3-(4- fluorobenzyl)morpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	524.5
5.24		(R)-2,6-Difluoro-3-(6-(3-(3- fluorobenzyl)morpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	524.5
5.25		(R)-2,6-Difluoro-3-(6-(3-(2- fluorobenzyl)morpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	524.5
5.26		(R)-3-(6-(2-Benzyl-4- methylpiperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	519.5
5.27		3-(6-((1-Benzylcyclobutyl)amino)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	490.8
5.28		(R)-2,6-Difluoro-3-(6-(3-(4- methoxybenzyl)morpholino)-1- methyl-1H-pyrazolo[3,4- d|pyrimidin-3-yl)-5- (trifluoromethyl)phenol	536.8
5.29		2,6-Difluoro-3-(1-methyl-6-(3- (pyrrolidin-1- ylmethyl)morpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	499.6
5.30		(R)-3-(6-(2-Benzylpyrrolidin-1-yl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	490.6
5.315		(R)-3-(6-(2-Benzylpiperazin-1-yl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	505.2
5.32		3-(6-(2-Benzylpiperidin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	510.7
5.33		3-(6-(3-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	547.8
5.34		3-(6-(2-((1H-1,2,4-Triazol-1- yl)methyl)piperidin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	495.6
5.351		2,6-Difluoro-3-(6-(3- isobutylmorpholino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	472.4
5.36		3-(6-((1-Benzylpiperidin-3- yl)(methyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	533.8
5.37		3-(6-(3-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	561.9
Alternate conditions used:
In some instances, Intermediate 2.06 was used instead of Intermediate 2.01.
Reaction temp varied: 120-150° C. in a microwave.
Reaction time varied: 0.5-15 h.
1DMA instead of NMP.
2TFA/CH2Cl2 (1:2), rt, 15 h was needed to remove THP PG.
3TFA/CH2Cl2 (1:5), rt, 6 h then 4 M HCl in dioxane/CH3OH (1:5), rt, 17 h and 50° C., 2 h to remove THP PG.
470° C., microwave, 1 h then TFA/CH2Cl2 (1:5), rt, 30 min to remove MOM PG.
5Synthesized from tert-butyl (R)-3-benzylpiperazine-1-carboxylate following the procedure described for Compound 5 then 4 M HCl/EtOAc, rt, 2 h to remove Boc and benzyl PGs (benzyl PG was partially cleaved during thermal coupling prior to deprotection).

Compound 6

Methyl(R)-3-benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate

Step 1: tert-Butyl(R)-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

A mixture of Intermediate 13.06 (1.03 g, 2.26 mmol), (R)-tert-butyl 3-benzylpiperazine-1-carboxylate (814 mg, 2.94 mmol), DIPEA (1.2 mL, 6.79 mmol), and NMP (20 mL) was stirred at 120° C. for 10 h. The reaction mixture was allowed to cool to rt, poured into H₂O (30 mL) slowly, and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate=30:1 to 3:1) to give (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 (705 mg, 44%) as a yellow oil and (R)-tert-butyl 3-benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (490 mg, 35%) as a yellow oil.

(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:

¹H NMR (400 MHZ, DMSO-d₆): δ 8.99 (s, 1H), 7.87 (t, 1H), 7.51-7.14 (m, 10H), 5.36 (s, 2H) 4.97 (s, 1H), 4.73 (d, 1H), 3.96 (s, 3H), 3.66-3.51 (m, 1H), 3.12-2.91 (m, 6H), 1.36 (s, 9H); LCMS: 695.1 [M+H]⁺.

(R)-tert-butyl 3-benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate:

¹H NMR (400 MHZ, DMSO-d₆): δ 8.97 (s, 1H), 7.52 (t, 1H), 7.34-7.22 (m, 5H), 4.96 (s, 1H), 4.64 (d, 1H), 3.96 (s, 3H), 3.78-3.66 (m, 1H), 3.09-2.86 (m, 6H), 1.46 (s, 9H); LCMS: 605.1 [M+H]⁺.

Step 2: (R)-3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride

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]⁺.

Step 3: Methyl(R)-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

Methyl carbonochloridate (0.075 mL, 0.975 mmol) was added to a mixture of (R)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.41 g, 0.649 mmol), Et₃N (0.45 mL, 3.25 mmol), and CH₂Cl₂ (5 mL) at 0° C. The mixture was stirred at rt for 2 h, poured into water (20 mL) slowly, and then extracted with CH₂Cl₂ (2×10 ml). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate=30:1 to 3:1) to give (R)-methyl 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 (203 mg, 47%) as a yellow oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.96 (d, 1H), 7.86 (t, 1H), 7.40-7.20 (m, 10H), 5.35 (s, 2H), 5.02 (s, 1H), 4.66 (d, 1H), 4.09-4.03 (m, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.16-2.76 (m, 6H); LCMS: 653.1 [M+H]⁺.

Step 4: Methyl(R)-3-benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate

A mixture of (R)-methyl 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 (188 mg, 0.288 mmol) and TFA (5 mL) was stirred at 70° C. for 2 h, allowed to cool to rt, concentrated, diluted with EtOAc (20 mL), adjusted to pH-˜ 7 with sat. aq. NaHCO₃, and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by reverse-phase HPLC [water (0.05% HCl)/CH₃CN] to give (R)-methyl 3-benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (145 mg, 89%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.41 (s, 1H), 8.96 (d, 1H), 7.57 (t, 1H), 7.32-7.26 (m, 4H), 7.19-7.15 (m, 1H), 5.02 (s, 1H), 4.65 (d, 1H), 4.08 (s, 1H), 3.95 (s, 4H), 3.69 (s, 3H), 3.31-3.30 (m, 1H), 3.05 (s, 2H), 2.91-2.76 (m, 2H); LCMS: 563.1 [M+H]⁺. The Compounds below were synthesized from Intermediate 13.06, the appropriate amine, and the appropriate acylating agent following the procedures described for Compound 6.

Cmpd	Structure	Name	[M + H]+
6.01		(R)-3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)- N,N-dimethylpiperazine-1- carboxamide	576.1
6.02		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one	547.1
6.03		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2-methoxyethan- 1-one	577.1
6.041		(S)-1-(2-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one	547.1
6.051		(R)-1-(2-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one	547.1
6.061		(S)-2-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	562.1
6.071,2		(S)-2-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)- N,N-dimethylpiperazine-1- carboxamide	576.1
6.081		Methyl (S)-2-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate	563.1
6.093,4		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)propan-1-one	561.4
6.103,4		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)butan-1-one	575.4
6.113,4		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3- methoxypropan-1-one	591.4
6.123,4		(R)-3-(6-(2-Benzyl-4-((2- methoxyethyl)sulfonyl)piperazin-1- yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	627.4
6.133,4,6		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2,2,2- trifluoroethan-1-one	601.5
6.143,4		(R)-3-(6-(2-Benzyl-4- (benzylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	659.4
6.153,4		(R)-3-(6-(2-Benzyl-4- (isopropylsulfonyl)piperazin-1-yl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	611.4
6.163,4		(R)-3-(6-(2-Benzyl-4- (cyclopropylsulfonyl)piperazin-1- yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	609.3
6.173,4		(R)-3-(6-(2-Benzyl-4- (isobutylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	625.3
6.187		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3- (dimethylamino)propan-1-one	604.4
6.197		(R)-1-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3- (methylamino)propan-1-one	590.3
6.207		(R)-N-(3-(3-Benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3- oxopropyl)acetamide	618.3
6.213,5		(R)-3-(6-(2-Benzyl-4-((2- ethoxyethyl)sulfonyl)piperazin-1- yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	641.4
6.223,5		(R)-3-(6-(2-Benzyl-4-(pyridin-3- ylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	646.3
6.238		(R)-2-((3-Benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)sulfonyl)acetic Acid	627.3
6.248		(R)-3-((3-Benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1- yl)sulfonyl)propanoic Acid	641.2
6.258		(R)-4-((3-Benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)sulfonyl)butanoic Acid	655.2
6.263,5		(R)-3-(6-(2-Benzyl-4-((2- hydroxyethyl)sulfonyl)piperazin-1- yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	613.2
6.273,5		(R)-3-(6-(2-Benzyl-4-(pyridin-2- ylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	646.1
6.283,5		(R)-3-(6-(2-Benzyl-4-((6- methoxypyridin-3- yl)sulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	676.1
6.29		Ethyl (R)-3-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate	577.1
6.30		Isopropyl (R)-3-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxylate	591.1
Alternate conditions used:
Step 1: KF, NMP, 90° C., overnight.
1Step 1: 110° C., 1.5-2 h. Step 2: 2:1 or 3:1 CH2Cl2/TFA, rt, 1.5-2.5 h.
2Step 3: 0-50° C., ON.
3From Compound 6, Step 2: Compound 6 (Step 3; DIEA instead of TEA, rt, 10 min-5 h) then deprotection [
4(10% palladium on carbon, THF, H2, rt, 25-30 min) or
5(2:1 CH2Cl2/TFA or TFA, 70° C., 20-60 min)].
6Acylation from residual TFA in sample during Step 3 conditions.
7From Compound 6, Step 2: HATU coupling (appropriate acid, HATU, DIEA, DMF, rt, 1 h) then deprotection (10% palladium on carbon, THF, H2, rt, 100 min).
8Hydrolysis step following Step 4 (1 N NaOH, 1:1 CH3OH/THF, rt, 1 h).

