SREBP inhibitors comprising a thiophene central ring

文档序号：1820637 发布日期：2021-11-09 浏览：27次中文

阅读说明：本技术 包括噻吩中心环的srebp抑制剂 (SREBP inhibitors comprising a thiophene central ring ) 是由麦可·约翰·格瑞 B·P·哈特于 2020-01-27 设计创作，主要内容包括：本文提供了包括三环核心的化合物,如式(I)、式(I-i)、式(I-A)、式(I-A-i)、式(I-A-i-1)、式(I-B)、式(I-B-i)、式(I-B-i-1)、式(II)、式(II-i)、式(II-A)、式(II-A-i)、式(II-A-i-1)、式(II-B)、式(II-B-i)和式(II-B-i-1)化合物和其药学上可接受的盐、溶剂化物、互变异构体、同位素或异构体。本文还提供了使用这些化合物或其药学上可接受的盐、溶剂化物、互变异构体、同位素或异构体来抑制甾醇调节元件结合蛋白(SREBP)途径的组分,如SREBP或SREBP裂解激活蛋白(SCAP)的方法。进一步提供了治疗有需要的受试者的病症,如肝病、非酒精性脂肪性肝炎、胰岛素抵抗或癌症的方法。(Provided herein are compounds comprising a tricyclic core, such as compounds of formula (I), formula (I-I), formula (I-A-I-1), formula (I-B-I-1), formula (II-I), formula (II-A-I-1), formula (II-B-I), and formula (II-B-I-1), and pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof. Also provided herein are methods of using these compounds, or pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof, to inhibit components of the Sterol Regulatory Element Binding Protein (SREBP) pathway, such as SREBP or SREBP Cleavage Activator Protein (SCAP). Further provided are methods of treating a disorder, such as liver disease, non-alcoholic steatohepatitis, insulin resistance, or cancer, in a subject in need thereof.)

1. A compound of the formula (II),

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

Wherein when X is S and Y is-CR^6aWhen R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-NR⁷S(O)₂R⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹or-NR⁸R⁹(ii) a And is

Wherein when Y is S and X is-CR^6bWhen R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹or-NR⁸R⁹；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is ⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo、-OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl-alkyl, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR ¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, orEach of said groups is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

each R²Independently selected from the group consisting of: halo, cyano, alkyl, cycloalkyl-alkyl, -OR¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

R⁴is alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, heterocycloalkenyl, -OR¹²、-C(O)NR¹²R¹²、-NR¹²C(O)NR¹²R¹²、-S(O)₂NR¹²R¹²、-S(O)_m3R¹²or-C (O) R¹²(ii) a n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R ⁴And one R⁵Said carbocyclic or heterocyclic group formed is independentlyUnsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴、-C(O)R¹⁴and-OC (O) R²²，

Wherein each alkyl, cycloalkyl-alkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, -C (O) OR¹⁷、-C(O)NR¹⁷R¹⁷、-NR¹⁷C(O)R¹⁷、-NR¹⁷C(O)NR¹⁷R¹⁷、-NR¹⁷R¹⁷、-S(O)₂NR¹⁷R¹⁷、-NR¹⁷S(O)₂R¹⁷、-S(O)_n4R¹⁷、-C(O)R¹⁷And- (OR)¹⁸)_n5OR¹⁷Wherein each R is¹⁷Independently hydrogen, alkyl or haloalkyl; each n4 is independently 0, 1 or 2; each n5 is independently an integer from 0 to 5; and each R¹⁸Independently is alkylene or haloalkylene;

R²²independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃，

Wherein each R²³Is (C)₁-C₆) An alkylene group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8;

R³、R^6aand R^6bIndependently selected from the group consisting of: hydrogen, halo, cyano, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl and-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

Each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R¹²And R¹³Independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R ²⁰Independently is alkylene or haloalkylene;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

2. A compound of the formula (I),

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituentsEach substituent is independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl-alkyl, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR ¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl; and from R⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴，

R³、R^6aAnd R^6bIndependently selected from the group consisting of: hydrogen, halo, cyano, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl and-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R¹²And R¹³Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR ¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently is alkylene or haloalkylene;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

3. The compound of claim 1, wherein the compound is of formula (II-a):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

4. The compound of claim 2, wherein the compound is of formula (I-a):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

5. The compound of claim 1 or 3, wherein the compound is of formula (II-a-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

6. The compound of claim 2 or 4, wherein the compound is of formula (I-a-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

7. The compound of claim 1, wherein the compound is of formula (II-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

8. The compound of claim 2, wherein the compound is of formula (I-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

9. The compound of claim 1 or 7, wherein the compound is of formula (II-B-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

10. The compound of claim 2 or 8, wherein the compound is of formula (I-B-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸、-NR⁷(SO)₂R⁹or-NR⁸R⁹。

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸or-NR⁸R⁹。

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹or-NR⁷S(O)₂NR⁸R⁹。

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)OR⁹、-NR⁷(SO)₂R⁹or-S (O)₂R⁹。

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁷And R⁸Are all hydrogen, and R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl, wherein said alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group of (I) wherein each R¹⁰Independently isHydrogen, alkyl or haloalkyl.

16. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, wherein said heterocycloalkyl group is unsubstituted OR substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, and-OR¹⁰Group of (I) wherein each R¹⁰Independently hydrogen, unsubstituted alkyl or haloalkyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein n1 is 0 or 1.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Independently is halo, alkyl OR-OR¹¹Wherein each R is¹¹Independently hydrogen, unsubstituted alkyl or haloalkyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Independently a halo group.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is ²Is chlorine.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is³And R^6aOr R^6bAre all hydrogen.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein n2 is 0.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁴Is alkyl or cycloalkyl, wherein said alkyl or cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halo, alkyl, OR by- (OR)¹⁸)_n5OR¹⁷Substituted alkyl, haloalkyl, by- (OR)¹⁸)_n5OR¹⁷Substituted haloalkyl, cycloalkyl and-OR¹⁴Wherein each R is¹⁴And R¹⁷Independently is hydrogen, unsubstituted alkyl or haloalkyl, and each R¹⁸Independently an alkylene group.

24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ⁴is-OR¹²And R is¹²Is heterocycloalkyl-alkyl.

25. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁴Is substituted by one or more-OC (O) R²²A substituted alkyl group; wherein R is²²is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃。

26. The compound of claim 25, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is²²is-R²³N(R²⁴)₂。

27. The compound of claim 25, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is²²Is- (CH)₂CH₂-O-)_n8CH₃。

28. The compound of any one of claims 1 to 6 or 11 to 27, selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

29. A compound according to any one of claims 1 to 27, the compound being selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

30. The compound of any one of claims 1 to 6 or 11 to 27, selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

32. A method of inhibiting Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting the SREBP or SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to claim 31.

33. A method of inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to claim 31.

34. The method of claim 32 or 33, wherein the SREBP is SREBP-1.

35. The method of claim 34, wherein the SREBP-1 is SREBP-1 a.

36. The method of claim 34, wherein the SREBP-1 is SREBP-1 c.

37. The method of claim 32 or 33, wherein the SREBP is SREBP-2.

38. The method of any one of claims 32 to 37, wherein SREBP is inhibited in a subject in need thereof.

39. The method of any one of claims 32 to 38, wherein SCAP is inhibited in a subject in need thereof.

40. The method of any one of claims 32 to 39, wherein following contacting the SREBP or SCAP with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition, expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

41. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to claim 31.

42. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP), the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to claim 31.

43. The method of claim 41 or 42, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy, or dyslipidemia.

44. The method of claim 43, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

45. The method of claim 43, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.

46. The method of claim 41 or 42, wherein the disorder is a hyperproliferative disorder.

47. The method of claim 46, wherein the hyperproliferative disorder is cancer.

48. The method of claim 47, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placental cancer, brain cancer, renal cancer, lung cancer, or bone cancer.

49. The method of claim 41 or 42, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

50. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in the inhibition of Sterol Regulatory Element Binding Protein (SREBP).

51. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

52. The compound for use according to claim 50 or 51, wherein the SREBP is SREBP-1.

53. The compound for use according to claim 52, wherein the SREBP-1 is SREBP-1 a.

54. The compound for use according to claim 53, wherein the SREBP-1 is SREBP-1 c.

55. The compound for use according to claim 50 or 51, wherein the SREBP is SREBP-2.

56. The compound for use according to any one of claims 50 to 55, wherein SREBP is inhibited in a subject in need thereof.

57. The compound for use according to any one of claims 50 to 56, wherein SCAP is inhibited in a subject in need thereof.

58. The compound for use according to any one of claims 50 to 57, wherein following contacting the SREBP or SCAP with the compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

59. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof.

60. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP).

61. The compound for use according to claim 59 or 60, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy or dyslipidemia.

62. The compound for use according to claim 61, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

63. The compound for use according to claim 61, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis or liver inflammation or a combination thereof.

64. The compound for use according to claim 59 or 60, wherein the disorder is a hyperproliferative disorder.

65. The compound for use according to claim 64, wherein the hyperproliferative disorder is cancer.

66. The compound for use according to claim 65, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematological cancer, placental cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.

67. The compound for use according to claim 59 or 60, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

68. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting Sterol Regulatory Element Binding Protein (SREBP).

69. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

70. The use according to claim 68 or 69, wherein the SREBP is SREBP-1.

71. The use of claim 70, wherein the SREBP-1 is SREBP-1 a.

72. The use of claim 70, wherein the SREBP-1 is SREBP-1 c.

73. The use according to claim 68 or 69, wherein the SREBP is SREBP-2.

74. The use of any one of claims 68-73, wherein SREBP is inhibited in a subject in need thereof.

75. The use of any one of claims 68-74, wherein SCAP is inhibited in a subject in need thereof.

76. The use of any one of claims 68-75, wherein following contacting the SREBP or SCAP with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

77. Use of a compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the manufacture of a medicament for treating a disorder in a subject in need thereof.

78. Use of a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP).

79. The use according to claim 77 or 78, wherein the condition is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy or dyslipidemia.

80. The use of claim 79, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

81. The use of claim 79, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.

82. The use of claim 77 or 78, wherein the disorder is a hyperproliferative disorder.

83. The use of claim 82, wherein the hyperproliferative disorder is cancer.

84. The use of claim 83, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placental cancer, brain cancer, renal cancer, lung cancer, or bone cancer.

85. The use of claim 77 or 78, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

Technical Field

The present disclosure relates to compounds comprising a tricyclic core, their use for inhibiting a component of the Sterol Regulatory Element Binding Protein (SREBP) pathway, such as SREBP or SREBP Cleavage Activator Protein (SCAP), and their use in therapeutic methods for treating conditions and disorders.

Background

SREBP is a membrane-bound transcription factor that regulates the biosynthesis of cholesterol, fatty acids and triglycerides and lipid uptake. Fatty acids and lipids are a source of energy and important components of many biological structures, such as the lipid membranes of cells. Cholesterol is an important component of biological processes and structures. In mammals, there are three known isoforms of SREBP: SREBP-1a, SREBP-1c and SREBP-2. SREBP-1a controls a wide range of target genes involved in the production of fatty acids, triglycerides, phospholipids and cholesterol. SREBP-1c primarily activates genes that control fatty acid and triglyceride synthesis. SREBP-2 activates genes involved in the synthesis of regulators of cholesterol metabolism, as demonstrated in mouse, human and Drosophila studies. The activity of SREBP is regulated by SREBP Cleavage Activator Proteins (SCAPs) which transport SREBP from the endoplasmic reticulum to the Golgi apparatus (Golgi apparatus) where it is proteolytically cleaved, releasing the transcription factor domain.

The pathways regulated by SREBP and SCAP are associated with metabolic disorders such as hypertension, dyslipidemia, obesity, type 2 diabetes, insulin resistance, fatty liver and non-alcoholic steatohepatitis (NASH). For example, NASH is liver inflammation and hepatocyte ballooning due to fat accumulation in the liver, which can lead to liver damage, such as cirrhosis. NASH may also be associated with other metabolic disorders, such as insulin resistance and metabolic syndrome.

The metabolism of fatty acids, cholesterol and triglycerides may also be associated with hyperproliferative disorders such as cancer. One characteristic of oncogenic transformation of cancer cells is the transition of metabolism from catabolic to anabolic processes. Many cancers require the synthesis of fatty acids and other lipids (such as cholesterol) as well as steroids (such as androgens). Thus, components of the SREBP pathway may play a role in hyperproliferative disorders (such as prostate cancer). SREBP-1c is the major transcriptional regulator of fatty acid biosynthesis, and expression of this transcription factor can be stimulated by androgens and epidermal growth factors in prostate cancer cells. Overexpression of SREBP-1c may drive the tumorigenicity and invasiveness of prostate cancer cells. In addition to regulating androgen synthesis, SREBP-2 itself is also androgen regulated in a direct feedback loop for androgen production. However, cholesterol homeostasis of prostate cancer cells is deregulated, leading to increased cholesterol accumulation and proliferation. This increase in cholesterol levels has been shown to be driven by modulation of increased SREBP-2 activity. SREBP-2 expression increases during disease progression and is significantly higher after castration than before.

Components that modulate SREBP pathways (e.g., SCAP or SREBP) are important therapeutic approaches for treating conditions such as metabolic diseases and cancer. Thus, there is a need for compounds that are capable of inhibiting components of the SREBP pathway (e.g., SREBP and SCAP).

Disclosure of Invention

In some aspects, provided herein is a compound of formula (II):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

each R²Independently of each other Selected from the group consisting of: halo, cyano, alkyl, cycloalkyl-alkyl, -OR¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, Heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴、-C(O)R¹⁴and-OC (O) R²²，

R²²independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃，

Wherein each R²³Is (C)₁-C₆) An alkylene group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8;

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R ¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

In some aspects, provided herein is a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl-alkyl, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and isEach n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR ¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclic or heterocyclic group formed being independently unsubstituted or substituted by one or more substituentsAnd (ii) said one or more substituents are independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴，

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

In some aspects, the compound has formula (I-A):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as defined for formula (I).

In certain aspects, the compound has the formula (I-A-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as defined for formula (I).

In other aspects, the compound has formula (I-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R^6bN1 and n2 are as defined for formula (I).

In certain aspects, the compound has the formula (I-B-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ¹、R²、R³、R⁴、R⁵、R^6bN1 and n2 are as defined for formula (I).

In some aspects, the compound has formula (II-a):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as defined for formula (II).

In certain aspects, the compound has the formula (II-A-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as defined for formula (II).

In other aspects, the compound has formula (II-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R^6bN1 and n2 are as defined for formula (II).

In certain aspects, the compound has the formula (II-B-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹、R²、R³、R⁴、R⁵、R^6bN1 and n2 are as defined for formula (I).

At one endIn some aspects, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸、-NR⁷(SO)₂R⁹or-NR⁸R⁹. In certain aspects, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸or-NR⁸R⁹. In a further aspect, R¹is-NR⁷C(O)NR⁸R⁹or-NR⁷S(O)₂NR⁸R⁹. In some aspects, R¹is-NR⁷C(O)OR⁹or-S (O)₂R⁹。

In some aspects, n1 is 0 or 1. In certain aspects, each R²Independently is halo, alkyl OR-OR ¹¹Wherein each R is¹¹Independently hydrogen, unsubstituted alkyl or haloalkyl. In some aspects, R³And R^6aOr R^6bAre all hydrogen.

In a further aspect, provided herein is a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

In still other aspects, provided herein is a method of inhibiting Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting SREBP or SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition as described herein. In some aspects, provided herein is a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in inhibiting Sterol Regulatory Element Binding Protein (SREBP). In still a further aspect, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for the inhibition of Sterol Regulatory Element Binding Protein (SREBP).

In certain aspects, provided herein is a method of inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition described herein. In some aspects, provided herein is a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP). In some aspects, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting the proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

In yet another aspect, provided herein is a method of treating a disorder in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition described herein. In some aspects, provided herein is a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof. In other aspects, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof.

In yet other aspects, provided herein is a method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP), the method comprising administering to a subject in need thereof an effective amount of a compound as described herein or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof or a pharmaceutical composition as described herein. In some aspects, provided herein is a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof. In other aspects, provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for the treatment of a disorder in a subject in need thereof.

In some aspects of the methods, compounds for use, or uses provided herein, the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy, or dyslipidemia. In some embodiments, the liver disease is non-alcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof. In other embodiments, the disorder is a hyperproliferative disorder, such as cancer, for example, breast, liver, ovarian, pancreatic, or prostate cancer.

In some aspects of the methods, compounds for use, or uses provided herein, the disorder is a hyperproliferative disorder, such as cancer, e.g., soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placental cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.

Detailed Description

The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that this description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

I. Compound (I)

In some aspects, provided herein is a compound of formula (II):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

each R²Independently selected from the group consisting of: halo, cyano, alkyl, cycloalkyl-alkyl, -OR ¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴、-C(O)R¹⁴and-OC (O) R²²，

Wherein each alkyl, cycloalkyl-alkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, -C (O) OR ¹⁷、-C(O)NR¹⁷R¹⁷、-NR¹⁷C(O)R¹⁷、-NR¹⁷C(O)NR¹⁷R¹⁷、-NR¹⁷R¹⁷、-S(O)₂NR¹⁷R¹⁷、-NR¹⁷S(O)₂R¹⁷、-S(O)_n4R¹⁷、-C(O)R¹⁷And- (OR)¹⁸)_n5OR¹⁷Wherein each R is¹⁷Independently hydrogen, alkyl or haloalkyl; each n4 is independently 0, 1 or 2; each n5 is independently an integer from 0 to 5; and each R¹⁸Independently is alkylene or haloalkylene;

R²²independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃，

Wherein each R²³Is (C)₁-C₆) An alkylene group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8;

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰Can be combined with the structureThe attached nitrogen atoms together form a heterocycloalkyl group; two R¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

Each R¹²And R¹³Independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently is alkylene or haloalkylene;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

In some embodiments, provided herein is a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR ^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl-alkyl, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo;

and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

each R²Is independently selected fromA group consisting of: halo, cyano, alkyl, cycloalkyl-alkyl, -OR¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR ¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycleAlkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴，

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and it isEach of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

In some embodiments, the compound of formula (I) is a compound of formula (I-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X, Y, R¹、R²、R³、R⁴、R⁵N1 and n2 are as described above for formula (I).

In some embodiments, the compound of formula (II) is a compound of formula (II-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X, Y, R¹、R²、R³、R⁴、R⁵N1 and n2 are as described above for formula (II).

In some embodiments of the compounds of formula (I), X is S and Y is CR⁶And the compound of formula (I) is a compound of formula (I-A):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-NR⁷S(O)₂R⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹or-NR⁸R⁹(ii) a And R is²、R³、R⁴、R⁵、R^6aN1 and n2 are as described above for formula (I).

In some embodiments of the compounds of formula (II), X is S and Y is CR⁶And the compound of formula (I) is a compound of formula (II-A):

In certain embodiments, the compound of formula (I) or formula (I-A) is a compound of formula (I-A-I):

In certain embodiments, the compound of formula (II) or formula (II-A) is a compound of formula (I-A-I):

In still further embodiments, the compound of formula (I), formula (I-A), or formula (I-A-I) is a compound of formula (I-A-I-1):

In still further embodiments, the compound of formula (II), formula (II-A), or formula (II-A-I) is a compound of formula (I-IA-I-1):

In other embodiments of the compounds of formula (I), Y is S and X is CR^6bAnd the compound of formula (I) is a compound of formula (I-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹or-NR⁸R⁹(ii) a And R is²、R³、R⁴、R⁵、R^6aN1 and n2 are as described above for formula (I).

In other embodiments of the compounds of formula (II), Y is S and X is CR^6bAnd the compound of formula (II) is a compound of formula (II-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹Or-NR⁸R⁹(ii) a And R is²、R³、R⁴、R⁵、R^6aN1 and n2 are as described above for formula (II).

In certain embodiments, the compound of formula (I) or formula (I-B) is a compound of formula (I-B-I):

In certain embodiments, the compound of formula (II) or formula (II-B) is a compound of formula (II-B-i):

In still further embodiments, the compound of formula (I), formula (I-B), or formula (I-B-I) is a compound of formula (I-B-I-1):

In still further embodiments, the compound of formula (II), formula (II-B), or formula (II-B-i) is a compound of formula (II-B-i-1):

As used herein, "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. Alkyl groups may be used alone or as part of another group (e.g., cycloalkyl-alkyl). In some embodiments, as herein describedThe alkyl groups used have from 1 to 50 carbon atoms ((C) _1-50) Alkyl group), 1 to 20 carbon atoms ((C)_1-20) Alkyl group), 1 to 12 carbon atoms ((C)_1-12) Alkyl group), 1 to 10 carbon atoms ((C)_1-10) Alkyl group), 1 to 8 carbon atoms ((C)_1-8) Alkyl group), 1 to 6 carbon atoms ((C)_1-6) Alkyl) or 1 to 4 carbon atoms ((C)_1-4) Alkyl groups). Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a particular carbon number is named, all geometric isomers having that carbon number may be encompassed. Thus, for example, "butyl" may comprise n-butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl" may comprise n-propyl and isopropyl.

As used herein, "alkylene" refers to a divalent group derived from a branched or unbranched alkyl group, such as, but not limited to, -CH₂CH₂CH₂CH₂-. In some embodiments, an alkylene group, as used herein, has from 1 to 50 carbon atoms ((C)_1-50) Alkylene group), 1 to 20 carbon atoms ((C)_1-20) Alkylene group), 1 to 12 carbon atoms ((C)_1-12) Alkylene group), 1 to 10 carbon atoms ((C)_1-10) Alkylene group), 1 to 8 carbon atoms ((C)_1-8) Alkylene), 1 to 6 carbon atoms ((C) _1-6) Alkylene) or 1 to 4 carbon atoms ((C)_1-4) Alkylene).

As used herein, "alkenyl" refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond. Alkenyl groups may be used alone or as part of another group (e.g., cycloalkyl-alkenyl). In some embodiments, alkenyl groups as used herein have from 1 to 50 carbon atoms ((C)_1-50) Alkenyl), 1 to 20 carbon atoms ((C)_1-20) Alkenyl), 1 to 12 carbon atoms ((C)_1-12) Alkenyl), 1 to 10 carbon atoms ((C)_1-10) Alkenyl), 1 to 8 carbon atoms ((C)_1-8) Alkenyl), 1 to 6 carbon atoms ((C)_1-6) Alkenyl) or 1 to 4 carbon atoms ((C)_1-4) Alkenyl). Alkenyl radicals, where valency permitsThere may be one, two, three, four, five or more carbon-carbon double bonds. When an alkenyl residue having a particular carbon number is named, all geometric isomers having that carbon number may be encompassed.

"carbocyclyl" refers to a monocyclic or polycyclic saturated or unsaturated hydrocarbon. Carbocyclyl groups include cycloalkyl, aryl, and non-aromatic unsaturated carbocyclic groups such as cycloalkenyl. In some embodiments, the carbocyclyl group has 3 to 50 carbon atoms ((C)_3-50) Carbocyclyl), 3 to 20 carbon atoms ((C)_3-20) Carbocyclyl), 3 to 12 carbon atoms ((C) _3-12) Carbocyclyl), 3 to 10 carbon atoms ((C)_3-10) Carbocyclyl), 3 to 8 carbon atoms ((C)_3-8) Carbocyclyl), 3 to 6 carbon atoms ((C)_3-6) Carbocyclyl) or 3 to 5 carbon atoms ((C)_3-4) Carbocyclyl).

As used herein, "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon. In some embodiments, cycloalkyl groups as used herein have from 3 to 50 carbon atoms ((C)_3-50) Cycloalkyl group), 3 to 20 carbon atoms ((C)_3-20) Cycloalkyl group), 3 to 12 carbon atoms ((C)_3-12) Cycloalkyl group), 3 to 10 carbon atoms ((C)_3-10) Cycloalkyl), 3 to 8 carbon atoms ((C)_3-8) Cycloalkyl), 3 to 6 carbon atoms ((C)_3-6) Cycloalkyl) or 3 to 5 carbon atoms ((C)_3-4) Cycloalkyl groups). Cycloalkyl groups include monocyclic and polycyclic groups such as fused bicyclic, bridged, and spiro rings. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-cyclopentadienyl, octahydro-1H-indene, decahydronaphthalene, cubane, bicyclo [3.1.0 ]]Hexane and bicyclo [1.1.1]Pentane.

As used herein, "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon containing at least one carbon-carbon double bond. In some embodiments, cycloalkenyl groups have 3 to 50 carbon atoms ((C)_3-50) Cycloalkenyl group), 3 to 20 carbon atoms ((C)_3-20) Cycloalkenyl group), 3 to 12 carbon atoms ((C) _3-12) Cycloalkenyl group), 3 to 10 carbon atoms ((C)_3-10) Cycloalkenyl group), 3 to 8 carbon atoms ((C)_3-8) Cycloalkenyl group), 3 to 6 carbon atoms ((C)_3-6) Cycloalkenyl) or 3 to 5 carbon atoms ((C)_3-4) Cycloalkenyl group). Cycloalkenyl groups comprise monocyclic and polycyclic groups and may have one, two, three, four, five or more carbon-carbon double bonds, where valency permits.

"cycloalkyl-alkyl" refers to a cycloalkyl group (as defined above) attached to an alkyl group (as defined above) wherein the alkyl group is attached to another moiety (e.g., the core structure of the molecule). Substituted cycloalkyl-alkyl groups may contain one or more additional linkages to substituents at any point of the cycloalkyl or alkyl group, as valency permits. Cycloalkyl-alkyl groups may include any combination of cycloalkyl and alkyl groups. In some embodiments, the cycloalkyl group has 3 to 50 carbon atoms ((C)_3-50) Cycloalkyl-alkyl), 3 to 20 carbon atoms ((C)_3-20) Cycloalkyl-alkyl), 3 to 12 carbon atoms ((C)_3-12) Cycloalkyl-alkyl), 3 to 10 carbon atoms ((C)_3-10) Cycloalkyl-alkyl), 3 to 8 carbon atoms ((C)_3-8) Cycloalkyl-alkyl), 3 to 6 carbon atoms ((C)_3-6) Cycloalkyl-alkyl) or 3 to 5 carbon atoms ((C)_3-4) Cycloalkyl-alkyl). In some embodiments, the alkyl group has 1 to 50 carbon atoms (cycloalkyl- (C) _1-50) Alkyl), 1 to 20 carbon atoms (cycloalkyl- (C)_1-20) Alkyl), 1 to 12 carbon atoms (cycloalkyl- (C)_1-12) Alkyl), 1 to 10 carbon atoms (cycloalkyl- (C)_1-10) Alkyl), 1 to 8 carbon atoms (cycloalkyl- (C)_1-8) Alkyl), 1 to 6 carbon atoms (cycloalkyl- (C)_1-6) Alkyl) or 1 to 4 carbon atoms (cycloalkyl- (C)_1-4) Alkyl groups). In certain embodiments, cycloalkyl-alkyl is (C)_3-20) Cycloalkyl (C)_1-20) Alkyl, (C)_3-12) Cycloalkyl (C)_1-12) Alkyl, (C)_3-10) Cycloalkyl (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl (C)_1-8) Alkyl, (C)_3-10) Cycloalkyl (C)_1-6) Alkyl, (C)_3-6) Cycloalkyl (C)_1-8) Alkyl, (C)_3-6) Cycloalkyl (C)_1-6) Alkyl or (C)_3-6) Cycloalkyl (C)_1-4) An alkyl group.

As used herein, "heterocycloalkyl" refers to a saturated hydrocarbon containing carbon and at least one heteroatom selected from the group consisting of O, N and SAnd monocyclic or polycyclic. Heterocycloalkyl groups can include 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocycloalkyl group). The heterocycloalkyl group can comprise a group comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O and S. Each ring S atom (when present) may independently be unoxidized sulfur (e.g., -S-) or oxidized sulfur, such as-S (O) -or-S (O) ₂-. In certain examples, heterocycloalkyl has 2 to 8 ring carbon atoms and 1 to 3 ring heteroatoms independently selected from N, O and S. In some embodiments, the heterocycloalkyl group is attached through a cyclic carbon atom, where the point of attachment of the heterocycloalkyl group to another group is a ring carbon atom of the heterocycloalkyl group. Heterocycloalkyl groups include polycyclic ring systems such as bridged, fused, and spiro rings that include at least one heteroatom in at least one of the rings. Examples of heterocycloalkyl include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl (azepinyl), oxapinyl (oxepinyl), diazepinyl, and tropyl.

As used herein, "heterocycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring containing carbon, at least one heteroatom selected from the group consisting of O, N and S, and at least one double bond. Each ring S atom, if present, may independently be a sulfur oxide, e.g., -S (O) -or-S (O) ₂-. Heterocycloalkenyl groups can include 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocycloalkenyl group). The heterocycloalkenyl group may contain 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatomWherein each heteroatom is independently selected from the group consisting of N, O and S. In certain embodiments, heterocycloalkenyl has 2 to 8 ring carbon atoms and 1 to 3 ring heteroatoms independently selected from N, O and S. In some embodiments, the heterocycloalkenyl is attached through a cyclic carbon atom, wherein the point of attachment of the heterocycloalkenyl to another group is a ring carbon atom of the heterocycloalkenyl. Where permitted by valence, the heterocycloalkenyl can have one, two, three, four, five, or more double bonds, and where permitted by valence, each double bond can be independently located between two ring carbon atoms, two ring heteroatoms, or between a ring carbon atom and a ring heteroatom.

"Heterocyclyl" means a saturated or unsaturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N and S. Each ring S atom, if present, may independently be a sulfur oxide, e.g., -S (O) -or-S (O) ₂-. Heterocyclyl includes heterocycloalkyl, heteroaryl and non-aromatic unsaturated heterocyclic groups such as heterocycloalkenyl. The heterocyclyl group may include 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more ring atoms (e.g., is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclyl group) and may include groups including 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O and S. In some embodiments, a heterocyclyl group is attached through a cyclic carbon atom, where the point of attachment of the heterocyclyl group to another group is a ring carbon atom of the heterocyclyl group.

"heterocycloalkyl-alkyl" refers to a heterocycloalkyl group (as defined above) attached to an alkyl group (as defined above) wherein the alkyl group is attached to another moiety (e.g., the core structure of the molecule). The alkyl group may be attached to the heterocycloalkyl group through a cyclic carbon atom of the heterocycloalkyl group or through a cyclic heteroatom of the heterocycloalkyl group (e.g., through a ring N atom). Substituted heterocycloalkyl-alkyl groups may contain one or more additional linkages to substituents at any point of the heterocycloalkyl or alkyl group, as valency permits. Heterocycloalkyl-alkyl groups may include heterocycloalkanes Any combination of alkyl and aryl groups. In some embodiments, heterocycloalkyl includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms. The heterocycloalkyl group can comprise a group comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O and S. In some embodiments, the alkyl group has 1 to 50 carbon atoms (heterocycloalkyl- (C)_1-50) Alkyl), 1 to 20 carbon atoms (heterocycloalkyl- (C)_1-20) Alkyl), 1 to 12 carbon atoms (heterocycloalkyl- (C)_1-12) Alkyl), 1 to 10 carbon atoms (heterocycloalkyl- (C)_1-10) Alkyl), 1 to 8 carbon atoms (heterocycloalkyl- (C)_1-8) Alkyl), 1 to 6 carbon atoms (heterocycloalkyl (C)_1-6) Alkyl) or 1 to 4 carbon atoms (heterocycloalkyl- (C)_1-4) Alkyl groups). In certain embodiments, heterocycloalkyl-alkyl is (3-20 membered) heterocycloalkyl (C)_1-20) Alkyl, (3-12 membered) heterocycloalkyl (C)_1-12) Alkyl, (3-12 membered) heterocycloalkyl (C)_1-10) Alkyl, (3-to 10-membered) heterocycloalkyl (C)_1-8) Alkyl, (3-to 10-membered) heterocycloalkyl (C)_1-6) Alkyl, (3-6 membered) heterocycloalkyl (C)_1-8) Alkyl, (3-6 membered) heterocycloalkyl (C)_1-6) Alkyl or (3-to 6-membered) heterocycloalkyl (C) _1-4) An alkyl group.