The Compounds below were synthesized from Compound 6 (Step 2) or Compound 6.04 (Step 2) using the following sequence: acylation (isocyanatotrimethylsilane, TEA, THF, rt, 2 h) and then deprotection (TFA, 70° C., 2 h).

Cmpd	Structure	Name	[M + H]+
7		(R)-3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxamide	548.2
7.01		(S)-2-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxamide	548.1

The Compound below was synthesized from Compound 6 (Step 2) using the following sequence: acylation (appropriate acid, HATU, TEA, CH₂Cl₂, rt, 2 h-ON), deprotection (TFA, 70° C., 2 h), and then hydrolysis (LiOH·H₂O, THF, H₂O, rt, 2 h).

The Compound below was synthesized from Compound 6 (Step 2) using the following sequence: acylation (TCFH, NMI, CH₃CN, rt, 2 h) and then deprotection (TFA, 70° C., 2 h).

Cmpd	Structure	Name	[M + H]+
9		(R)-3-(3-Benzyl-4-(3-(2,4-difluoro- 3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-3- oxopropanenitrile	572.1

Compound 10

(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

Step 1: (R)-3-(6-(2-Benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride

A mixture of (R)-tert-butyl 3-benzyl-4-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (Compound 6, Step 1:950 mg, 1.57 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-(6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride (562 mg) as a yellow solid and used directly in the next step without further purification. ¹H NMR (400 MHZ, DMSO-d₆): δ 9.66 (s, 1H), 9.51 (s, 1H), 8.99 (d, 1H), 7.45-7.27 (m, 5H), 7.17 (t, 1H), 5.25 (s, 1H), 4.90 (d, 1H), 3.96 (s, 3H), 3.49-3.36 (m, 4H), 3.13-2.98 (m, 4H); LCMS: 505.2 [M+H]⁺.

Step 2: (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

(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]⁺.

Compound 11

(R)-3-(6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro-2-fluorophenol

Intermediate 14 (40 mg, 0.078 mmol), 4-chloro-2-fluoro-3-hydroxyphenylboronic acid (22 mg, 0.12 mmol), Pd(dppf)Cl₂ (6 mg, 0.008 mmol), DME (1 mL), water (200 μL), and potassium carbonate (35 mg, 0.25 mmol) were combined in a microwave vial. The reaction was heated in a microwave at 90° C. for 20 min, allowed to cool to rt, and then diluted with 10 mL ethyl acetate. The organic layer was washed with 10 mL water, washed with 10 mL brine, dried (Na₂SO₄), filtered, concentrated, and then purified by reverse-phase HPLC [40-90% CH₃CN in water (with 0.1% TFA)] to give (R)-3-(6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-6-chloro-2-fluorophenol (28 mg, 68%) as a pale yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 10.71-10.60 (m, 1H), 8.98 (d, J=2.4 Hz, 1H), 7.39-7.27 (m, 6H), 7.22-7.15 (m, 1H), 5.23-5.11 (m, 1H), 4.92-4.80 (m, 1H), 3.96 (s, 3H), 3.72 (br d, J=12.1 Hz, 1H), 3.51 (br d, J=11.7 Hz, 1H), 3.41-3.30 (m, 1H), 3.12 (dd, J=9.7, 12.7 Hz, 1H), 2.93-2.77 (m, 6H); LCMS: 531.6 [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.

Cmpd	Structure	Name	[M + H]+
11.011		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6- difluorophenol	515.6
11.021		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2-chloro-6- fluorophenol	531.6
11.031		(R)-5-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,3- difluorophenol	515.6
11.04		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,4,6- trifluorophenol	533.6
11.05		3-(6-((4-Benzyltetrahydro-2H- pyran-4-yl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	520.6
11.062		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-6-chloro-2- fluoro-5-(trifluoromethyl)phenol	599.6
11.07		3-(6-((4-Benzyltetrahydro-2H- pyran-4-yl)(methyl)amino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	534.6
11.081		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- methylphenol	529.6
11.09		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,5,6- trifluorophenol	533.6
11.102		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-6-chloro-2,5- difluorophenol	549.5
11.112		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)phenol	479.7
11.122		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-chloro-2,6- difluorophenol	549.6
11.13		3-(6-(2-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	547.5
11.14		1-(3-(Cyclopropylmethyl)-4-(3- (2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2,2,2- trifluoroethan-1-one	565.6
11.151,3		(R)-6-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,3-difluoro-4- hydroxybenzonitrile	540.2
11.164		2-(6-((R)-2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-3,5-difluoro-4- hydroxybenzonitrile	540.1
11.171,5		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5-ethynyl-2,6- difluorophenol	539.1
11.181,3		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (prop-1-yn-1-yl)phenol	553.3
11.195,6		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2-fluoro-6- methyl-5-(trifluoromethyl)phenol	579.3
11.205,6		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,5-difluoro-6- methylphenol	529.3
11.21		3-(Cyclopropylmethyl)-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)- N,N-dimethylpiperazine-1- carboxamide	540.7
11.226		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- ethyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	597.3
11.23		Methyl (S)-4-(3-(2,4-difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholine-3-carboxylate	474.3
11.247		(S)-4-(3-(2,4-Difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)-N- isopropylmorpholine-3- carboxamide	501.2
11.257		(S)-N-Cyclohexyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholine-3-carboxamide	541.2
11.267		(S)-(4-(3-(2,4-Difluoro-3-hydroxy- 5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)morpholin-3- yl)(piperidin-1-yl)methanone	527.3
11.27		3-(6-(2-(Cyclobutylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	561.5
11.28		3-(Cyclopropylmethyl)-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazine-1-carboxamide	512.4
Alternate conditions used:
Reaction time varied: 10 min-2 h. In some instances, conventional heating was used instead of the microwave. In some instances, 2:1 or 5:1 CH2Cl2/TFA was needed to remove protecting group.
1Used appropriate methoxy boronic acid or boronic ester and then demethylated (1 M BBr3 in CH2Cl2, CH2Cl2, −78° C.-rt, 1-41 h).
2K2CO3, Pd(dppf)Cl2, CH3CN or dioxane, microwave, 90-100° C., 10-30 min.
3K2CO3, Pd(dppf)Cl2, dioxane/H2O (2:1), 80° C. or 100° C., 2 h.
4Synthesized from Intermediate 14 and the appropriate methoxy boronic acid using the following sequence: Suzuki coupling (Pd(PPh3)4, 2 M Na2CO3, dioxane, 100° C., 12 h), nitrile hydrolyzed during coupling so amide dehydration (TFAA, CH2Cl2, rt, 1 h), and then demethylation (1 M BBr3 in CH2Cl2, CH2Cl2, −78° C., 30 min, rt, 2 h).
5Pd(PPh3)4, 2 M Na2CO3, dioxane/H2O (2:1), 80° C., 2 h.
6Used appropriate benzyl protected boronic acid or boronic ester and then debenzylated (TFA, 70° C., 30 min-2 h or 10% palladium on carbon, THF, H2, rt, 2 h).
7Synthesized from Intermediate 14.06 and Intermediate 7 using the following sequence: Compound 11 coupling, hydrolysis (1 N NaOH, 2:1 THF/CH3OH, rt, 3 h), HATU coupling (appropriate amine, HATU, DMF, rt, 15-20 min), and then deprotection (10% palladium on carbon, THE, H2, rt, 30-100 min).

Compound 12

(S)-3-(6-(2-Benzylmorpholino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluromethyl)phenol

Step 1: (R)-(4-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) morpholin-2-yl)methanol

A mixture of Intermediate 13 (504 mg, 1.23 mmol), (R)-morpholin-2-ylmethanol hydrochloride (381 mg, 2.48 mmol), NMP (1 mL), and DIEA (0.85 mL, 4.93 mmol) was stirred at 60° C. for 1 h, allowed to cool to rt, and then diluted with 20 mL EtOAc. The organic layer was washed with water (2×20 mL), washed with 15 mL brine, dried (Na₂SO₄), concentrated, and then purified by silica gel chromatography (10-60% EtOAc in heptane) to give (R)-(4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) morpholin-2-yl)methanol (350 mg, 58%). ¹H NMR (400 MHZ, DMSO-d₆): δ 9.01 (d, J=3.1 Hz, 1H), 7.93 (t, J=7.2 Hz, 1H), 5.33 (s, 2H), 5.02-4.79 (m, 1H), 4.75 (br d, J=12.8 Hz, 1H), 4.59 (br d, J=13.2 Hz, 1H), 4.04-3.95 (m, 1H), 3.93 (s, 3H), 3.61-3.49 (m, 5H), 3.49-3.40 (m, 2H), 3.14-3.02 (m, 1H), 2.91-2.77 (m, 1H); LCMS: 490.6 [M+H]⁺.

Step 2: (R)-4-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine-2-carbaldehyde

Dess-martin periodinane (28 mg, 0.07 mmol) was added to a solution of (R)-(4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) morpholin-2-yl)methanol (30 mg, 0.06 mmol) and CH₂Cl₂ (1 mL) at rt. The mixture was stirred for 50 min, diluted with 20 mL EtOAc, washed (15 mL 1:1 saturated Na₂S₂O₃: saturated NaHCO₃ and then 15 mL brine), dried (Na₂SO₄), and then concentrated to give (R)-4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine-2-carbaldehyde. ¹H NMR (400 MHZ, CDCl₃): δ 9.69 (s, 1H), 8.84 (d, J=3.2 Hz, 1H), 7.91 (t, J=7.2 Hz, 1H), 5.19 (s, 2H), 4.75 (dd, J=2.9, 13.5 Hz, 1H), 4.48 (br d, J=13.7 Hz, 1H), 4.12-3.98 (m, 2H), 3.93 (s, 3H), 3.72 (br t, J=10.2 Hz, 1H), 3.58 (s, 3H), 3.41-3.30 (m, 1H), 3.25 (dd, J=9.8, 13.2 Hz, 1H).

Step 3: (R,E)-N′-((4-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) morpholin-2-yl)methylene)-4-methylbenzenesulfonohydrazide

(R)-4-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine-2-carbaldehyde was dissolved in methanol (2 mL). Hydrazino (4-methylphenyl) sulfone (12 mg, 0.06 mmol) was added to the solution. The mixture was stirred at rt over the weekend, concentrated, and then purified by silica gel chromatography (0-40% EtOAc in heptane) to give (R,E)-N′-((4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) morpholin-2-yl)methylene)-4-methylbenzenesulfonohydrazide (50 mg). ¹H NMR (400 MHZ, DMSO-d₆): δ 11.42 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 7.95 (br t, J=7.0 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.42 (br d, J=7.8 Hz, 2H), 7.25 (d, J=3.8 Hz, 1H), 5.34 (s, 2H), 4.62-4.53 (m, 1H), 4.50 (br d, J=12.8 Hz, 1H), 4.11-4.03 (m, 1H), 3.98-3.86 (m, 4H), 3.63-3.51 (m, 4H), 3.24-3.14 (m, 1H), 3.07 (dd, J=10.6, 13.1 Hz, 1H), 2.39 (s, 3H); LCMS: 656.6 [M+H]⁺.

Step 4: (S)-2-Benzyl-4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine

A mixture of (R,E)-N′-((4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) morpholin-2-yl)methylene)-4-methylbenzenesulfonohydrazide (50 mg, 0.08 mmol), potassium carbonate (35 mg, 0.25 mmol), phenylboronic acid (15 mg, 0.12 mmol), and dioxane (1.00 mL) was stirred at 100° C. for 20 min, cooled to rt, and then diluted with 20 mL EtOAc. The organic layer was washed (15 mL water and then 15 mL brine), dried (Na₂SO₄), concentrated, and then purified by silica gel chromatography (0-20% EtOAc in heptane) to give(S)-2-benzyl-4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine. LCMS: 550.6 [M+H]⁺.

Step 5: (S)-3-(6-(2-Benzylmorpholino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

(S)-2-Benzyl-4-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine was stirred in 2 mL CH₂Cl₂ and 1 mL TFA at rt for 20 min, concentrated, and then purified by RP-HPLC (20-80% CH₃CN in water with 0.1% TFA) to give(S)-3-(6-(2-benzylmorpholino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol (10 mg, 26%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.41 (s, 1H), 8.94 (d, J=2.3 Hz, 1H), 7.57 (t, J=7.2 Hz, 1H), 7.37-7.28 (m, 4H), 7.24 (br d, J=6.7 Hz, 1H), 4.65 (br d, J=13.0 Hz, 1H), 4.57 (br d, J=13.2 Hz, 1H), 3.97 (br d, J=10.4 Hz, 1H), 3.89 (s, 3H), 3.73-3.64 (m, 1H), 3.55-3.45 (m, 1H), 3.17-3.04 (m, 1H), 2.93-2.81 (m, 3H); LCMS: 506.6 [M+H]⁺.

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.

Cmpd	Structure	Name	[M + H]+
12.01		(S)-2,6-Difluoro-3-(1-methyl-6-(2- (pyridin-3-ylmethyl)morpholino)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 5-(trifluoromethyl)phenol	507.6
12.02		(S)-4-((4-(3-(2,4-Difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholin-2- yl)methyl)benzonitrile	531.6
12.03		(S)-3-((4-(3-(2,4-Difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholin-2- yl)methyl)benzonitrile	531.6
12.04		(S)-4-((4-(3-(2,4-Difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholin-2- yl)methyl)benzamide	549.6
12.05		(S)-3-((4-(3-(2,4-Difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholin-2- yl)methyl)benzamide	549.7
12.06		(S)-3-((4-(3-(2,4-Difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholin-2- yl)methyl)benzenesulfonamide	585.7
12.07		(S)-2,6-Difluoro-3-(1-methyl-6-(2- (3-methylbenzyl)morpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	520.8
12.08		(S)-4-((4-(3-(2,4-Difluoro-3- hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)morpholin-2- yl)methyl)benzenesulfonamide	585.6
Alternate conditions used:
Step 4: 100-110° C., 15 min-3 h.

The Compound below was synthesized from Compound 12, Step 2 using the following sequence: Grignard addition (THF, 1 M tosylmagnesium bromide, 0° C., 20 min, rt, 3.5 h) and then deprotection (2:1 CH₂Cl₂/TFA, rt, 25 min).

Cmpd	Structure	Name	[M + H]+
13		2,6-Difluoro-3-(6-((R)-2-((R)- hydroxy(p- tolyl)methyl)morpholino)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	536.7

Compound 14

3-(6-(1-Benzylpiperidin-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride

Step 1: tert-Butyl 6-(3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4-dihydropyridine-1 (2H)-carboxylate

Pd(dppf)Cl₂ (321.8 mg, 0.44 mmol) was added to a mixture of Intermediate 21 (1.63 g, 5.28 mmol), Intermediate 13.06 (2.00 g, 4.40 mmol), K₃PO₄ (2.33 g, 11.0 mmol), H₂O (2 mL), and dioxane (10 mL). The mixture was degassed with 3 vacuum/N2 cycles, heated at 80° C. overnight. allowed to cool to rt, quenched with H₂O (10 mL), and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1 to 5/1) to give tert-butyl 6-(3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4-dihydropyridine-1 (2H)-carboxylate (610 mg, 23%) as a yellow oil. ¹H NMR (400 MHZ, DMSO-d₆) δ 9.41-9.37 (m, 1H), 8.02 (t, 1H), 7.58 (d, 2H), 7.53-7.44 (m, 3H), 6.28-6.15 (m, 1H), 5.45 (s, 2H), 4.24 (s, 1H), 4.18 (s, 2H), 3.76-3.67 (m, 1H), 3.38-3.36 (m, 1H), 2.40-2.46 (m, 2H), 1.96-1.84 (m, 2H), 1.14 (s, 3H), 1.11-0.86 (m, 6H); LCMS: 602.2 [M+H]⁺.