As used herein, "aryl" refers to an aromatic hydrocarbon monocyclic or polycyclic group. Aryl groups can include groups having a single aromatic ring (e.g., phenyl) and multiple fused aromatic rings (e.g., naphthyl, anthracenyl). In some embodiments, aryl as used herein has 6 to 14 cyclic carbon atoms ((C)_6-14) Aryl) or 6 to 10 cyclic carbon atoms ((C)_6-10) Aryl).

"aryl-alkyl" refers to an aryl group (as defined above) attached to an alkyl group (as defined above) wherein the alkyl group is attached to another moiety (e.g., the core structure of the molecule). Substituted aryl-alkyl groups may contain one or more additional linkages to substituents at any point of the aryl or alkyl group, as valency permits. Aryl-alkyl groups may include any combination of aryl and alkyl groups. In some implementationsIn examples, the aryl group has 6 to 14 cyclic carbon atoms ((C)_6-14) Aryl-alkyl) or 6 to 10 cyclic carbon atoms ((C)_6-10) Aryl-alkyl). In some embodiments, the alkyl group has 1 to 50 carbon atoms (aryl- (C)_1-50) Alkyl), 1 to 20 carbon atoms (aryl- (C)_1-20) Alkyl), 1 to 12 carbon atoms (aryl- (C)_1-12) Alkyl group), 1 to 10 carbon atoms (aryl group- (C)_1-10) Alkyl), 1 to 8 carbon atoms (aryl- (C) _1-8) Alkyl), 1 to 6 carbon atoms (aryl- (C)_1-6) Alkyl) or 1 to 4 carbon atoms (aryl- (C)_1-4) Alkyl groups). In certain embodiments, aryl-alkyl is (C)_6-14) Aryl radical (C)_1-20) Alkyl, (C)_6-14) Aryl radical (C)_1-12) Alkyl, (C)_6-14) Aryl radical (C)_1-10) Alkyl, (C)_6-14) Aryl radical (C)_1-8) Alkyl, (C)_6-14) Aryl radical (C)_1-6) Alkyl, (C)_6-10) Aryl radical (C)_1-10) Alkyl, (C)_6-10) Aryl radical (C)_1-8) Alkyl or (C)_6-10) Aryl radical (C)_1-6) Alkyl or (C)_6-10) Aryl radical (C)_1-4) An alkyl group.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O and S (e.g., pyridine, pyrazine, furan, thiophene, quinoline). Each ring S atom, if present, may independently be unoxidized sulfur (e.g., -S-) or oxidized sulfur, such as-S (O) -or-S (O)₂-. Heteroaryl groups may comprise groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O and S. In certain examples, heteroaryl groups have from 3 to 8 ring carbon atoms and from 1 to 3 ring heteroatoms independently selected from N, O and S. Heteroaryl groups can include 5, 6, 7, 8, 9, 10, 11, 12, or more cyclic atoms (e.g., are 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl groups) wherein the cyclic atoms are present in one or more rings. Heteroaryl groups may include, for example, 1 to 14 cyclic carbon atoms ((C)_1-14) Heteroaryl), 1 to 10 cyclic carbon atoms ((C)_1-10) Heteroaryl), 1 to 6 cyclic carbon atoms ((C)_1-6) Heteroaryl), 1 to 5 cyclic carbon atoms ((C)_1-5) Heteroaryl) or 2 to 5 cyclic carbon atoms ((C)_2-5) Heteroaryl). In some embodiments, the heteroaryl group is attached through a cyclic carbon atom, wherein the point of attachment of the heteroaryl group to another group is a ring carbon atom of the heteroaryl group. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, furanyl, and pyrazolyl.

"heteroaryl-alkyl" refers to a heteroaryl group (as defined above) attached to an alkyl group (as defined above) wherein the alkyl group is attached to another moiety (e.g., the core structure of the molecule). Substituted heteroaryl-alkyl groups may contain one or more additional linkages to substituents at any point of the heteroaryl or alkyl group, as valency permits. The alkyl group may be attached to the heteroaryl group through a cyclic carbon atom of the heteroaryl group or through a cyclic heteroatom of the heteroaryl group. Heteroaryl-alkyl groups may include any combination of heteroaryl and alkyl groups. Heteroaryl groups can have 3 to 8 ring carbon atoms and 1 to 3 ring heteroatoms independently selected from N, O and S. Heteroaryl groups can include 5, 6, 7, 8, 9, 10, 11, 12, or more cyclic atoms (e.g., are 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl groups) wherein the cyclic atoms are present in one or more rings. In some embodiments, the alkyl group has 1 to 50 carbon atoms (heteroaryl- (C) _1-50) Alkyl), 1 to 20 carbon atoms (heteroaryl- (C)_1-20) Alkyl), 1 to 12 carbon atoms (heteroaryl- (C)_1-12) Alkyl), 1 to 10 carbon atoms (heteroaryl- (C)_1-10) Alkyl), 1 to 8 carbon atoms (heteroaryl- (C)_1-8) Alkyl), 1 to 6 carbon atoms (heteroaryl- (C)_1-6) Alkyl) or 1 to 4 carbon atoms (heteroaryl- (C)_1-4) Alkyl groups). In certain embodiments, heteroaryl-alkyl is (C)_1-14) Heteroaryl (C)_1-20) Alkyl, (C)_1-10) Heteroaryl (C)_1-12) Alkyl, (C)_1-6) Heteroaryl (C)_1-10) Alkyl, (C)_1-5) Heteroaryl (C)_1-8) Alkyl group (a)C_1-5) Heteroaryl (C)_1-6) Alkyl, (C)_1-5) Heteroaryl (C)_1-8) Alkyl, (C)_1-5) Heteroaryl (C)_1-6) Alkyl or (C)_1-5) Heteroaryl (C)_1-4) An alkyl group.

It will be understood that when a range of values is recited, each value and subrange within the range is intended to be encompassed. For example, "(C)_1-6) Alkyl "(which may also be referred to as C1-C6 alkyl, C)_1-C₆Alkyl or C1-6 alkyl) is intended to encompass C₁、C₂、C₃、C₄、C₅、C₆、C_1-6、C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-5、C_2-4、C_2-3、C_3-6、C_3-5、C_3-4、C_4-6、C_4-5And C_5-6An alkyl group.

As used herein, "hydroxy" refers to the group-OH.

As used herein, "halo" refers to a fluoro, chloro, bromo, or iodo group.

"cyano" means the group-CN.

As used herein, "oxo" refers to a group ═ O.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), the compound is a solvate. In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), the solvate is a hydrate.

In some embodiments, pharmaceutically acceptable salts of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1) are provided.

"pharmaceutically acceptable" includes materials that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes materials that are acceptable for veterinary use as well as human pharmaceutical use. For example, provided herein is a pharmaceutical composition comprising a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

"pharmaceutically acceptable salts" include salts that are generally safe, non-toxic, and not biologically or otherwise undesirable, and include salts that are acceptable for veterinary use as well as human pharmaceutical use. Such salts may comprise acid addition salts and base addition salts. Acid addition salts may be formed from inorganic or organic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, Naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid or undecylenic acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases may include, but are not limited to, primary, secondary or tertiary amine salts; substituted amines, including naturally occurring substituted amines; a cyclic amine; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, danitol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine (procaine), hydrabamine (hydrabamine), choline, betaine, benzphetamine (benethamine), benzathine (benzathine), ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, or N-ethylpiperidine.

In some embodiments, isotopes of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1) are provided.

Unless otherwise indicated, the structures depicted herein, such as compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or pharmaceutically acceptable salts, solvates, tautomers, or isomers thereof, are also intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, e.g., isotopically-labeled, compounds of formula (I), (I-I), (I-A-I), (I-A-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or pharmaceutically acceptable salts, solvates, tautomers, or isomers thereof, wherein a fraction of one or more atoms is replaced by an isotope of the same element. Compounds that can be incorporated into the compounds of the present invention Exemplary isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵O、¹⁷O、³⁵S、¹⁸F、³⁶And (4) Cl. Certain isotopically-labeled compounds (for example,³h and¹⁴C) can be used for compound or substrate tissue distribution research. In some embodiments, such as deuterium (b) ((iii))²H) The incorporation of heavier isotopes may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

The compounds disclosed herein, such as compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or pharmaceutically acceptable salts, solvates, tautomers, or isotopes thereof, may contain one or more asymmetric centers and, thus, may produce one or more isomers.

In some embodiments, tautomers of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I), (II-A-1), (II-B-I), or (II-B-I-1) are provided.

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, n2 is 0. In some embodiments, R ³Is hydrogen. In certain embodiments, R^6aOr R^6bIs hydrogen. In some embodiments, n1 is 0 or 1. In some embodiments, R²Is a halo group.

R⁷、R⁸and R⁹Independently selected from the group consisting of: hydrogen, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl, (C)_6-10) Aryl, aryl- (C)_1-10) Alkyl, heteroaryl and heteroaryl (C)_1-10) An alkyl group; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, ( _1-10) Alkyl, (C)_2-10) Alkenyl, (C)_2-10) Alkynyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl, aryl- (C)_1-10) Alkyl, heteroaryl- (C)_1-10) Alkyl, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Each of which (C)_1-10) Alkyl, (C)_2-10) Alkenyl, (C)_2-10) Alkynyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl, aryl- (C)_1-10) Alkyl, heteroaryl and heteroaryl- (C)_1-10) Alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

each R²Independently selected from the group consisting of: halo, cyano, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, -OR¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹And-C(O)R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

R⁴Is (C)_1-10) Alkyl, (C)_2-10) Alkenyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, (C)_3-10) Cycloalkenyl, heterocycloalkyl- (C)_1-10) Alkyl, heterocycloalkenyl, -OR¹²、-C(O)NR¹²R¹²、-NR¹²C(O)NR¹²R¹²、-S(O)₂NR¹²R¹²、-S(O)_m3R¹²or-C (O) R¹²；

n2 is 0, 1, 2 or 3;

each R⁵Independently is halogeno, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atom to which they are attached form (C)_4-10) Carbocyclyl or heterocyclyl;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴，

Each of which (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl and heterocycloalkyl are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, -C (O) OR ¹⁷、-C(O)NR¹⁷R¹⁷、-NR¹⁷C(O)R¹⁷、-NR¹⁷C(O)NR¹⁷R¹⁷、-NR¹⁷R¹⁷、-S(O)₂NR¹⁷R¹⁷、-NR¹⁷S(O)₂R¹⁷、-S(O)_n4R¹⁷、-C(O)R¹⁷And- (OR)¹⁸)_n5OR¹⁷Wherein each R is¹⁷Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group; each n4 is independently 0, 1 or 2; each n5 is independently an integer from 0 to 5; and each R¹⁸Independently is (C)_1-10) Alkylene or (C)_1-10) A haloalkylene group;

R³、R^6aand R^6bIndependently selected from the group consisting of: hydrogen, halogeno, cyano, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl and-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R¹²And R¹³Independently hydrogen, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C) _1-10) Alkyl or heterocycloalkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently is (C)_1-10) Alkylene or (C)_1-10) A haloalkylene group;

each R²¹Independently is (C)_1-10) Alkylene or (C)_1-10) A haloalkylene group;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

In some embodiments of the genus of the preceding paragraph, n2 is 0 or 1. In some embodiments, n2 is 0. In some embodiments, R³Is hydrogen. At a certain pointIn some embodiments, R^6aOr R^6bIs hydrogen. In some embodiments, n1 is 0 or 1. In some embodiments, R²Is a halo group.

In some embodiments of compounds of formula (II), (II-i), (II-A-i-1), (II-B-i), or (II-B-i-1), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof:

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR ¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R ⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴、-C(O)R¹⁴and-OC (O) R²²，

R²²independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃，

Wherein each R²³Is (C)₁-C₆) An alkyl group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

In some embodiments of the genus of the preceding paragraph, n2 is 0 or 1. In some embodiments, n2 is 0. In some embodiments, R³Is hydrogen. In certain embodiments, R^6aOr R^6bIs hydrogen. In some embodiments, n1 is 0 or 1. In some embodiments, R²Is a halo group.

In certain embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof:

R⁷is hydrogen;

R⁸and R⁹Independently hydrogen, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl or heterocycloalkyl-, (C_1-10) An alkyl group; wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR ¹⁰A group of (a);

or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl and-OR¹⁰；

n1 is 0 or 1;

R²is a halo group;

R⁴is (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl or heterocycloalkyl- (C)_1-10) An alkyl group, a carboxyl group,

wherein R is⁴May be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl, -OR¹⁴and-C (O) OR¹⁴，

Wherein (C)_1-10) Alkyl and (C)_3-10) Cycloalkyl groups may be independently unsubstituted or substituted by one or more halo groups, -OH, -O (C)_1-10) Alkyl or-O (C)_1-10) Haloalkyl or any combination thereof;

or R⁴And R⁵(if present) together with the nitrogen atom to which it is attached form a 5-or 8-membered heterocyclyl, which heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, -OH, -O (C) _1-10) Alkyl and-O (C)_1-10) A haloalkyl group;

n2 is 0 or 1;

R³、R^6aand R^6bIndependently selected from the group consisting ofThe group consisting of: hydrogen, halogeno, (C)_1-10) Alkyl and (C)_1-10) A haloalkyl group;

each R¹⁰And R¹⁴Independently hydrogen, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, (C)_3-10) Cycloalkyl or (C)_3-10) A halocycloalkyl group.

In certain embodiments of compounds of formula (II), (II-i), (II-A-i-1), (II-B-i), or (II-B-i-1), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof:

R⁷is hydrogen;

R⁸and R⁹Independently hydrogen, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl or heterocycloalkyl- (C)_1-10) An alkyl group; wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰A group of (a);

n1 is 0 or 1;

R²is a halo group;

R⁴is (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl OR-OR¹²，

Wherein R is⁴May be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl, -OR¹⁴、-C(O)OR¹⁴and-OC (O) R²²,

n2 is 0 or 1;

R³、R^6aand R^6bIndependently selected from the group consisting of: hydrogen, halogeno, (C)_1-10) Alkyl and (C)_1-10) A haloalkyl group;

each R¹⁰And R¹⁴Independently hydrogen, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, (C)_3-10) Cycloalkyl or (C)_3-10) A halocycloalkyl group;

R¹²independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl,

Wherein each R¹²Independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: cyano, -OH, -OCH₃and-NH₂；

R²²Independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃，

Wherein each R²³Is (C)₁-C₆) An alkyl group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8.