Step 2: tert-Butyl 2-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-1-carboxylate

A mixture of tert-butyl 6-(3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4-dihydropyridine-1 (2H)-carboxylate (425.3 mg, 0.71 mmol), 10% Pd/C (291 mg), and THF (5 mL) was degassed 3 vacuum/H₂ cycles and then stirred at rt for 2 h under H₂ (15 psi). The reaction mixture was diluted with THF (50 mL) and then filtered. The filtrate was concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1 to 3/1) to give tert-butyl 2-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-1-carboxylate (210 mg, 58%) as a colorless oil. LCMS: 514.3 [M+H]⁺.

Step 3:2,6-Difluoro-3-(1-methyl-6-(piperidin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol

A mixture of tert-butyl 2-(3-(2,4-difluoro-3-hydroxy-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-1-carboxylate (210.0 mg, 0.41 mol) and HCl/EtOAc (10 mL, 4 M) was stirred at rt for 0.5 h and then concentrated to give 2,6-difluoro-3-(1-methyl-6-(piperidin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (180 mg) as a white solid. LCMS: 414.1 [M+H]⁺.

Step 4:3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(1-benzylpiperidin-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride

BnBr (91 μL, 0.77 mmol) was added to a mixture of 2,6-difluoro-3-(1-methyl-6-(piperidin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (115 mg, 0.26 mmol), K₂CO₃ (177 mg, 1.28 mmol), and DMF (2 mL) at rt. The reaction was heated at 70° C. for 2 h under N₂, allowed to cool to rt, quenched with H₂O (30 mL), and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na₂SO₄, filtered, concentrated, and then purified by prep-TLC (PE/EA; 1:1) to give 3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(1-benzylpiperidin-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (70 mg, 46%) as a colorless oil. ¹H NMR (400 MHZ, CDCl₃): δ 9.19 (d, 1H), 7.89-7.81 (m, 1H), 7.44-7.37 (m, 2H), 7.37-7.26 (m, 6H), 7.25-7.22 (m, 2H), 5.24 (s, 2H), 4.14 (s, 3H), 3.68-3.59 (m, 1H), 3.58-3.51 (m, 1H), 3.11 (d, 1H), 3.00 (d, 1H), 2.09-2.01 (m, 1H), 1.73-1.53 (m, 4H), 1.46-1.29 (m, 2H); LCMS: 594.2 [M+H]⁺.

Step 5:3-(6-(1-Benzylpiperidin-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride

A mixture of 3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(1-benzylpiperidin-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (120.0 mg, 0.20 mmol) and TFA (10 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled to rt, concentrated, and then purified by prep-HPLC (water (HCl)-ACN) to give 3-(6-(1-benzylpiperidin-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride (85 mg, 77.9%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.58 (s, 1H), 10.35 (s, 1H), 9.54 (d, 1H), 7.65 (t, 1H), 7.47-7.36 (m, 5H), 4.70 (t, 1H), 4.34 (d, 1H), 4.23 (s, 3H), 4.16 (d, 1H), 3.48-3.40 (m, 1H), 3.32-3.11 (m, 1H), 2.20 (d, 1H), 1.99-1.78 (m, 4H), 1.78-1.60 (m, 1H); LCMS: 504.1 [M+H]⁺.

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).

Cmpd #	Structure	Name	[M + H]+
14.01		3-(6-(1-Benzylpiperidin-3-y)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol hydrochloride	504.1
Alternate conditions used:
Step 1: 3 h.
Step 2: EtOAc instead of THF as solvent.
Step 2: rt, 0.5 h.
Step 3: 2 h.

Compound 15

3-(6-(2-(Cyclohexylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

Step 1:3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

A mixture of Intermediate 13.06 (507 mg, 1.11 mmol), Intermediate 17 (581 mg, 2.23 mmol), KF (324 mg, 5.57 mmol), and NMP (10 mL) was stirred at 120° C. overnight. The reaction mixture was cooled to rt, poured into H₂O (10 mL), and then extracted with EtOAc (5 mL×3). The organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 50/1 to 5/1) to give 3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (276 mg, 36%) as a yellow oil. LCMS: 679.3 [M+H]⁺.

Step 10:3-(6-(2-(Cyclohexylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (268 mg, 0.395 mmol) was added to a mixture of 10% Pd/C (100 mg) and THF (5 mL) under N₂. The mixture was degassed with 3 vacuum/H₂ cycles, stirred under H₂ (15 Psi) at rt for 2 h, and then filtered through Celite with THF (500 mL) washing. The filtrate was concentrated and then purified by reverse-phase HPLC (water (0.05% HCl)-MeCN) to give 3-(6-(2-(cyclohexylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol (96 mg, 41%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.38 (s, 1H), 8.96 (s, 1H), 7.57 (t, 1H), 5.26-5.15 (m, 1H), 4.85-4.82 (m, 1H), 3.92 (s, 3H), 3.62-3.59 (m, 1H), 3.52-3.49 (m, 1H), 3.26-3.20 (m, 1H), 2.94-2.90 (m, 1H), 2.87 (s, 3H), 2.82-2.76 (m, 1H), 1.91-1.77 (m, 2H), 1.66-1.55 (m, 5H), 1.17-0.92 (m, 6H); LCMS: 589.1 [M+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.

Cmpd #	Structure	Name	[M + H]+
15.011		(S)-3-(6-(2-(Cyclohexylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	589.1
15.021		(R)-3-(6-(2-(Cyclohexylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	589.1
15.03		3-(6-(3- (Cyclohexylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	512.1
15.042		(R)-3-(6-(3- (Cyclohexylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	512.1
15.052		(S)-3-(6-(3- (Cyclohexylmethyl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	512.2
15.06		2,6-Difluoro-3-(1-methyl-6-(3- (pyridin-2-ylmethyl)morpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	507.2
15.07		2,6-Difluoro-3-(1-methyl-6-(3- (pyridin-3-ylmethyl)morpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	507.1
15.08		2,6-Difluoro-3-(1-methyl-6-(3- (pyridin-4-ylmethyl)morpholino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol	507.0
15.09		(R)-5-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)piperazin-2-one	519.2
15.103		(R)-3-(6-(2-Benzylazetidin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	476.1
15.113		(S)-3-(6-(2-Benzylazetidin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluroo-5- (trifluoromethyl)phenol	476.1
15.124		(R)-3-(6-(3-Benzylmorpholino)-1- ethyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	520.4
15.13		(S)-2,6-Difluoro-3-(6-(3-(2- hydroxypropan-2-yl)morpholino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-5-(trifluoromethyl)phenol	474.3
Alternate conditions used:
Step 1: 100-120° C., 2 h-overnight.
Step 2: 1-2 h.
1Separated by SFC from Compound 15 (DAICEL CHIRALPAK IC: 250 mm × 30 mm, 10 μM; 0.1% NH3 H2O in i-PrOH); Compound 15.01 was the first eluting enantiomer.
2Separated by SFC from Compound 15.03 (DAICEL CHIRALPAK AD: 250 mm × 30 mm, 10 μM; 0.1% NH3 H2O in EtOH); Compound 15.04 was the first eluting enantiomer.
3Separated enantiomers by SFC (DAICEL CHIRALCEL OJ: 250 mm × 30 mm, 10 μm; 0.1% NH3 H2O in MeOH; B%: 5-30%, 13 min); Compound 15.10 was the first eluting isomer.
4Step 2: TFA, 70° C., 30 min.

The Compound below was synthesized from Intermediate 13.06 and Intermediate 19 using the following sequence: Compound 15 (Step 1), oxidation (oxone, 1:1 THF/H₂O, rt, 2 h), and then Compound 15 (Step 2).

Cmpd #	Structure	Name	[M + H]+
16		3-(6-((2R)-2-Benzyl-3- (methylsulfonyl)azetidin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	554.0

Compound 17

3-(6-((4-Benzyl-1-(methylsulfonyl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

Step 1: 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

A mixture of Intermediate 13.06 (1.01 g, 2.20 mmol), Intermediate 18 (830 mg, 2.86 mmol), KF (383 mg, 6.60 mmol), and NMP (50 mL) was stirred at 120° C. for 2 h, allowed to cool to rt, poured into H₂O (100 mL), and then extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with brine (100 mL×3), dried with anhydrous Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1 to 0/1) to give tert-butyl 4-benzyl-4-((3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)piperidine-1-carboxylate (211 mg, 13%) as a yellow oil. LCMS: 709.4 [M+H]⁺.

Step 2: 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

NaH (23.1 mg, 0.578 mmol, 60% purity) was added to 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)amino)piperidine-1-carboxylate (205 mg, 289 umol) and DMF (5 mL) at 0° C. under N₂. The reaction was stirred at rt for 0.5 h, and then Mel (27 μL, 0.434 mmol) was added. The reaction was stirred at rt for an additional hour, poured into H₂O (40 mL), and then extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (50 mL×3), dried with anhydrous Na₂SO₄, filtered, concentrated, and then purified by prep-TLC (petroleum ether/ethyl acetate: 5/1) to give 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, 50%) as a yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 8.92 (d, 1H), 7.94 (t, 1H), 7.53-7.46 (m, 2H), 7.43-7.37 (m, 3H), 7.26-7.16 (m, 5H), 5.30 (s, 2H), 4.01 (s, 3H), 3.97-3.87 (m, 2H), 3.83-3.71 (m, 2H), 3.65 (s, 2H), 2.92 (s, 3H), 2.16-2.03 (m, 2H), 1.95-1.86 (m, 2H), 1.56 (s, 9H); LCMS: 723.4 [M+H]⁺.

Step 3:3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N-(4-benzylpiperidin-4-yl)-N,1-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

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.

Step 4: N-(4-benzyl-1-(methylsulfonyl)piperidin-4-yl)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Methanesulfonyl chloride (0.02 mL, 0.244 mmol) was added to a solution of 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 (91 mg, 0.146 mmol), TEA (0.06 mL, 0.438 mmol), and DCM (4 mL). The reaction was stirred at rt for 2 h, poured into H₂O (15 mL), and extracted with DCM (10 mL×3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered, concentrated, and then purified by prep-TLC (petroleum ether/ethyl acetate: 2/1) to give N-(4-benzyl-1-(methylsulfonyl)piperidin-4-yl)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N, 1-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (55 mg, 53%) as a white solid. ¹H NMR (400 MHZ, CDCl₃): δ 8.93 (d, 1H), 7.94 (t, 1H), 7.55-7.45 (m, 2H), 7.44-7.37 (m, 3H), 7.24-7.20 (m, 3H), 7.05-6.99 (m, 2H), 5.30 (s, 2H), 4.02 (s, 3H), 3.65-3.55 (m, 2H), 2.94 (s, 3H), 2.91-2.84 (m, 3H), 2.75-2.70 (m, 4H), 2.04-1.93 (m, 2H), 1.28-1.25 (m, 2H); LCMS: 701.4 [M+H]⁺.

Step 5:3-(6-((4-Benzyl-1-(methylsulfonyl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

BCl₃ (1 M in DCM, 0.46 mL) was added to a solution of N-(4-benzyl-1-(methylsulfonyl)piperidin-4-yl)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N, 1-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (106 mg, 0.151 mmol) and DCM (10 mL) at −70° C. The mixture was stirred at −70° C. for 1 h, poured (while still cold) into a stirring mixture of MeOH (5 mL) and sat. aq. NaHCO₃ (20 mL), stirred for 5 min, and then extracted with DCM (15 mL×3). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered, concentrated, and then purified by reverse-phase HPLC (Phenomenex Luna C₁₈; water (HCl)-ACN) to give 3-(6-((4-benzyl-1-(methylsulfonyl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol (24.4 mg, 26%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.40 (s, 1H), 9.01 (d, 1H), 7.61 (t, 1H), 7.26-7.14 (m, 3H), 7.05-7.69 (m, 2H), 3.95 (s, 3H), 3.54-3.25 (m, 4H), 3.11-2.76 (m, 10H), 2.07-1.94 (m, 2H); LCMS: 611.1 [M+H]⁺.

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

Cmpd #	Structure	Name	[M + H]+
17.01		3-(6-((3-Benzyl-1- (methylsulfonyl)piperidin-3- yl)(methyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	611.2

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).

Cmpd #	Structure	Name	[M + H]+
18		(R)-2,6-Difluoro-3-(1-methyl-6-(2- methyl-4-(methylsulfonyl)piperazin- 1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-5-(trifluoromethyl)phenol	507.1
18.01		(R)-3-(6-(2-Ethyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	521.2
18.02		(R)-2,6-Difluoro-3-(1-methyl-6-(4- (methylsulfonyl)-2-propylpiperazin- 1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3- yl)-5-(trifluoromethyl)phenol	535.2
18.03		(S)-2,6-Difluoro-3-(6-(2- (methoxymethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-5-(trifluoromethyl)phenol	537.2
18.04		2,6-Difluroo-3-(6-(2-isobutyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-5-(trifluoromethyl)phenol	549.3
18.051		(S)-2,6-Difluoro-3-(6-(2-isobutyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-5-(trifluoromethyl)phenol	549.3
18.061		(R)-2,6-Difluoro-3-(6-(2-isobutyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-5-(trifluoromethyl)phenol	549.3
Alternate conditions used:
1Separated by SFC from Compound 18.04 (DAICEL CHIRALPAK IC: 250 mm × 30 mm, 10 μM; [0.1% NH3 H2O in i-PrOH] B%: 28%-28%, 10 min); Compound 18.05 was the first eluting enantiomer.

Compound 19

(R)-3-(6-(2-(Cyclopropylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol

(R)-3-(6-(2-(Cyclopropylmethyl)-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol was synthesized from Intermediate 13.06 and tert-butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate using the following sequence: Compound 17 [Steps 1 (110° C., overnight), 3, & 4 (overnight)], deprotection (10% Pd/C, THF, H₂, rt, 2 h), and then SFC separation (2nd eluting enantiomer from DIACEL CHIRALPAK IG: 250 mm×30 mm, 10 μM; 0.1% NH₃·H₂O in CH₃OH). 1H NMR (400 MHZ, DMSO-d₆): δ 11.66-11.19 (m, 1H), 8.97 (d, 1H), 7.55 (t, 1H), 3.93 (s, 3H), 3.73 (d, 1H), 3.62 (d, 1H), 3.24-3.15 (m, 1H), 2.98-2.92 (m, 1H), 2.92-2.88 (m, 3H), 2.82 (d, J=11.9, 1H), 2.37-2.28 (m, 1H), 1.82-1.71 (m, 1H), 1.51-1.38 (m, 1H), 0.66 (d, 1H), 0.46-0.28 (m, 2H), 0.13-0.22 (m, 1H), 0.22-0.13 (m, 1H), 0.13-0.2 (m, 1H); LCMS: 547.1 [M+H]⁺.

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

Cmpd	Structure	Name	[M + H]+
19.01		(S)-3-(6-(2-(Cyclopropylmethyl)-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	547.1

The Compounds below were synthesized from Compound 19 (Step 2) using the following sequence: acylation (TFAA, TEA, CH₂Cl₂, rt, 1 h), SFC separation (DIACEL CHIRALPAK IG: 250 mm×30 mm, 10 μM; [0.1% NH₃·H₂O in CH₃OH]B %: 25%-25%, 11 min), and then each isomer was deprotected separately (TFA, 50° C., 2 h).

Cmpd	Structure	Name	[M + H]+
20		(S)-1-(3-(Cyclopropylmethyl)-4-(3- (2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2,2,2- trifluoroethan-1-one	565.2
20.01		(R)-1-(3-(Cyclopropylmethyl)-4-(3- (2,4-difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)-2,2,2- trifluoroethan-1-one	565.1
(S)-1-(4-(3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-(cyclopropylmethyl)piperazin-1-yl)-2,2,2-trifluoroethan-1-one was the first eluting enantiomer.

Compound 21

(R)-5-(6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-difluoro-3-hydroxybenzonitrile

Step 1: (R)-5-(6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-difluoro-3-methoxybenzonitrile

Pd(PPh₃)₂Cl₂ (13.7 mg, 19.5 umol) and CuI (7.4 mg, 39 umol) was added to a solution of Intermediate 14 (0.1 g, 195 umol), Intermediate 7.01 (89.4 mg, 195 umol), and dioxane (5 mL) under N₂. The mixture was stirred at 100° C. for 16 h, cooled to rt, poured into H₂O (30 mL), and then extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 9/1 to 3/1) to give (R)-5-(6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-difluoro-3-methoxybenzonitrile (246 mg, 54%) as a yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 8.96 (d, 1H), 7.96 (t, 1H), 7.41-7.46 (m, 2H), 7.33 (t, 2H), 7.18-7.25 (m, 1H), 5.19-5.30 (m, 1H), 4.92-5.04 (m, 1H), 4.13-4.18 (m, 3H), 4.04 (s, 3H), 3.91-3.99 (m, 1H), 3.76 (d, 1H), 3.40-3.52 (m, 1H), 3.23-3.33 (m, 1H), 2.74-2.90 (m, 6H); LCMS: 554.2 [M+H]⁺.