In the formulae (I), (I-I), (I-A-I-1), (I-B-i) In some embodiments of the compounds of (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸or-NR⁸R⁹. In certain embodiments, R¹is-NR⁷C(O)NR⁸R⁹or-NR⁷S(O)₂NR⁸R⁹. In some embodiments, R¹is-NR⁷C(O)OR⁹or-S (O)₂R⁹。

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (II-I), (II-A-I), or (II-A-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-NR⁷S(O)₂R⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹or-NR⁸R⁹. In certain embodiments, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-NR⁷S(O)₂R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹or-NR⁷C(O)SR⁹. In still other embodiments, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-NR⁷S(O)₂R⁹or-S (O)₂R⁹. In certain embodiments, R ¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸、-NR⁷(SO)₂R⁹or-NR⁸R⁹。

In some embodiments of compounds of formula (I), (I-I), (I-B-I-1), (II-I), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-SR⁹、-S(O)R⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹、-NR⁷C(O)SR⁹or-NR⁸R⁹. In certain embodiments, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹、-S(O)₂R⁹、-NR⁷C(S)NR⁸R⁹or-NR⁷C(O)SR⁹. In still other embodiments, R¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁹or-S (O)₂R⁹。

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R⁹Is hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl; wherein alkyl, cycloalkyl-alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰and-C (O) R¹⁰. In some embodiments, R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl OR heterocycloalkyl-alkyl, and is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In certain embodiments, each R¹⁰Independently hydrogen, alkyl or haloalkyl. In still further embodiments, each R¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In still other embodiments，R⁹Is (C)_1-10) Alkyl, (C)_3-8) Cycloalkyl group, (C)_3-8) Cycloalkyl- (C)_1-10) Alkyl, (5-to 7-membered) heterocycloalkyl or (5-to 7-membered) heterocycloalkyl- (C)_1-10) An alkyl group, said group being unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R¹⁰Is hydrogen, alkyl or haloalkyl. In still other embodiments, R⁹Is (C)_1-10) Alkyl, unsubstituted or substituted by one or more halo groups, -OH, -O (C)_1-10) Alkyl or-O (C)_1-10) Haloalkyl substitution. In some embodiments, R⁹Is (C)_3-8) Cycloalkyl, unsubstituted or substituted by one or more halo, -OH, -O (C) _1-10) Alkyl or-O (C)_1-10) Haloalkyl substitution. In some embodiments, R⁹Is (C)_3-8) Cycloalkyl- (C)_1-10) Alkyl, unsubstituted or substituted by one or more halo groups, -OH, -O (C)_1-10) Alkyl or-O (C)_1-10) Haloalkyl substitution. In some embodiments, R⁹Is (5-to 7-membered) heterocycloalkyl which is unsubstituted or substituted by one or more halo groups, -OH, -O (C)_1-10) Alkyl or-O (C)_1-10) Haloalkyl substitution. In still other embodiments, R⁹Is (5-to 7-membered) heterocycloalkyl- (C)_1-10) Alkyl, unsubstituted or substituted by one or more halo groups, -OH, -O (C)_1-10) Alkyl or-O (C)_1-10) Haloalkyl substitution. In certain embodiments, R⁹Selected from the group consisting of: methyl, ethyl, propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentane-methyl, cyclopentane-ethyl, cyclohexane-methyl, cyclohexane-ethyl, pyrrolidinyl, pyrrolidine-ethyl, pyrrolidine-methyl, piperidinyl-methyl, or piperidinyl-ethyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo groups, one or more-OH, or any combination thereof.

In the formulae (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I) ) In some embodiments of the compounds of (II-A), (II-A-i-1), (II-B-i), or (II-B-i-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R is⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -C (O) NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-OR¹⁰、-NR¹⁰R¹⁰、-C(O)OR¹⁰and-C (O) R¹⁰. In some embodiments, the heterocycloalkyl group is a 4-to 8-membered heterocycloalkyl group. In certain embodiments, the heterocycloalkyl group is a 5-to 7-membered heterocycloalkyl group. In some embodiments, in addition to being connected to R⁸And R⁹The heterocycloalkyl group includes 0 to 3 heteroatoms selected from the group consisting of O, N and S in addition to one of the nitrogens of both. In other embodiments, other than being connected to R⁸And R⁹And in addition to N, heterocycloalkyl also includes 0, 1, or 2 heteroatoms selected from the group consisting of O, N and S. In some embodiments, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocycloalkyl group, except for attachment to R ⁸And R⁹Both, in addition to one N, heterocycloalkyl include 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S. In some embodiments, the heterocycloalkyl group is unsubstituted or substituted with one to three substituents selected from the group consisting of: halo, cyano, oxo, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl, -C (O) NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-OR¹⁰、-NR¹⁰R¹⁰、-C(O)OR¹⁰and-C (O) R¹⁰. In other embodiments, the heterocycloalkyl group is unsubstituted or substituted with one to three substituents,the one to three substituents are independently selected from the group consisting of halogen, oxo, and-OR¹⁰Group (d) of (a). In some embodiments, each R is¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group.

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1) (examples as described herein) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R is as described herein¹is-NR⁷C(O)NR⁸R⁹. In some embodiments, R⁷Is hydrogen, alkyl or haloalkyl. In certain embodiments, R ⁷Is hydrogen. In some embodiments, R⁸And R⁹Independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl; wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R⁸Is hydrogen. In certain embodiments, R⁹Is (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl or heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is a 5-or 6-membered heterocycloalkyl group. In other embodiments, R⁹Is 5-or 6-membered heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutane-ethyl, cyclopentane-methyl, cyclopentane-ethyl, cyclohexane-methyl, cyclohexane-ethyl, pyrrolidinyl, piperidinyl, pyrrolidine-methyl, pyrrolidine-ethyl, pyrrolidine-propyl, piperidine-methyl, piperidine-ethyl or piperidine-propyl. In other embodiments, R ⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group. For example, in some embodimentsIn, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycloalkyl group. In certain embodiments, R⁹Or by R⁸And R⁹Each of the heterocycloalkyl groups formed together is unsubstituted OR substituted with one to three substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In certain embodiments, each R¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R¹⁰is-OH. In certain embodiments, R¹The method comprises the following steps:

in other embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1) (such as the embodiments described herein) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R ¹is-NR⁷S(O)₂NR⁸R⁹. In some embodiments, R⁷Is hydrogen, alkyl or haloalkyl. In certain embodiments, R⁷Is hydrogen. In some embodiments, R⁸And R⁹Independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl; wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R⁸Is hydrogen. In certain embodiments, R⁹Is (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl or heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is a 5-or 6-membered heterocycloalkyl group. In other embodiments, R⁹Is 5-or 6-membered heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutane-ethyl, cyclopentane-methyl, cyclopentane-ethyl, cyclohexane-methyl, cyclohexane-ethyl, pyrrolidinyl, piperidinyl, pyrrolidine-methyl, pyrrolidine-ethyl, pyrrolidine-propyl, piperidine-methyl, piperidine-ethyl or piperidine-propyl. In other embodiments, R ⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group. For example, in some embodiments, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycloalkyl group. In certain embodiments, R⁹Or by R⁸And R⁹Each of the heterocycloalkyl groups formed together is unsubstituted OR substituted with one to three substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In certain embodiments, each R¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R¹⁰is-OH. In some embodiments, R⁷And R⁸Is hydrogen, and R⁹Is (C)_1-4) Alkyl or (C)_3-6) A cycloalkyl group. In some embodiments, R⁷And R⁸Is hydrogen, and R⁹Is cyclopropyl. In some embodiments, R⁷And R⁸Is hydrogen, and R⁹Is propyl, such as n-propyl or isopropyl. In certain embodiments, R¹The method comprises the following steps:

in the formulae (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II)In still further embodiments (such as the embodiments described herein) of the compounds of (i-B), (II-B-i), or (II-B-i-1), or pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof, R ¹is-NR⁸R⁹. In some embodiments, R⁸And R⁹Independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl; wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R⁸And R⁹Independently hydrogen, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, (C)_3-10) Cycloalkyl or (C)_3-10) A halocycloalkyl group. In some embodiments, R⁸And R⁹Both are hydrogen, and R¹is-NH₂. In still other embodiments, R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which may be unsubstituted or substituted. In some embodiments, the heterocycloalkyl group is a 5-to 7-membered heterocycloalkyl group. In certain embodiments, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocycloalkyl group, except for attachment to R⁸And R⁹Both of which, N, heterocycloalkyl further includes 0, 1, OR 2 heteroatoms selected from the group consisting of O, N and S, and wherein heterocycloalkyl is unsubstituted OR substituted with one to three substituents independently selected from halo, oxo, and-OR ¹⁰Group of (I) wherein each R¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In certain embodiments, R¹The method comprises the following steps:

in the compounds of formula (I), (I-I), (I-A-I-1), (II-I), (II-A-I) or (II-A-I-1) or the medicaments thereofIn still further embodiments of the pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers (such as the embodiments described herein), R¹is-NR⁷S(O)₂R⁹. In some embodiments, R⁷Is hydrogen, alkyl or haloalkyl. In certain embodiments, R⁷Is hydrogen. In certain embodiments, R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl, wherein each of the foregoing is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R⁹Is a 5-or 6-membered heterocycloalkyl group. In other embodiments, R⁹Is 5-or 6-membered heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutane-ethyl, cyclopentane-methyl, cyclopentane-ethyl, cyclohexane-methyl, cyclohexane-ethyl, pyrrolidinyl, piperidinyl, pyrrolidine-methyl, pyrrolidine-ethyl, pyrrolidine-propyl, piperidine-methyl, piperidine-ethyl or piperidine-propyl. In certain embodiments, R ⁹Each of the foregoing moieties of (a) is unsubstituted OR substituted with one to five substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In certain embodiments, each R¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R¹⁰is-OH. In some embodiments, R⁷Is hydrogen, and R⁹Is methyl or halomethyl, such as trifluoromethyl. In some embodiments, R¹Is that

Still further embodiments are provided in compounds of formula (I), (I-I), (I-A-I-1), (II-I), (II-A-I), or (II-A-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereofIn the examples (examples as described herein), R¹is-NR⁷S(O)₂R⁹. In some embodiments, R⁷Is hydrogen, alkyl or haloalkyl. In certain embodiments, R⁷Is methyl. In certain embodiments, R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl, wherein each of the foregoing is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R ⁹Is a 5-or 6-membered heterocycloalkyl group. In other embodiments, R⁹Is 5-or 6-membered heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutane-ethyl, cyclopentane-methyl, cyclopentane-ethyl, cyclohexane-methyl, cyclohexane-ethyl, pyrrolidinyl, piperidinyl, pyrrolidine-methyl, pyrrolidine-ethyl, pyrrolidine-propyl, piperidine-methyl, piperidine-ethyl or piperidine-propyl. In certain embodiments, R⁹Each of the foregoing moieties of (a) is unsubstituted OR substituted with one to five substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In certain embodiments, each R¹⁰Independently hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R¹⁰is-OH. In some embodiments, R⁷Is hydrogen, and R⁹Is methyl or halomethyl, such as trifluoromethyl. In some embodiments, R¹Is that

In still another embodiment of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof (e.g., the examples described herein) In example), R¹is-S (O)₂R⁹. In certain embodiments, R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl, wherein each of the foregoing is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In some embodiments, R⁹Is a 5-or 6-membered heterocycloalkyl group. In other embodiments, R⁹Is 5-or 6-membered heterocycloalkyl- (C)_1-10) An alkyl group. In some embodiments, R⁹Is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutane-methyl, cyclobutane-ethyl, cyclopentane-methyl, cyclopentane-ethyl, cyclohexane-methyl, cyclohexane-ethyl, pyrrolidinyl, piperidinyl, pyrrolidine-methyl, pyrrolidine-ethyl, pyrrolidine-propyl, piperidine-methyl, piperidine-ethyl or piperidine-propyl. In certain embodiments, R⁹Each of the foregoing moieties of (a) is unsubstituted OR substituted with one to five substituents independently selected from the group consisting of halo and-OR¹⁰Group (d) of (a). In certain embodiments, each R¹⁰Independently hydrogen, (C) _1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R¹⁰is-OH. In certain embodiments, R⁹Is methyl, propyl or cyclopentane-ethyl. In some embodiments, R¹Is that

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, n1 is 0, 1, or 2. In some embodiments, n1 is 0 or 1. In certain embodiments, n1 is 1. In some embodiments, wherein n1 is 1 or 2 (e.g., when n1 is 1), each R is²Independently selected from the group consisting ofGroup (b): halo, cyano, alkyl, cycloalkyl-alkyl, -OR¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In some embodiments, each R is²Independently selected from the group consisting of: halo, cyano, alkyl, cycloalkyl-alkyl, -OR¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹R¹¹、-S(O)_m2R¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In still further embodiments, each R ²Independently is halo, alkyl, haloalkyl OR-OR¹¹Wherein each R is¹¹Independently hydrogen, alkyl or haloalkyl. In still other embodiments, each R²Independently a halo group. In some embodiments, at least one R²Is a halo group. In certain embodiments, at least one R²Is chlorine. In still other embodiments, n1 is 1, and R²Is chlorine.

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (II-I), (II-A-I), or (II-A-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R^6aIs hydrogen, halo, cyano, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl OR-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. For example, in some embodiments, R^6aIs hydrogen, halo, cyano, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C) _1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl OR-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In certain embodiments, R^6aIs hydrogen, halo, cyano, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl OR-OR¹⁵Wherein R is¹⁵Is hydrogen, (C)_1-10) Alkyl or (C)_1-10) HalogenatedAn alkyl group. In some embodiments, R^6aIs hydrogen, halo, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In still other embodiments, R^6aIs hydrogen.

In some embodiments of compounds of formula (I), (I-I), (I-B-I-1), (II-I), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R^6bIs hydrogen, halo, cyano, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl OR-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. For example, in some embodiments, R^6bIs hydrogen, halo, cyano, (C) _1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl OR-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In certain embodiments, R^6bIs hydrogen, halo, cyano, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl OR-OR¹⁵Wherein R is¹⁵Is hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R^6bIs hydrogen, halo, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In still other embodiments, R^6bIs hydrogen.

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R³、R^6aAnd R^6bIndependently hydrogen, halo, cyano, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl OR-OR¹⁵Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In certain embodiments, R ³、R^6aAnd R^6bIndependently hydrogen, halo, cyano, (C)_1-10) Alkyl, (C)_1-10) Haloalkyl OR-OR¹⁵Wherein R is¹⁵Is hydrogen, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In some embodiments, R³、R^6aAnd R^6bIndependently hydrogen, halo, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group. In still other embodiments, R³、R^6aAnd R^6bAre all hydrogen.

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, n2 is 0, 1, 2, or 3. In some embodiments, n2 is 0, 1, or 2. In certain embodiments, n2 is 0 or 1. In some embodiments, n2 is 0. In other embodiments, n2 is 1. In some embodiments, each R is⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³(ii) a Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, -OR ¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In some embodiments, each R is⁵Independently is halogeno, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, heterocycloalkyl- (C)_1-10) Alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³(ii) a Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups. In still further embodiments, each R⁵Independently is halogeno, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, (5-to 7-membered) heterocycloalkyl- (C)_1-10) Alkyl OR-OR¹³(ii) a Wherein each alkyl, cycloalkyl-alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, (C) _1-10) Alkyl, (C)_1-10) Haloalkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Halocycloalkyl, -OR¹⁴or-NR¹⁴R¹⁴. In still further embodiments, each R⁵Independently is halogeno, (C)_1-10) Alkyl or (C)_1-10) A haloalkyl group.

In some embodiments of compounds of formula (II), (II-i), (II-A-i-1), (II-B-i), or (II-B-i-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R is⁴Is alkyl, alkenyl, cycloalkaneAlkyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, heterocycloalkenyl, -OR¹²、-C(O)NR¹²R¹²、-NR¹²C(O)NR¹²R¹²、-S(O)₂NR¹²R¹²、-S(O)_m3R¹²or-C (O) R¹²(ii) a Wherein each alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴、-C(O)R¹⁴and-OC (O) R²²Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups.

In some embodiments, R⁴Is alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, heterocycloalkenyl, -OR¹²、-C(O)NR¹²R¹²、-NR¹²C(O)NR¹²R¹²、-S(O)₂NR¹²R¹²、-S(O)_m3R¹²or-C (O) R¹²(ii) a Wherein each alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl is independently unsubstituted or substituted with one or more-OC (O) R ²²And (4) substitution.

In some embodiments, R⁴Is substituted by one or more-OC (O) R²²A substituted alkyl group. In some embodiments, R⁴Is substituted by one or more-OC (O) R²²Substituted (C)₃-C₄) An alkyl group. In some embodiments, R²²Independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃Wherein each R is²³Is (C)₁-C₆) An alkylene group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8. In some embodiments, R⁴The method comprises the following steps:

in some embodiments, R⁴Is that

In some embodiments, R⁴is-OR¹². In some embodiments, R¹²Is hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl; wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently an alkylene or haloalkylene group. In some embodiments, R⁴The method comprises the following steps:

in some embodiments, R⁴Is (C)_1-10) Alkyl, (C) _2-10) Alkenyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, (C)_3-10) Cycloalkenyl, (5-to 7-membered) heterocycloalkyl- (C)_1-10) Alkyl, (5-to 7-membered) heterocycloalkenyl, -OR¹²、-C(O)NR¹²R¹²、-NR¹²C(O)NR¹²R¹²、-S(O)₂NR¹²R¹²、-S(O)_m3R¹²or-C (O) R¹²(ii) a Wherein each alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, (C)_1-10) Alkyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo groups.

In some embodiments, R⁴Is (C)_1-10) Alkyl, (C)_1-10) Alkenyl, (C)_3-10) Cycloalkyl group, (C)_3-10) Cycloalkenyl, (5-to 7-membered) heterocycloalkyl, or (5-to 7-membered) heterocycloalkenyl. In certain embodiments, R⁴Is (C)_1-10) Alkyl, (C)_1-10) Alkenyl, (C)_3-10) Cycloalkyl, (5-to 7-membered) heterocycloalkyl, or (5-to 7-membered) heterocycloalkenyl. In still other embodiments, R⁴Is (a)C_1-10) Alkyl, (C)_3-10) Cycloalkyl or (5-to 7-membered) heterocycloalkyl. In some embodiments, R ⁴Is (C)_1-8) Alkyl, (C)_1-6) Alkyl or (C)_1-4) Alkyl groups, such as hexyl, pentyl, butyl, propyl, ethyl or methyl, which may be unsubstituted or substituted. In some embodiments, R⁴Is (C)_1-8) Alkenyl, (C)_1-6) Alkenyl or (C)_1-4) Alkenyl, wherein alkenyl comprises one or two C-C double bonds, and wherein alkenyl may be unsubstituted or substituted. In other embodiments, R⁴Is a 4-, 5-or 6-membered heterocycloalkyl group comprising one to three heteroatoms independently selected from O and N. In some embodiments, wherein R⁴Is heterocycloalkyl, which is attached through a cyclic carbon atom. For example, in some embodiments, R⁴Is C comprising one or two O atoms_3-5A cycloalkyl group. In still other embodiments, R⁴Is a 5-or 6-membered heterocycloalkenyl group including one to three heteroatoms independently selected from O and N. In some embodiments, wherein R⁴Is a heterocycloalkenyl group attached through a cyclic carbon atom. In still other embodiments, R⁴Is (C)_3-10) Cycloalkyl radicals, e.g. (C)_3-8) Cycloalkyl group, (C)_3-6) Cycloalkyl or (C)_4-6) A cycloalkyl group. In some embodiments, R⁴Is (C)_1-6) Alkyl or (C)_3-6) Cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or substituted with one to six substituents selected from the group consisting of halo, (C) _1-10) Alkyl, (C)_3-10) Cycloalkyl and-OR¹⁴Group of (C) wherein_1-10) Alkyl and (C)_3-10) Cycloalkyl is independently unsubstituted OR substituted by one OR more halo OR- (OR)¹⁸)_n5OR¹⁷Or a combination thereof. Thus, in some embodiments, R⁴Is (C)_1-6) Alkyl or (C)_3-6) Cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or substituted with one to six substituents selected from the group consisting of: a halo group; (C)_1-10) An alkyl group; is- (OR)¹⁸)_n5OR¹⁷Substituted (C)_1-10) An alkyl group; is- (OR)¹⁸)_n5OR¹⁷Substituted (C)_1-10) A haloalkyl group; (C)_3-10) A cycloalkyl group; (C)_3-10) A halocycloalkyl group; and-OR¹⁴. In some embodiments, n5 is 0 or 1. In certain embodiments, R¹⁸Is alkylene, e.g. (C)_1-4) An alkylene group. In still other embodiments, R¹⁷Is hydrogen, (C)_1-6) Alkyl or (C)_1-6) A haloalkyl group. In some embodiments, R⁴Is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is unsubstituted or substituted with one to six substituents selected from the group consisting of: halo, (C)_3-10) Cycloalkyl group, (C)_3-10) Halocycloalkyl and-OR¹⁴. In other embodiments, R⁴Is cyclopropyl, cyclobutyl or cyclopentyl, each of said groups being unsubstituted or substituted with one to six substituents selected from the group consisting of: halo, (C) _1-10) Alkyl, quilt- (OR)¹⁸)_n5OR¹⁷Substituted (C)_1-10) Alkyl, (C)_1-10) Haloalkyl, quilt- (OR)¹⁸)_n5OR¹⁷Substituted (C)_1-10) Haloalkyl and-OR¹⁴. In still other embodiments, R⁴Is cyclopropyl, cyclobutyl or cyclopentyl, each of said groups being unsubstituted or substituted with one to six substituents selected from the group consisting of: a halo group; (C)_1-10) An alkyl group; (C) substituted by-O_1-10) Alkyl, -O (C)_1-6) Alkyl or-O (C)_1-6) A haloalkyl group; (C)_1-10) A haloalkyl group; (C) substituted by-O_1-10) Haloalkyl, -O (C)_1-6) Alkyl or-O (C)_1-6) A haloalkyl group; and-OR¹⁴. In some embodiments, R⁴The method comprises the following steps:

in some embodiments, R⁴The method comprises the following steps:

in still further embodiments, n2 is 1, 2, or 3, and R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group. In some embodiments, R⁴And R⁵Together with the atoms to which they are attached form a 5-to 8-membered carbocyclic or heterocyclic group. In certain embodiments, heterocyclyl includes one or two heteroatoms independently selected from the group consisting of O, N and S. In certain embodiments, heterocyclyl includes one or two O heteroatoms. In some embodiments, heterocyclyl is a 5-or 6-membered heterocyclyl including one or two O heteroatoms. In certain embodiments: Is that

In some embodiments of compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each R is R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵And R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; or hydrogen, (C)_1-10) Alkyl, (C)_3-8) Cycloalkyl group, (C)_3-10) Cycloalkyl- (C)_1-10) Alkane (I) and its preparation methodA group or (5-to 7-membered) heterocycloalkyl; or hydrogen, (C)_1-10) Alkyl or (C)_3-8) A cycloalkyl group; or hydrogen or (C)_1-10) An alkyl group; wherein each of the foregoing is independently unsubstituted or substituted with one or more halo groups. In some embodiments, two R¹⁰May form a heterocycloalkyl group (e.g., a (5-to 7-membered) heterocycloalkyl group) together with the nitrogen atom to which it is attached; two R¹¹May form a heterocycloalkyl group (e.g., a (5-to 7-membered) heterocycloalkyl group) together with the nitrogen atom to which it is attached; two R¹²May form a heterocycloalkyl group (e.g., a (5-to 7-membered) heterocycloalkyl group) together with the nitrogen atom to which it is attached; two R¹³May form a heterocycloalkyl group (e.g., a (5-to 7-membered) heterocycloalkyl group) together with the nitrogen atom to which it is attached; or two R ¹⁴May form a heterocycloalkyl group (e.g., a (5-to 7-membered) heterocycloalkyl group) together with the nitrogen atom to which it is attached; wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo groups.

In certain embodiments, the compound of formula (I), formula (I-I), formula (I-A-I), formula (II-I), formula (II-A), or formula (II-A-I) is:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

In certain embodiments, the compound of formula (I), formula (I-I), formula (I-A-I), formula (II-I), formula (II-A), or formula (II-A-I) is:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

Further provided is a pharmaceutical composition comprising any of the compounds disclosed herein, such as a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

The compounds disclosed herein, such as compounds of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I), or (II-B-I-1), or pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers thereof, can be prepared, for example, by the reaction pathways depicted in general schemes I and II.

General reaction scheme I

General reaction scheme I provides two routes to compound I-6, which is an example of a compound of formula (I), (I-a-I), (I-B-I), (II-I), (II-a-I), (II-B), or (II-B-I) as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. On the upper roadIn one embodiment, compound I-1 is coupled with compound I-2 in the presence of a palladium catalyst and a base to produce compound I-3. In the next step, compound I-3 is reacted with compound I-4 in the presence of a palladium catalyst and a base to produce compound I-6. In the second pathway (below), compound I-4 is coupled with compound I-1 to give compound I-5, which is then coupled with compound I-2 to give compound I-6. A suitable palladium catalyst for the first step of either route may comprise, for example, tetrakis (triphenylphosphine) palladium (0). Suitable palladium catalysts for this second step of either route may comprise, for example, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II); [1,1' -bis (diphenylphosphino) ferrocene ]Palladium (II) dichloride; or tetrakis (triphenylphosphine) palladium (0). Suitable bases for either of the two path steps may comprise, for example, aqueous sodium carbonate or aqueous potassium carbonate. Any of the steps depicted in general reaction scheme I may further comprise a solvent, for example, dioxane or dimethoxyethane. In some embodiments, the reaction is carried out between 60 ℃ and 120 ℃ for 8 hours to 24 hours. In some embodiments of general reaction scheme I, X is S and Y is CR^6a. In other embodiments, X is CR^6bAnd Y is S.

General reaction scheme II

In some embodiments, a compound of formula (I), (I-I), (I-A-I), (II-I), (II-A), or (II-A-I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is hydrogen, an alkyl, aryl, or heteroaryl group¹is-NR⁷SO₂R⁹、-NR⁷C(O)NR⁸R⁹or-NR⁷C(O)OR⁹It can be prepared following the various routes provided in general reaction scheme II above starting from compound II-1. Compound II-1 can be prepared, for example, as described in general reaction scheme I above, wherein R¹is-NH₂. Compound II-3 can be prepared, for example, according to the above route, so that the compoundII-1 is reacted with a carbamoyl chloride compound II-2 in the presence of an organic base such as diisopropylethylamine or triethylamine. The reaction may be carried out in a solvent such as dichloromethane at room temperature for 4 hours to 24 hours. Alternatively, the compound II-3 can be prepared by reacting the compound II-1 with phenyl chloroformate in the presence of triethylamine (Et) ₃N) at room temperature for about 16 hours and then with amine HNR⁸R⁹The resulting phenyl carbamate is treated in tetrahydrofuran at 0 ℃ to room temperature for 4 hours to 24 hours. The compound II-5 can be prepared, for example, by reacting the compound II-1 with a chloroformate compound II-4 in the presence of an organic base such as diisopropylethylamine or triethylamine. The reaction may be carried out in a solvent such as dichloromethane at room temperature for 4 hours to 24 hours. Compound II-7 can be prepared, for example, by reacting compound II-1 with sulfonyl chloride or sulfonyl fluoride compound II-6. The reaction can be carried out in the presence of an organic base such as triethylamine in a solvent such as pyridine at room temperature for 4 hours to 24 hours. In the compounds II-3, II-5 and II-7, the moiety R⁷May be hydrogen or may be another group as defined herein for formula (I). When R is⁷When not hydrogen, it can be preceded by R, for example, by the coupling reaction depicted in general reaction scheme II⁷Instead of one hydrogen on the free amine in compound II-1, or it can be introduced into the intermediate compound after the coupling reaction depicted in general scheme II.

Variable R in Compounds of general reaction schemes I and II ¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as described herein for formula (I). Although general reaction schemes I and II depict the preparation of compounds of formulae (I), (I-a) and (I-a-I), or pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers thereof, in some embodiments, compounds of formulae (I-B) and (I-B-I), or pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers thereof, may also be prepared according to similar reaction schemes. For preparing compounds of the formula (I), (I-I), (I-A) according to the general reaction scheme I or II or by other routes,The (I-A-I), (I-B) or (I-B-I), (II-I), (II-A-I), (II-B) or (II-B-I) compounds or their pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers of the reactants, solvents, coupling agents, catalysts and other compounds are commercially available and can be prepared according to organic chemistry techniques.

Methods of using the compounds and pharmaceutical compositions comprising the compounds

Provided herein are methods of using compounds disclosed herein, such as compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I), (II-A-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. These include methods of inhibiting a component of the SREBP pathway (e.g., SREBP or SCAP); and methods of treating a disorder in a subject in need thereof. In some embodiments, the disorder is mediated by SREBP or SCAP.

The term "treatment" or "treating" refers to any indicator of success in ameliorating a disorder (e.g., injury, disease pathology or condition), including any objective or subjective parameter, such as remission; (iii) alleviating; disappearance of symptoms or making the disorder more tolerable to the subject; slowing or stopping the rate of degeneration, decline or progression; slowing the progression of the condition; make the end point of the degradation less debilitating; improving physical or mental health of a subject; or to alleviate or cause regression of the condition. Treatment of symptoms, including amelioration of symptoms, may be based on objective or subjective parameters, which may include results of physical examination, neuropsychiatric examination, and/or psychiatric assessment. Certain methods and uses disclosed herein can treat cancer by, for example, reducing the incidence of cancer, causing remission of cancer, slowing the growth rate of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis or reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combination thereof.

The embodiments of the treatment methods described herein should also be considered applicable to: use of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing, for the treatment of a disorder; and the use of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing, for inhibiting SREBP or inhibiting the proteolytic activation of SREBP; and other uses of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing; and the use of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof, in the manufacture of a medicament.

A. Inhibition of SREBP or SCAP

Provided herein are uses and methods of inhibiting a component of the SREBP pathway, such as SREBP or SCAP. In some embodiments, a combination of SREBP and SCAP is inhibited. Such methods may comprise contacting the SREBP with: a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Such uses and methods may further comprise contacting the SCAP with: a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.

In certain embodiments, a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to a subject in need thereof to inhibit a component of the SREBP pathway. In other embodiments, a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I), (II-A-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to a subject in need thereof. In certain embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is between about 0.01mg/kg and about 100mg/kg relative to the body weight of the subject. In certain embodiments, a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt thereof, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day, is administered to a subject in need thereof, Solvates, tautomers, isotopes or isomers, to inhibit components of the SREBP pathway. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

The component of the SREBP pathway that is inhibited by the methods and uses described herein can be SREBP or SCAP. In some embodiments, SREBP is inhibited. The SREBP may be, for example, SREBP-1 (e.g., SREBP-1a or SREBP-1c) or SREBP-2. In certain variants, two or three of SREBP-1a, SREBP-1c and SREBP-2 are inhibited. In some embodiments, the component is SREBP-1. In other embodiments, SREBP is SREBP-1 a. In certain embodiments, component is SREBP-1 c. In still other embodiments, the SREBP is SREBP-2. In other embodiments, the component of the SREBP pathway is a SCAP. In some embodiments, both SREBP and SCAP are inhibited. In certain embodiments, two or three of SREBP-1a, SREBP-1c, and SREBP-2 are inhibited, and SCAP is inhibited.