Step 2: (R)-5-(6-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-difluoro-3-hydroxybenzonitrile

BBr₃ (429 μL, 4.45 mmol) was added to a solution of (R)-5-(6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-difluoro-3-methoxybenzonitrile (246 mg, 445 umol) and DCM (5 mL) at 0° C. The mixture was stirred at rt for 16 h, quenched with dropwise addition of MeOH (10 mL), stirred for 10 min at rt, poured into H₂O (20 mL), and then extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and then purified by prep-HPLC (Phenomenex Luna C₁₈; water (HCl)-ACN) to give (R)-5-(6-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-difluoro-3-hydroxybenzonitrile (52 mg, 22%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.50 (s, 1H), 9.03 (d, 1H), 7.80 (t, 1H), 7.23-7.42 (m, 4H), 7.11-7.22 (m, 1H), 5.07-5.33 (m, 1H), 4.69-4.97 (m, 1H), 3.97 (s, 3H), 3.67-3.79 (m, 1H), 3.46-3.57 (m, 2H), 3.04-3.18 (m, 1H), 2.75-2.94 (m, 6H); LCMS: 540.2 [M+H]⁺.

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).

Cmpd #	Structure	Name	[M + H]+
21.01		3-(6-((R)-2-Benzyl-4- (methylsulfonyl)piperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-6-chloro-2,4-difluorophenol	549.0
Alternate conditions used: Step 1: 2 h.

Compound 22

(R)-3-(6-(2-Benzyl-4-ethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride

Step 1: (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

Pd(dppf)Cl₂·CH₂Cl₂ (321 mg, 0.392 mmol) was added to a mixture of Intermediate 14.03 (2.1 g, 3.93 mmol), Intermediate 7 (1.95 g, 4.72 mmol), Na₂CO₃ (2 M in H₂O, 4.9 mL), and dioxane (40 mL) under N₂. The mixture was degassed with 3 vacuum/N2 cycles, stirred at 80° C. for 2 h under N₂, allowed to cool to rt, poured into H₂O (100 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 5/1) to give (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 (2.2 g, 80%) as yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.98 (s, 1H), 7.86 (t, 1H), 7.55-7.46 (m, 2H), 7.46-7.24 (m, 7H), 7.21 (d, 1H), 5.35 (s, 2H), 5.09-4.82 (m, 1H), 4.63 (d, 1H), 4.16-4.06 (m, 1H), 4.00-3.91 (m, 3H), 3.90-3.77 (m, 1H), 3.13-2.83 (m, 3H), 2.73 (d, 1H), 1.46 (s, 9H), 1.32-1.25 (m, 1H); LCMS: 695.7 [M+H]⁺.

Step 2: (R)-3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride

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 (1.8 g, 2.59 mmol) and HCl/EtOAc (4 M, 50 mL) was stirred at rt for 2 h and then concentrated 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 (1.9 g) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.75 (d, 1H), 9.57 (d, 1H), 9.00 (d, 1H), 7.87 (t, 1H), 7.53-7.47 (m, 2H), 7.46-7.36 (m, 5H), 7.30 (t, 2H), 7.21-7.15 (m, 1H), 5.36 (s, 2H), 5.25 (d, 1H), 4.92 (d, 1H), 3.96 (s, 3H), 3.56-3.31 (m, 3H), 3.21-2.96 (m, 4H); LCMS: 595.2 [M+H]⁺.

Step 3: (R)-6-(2-Benzyl-4-ethylpiperazin-1-yl)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Iodoethane (0.03 mL, 0.48 mmol) was added to a mixture of (R)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (150 mg, 0.237 mmol), K₂CO₃ (98.6 mg, 0.713 mmol), and acetone (5 mL). The mixture was stirred at 50° C. overnight, allowed to cool to rt, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 1/1) to give (R)-6-(2-benzyl-4-ethylpiperazin-1-yl)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (92 mg, 62%) as a yellow oil. ¹H NMR (400 MHZ, DMSO-d₆): δ 8.96 (d, 1H), 7.87 (t, 1H), 7.61-7.08 (m, 9H), 7.63-7.02 (m, 1H), 5.36 (s, 2H), 5.05-4.90 (m, 1H), 4.73-4.58 (m, 1H), 4.07-3.87 (m, 3H), 3.18 (dd, 1H), 3.02 (d, 1H), 2.79 (d, 2H), 2.36-2.20 (m, 1H), 2.09-1.94 (m, 1H), 1.93-1.85 (m, 1H), 1.37-1.14 (m, 2H), 1.04 (t, 3H); LCMS: 623.3 [M+H]⁺.

Step 4: (R)-3-(6-(2-Benzyl-4-ethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride

A mixture of (R)-3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-6-(2-benzylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (70 mg, 0.106 mmol) and TFA (3 mL) was stirred at 70° C. for 2 h under N₂, allowed to cool to rt, concentrated, and then purified by prep-HPLC (water (0.05% HCl)/CH₃CN) to give (R)-3-(6-(2-benzyl-4-ethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol hydrochloride (45 mg, 73%) as a white solid. ¹H NMR (400 MHZ, DMSO-d₆,): δ 11.42 (s, 1H), 11.02-10.36 (m, 1H), 9.00 (d, 1H), 7.58 (t, 1H), 7.45 (s, 2H), 7.35-7.26 (m, 1H), 7.30 (t, 1H), 7.23-7.15 (m, 1H), 5.54-5.19 (m, 1H), 5.13-4.84 (m, 1H), 3.97 (s, 3H), 3.73-3.45 (m, 3H), 3.26-2.94 (m, 6H), 1.40-1.23 (m, 3H). LCMS: 533.3 [M+H]⁺.

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

Cmpd #	Structure	Name	[M + H]+
22.01		(R)-3-(6-(2-Benzyl-4- propylpiperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol hydrochloride	547.1
22.02		(R)-3-(6-(2-Benzyl-4- isopropylpiperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	547.1
22.031		(S)-3-(6-(3-Benzylpiperazin-1-yl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin- 3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol hydrochloride	505.3
22.042		(S)-3-(6-(3-Benzyl-4- methylpiperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	519.3
22.053		(S)-3-(6-(3-Benzyl-4-ethylpiperazin- 1-yl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	533.1
22.064		(S)-3-(6-(3-Benzyl-4- propylpiperazin-1-yl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2,6- difluoro-5-(trifluoromethyl)phenol	547.1
22.074		(S)-3-(6-(3-Benzyl-4- isopropylpiperazin-1-yl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2,6-difluoro-5- (trifluoromethyl)phenol	547.1
22.081		(R)-3-(6-(3-Benzylthiomorpholino)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-3-yl)-2,6-difluoro-5- (trifluoromethyl)phenol	522.0
Alternate conditions used: Step 3: CH3CN instead of acetone as solvent. Step 3: 80° C.
1Step 1 then Step 4.
2Synthesized from Compound 22.03 (Step 1) using the following sequence: Boc deprotection (4 M HCl in EtOAc, rt, 2 h) and then methylation (formaldehyde in formic acid, 100° C., overnight).
3Synthesized from Compound 22.03 (Step 1) using the following sequence: Boc deprotection (4 M HCl in EtOAc, rt, 2 h) and then Compound 22 (Steps 3-4).
4Synthesized from Compound 22.03 (Step 1) using the following sequence: Boc deprotection (4 M HCl in EtOAc, rt, 2 h), alkylation (appropriate alkylating agent, K2CO3, CH3CN, 80° C., overnight), and then Compound 22 (Step 4).

The Compounds below were synthesized from Compound 22.08 (Step 1) by oxidation (oxone, 1:1 THF, H₂O, 0° C., 1 h), prep-TLC separation, and then deprotection (Compound 22, Step 4).