Components that inhibit the SREBP pathway (e.g., SREBP or SCAP) may comprise partial inhibition or complete inhibition. Partial inhibition may comprise reducing the activity of a component of the SREBP pathway to a still detectable level. Complete inhibition may comprise all activity of a component that terminates the SREBP pathway (e.g., activity that terminates SREBP or SCAP), or reducing the activity of a component of the SREBP pathway below a level that is detected. Inhibition of a component of the SREBP pathway can be measured directly or indirectly using any method known in the art.

In some embodiments, inhibition of a component of the SREBP pathway is measured directly, e.g., by measuring the product of a reaction catalyzed by the component of the SREBP pathway. In some embodiments, inhibition of SREBP activation (e.g., by inhibition of SCAP) can be demonstrated by western blotting and quantitative assessment of full length and levels of cleaved SREBP-1 and/or SREBP-2 protein from a cell line (e.g., a liver cell line) or primary cell (e.g., a primary liver cell of mouse, rat, or human origin).

In some embodiments, inhibition of a component of the SREBP pathway is measured indirectly, e.g., by measuring the expression level of one or more genes regulated by SREBP. Inhibition of a component of the SREBP pathway, such as SREBP or SCAP, can reduce the expression of one or more genes regulated by SREBP, such as SREBP-1 (e.g., SREBP-1a or SREBP-1c) or SREBP-2. SCAPs play a role in activating SREBPs, and thus inhibiting the activity of SCAPs may reduce the expression of one or more genes regulated by SREBPs. SREBP pathway inhibition may also be determined by assessing the gene transcript level of one or more target genes of SREBP-1 and/or SREBP-2, such as one or more of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACCA, or ACACACACACACCB. Transcript levels can be assessed, for example, by transcriptomic analysis, including but not limited to q-PCR. A decrease in one, two, three, four, five, or more of these genes may indicate inhibition of SREBP activation. Such assessment of endogenous SREBP gene expression can be assessed in cell lines (e.g., liver cell lines) or primary cells (e.g., primary liver cells of mouse, rat, or human origin). In some embodiments, the level of gene transcription of PCSK9 or PNPLA3, or a combination thereof, is assessed.

Thus, provided herein are uses and methods of reducing the expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACA, and ACACACACACACACACACACABCB, comprising reacting SREBP or SCAP with a compound of formula (I), (I-I), (I-A), (I-A-I), (I-1), (I-B), (I-I), (II-I-1), (II-I-1), (II-I), (II-I-1), (II-I), (II-I), (II-I-1), (II-I) or a-II-I-II-I, or a-II-I, or a-II-I-II-I, or a-II, or a-II-I, or a pharmaceutically acceptable salt thereof, or a-I or a pharmaceutically acceptable salt thereof, or a-I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt, Solvates, tautomers, isotopes or isomer contacts. In some embodiments, expression of PCSK9 is reduced. In other embodiments, expression of PNPLA3 is reduced. In still further embodiments, the expression of both PCSK9 and PNPLA3 is decreased. In certain embodiments, one or more SREBPs, such as SREBP-1 (e.g., SREBP-1a or SREBP-1c) or SREBP-2, or any combination thereof, are contacted. In other embodiments, the SCAP is contacted. In still further embodiments, one or more of SREBP-1a, SREBP-1c, SREBP-2, and SCAP are contacted. In certain embodiments, inhibition of a component of the SREBP pathway can treat a disorder mediated by SREBP, such as the disorders described herein. Thus, in certain embodiments, the expression of one or more genes as described above is reduced in a subject in need thereof.

Another method for indirectly detecting inhibition of the SREBP pathway may comprise: the luciferase-expressing liver cell line (HepG2) was serum starved under the control of the LSS promoter to induce SREBP activation and increased luciferase expression. The cells may then be treated with a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. After treatment, the reduction in luciferase activity reflects inhibition of SREBP activation, and the non-cytotoxicity of the compounds can be assessed by LDH release.

B. Treating disorders

In other aspects, provided herein are uses and methods of treating a disorder in a subject in need thereof, the method comprises administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain aspects, provided herein are uses and methods of treating a disorder in a subject in need thereof, comprising administering to a subject in need thereof a composition comprising a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or pharmaceutically acceptable salt thereof, A pharmaceutical composition of an isotope or isomer and a pharmaceutically acceptable excipient. In certain embodiments, the compound is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of formula (I-I) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of formula (I-a) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (I-a-I) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In still further embodiments, the compound is a compound of formula (I-a-I-1) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (I-B) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of formula (I-B-I) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (I-B-I-1) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of formula (II-i) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of formula (II-a) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (II-a-i) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In still further embodiments, the compound is a compound of formula (II-a-i-1) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (II-B) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of formula (II-B-i) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of formula (II-B-i-1) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the disorder is mediated by SREBP.

The uses and methods of treatment described herein may employ a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

1. Metabolic disorders

In some embodiments, the disorder is a metabolic disorder, such as a disorder that affects lipid metabolism, cholesterol metabolism, or insulin metabolism. In certain embodiments, the disorder is associated with lipid metabolism, cholesterol metabolism, or insulin metabolism, e.g., liver disease or cardiovascular disease due to the accumulation of fat in the liver.

In some embodiments, the disorder is a liver disease, such as chronic liver disease. In some embodiments, the liver disease is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP). In some embodiments, the liver disease is mediated by SREBP. In certain embodiments, liver disease is mediated by a gene target downstream of SREBP (e.g., PNPLA-3). In other embodiments, the liver disease is mediated by SCAP. Thus, in some aspects, provided herein are uses and methods of treating liver disease in a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or pharmaceutically acceptable salt thereof, An isotope or isomer; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. The chronic liver disease can be, for example, primary alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH). In some embodiments, the liver disease is liver fat, liver inflammation, or liver fibrosis, or a combination thereof.

In certain embodiments, the liver disease is non-alcoholic fatty liver disease (NAFLD). NAFLD is a group of conditions associated with fat accumulation in the liver. Nonalcoholic steatohepatitis (NASH) is a form of NAFLD that involves inflammation of the liver. In NASH, liver inflammation may lead to liver damage and scarring, which is irreversible, and may also progress to cirrhosis and liver failure. NAFLD and NASH are associated with metabolic disorders such as obesity, dyslipidemia, insulin resistance and type 2 diabetes. Other conditions associated with NAFLD and NASH include increased abdominal fat and hypertension. In some embodiments, NASH is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP).

In other aspects, provided herein are uses and methods of treating NASH in a subject in need thereof, the method comprises administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Treatment of NASH may involve a reduction in mean liver fat content, which may be assessed by, for example, Magnetic Resonance Imaging (MRI), Magnetic Resonance Elastography (MRE), ultrasound, or Computerized Tomography (CT); a decrease in the liver enzyme alanine Aminotransferase (ALT); a decrease in the liver enzyme aspartate Aminotransferase (ALT); reduction of liver inflammation as assessed by histological scoring of liver biopsies; reduction of liver fibrosis assessed by histological scoring of liver biopsies; reduction of liver fat content assessed by histological scoring of liver biopsies; or any combination thereof. Treatment of NASH can be assessed using the following: NAFLD Activity Score (NAS); or steatosis, liveness and fibrosis Score (SAF); or other NASH diagnostic and/or scoring metrics (e.g., FIB4 or ELF).

Further provided herein are uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is liver fibrosis associated with NASH, comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I), (II-A-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt thereof, A solvate, tautomer, isotope, or isomer; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, liver fibrosis is mediated by SREBP. Treatment of liver fibrosis can be assessed, for example, by: magnetic Resonance Imaging (MRI), Magnetic Resonance Elastography (MRE), ultrasound or Computed Tomography (CT); a decrease in the liver enzyme alanine Aminotransferase (ALT); a decrease in the liver enzyme aspartate Aminotransferase (ALT); reduction of liver inflammation and/or fibrosis assessed by histological scoring of liver biopsies; or any combination thereof.

Further provided herein are uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is fatty liver disease, comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, Tautomers, isotopes, or isomers; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the fatty liver disease is mediated by SREBP. In certain embodiments, the subject may have fatty liver disease when the fat content of the liver of the subject is 5% or greater. In some embodiments, a subject with fatty liver disease has NASH or liver fibrosis associated with NASH. In certain embodiments, a subject having fatty liver disease is diagnosed as not having NASH or liver fibrosis associated with NASH. Treatment of fatty liver disease can be assessed, for example, by: magnetic Resonance Imaging (MRI), Magnetic Resonance Elastography (MRE), ultrasound or Computed Tomography (CT); a decrease in the liver enzyme alanine Aminotransferase (ALT); a decrease in the liver enzyme aspartate Aminotransferase (ALT); reduction of liver inflammation as assessed by histological scoring of liver biopsies; reduction of liver fibrosis assessed by histological scoring of liver biopsies; reduction of liver fat content assessed by histological scoring of liver biopsies; or any combination thereof.

In some embodiments of the uses and methods of treating liver disease provided herein (e.g., methods of treating liver fibrosis, fatty liver disease, or NASH), a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, is administered to a subject at between about 0.01mg/kg and about 100mg/kg relative to the subject's body weight, Solvates, tautomers, isotopes or isomers. In some embodiments, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, a, Solvates, tautomers, isotopes or isomers. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

Other metabolic disorders that may be treated with a compound or pharmaceutical composition described herein may include, for example, insulin resistance, hyperglycemia, diabetes, dyslipidemia, lipopathy, obesity, and metabolic syndrome. In some embodiments, the metabolic disorder is mediated by a genetic factor. In other embodiments, the metabolic disorder is mediated by one or more environmental factors, such as a fat-rich diet or a sugar-rich diet, or a combination thereof. In some embodiments, the metabolic disorder is mediated by SREBP. In some embodiments, the diabetes is type I diabetes. In certain embodiments, the diabetes is type II diabetes.

Provided herein are uses and methods of treating diabetes in a subject in need thereof, the methods comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II), (II-i), (II-a-i-1), (II-B-i) or (II-B-i-1) compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Diabetes (diabetes, also known as diabetes mellitis) refers to a disease or condition often characterized by a metabolic defect in the production and utilization of glucose, which results in the failure to maintain proper blood glucose levels in the body. In some embodiments, the diabetes is type II diabetes, characterized by insulin resistance, wherein insulin loses its ability to exert its biological effects over a wide range of concentrations. In some embodiments, diabetes is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP).

Further provided herein are uses and methods of treating insulin resistance in a subject in need thereof, the methods comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II), (II-i), (II-a-i-1), (II-B-i) or (II-B-i-1) compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Insulin resistance has been hypothesized to unify the accumulation of hypertension, glucose intolerance, hyperinsulinemia, elevated triglyceride levels, reduced HDL cholesterol, and central and global obesity. "metabolic syndrome" refers to a group of similar conditions that may include abdominal obesity, hypertension, hyperglycemia, high serum triglycerides (e.g., elevated fasting serum triglycerides), and low HDL levels, and that are associated with a risk of developing cardiovascular disease and/or type II diabetes. Further provided herein are uses and methods of treating metabolic syndrome in a subject in need thereof, the methods comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II), (II-i), (II-a-i-1), (II-B-i) or (II-B-i-1) compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the metabolic syndrome or insulin resistance is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP).

In some embodiments of the uses and methods of treating insulin resistance, hyperglycemia, diabetes, obesity, or metabolic syndrome provided herein, between about 0.01mg/kg and about 100mg/kg of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, is administered to the subject, Solvates, tautomers, isotopes or isomers. In some embodiments, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, a, Solvates, tautomers, isotopes or isomers. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

In other embodiments, the metabolic disorder is dyslipidemia. Thus, in other aspects, provided herein are uses and methods of treating dyslipidemia in a subject in need thereof, the methods comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or pharmaceutically acceptable salt thereof, An isotope or isomer; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Dyslipidemia refers to abnormal plasma levels of one or more lipids or one or more lipoproteins, or any combination thereof. Dyslipidemia can comprise a reduced level or an increased level, or a combination of reduced and increased levels, of one or more lipids and/or one or more lipoproteins (e.g., increased levels of one lipid and reduced levels of another lipid and/or lipoprotein). Dyslipidemia may include, but is not limited to, elevated low density lipoprotein cholesterol (LDL), elevated apolipoprotein B, elevated Triglycerides (TG), elevated lipoprotein (a), elevated apolipoprotein a, reduced high density lipoprotein cholesterol (HDL), or reduced apolipoprotein a1, or any combination thereof. Dyslipidemia, such as abnormal cholesterol or abnormal TG levels, is associated with an increased risk of vascular diseases, such as heart attack or stroke, atherosclerosis and coronary artery disease. In some embodiments of the uses and methods provided herein, the dyslipidemia is hyperlipidemia. Hyperlipidemia refers to an abnormally elevated level of lipids in the blood, and may include (1) hypercholesterolemia (elevated cholesterol levels); (2) hypertriglyceridemia (elevated triglyceride levels); and (3) combined hyperlipidemia (a combination of hypercholesterolemia and hypertriglyceridemia). Dyslipidemia may be caused by both genetic predisposition and diet, and may be associated with overweight, diabetes or metabolic syndrome. Certain drugs, such as those used in anti-rejection protocols for organ or tissue transplant patients, may also cause dyslipidemia. In some embodiments, dyslipidemia (e.g., hyperlipidemia) is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP). Thus, in some aspects, provided herein are uses and methods of reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating dietary cholesterol absorption, reversing cholesterol transport, or reducing triglycerides in a subject in need thereof, the method comprising administering to a subject in need thereof a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically thereof An acceptable salt, solvate, tautomer, isotope, or isomer; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.

In some embodiments of the uses and methods of treating dyslipidemia provided herein, reducing cholesterol levels, regulating cholesterol metabolism, regulating cholesterol catabolism, regulating dietary cholesterol absorption, reversing cholesterol transport, or reducing triglycerides in a subject in need thereof, as provided herein, between about 0.01mg/kg and about 100mg/kg of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I), (II-A) and (III) is administered to the subject relative to the subject's body weight, (II-A-i-1), (II-B-i) or (II-B-i-1) compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof. In some embodiments, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, a, Solvates, tautomers, isotopes or isomers. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

In still other aspects, provided herein are uses and methods of treating a lipopathy in a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I), (II-a-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or pharmaceutically acceptable salt thereof, An isotope or isomer; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the steatosis is associated with metabolic syndrome. In some embodiments, the fatty pathology is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP).

In certain aspects, provided herein are uses and methods of treating gallstones in a subject in need thereof, the method comprises administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Gallstones may be associated with gallbladder inflammation, pancreatic inflammation, or liver inflammation. In certain embodiments, the gallstones are cholesterol gallstones, which may form when the bile contains high concentrations of cholesterol and the bile salts are deficient. In some embodiments, gallstones that may comprise cholesterol lithiasis are mediated by components of the SREBP pathway (e.g., SREBP or SCAP).

In other embodiments, the disorder is pancreatitis. In yet other embodiments, the disorder is endotoxic shock, systemic inflammation, or xanthoma. In still further embodiments, the disorder is atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis. In certain embodiments, any of the foregoing disorders is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP).

In some embodiments of the uses and methods of treating gallstones, pancreatitis, endotoxic shock, systemic inflammation, xanthoma, atherosclerosis, coronary artery disease, angina, carotid artery disease, stroke, or cerebral arteriosclerosis provided herein, between about 0.01mg/kg and about 100mg/kg of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), or (I-A-I) relative to the weight of the subject, (II-B-i) or (II-B-i-1) compounds or pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers thereof. In some embodiments, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, a, Solvates, tautomers, isotopes or isomers. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

In some of any of the above embodiments, the subject is overweight, obese, has insulin resistance, is pre-diabetic, or has type II diabetes. In certain embodiments of any of the preceding embodiments, the subject has NASH.

2. Hyperproliferative disorders

In another embodiment, the disorder is a hyperproliferative disorder. Thus, in some aspects, provided herein are uses and methods of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I) or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, or solvate thereof, Tautomers, isotopes, or isomers; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.

As mentioned above, the metabolism of fatty acids, cholesterol and triglycerides may play a role in hyperproliferative disorders, such as cancer. Typically, during transformation of a non-cancerous cell into a cancer cell, cellular metabolism is shifted from catabolic to anabolic processes. Depending on the type of tumor, tumor cells can synthesize up to 95% of saturated and monounsaturated fatty acids. Some cancers exhibit increased synthesis of fatty acids and other lipids (e.g., cholesterol) as well as steroids (e.g., androgens). Elevated expression of Fatty Acid Synthase (FAS) can induce cancer cells to progress to S phase, while inhibition of FAS expression can reduce cell growth and can induce apoptosis. Thus, components of the SREBP pathway may play a role in hyperproliferative disorders.

Hyperproliferative disorders as disorders associated with some degree of abnormal cell proliferation may be benign or malignant. Benign hyperproliferative disorders may include precancerous conditions.

In some embodiments of the uses and methods provided herein, the disorder is a benign hyperproliferative disorder. In some embodiments, a benign hyperproliferative disorder is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP). In other embodiments, the disorder is a malignant hyperproliferative disorder. In some embodiments, the malignant hyperproliferative disorder is mediated by a component of the SREBP pathway (e.g., SREBP or SCAP).

In some embodiments, the hyperproliferative disorder is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

In some embodiments, the hyperproliferative disorder is soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placental cancer, brain cancer, kidney cancer, lung cancer, or bone cancer. Sarcomas can comprise cancers that originate in bone and soft tissue. Sarcomas include, for example, connective tissue cancers, such as muscle cancer.

In some embodiments of the uses and methods of treating a hyperproliferative disorder in a subject in need thereof as described herein, between about 0.01mg/kg to about 100 mg/kg. In some embodiments, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof, Solvates, tautomers, isotopes or isomers. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

Dosage and method of administration

The dosage of a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I), (II-a-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, administered to a subject in need thereof according to any of the disclosed methods may vary according to: a particular compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; a method of administration; the particular condition being treated; and a characteristic of the subject (e.g., weight, sex, and/or age). In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is a therapeutically effective amount.

In some embodiments, the effective amount of the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, can be between about 0.01mg/kg and about 100mg/kg relative to the body weight of the subject. In some embodiments, about 0.7mg to about 7g per day, or about 7mg to about 350mg per day, or about 350mg to about 1.75g per day, or about 1.75 to about 7g per day of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt thereof, a, Solvates, tautomers, isotopes or isomers. In certain embodiments, the compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.

Any of the uses and methods provided herein can comprise administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound provided herein, such as a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or pharmaceutical composition thereof, A tautomer, isotope, or isomer, and a pharmaceutically acceptable excipient.

A compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I), (II-A-1), (II-B-I) or (II-B-I-1), as provided herein, or a pharmaceutically acceptable salt, solvate, transdermal or transdermal thereof, as provided herein, may be administered to a subject by any suitable route, including, for example, intravenous, intramuscular, subcutaneous, oral or transdermal routes, Tautomers, isotopes or isomers, or pharmaceutical compositions as provided herein comprising these and pharmaceutically acceptable excipients.

In certain aspects, the invention provides methods of treating a condition associated with a disorder by administering to a subject in need thereof an effective amount of a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a), (II-a-I-1), (II-B-I), or (II-B-I-1) as provided herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a medicament comprising an effective amount of any of the foregoing and a pharmaceutically acceptable excipient as provided herein Use and method of the compositions to treat a disorder in a subject in need thereof. In some embodiments, the disorder is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. In other embodiments, the disorder is fatty liver disease. In certain embodiments, the disorder is NASH. In some embodiments, the route of administration is intravenous, intraarterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is transdermal.

In some aspects, provided herein include compounds of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II), a pharmaceutical composition of a compound of (II-i), (II-a-i-1), (II-B-i), or (II-B-i-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient, for use in the treatment of a condition as described herein. In some embodiments, the disorder is prevented, or is delayed in onset, or is delayed in progression. In some embodiments, the disorder is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. In some embodiments, the disorder is fatty liver disease. In certain embodiments, the disorder is NASH. In certain embodiments, the compositions include pharmaceutical formulations that are presented in one or more unit dosage forms, e.g., one, two, three, four, or more unit dosage forms.

IV. reagent kit

Also provided are articles of manufacture comprising formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II), (II-i), (II-a-i-1), (II-B-i) or (II-B-i-1) compounds or pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers thereof, or pharmaceutical compositions comprising any of the foregoing or unit doses comprising any of these, in suitable packaging as described herein for use in the methods described herein. Suitable packaging may include, for example, vials, vessels, ampoules, bottles, jars, flexible packaging, and the like. The article may be further sterilized and/or the kit may be sealed.

Further provided herein are kits comprising: a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. The kit may be used in any of the uses and methods described herein. In some embodiments, the kit further comprises instructions. The kit may be used for any one or more of the uses described herein, and thus may contain instructions for treating a hyperproliferative disorder (such as cancer), fatty liver disease, or NASH. The kit may comprise one or more containers. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in one container, as cross-reactivity and shelf-life permits.

The kits can be in unit dosage form, in bulk packaging (e.g., multi-dose packaging), or in sub-unit doses. For example, a pharmaceutical composition containing a sufficient dose of a compound of formula (I), (I-a-I-1), (I-B-I-1), (II-I), (II-a-I-1), (II-B-I), or (II-B-I-1), as disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or comprising any of the foregoing and a pharmaceutically acceptable excipient, and/or for use in the conditions detailed herein, can be provided A kit of a second pharmaceutically active compound to provide effective treatment of a subject over an extended period of time, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or longer. The kit can further comprise a plurality of unit doses of a compound of formula (I), (I-I), (I-A-I-1), (I-B-I-1), (II-I), (II-A-I-1), (II-B-I), or (II-B-I-1), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, along with instructions for use, and packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy or compound pharmacy).

The kit may optionally contain a set of instructions, typically written instructions, regarding the use of the components of the uses and methods described herein, although electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable. The instructions contained in the kit may contain information about the components and their administration to the individual.

Illustrative examples

Example I-1A compound of formula (I),

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo;

and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

each R²Independently selected from the group consisting of: halo, cyano, alkyl, cycloalkyl-alkyl, -OR ¹¹、-C(O)NR¹¹R¹¹、-NR¹¹C(O)R¹¹、-NR¹¹C(O)NR¹¹R¹¹、-NR¹¹R¹¹、-S(O)₂NR¹¹R¹¹、-NR¹¹S(O)₂R¹¹、-S(O)_m2R¹¹、-NR¹¹C(O)OR¹¹、-C(O)OR¹¹and-C (O) R¹¹Wherein each alkyl, cycloalkyl, and cycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclic or heterocyclic group formed is independently unsubstituted or substituted with one or more substituents selected fromThe substituents are independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴，

Wherein each alkyl, cycloalkyl-alkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, -C (O) OR ¹⁷、-C(O)NR¹⁷R¹⁷、-NR¹⁷C(O)R¹⁷、-NR¹⁷C(O)NR¹⁷R¹⁷、-NR¹⁷R¹⁷、-S(O)₂NR¹⁷R¹⁷、-NR¹⁷S(O)₂R¹⁷、-S(O)_n4R¹⁷、-C(O)R¹⁷And- (OR)¹⁸)_n5OR¹⁷Wherein each R is¹⁷Independently hydrogen, alkyl or haloalkyl; each n4 is independently 0, 1 or 2; each n5 is independently an integer from 0 to 5; and each R¹⁸Independently is alkylene or haloalkylene;

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹¹Can be connected withThe nitrogen atoms together form a heterocycloalkyl group; two R¹⁴May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R¹²And R¹³Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R ¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently is alkylene or haloalkylene;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

The compound of embodiment I-1, wherein the compound has the formula (I-A):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as defined for formula (I).

The compound of embodiment I-1 or I-2, wherein the compound has the formula (I-A-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ¹、R²、R³、R⁴、R⁵、R^6aN1 and n2 are as defined for formula (I).

The compound of embodiment I-1, wherein the compound has the formula (I-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R^6bN1 and n2 are as defined for formula (I).

The compound of embodiment I-1 or I-4, wherein the compound has the formula (I-B-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹、R²、R³、R⁴、R⁵、R^6bN1 and n2 are as defined for formula (I).

Examples I-6 according to the examplesA compound of any one of I-1 to I-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸、-NR⁷(SO)₂R⁹or-NR⁸R⁹。

An embodiment I-7. the compound according to any one of embodiments I-1 to I-6, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸or-NR⁸R⁹。

An embodiment I-8. the compound according to any one of embodiments I-1 to I-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ¹is-NR⁷C(O)NR⁸R⁹or-NR⁷S(O)₂NR⁸R⁹。

An embodiment I-9. the compound according to any one of embodiments I-1 to I-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)OR⁹、-NR⁷(SO)₂R⁹or-S (O)₂R⁹。

An embodiment I-10. the compound according to any one of embodiments I-1 to I-9, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁷And R⁸Are all hydrogen, and R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl, wherein said alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group of (I) wherein each R¹⁰Independently hydrogen, alkyl or haloalkyl.

A compound according to any one of embodiments I-1 to I-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, wherein said heterocycloalkyl group is unsubstituted OR substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, and-OR ¹⁰Group of (I) wherein each R¹⁰Independently hydrogen, unsubstituted alkyl or haloalkyl.

A compound according to any one of embodiments I-1 to I-11, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein n1 is 0 or 1.

An embodiment I-13. the compound according to any one of embodiments I-1 to I-12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Independently is halo, alkyl OR-OR¹¹Wherein each R is¹¹Independently hydrogen, unsubstituted alkyl or haloalkyl.

An embodiment I-14. the compound according to any one of embodiments I-1 to I-13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Independently a halo group.

An embodiment I-15. the compound according to any one of embodiments I-1 to I-14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Is chlorine.

A compound according to any one of embodiments I-1 to I-15, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ³And R^6aOr R^6bAre all hydrogen.

A compound according to any one of embodiments I-1 to I-16, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein n2 is 0.

A compound according to any one of embodiments I-1 to I-17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁴Is alkyl or cycloalkyl, wherein said alkyl or cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halo, alkyl, OR by- (OR)¹⁸)_n5OR¹⁷Substituted alkyl, haloalkyl, by- (OR)¹⁸)_n5OR¹⁷Substituted haloalkyl, cycloalkyl and-OR¹⁴Wherein each R is¹⁴And R¹⁷Independently is hydrogen, unsubstituted alkyl or haloalkyl, and each R¹⁸Independently an alkylene group.

The compound according to any one of embodiments I-1 to I-3 or I-6 to I-18, selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

A pharmaceutical composition comprising a compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

Example I-21. a method of inhibiting Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting the SREBP or SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound according to any one of examples I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to example I-20.

Example I-22. a method of inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound according to any one of examples I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to example I-20.

Example I-23. the method of example I-21 or I-22, wherein the SREBP is SREBP-1.

Example I-24. the process of example I-23, wherein the SREBP-1 is SREBP-1 a.

Example I-25. the method of example I-23, wherein the SREBP-1 is SREBP-1 c.

Example I-26. the method of example I-21 or I-22, wherein the SREBP is SREBP-2.

Example I-27. the method of any one of examples I-21 to I-26, wherein SREBP is inhibited in a subject in need thereof.

Example I-28. the method of any one of examples I-21 to I-27, wherein SCAP is inhibited in a subject in need thereof.

Embodiment I-29 the method of any one of embodiments I-21 to I-28, wherein expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

An embodiment I-30. a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to embodiments I-20.

An embodiment I-31. a method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP), the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to embodiments I-20.

Examples I-32. the method of examples I-30 or I-31, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy, or dyslipidemia.

Examples I-33. the method of examples I-32, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

Examples I-34 the method of examples I-32, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis or liver inflammation, or a combination thereof.

Examples I-35 the method of examples I-30 or I-31, wherein the disorder is a hyperproliferative disorder.

Examples I-36. the method of examples I-35, wherein the hyperproliferative disorder is cancer.

Examples I-37 the method of examples I-36, wherein the cancer is breast, liver, ovarian, pancreatic or prostate cancer.

Examples I-38. the method of examples I-30 or I-31, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

A compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in the inhibition of Sterol Regulatory Element Binding Protein (SREBP).

A compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in inhibiting the proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

Example I-41. the compound for use according to example I-39 or I-40, wherein the SREBP is SREBP-1.

Examples I-42. the compounds for use according to examples I-41, wherein the SREBP-1 is SREBP-1 a.

Examples I-43. Compounds for use according to examples I-42, wherein the SREBP-1 is SREBP-1 c.

Examples I-44. Compounds for use according to examples I-39 or I-40, wherein the SREBP is SREBP-2.

Example I-45. the compound for use according to any one of examples I-39 to I-44, wherein SREBP is inhibited in a subject in need thereof.

Example I-46. the compound for use according to any one of examples I-39 to I-45, wherein SCAP is inhibited in a subject in need thereof.

Example I-47 the compound for use according to any one of examples I-39 to I-46, wherein expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

A compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof.

Examples I-50 the compound for use according to examples I-48 or I-49, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy or dyslipidemia.

Examples I-51. the compound for use according to examples I-50, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

Examples I-52 the compound for use according to examples I-50, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis or liver inflammation, or a combination thereof.

A compound for use according to embodiments I-48 or I-49, wherein the disorder is a hyperproliferative disorder.

The compound for use according to embodiments I-53, wherein the hyperproliferative disorder is cancer.

The compound for use according to embodiments I-54, wherein the cancer is breast, liver, ovarian, pancreatic or prostate cancer.

Examples I-56. Compounds for use according to examples I-48 or I-49, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

Use of a compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the manufacture of a medicament for the inhibition of Sterol Regulatory Element Binding Protein (SREBP).

Use of a compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the manufacture of a medicament for inhibiting the proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

Example I-59. the use according to example I-57 or I-58, wherein the SREBP is SREBP-1.

Example I-60. the use according to example I-59, wherein the SREBP-1 is SREBP-1 a.

Example I-61. the use according to example I-59, wherein the SREBP-1 is SREBP-1 c.

Example I-62. the use according to example I-57 or I-58, wherein the SREBP is SREBP-2.

Example I-63 the use according to any one of examples I-57 to I-62, wherein SREBP is inhibited in a subject in need thereof.

Example I-64 the use according to any one of examples I-57 to I-63, wherein SCAP is inhibited in a subject in need thereof.

Embodiment I-65 the use of any one of embodiments I-57 to I-64, wherein expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

Use of a compound according to any one of embodiments I-1 to I-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the manufacture of a medicament for the treatment of a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP).

Examples I-68. the use according to examples I-66 or I-67, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy or dyslipidemia.

Examples I-69 the use of examples I-68 wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

Examples I-70. the use of examples I-68, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis or liver inflammation, or a combination thereof.

Examples I-71. the use according to examples I-66 or I-67, wherein the disorder is a hyperproliferative disorder.

Examples I-72 the use according to examples I-71, wherein the hyperproliferative disorder is cancer.

Examples I-73. the use according to examples I-72, wherein the cancer is breast, liver, ovarian, pancreatic or prostate cancer.