Cmpd #	Structure	Name	[M + H]+
23		(R)-3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)thiomorpholine 1,1- dioxide	554.0
23.01		(3R)-3-Benzyl-4-(3-(2,4-difluoro-3- hydroxy-5-(trifluoromethyl)phenyl)- 1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)thiomorpholine 1- oxide	538.0

The Compound below was synthesized from Compound 22 (Step 2) using the following sequence: acylation ((4-nitrophenyl) carbonochloridate, TEA, CH₂Cl₂, 0° C.-rt, 2 h), alkylation (azetidine, K₂CO₃, DMF, rt, overnight), and then deprotection (10% palladium on carbon, THF, H₂, rt, 2 h).

Cmpd #	Structure	Name	[M + H]+
24		(R)-Azetidin-1-yl(3-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)methanone	588.2

The Compound below was synthesized from Compound 22.03 (Step 1) using the following sequence: Boc deprotection (4 M HCl in EtOAc, rt, 2 h), acylation ((4-nitrophenyl) carbonochloridate, TEA, CH₂Cl₂, 0° C.-rt, 2 h), alkylation (azetidine, K₂CO₃, DMF, 80° C., overnight), and then deprotection (10% palladium on carbon, THF, H₂, rt, 2 h).

Cmpd #	Structure	Name	[M + H]+
25		(S)-Azetidin-1-yl(2-benzyl-4-(3-(2,4- difluoro-3-hydroxy-5- (trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperazin-1-yl)methanone	588.3

Compound 26

(R)-3-(5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2-fluoro-5-(trifluoromethyl)phenol

Step 1:5-Chloro-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine

SEM-Cl (6.6 mL, 37.4 mmol) was added dropwise to a solution of Intermediate 8, Step 1 (7.0 g, 25.0 mmol), DIEA (13.1 mL, 74.9 mmol), and DMF (50 mL) at 0° C. The reaction was stirred at 25° C. for 2 h, poured into H₂O (200 mL), and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 30/1→3/1) to give 5-chloro-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (5.5 g, 54%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.52 (s, 1H), 5.87 (s, 2H), 3.57-3.55 (t, 2H), 0.83-0.80 (t, 2H), 0.10 (s, 9H); LCMS: 411.0 [M+H]⁺.

Step 2: (R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine

KF (2.84 g, 48.9 mmol) was added to a solution of 5-chloro-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (2.0 g, 4.9 mmol) and Intermediate 2.06 (2.48 g, 9.74 mmol) in water (60 mL). The mixture was stirred at 100° C. for 16 h, additional KF (2.83 g, 48.7 mmol) was added, and the mixture was stirred at 100° C. for an additional 24 h. The reaction was cooled to rt and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 20/1→1/1) to give (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (1.1 g, 36%) as yellow oil. ¹H NMR (400 MHZ, CDCl₃): δ 8.92 (s, 1H), 7.56-7.55 (m, 2H), 7.38-7.34 (m, 2H), 7.29-7.23 (m, 1H), 5.72 (s, 2H), 5.19-5.09 (m, 1H), 4.97-4.88 (m, 1H), 3.96-3.94 (m, 1H), 3.79-3.76 (m, 1H), 3.66-3.61 (m, 2H), 3.59-3.57 (m, 1H), 3.30-3.24 (m, 1H), 2.88-2.75 (m, 6H), 0.93 (t, 2H), 0.01 (s, 9H); LCMS: 629.2 [M+H]⁺.

Step 3: (R)-5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine

TFA (20 mL, 270 mmol) was added to a solution of (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine (3.7 g, 5.9 mmol) and DCM (40 mL). The reaction was stirred at 20° C. for 16.5 h, concentrated, and then diluted with THF (50 mL) and 1 M NaOH (20 mL). This mixture was stirred at 20° C. for 0.5 h, diluted with water (30 mL), and then extracted with EtOAc (30 mL×3). The combined organic extracts were dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 10/1→0/1) to give (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (1.8 g, 48%) as a yellow solid. ¹H NMR (400 MHZ, CDCl₃): δ 8.88 (s, 1H), 7.54-7.52 (m, 2H), 7.35-7.31 (m, 2H), 7.23-7.20 (m, 1H), 5.11-5.09 (m, 1H), 4.88-4.85 (d, 1H), 3.93 (d, 1H), 3.75 (d, 1H), 3.42 (t, 1H), 3.23-3.18 (m, 2H), 2.87-2.73 (m, 6H); LCMS: 499.0 [M+H]⁺.

Step 4: (R)-3-(5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2-fluoro-5-(trifluoromethyl)phenol

TEA (10.0 mL, 71.9 mmol), Cu(OAc)₂ (1.82 g, 10.0 mmol), and pyridine (10.0 mL, 124 mmol) were added to a solution of (R)-5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (1.0 g, 2.0 mmol), Intermediate 6.02 (1.02 g, 3.01 mmol), and DCM (10 mL). The mixture was degassed with 3 vacuum/O₂ cycles, heated at 40° C. for 16 h under O₂, cooled to rt, concentrated, diluted with 0.5 M HCl (50 mL), and then extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and then purified by reverse-phase HPLC (Phenomenex Luna; water (HCl)-ACN) to give (R)-3-(5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2-fluoro-5-(trifluoromethyl)phenol (0.6 g, 40%) as a yellow solid. 1H NMR (400 MHZ, CD₃OD): δ 8.82 (d, 1H), 7.58 (d, 1H), 7.49 (d, 2H), 7.26 (t, 2H), 7.15 (t, 1H), 5.10-5.08 (m, 1H), 4.87-4.84 (m, 1H), 3.85 (d, 1H), 3.67 (d, 1H), 3.43-3.37 (m, 1H), 3.15-3.14 (m, 1H), 2.91-2.81 (m, 6H); LCMS: 710.9 [M+H]⁺.

Step 5: (R)-3-(5-(2-Benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2-fluoro-5-(trifluoromethyl)phenol

Xantphos (40 mg, 69 umol), Cs₂CO₃ (140 mg, 430 umol), and Xantphos Pd G4 (40 mg, 42 μmol) were added to a solution of (R)-3-(5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2-fluoro-5-(trifluoromethyl)phenol (100 mg, 141 μmol), methyl amine (2 M in THF, 1 mL), and amyl alcohol (3 mL). The reaction was degassed with 3 vacuum/N2 cycles, heated at 80° C. for 16 h in a sealed reactor, cooled to rt, diluted with 0.5 M HCl (50 mL), and then extracted with EtOAc (30 mL×3; the reaction was run in 6 parallel batches and combined for work up). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate: 5/1→0/1) followed by reverse-phase HPLC (Phenomenex Luna; water (HCl)-ACN) to give (R)-3-(5-(2-benzyl-4-(methylsulfonyl)piperazin-1-yl)-3-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-6-chloro-2-fluoro-5-(trifluoromethyl)phenol (120 mg, 23%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d₆): δ 11.59 (s, 1H), 8.81 (d, 1H), 7.49 (d, 1H), 7.34-7.32 (m, 2H), 7.30-7.26 (m, 2H), 7.20-7.16 (m, 1H), 6.44 (s, 1H), 5.08-5.06 (m, 1H), 4.71 (d, 1H), 3.70 (d, 1H), 3.46 (d, 1H), 3.36-3.29 (m, 1H), 3.09 (dd, 1H), 2.95 (s, 3H), 2.89 (s, 3H), 2.86-2.82 (m, 2H), 2.74 (dd, 1H); LCMS: 614.0 [M+H]⁺.

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

Cmpd #	Structure	Name	[M + H]+
27		(R)-3-(5-(2-Benzyl-4- (methylsulfonyl)piperazin-1- yl)benzo[d]oxazol-2-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol	568.1
27.01		(R)-3-(6-(2-Benzyl-4- (methylsulfonyl)piperazin-1- yl)benzo[d]oxazol-2-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol	568.0
27.02		(S)-3-(5-(3-Benzyl-4- (methylsulfonyl)piperazin-1- yl)benzo[d]oxazol-2-yl)-2,6-difluoro- 5-(trifluoromethyl)phenol	568.1

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.

Example B-1: HSD17b13 NAD (P) H-Glo Biochemical Assay

Materials

Recombinant human HSD17B13 enzyme. Substrate: estradiol (Sigma β-Estradiol E8875), 100 mM in DMSO. Cofactor: NAD+ Grade I free acid (Sigma 10127965001), 20 mM in H₂O. Assay buffer final concentration: 20 mM Tris pH7.4 with 0.002% Tween-20 and 0.02% BSA. Assay performed in 384 well solid bottom plate (Corning 3570). Enzymatic activity detected by NAD (P) H-Glo™ Detection System (Promega G9062).

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.

TABLE 3
      HSD17β13
Cmpd  IC50 (uM)
1     +++
1.01  ++
1.02  +++
1.03  +++
1.04  ++
1.05  ++
1.06  +++
1.07  +++
1.08  +++
1.09  +++
1.10  +++
2     +++
2.01  +++
2.02  +++
2.03  ++
2.04  +++
2.05  ++
2.06  +++
2.07  +++
2.08  +++
2.09  +++
2.10  +++
2.11  +++
2.12  +++
2.13  +++
2.14  +++
2.15  +++
2.16  +++
2.17  ++
2.18  +++
2.19  +++
2.20  +++
2.21  +++
2.22  +++
2.23  +++
2.24  +++
2.25  +++
2.26  ++
2.27  +++
2.28  +++
2.29  44% at 10
      uM
2.30  +
2.31  +++
2.32  +++
2.33  +++
2.34  +++
2.35  +++
2.36  +++
5     +++
5.01  +++
5.02  +++
5.03  +++
5.04  +++
5.05  ++
5.06  +++
5.07  +++
5.08  +++
5.09  +++
5.10  +++
5.11  +++
5.12  +++
5.13  +++
5.14  +++
5.15  +++
5.16  +++
5.17  +++
5.18  +++
5.19  +++
5.20  +++
5.21  +++
5.22  +++
5.23  +++
5.24  +++
5.25  +++
5.26  +++
5.27  +++
5.28  +++
5.29  ++
5.30  +++
5.31  +++
5.32  +++
5.33  +++
5.34  ++
5.35  +++
5.36  +++
5.37  +++
6     +++
6.01  +++
6.02  +++
6.03  +++
6.04  +++
6.05  +++
6.06  +++
6.07  ++
6.08  +++
6.09  +++
11.07 +++
11.08 +++
11.09 +++
11.10 +++
11.11 +
11.12 +++
11.13 +++
11.14 +++
11.15 +++
11.16 +++
11.17 +++
11.18 +++
11.19 +++
11.20 +++
11.21 +++
11.22 +++
11.23 +++
11.24 +++
11.25 +++
11.26 +++
11.27 +++
11.28 +++
12    +++
12.01 +++
12.02 +++
12.03 +++
12.04 +++
12.05 +++
12.06 +++
12.07 +++
12.08 +++
13    +++
14    ++
14.01 ++
15    +++
15.01 +++
15.02 +++
15.03 +++
15.04 +++
15.05 +++
15.06 +++
15.07 +++
15.08 +++
15.09 +++
15.10 +++
15.11 +++
15.12 +++
15.13 +++
where ‘+++’ means IC50 ≤ 0.1 μM; where ‘++’ means 0.1 μM < IC50 ≤ 1 μM; where ‘+’ means 1.0 μM < IC50 ≤ 30 μM.

Example B-2: HSD17b1 NAD (P) H-Glo Biochemical Assay

Materials

Recombinant human HSD17B1 enzyme. Substrate: testosterone (Sigma T1500), 100 mM in DMSO. Cofactor: NADP disodium salt (Sigma 10128031001), 20 mM in H₂O. Assay buffer final concentration: 20 mM Tris pH 7.4 with 0.002% Tween-20 and 0.02% BSA. Assay performed in 384 well solid bottom plate (Corning 3570). Enzymatic activity detected by NAD (P) H-Glo™ Detection System (Promega G9062).

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.

Example B-3: HSD17b2 NAD (P) H-Glo Biochemical Assay

Materials and Setup

Recombinant human HSD17B2 enzyme. Substrate: estradiol (Sigma β-Estradiol E8875)₂ mM in DMSO. Cofactor: NAD+ Grade I free acid (Sigma 10127965001), 20 mM in H₂O. Assay buffer final concentration: 20 mM Tris pH7.4 with 0.002% Tween-20 and 0.02% BSA. Assay performed in 384 well solid bottom plate (Corning 3570). Enzymatic activity detected by NAD (P) H-Glo™ Detection System (Promega G9062).

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

HEK293 cells were plated at 4,000,000 cells per T75 flask with EMEM (ATCC Cat #30-2003) and 10% FBS (Sigma Cat #F2442) and then incubated at 37° C. in 5% CO₂ for 18 hours.

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% CO₂ for 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% CO₂ for 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% CO₂ for 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

HEK293 cells were plated at 4,000,000 cells per T75 flask with EMEM (ATCC Cat #30-2003) and 10% FBS (Sigma Cat #F2442) and then incubated at 37° C. in 5% CO₂ for 18 hours.

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% CO₂ for 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% CO₂ for 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% CO₂ for 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.

Example B-6: NASH Activity Study (AMLN Model)

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.

Example B-7: CCl₄ Fibrosis Model

Fibrosis is induced in C57BL/6 male mice by bi-weekly oral administration of CCl₄. CCl₄ is 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 CCl₄ administration. 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), C_max, T_max, elimination half-life (T_1/2), 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.

Claims

1. A compound of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof:

2. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II′):

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is N(R9).

5. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from H and C1-6alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is H.

7. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is C1-6alkyl.

8. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III′):

9. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IV′):

10. The compound of claim 8 or claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein Y3 is N.

11. The compound of claim 8 or claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein Y3 is CR4.

12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is H, halogen, C1-6alkyl, C1-6haloalkyl, —N(R10)(R11), or —C(O)R13.

13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is H, halogen, C1-6alkyl, or —N(R10)(R11).

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3 are CR3.

16. The compound of claim 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa′):

17. The compound of any one of claims 8, 12, and 13, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa′):

18. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa′):

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein Z2 is N.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein Z2 is CR5.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 and Z3 are CR5.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is N; and Z3 are CR5.

23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein Z3 is N; and Z1 is CR5.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein Z4 is N.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein Z4 is CR5.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is independently selected from H, halogen, —CN, C1-6alkyl, and —OR10.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is H.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is unsubstituted C1-6alkylene.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein L2 is —CH2—.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is phenyl optionally substituted with one, two, or three R14.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is unsubstituted phenyl.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C1-9heteroaryl optionally substituted with one, two, or three R14.

33. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is unsubstituted C1-9heteroaryl.

34. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C2-9heterocycloalkyl optionally substituted with one, two, or three R14.

35. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is unsubstituted C2-9heterocycloalkyl.

36. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C3-6cycloalkyl optionally substituted with one, two, or three R14.

37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is unsubstituted C3-6cycloalkyl.

38. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C2-6alkyl optionally substituted with one, two, or three R14.

39. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is unsubstituted C2-6alkyl.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond.

41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is —N(R10)—.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C2-9heterocycloalkyl optionally substituted with one, two, or three R6.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C2-9heterocycloalkyl selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, and diazepanyl, wherein piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanyl, azetidinyl, aziridinyl, azepanyl, and diazepanyl are optionally substituted with one, two, or three R6.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8 is

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is 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).

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof, wherein —R1-L2-R8 is

47. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C3-8cycloalkyl optionally substituted with one, two, or three R6.

48. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C6-10aryl substituted with one, two, or three R7.

49. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-9heteroaryl substituted with one, two, or three R7.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from H, halogen, —CN, C1-6alkyl, C1-6haloalkyl, and —OR 10.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from H, halogen, and C1-6haloalkyl.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H.

53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen.

54. A compound selected from:

55. A compound selected from:

56. A pharmaceutical composition comprising a compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

57. The pharmaceutical composition of claim 56, wherein 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.

58. The pharmaceutical composition of claim 56, wherein 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.

59. A method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof.

60. The method of claim 59, wherein the liver disease or condition is an alcoholic liver disease or condition.

61. The method of claim 59, wherein the liver disease or condition is a nonalcoholic liver disease or condition.

62. The method of claim 59, wherein the liver disease or condition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof.

63. The method of claim 59, wherein the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof.

64. A method of treating or preventing a disease or condition in a mammal that would benefit from treatment with an HSD17B13 inhibitor, comprising administering to the mammal a compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof.

65. The method of claim 64, wherein the disease or condition in the mammal that would benefit from treatment with an HSD17B13 inhibitor mammal is a liver disease or condition as described in claim 62 or claim 63.

66. A method of modulating hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) activity in a mammal comprising administering to the mammal a compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof.

67. The method of claim 66, wherein modulating comprises inhibiting HSD17B13 activity.

68. The method of claim 66 or claim 67, wherein the mammal has a liver disease or condition as described in claim 62 or claim 63.