Examples I-74. the use according to examples I-66 or I-67, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

Example II-1A compound of formula (II),

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

X is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, which is unsubstituted or substituted by one or more substituents, said oneThe one or more substituents are independently selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl-alkyl, -OR ¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR ¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴、-C(O)R¹⁴and-OC (O) R²²，

R²²Independently is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃，

Wherein each R²³Is (C)₁-C₆) An alkylene group; each R²⁴Independently is H or-CH₃(ii) a And each n8 is independently an integer from 2 to 8;

each R¹⁰、R¹¹、R¹⁴And R¹⁵Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl; two R¹⁰May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹¹May form a heterocycloalkyl group together with the nitrogen atom to which it is attached; two R¹⁴With nitrogen atoms to which they may be attachedTogether, the substituents form a heterocycloalkyl group; and wherein each of the foregoing moieties is independently unsubstituted or substituted with one or more halo;

each R¹²And R¹³Independently hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R ¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently is alkylene or haloalkylene;

each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

Example II-2A Compound of formula (I),

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:

x is S and Y is-CR^6aOr Y is S and X is-CR^6b；

R⁷、R⁸And R⁹Independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl; wherein R is ⁷、R⁸And R⁹Each alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl of (a) is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, alkyl, haloalkyl, cyano, oxo, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Or R⁸And R⁹To which it is connectedThe vicinal nitrogen atoms together form a heterocycloalkyl, which heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl-alkyl, -OR¹⁰、-C(O)NR¹⁰R¹⁰、-NR¹⁰C(O)R¹⁰、-NR¹⁰C(O)OR¹⁰、-NR¹⁰C(O)NR¹⁰R¹⁰、-NR¹⁰R¹⁰、-S(O)₂NR¹⁰R¹⁰、-NR¹⁰S(O)₂R¹⁰、-S(O)_m1R¹⁰、-C(O)OR¹⁰、-C(O)R¹⁰And- (OR)²¹)_n6OR¹⁰；

Wherein each alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, oxo, alkyl, haloalkyl, -OR ¹⁶、-C(O)NR¹⁶R¹⁶、-NR¹⁶C(O)R¹⁶、-NR¹⁶C(O)OR¹⁶、-NR¹⁶C(O)NR¹⁶R¹⁶、-NR¹⁶S(O)₂R¹⁶and-S (O)_n3R¹⁶(ii) a Wherein each R¹⁶Independently hydrogen, alkyl, cycloalkyl-alkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with one or more halo; and each n3 is independently 0, 1 or 2;

n1 is 0, 1 or 2;

n2 is 0, 1, 2 or 3;

each R⁵Independently halo, alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, -OR¹³、-C(O)NR¹³R¹³、-S(O)₂NR¹³R¹³、-S(O)_m4R¹³or-C (O) R¹³；

Or R⁴And one R⁵Together with the atoms to which they are attached form a carbocyclic or heterocyclic group;

wherein R is⁴Each of alkyl, alkenyl, cycloalkyl-alkyl, cycloalkenyl, heterocycloalkyl-alkyl, and heterocycloalkenyl of (a); r⁵Alkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl of (a); and from R ⁴And one R⁵Said carbocyclyl or heterocyclyl formed is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, cycloalkyl-alkyl, heterocycloalkyl, -OR¹⁴、-C(O)OR¹⁴、-C(O)NR¹⁴R¹⁴、-NR¹⁴C(O)R¹⁴、-NR¹⁴C(O)NR¹⁴R¹⁴、-NR¹⁴R¹⁴、-S(O)₂NR¹⁴R¹⁴、-NR¹⁴S(O)₂R¹⁴、-S(O)_m4R¹⁴and-C (O) R¹⁴，

each R¹²And R¹³Independently hydrogen, alkyl, cycloalkyl-alkyl orHeterocycloalkyl, or two R¹²May form a heterocycloalkyl group together with the nitrogen atom to which it is attached, or two R¹³May form, together with the nitrogen atom to which they are attached, a heterocycloalkyl group, wherein each of the foregoing is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halo, cyano, oxo, alkyl, haloalkyl, -C (O) OR¹⁹、-C(O)NR¹⁹R¹⁹、-NR¹⁹C(O)R¹⁹、-NR¹⁹C(O)NR¹⁹R¹⁹、-NR¹⁹R¹⁹、-S(O)₂NR¹⁹R¹⁹、-NR¹⁹S(O)₂R¹⁹、-S(O)_n6R¹⁹、-C(O)R¹⁹And- (OR)²⁰)_n7OR¹⁹Wherein each R is¹⁹Independently hydrogen, alkyl or haloalkyl; each n6 is independently 0, 1 or 2; each n7 is independently an integer from 0 to 5; and each R²⁰Independently is alkylene or haloalkylene;

Each R²¹Independently is alkylene or haloalkylene;

each n6 is independently an integer from 1 to 5; and is

Each m1, m2, m3, and m4 is independently 0, 1, or 2.

An embodiment II-3. the compound of embodiment II-1, wherein the compound has the formula (II-A):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

An embodiment II-4. the compound of embodiment II-2, wherein the compound has the formula (I-A):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

Embodiment II-5. the compound of embodiment II-1 or II-3, wherein the compound has the formula (II-A-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

An embodiment II-6. the compound of embodiment II-2 or II-4, wherein the compound has the formula (I-A-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

An embodiment II-7. the compound of embodiment II-1, wherein the compound has the formula (II-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

An embodiment II-8. the compound of embodiment II-2, wherein the compound has the formula (I-B):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

Embodiment II-9. the compound of embodiment II-1 or II-7, wherein the compound has the formula (II-B-i):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

An embodiment II-10. the compound of embodiment II-2 or II-8, wherein the compound has the formula (I-B-I):

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.

An embodiment II-11. the compound according to any one of embodiments II-1 to II-10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸、-NR⁷(SO)₂R⁹or-NR⁸R⁹。

Embodiment II-12. the compound according to any one of embodiments II-1 to II-11, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)NR⁸R⁹、-NR⁷S(O)₂NR⁸R⁹、-NR⁷C(O)OR⁸、-S(O)₂R⁸or-NR⁸R⁹。

An embodiment II-13. the compound according to any one of embodiments II-1 to II-12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ¹is-NR⁷C(O)NR⁸R⁹or-NR⁷S(O)₂NR⁸R⁹。

Examples II to 14.A compound according to any one of embodiments II-1 to II-12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is¹is-NR⁷C(O)OR⁹、-NR⁷(SO)₂R⁹or-S (O)₂R⁹。

An embodiment II-15. the compound according to any one of embodiments II-1 to II-14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁷And R⁸Are all hydrogen, and R⁹Is alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl, wherein said alkyl, cycloalkyl-alkyl, heterocycloalkyl, OR heterocycloalkyl-alkyl is unsubstituted OR substituted with one OR more substituents independently selected from the group consisting of halo and-OR¹⁰Group of (I) wherein each R¹⁰Independently hydrogen, alkyl or haloalkyl.

An embodiment II-16. the compound according to any one of embodiments II-1 to II-13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁸And R⁹Together with the nitrogen atom to which they are attached form a heterocycloalkyl group, wherein said heterocycloalkyl group is unsubstituted OR substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, and-OR ¹⁰Group of (I) wherein each R¹⁰Independently hydrogen, unsubstituted alkyl or haloalkyl.

Embodiment II-17 the compound of any one of embodiments II-1 to II-16, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein n1 is 0 or 1.

An embodiment II-18. the compound according to any one of embodiments II-1 to II-17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Independently is halo, alkyl OR-OR¹¹Wherein each R is¹¹Independently hydrogen, unsubstituted alkyl or haloalkyl.

Embodiment II-19. the compound according to any one of embodiments II-1 to II-18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Independently a halo group.

An embodiment II-20. the compound according to any one of embodiments II-1 to II-19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R is²Is chlorine.

An embodiment II-21. the compound according to any one of embodiments II-1 to II-20, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is ³And R^6aOr R^6bAre all hydrogen.

An embodiment II-22 the compound according to any one of embodiments II-1 to II-21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein n2 is 0.

An embodiment II-23. the compound according to any one of embodiments II-1 to II-22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁴Is alkyl or cycloalkyl, wherein said alkyl or cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halo, alkyl, OR by- (OR)¹⁸)_n5OR¹⁷Substituted alkyl, haloalkyl, by- (OR)¹⁸)_n5OR¹⁷Substituted haloalkyl, cycloalkyl and-OR¹⁴Wherein each R is¹⁴And R¹⁷Independently is hydrogen, unsubstituted alkyl or haloalkyl, and each R¹⁸Independently an alkylene group.

An embodiment II-24. the compound according to any one of embodiments II-1 to II-22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is⁴is-OR¹²And R is¹²Is heterocycloalkyl-alkyl.

Example II-25 according to any of examples II-1 to II-22The compound or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof, wherein R is ⁴Is substituted by one or more-OC (O) R²²A substituted alkyl group; wherein R is²²is-R²³N(R²⁴)₂Or- (CH)₂CH₂-O-)_n8CH₃。

Examples II-26 the compound of examples II-25 or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R is²²is-R²³N(R²⁴)₂。

Examples II-27. the compounds according to examples II-25, or pharmaceutically acceptable salts, solvates, tautomers, isotopes or isomers thereof, wherein R²²Is- (CH)₂CH₂-O-)_n8CH₃。

Embodiment II-28. the compound of any one of embodiments II-1 to II-6 or II-11 to II-27, selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

Embodiment II-29. the compound according to any one of embodiments II-1 to II-27, selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

Embodiment II-30 the compound of any one of embodiments II-1 to II-6 or II-11 to II-27, selected from the group consisting of:

Or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing compounds.

A pharmaceutical composition comprising a compound according to any one of embodiments II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.

Example II-32 a method of inhibiting Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting the SREBP or SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound according to any one of examples II-1 to II-30 or a pharmaceutically acceptable salt, solvate, tautomer, isotope or isomer thereof or a pharmaceutical composition according to example II-31.

Example II-33 a method of inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP), the method comprising contacting SREBP Cleavage Activating Protein (SCAP) with an effective amount of a compound according to any one of examples II-1 to II-30 or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to example II-31.

Example II-34. the method of example II-32 or II-33, wherein the SREBP is SREBP-1.

Examples II-35. the process of examples II-34, wherein the SREBP-1 is SREBP-1 a.

Examples II-36. the process of examples II-34, wherein the SREBP-1 is SREBP-1 c.

Example II-37. the method of example II-32 or II-33, wherein the SREBP is SREBP-2.

Example II-38. the method of any one of examples II-32 to II-37, wherein SREBP is inhibited in a subject in need thereof.

Example II-39 the method of any one of examples II-32 to II-38, wherein SCAP is inhibited in a subject in need thereof.

Embodiment II-40 the method of any one of embodiments II-32 to II-39, wherein expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

Embodiment II-41 a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of embodiments II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to embodiment II-31.

Example II-42. a method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP), the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of examples II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition according to example II-31.

Example II-43 the method of example II-41 or II-42, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy, or dyslipidemia.

Examples II-44. the method of examples II-43, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

Example II-45 the method of example II-43, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.

Examples II-46. the method of examples II-41 or II-42, wherein the disorder is a hyperproliferative disorder.

Embodiments II-47 the method of embodiments II-46, wherein the hyperproliferative disorder is cancer.

Embodiments II-48 the method of embodiments II-47, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placental cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.

Examples II-49 the method of examples II-41 or II-42, wherein the condition is endotoxin shock, systemic inflammation or atherosclerosis.

An embodiment II-50 a compound according to any one of embodiments II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in the inhibition of Sterol Regulatory Element Binding Protein (SREBP).

Example II-51. a compound according to any one of examples II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in inhibiting the proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

Example II-52. the compound for use according to example II-50 or II-51, wherein the SREBP is SREBP-1.

Example II-53. the compound for use according to example II-52, wherein the SREBP-1 is SREBP-1 a.

Examples II-54. Compounds for use according to examples II-53, wherein the SREBP-1 is SREBP-1 c.

Example II-55. the compound for use according to example II-50 or II-51, wherein the SREBP is SREBP-2.

Example II-56. the compound for use according to any one of examples II-50 to II-55, wherein SREBP is inhibited in a subject in need thereof.

Example II-57 the compound for use according to any one of examples II-50 to II-56, wherein SCAP is inhibited in a subject in need thereof.

Example II-58 the compound for use according to any one of examples II-50 to II-57, wherein expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

An embodiment II-59 the compound according to any one of embodiments II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof.

An embodiment II-60 the compound according to any one of embodiments II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP).

Example II-61. the compound for use according to example II-59 or II-60, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy or dyslipidemia.

Examples II-62. the compound for use according to examples II-61, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

Example II-63. the compound for use according to example II-61, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis or liver inflammation, or a combination thereof.

Examples II-64 Compounds for use according to examples II-59 or II-60, wherein the disorder is a hyperproliferative disorder.

Examples II-65. the compound for use according to examples II-64, wherein the hyperproliferative disorder is cancer.

Examples II-66 the compound for use according to examples II-65, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematological cancer, placental cancer, brain cancer, kidney cancer, lung cancer or bone cancer.

Examples II-67. Compounds for use according to examples II-59 or II-60, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

Example II-68 use of a compound according to any one of examples II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for the inhibition of Sterol Regulatory Element Binding Protein (SREBP).

Example II-69 use of a compound according to any one of examples II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting proteolytic activation of Sterol Regulatory Element Binding Protein (SREBP).

Example II-70. the use of example II-68 or II-69, wherein the SREBP is SREBP-1.

Example II-71. the use according to example II-70, wherein the SREBP-1 is SREBP-1 a.

Example II-72. the use according to example II-70, wherein the SREBP-1 is SREBP-1 c.

Example II-73. the use of example II-68 or II-69, wherein the SREBP is SREBP-2.

Example II-74. the use according to any one of examples II-68 to II-73, wherein SREBP is inhibited in a subject in need thereof.

Example II-75 the use according to any one of examples II-68 to II-74, wherein SCAP is inhibited in a subject in need thereof.

Embodiment II-76 the use of any one of embodiments II-68 to II-75, wherein expression of one or more genes selected from the group consisting of: ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SRF 1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMO1, ACACACACACACACACACACACCB.

Use of a compound according to any one of embodiments II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the manufacture of a medicament for treating a disorder in a subject in need thereof.

Example II-78 use of a compound according to any one of examples II-1 to II-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein the disorder is mediated by Sterol Regulatory Element Binding Protein (SREBP).

Example II-79 the use according to example II-77 or II-78, wherein the disorder is metabolic syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, lipopathy or dyslipidemia.

Examples II-80. the use according to examples II-79, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.

Example II-81 the use of example II-79, wherein the liver disease is non-alcoholic steatohepatitis, liver fibrosis or liver inflammation, or a combination thereof.

Embodiment II-82. the use according to embodiment II-77 or II-78, wherein the disorder is a hyperproliferative disorder.

Embodiment II-83 the use according to embodiment II-82, wherein the hyperproliferative disorder is cancer.

Embodiment II-84 the use of embodiment II-83, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematological cancer, placental cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.

Example II-85. the use according to example II-77 or II-78, wherein the condition is endotoxic shock, systemic inflammation or atherosclerosis.

Examples of the invention

The following examples are illustrative only and are not intended to limit any aspect of the disclosure in any way.

Synthesis example 1: 2- (tert-butyl) -4- (5- (4- (isopropylsulfonyl) phenyl) thiophen-3-yl) pyridine (Compound I-8728)

Step 1: 4-bromo-2- (4- (isopropylsulfonyl) phenyl) thiophene. A10 mL glass-sealed tube was charged with a solution of 2, 4-dibromothiophene (0.150g, 0.620mmol), (4- (isopropylsulfonyl) phenyl) boronic acid (0.169g, 0.744mmol), potassium carbonate (0.171g, 1.24mmol) in dioxane to water (2.4:0.6mL) and N₂Gas purge for 10 minutes. Palladium four (0.071g, 0.062mmol) was added and the mixture was purged again with nitrogen for 10 minutes. The tube was sealed and heated to 85 ℃ for 16 hours. After completion, the reaction mixture was cooled to Room Temperature (RT) and the solvent was evaporated. 5mL of water was added and the product was extracted into ethyl acetate (EtOAc; 3X 15 mL). The extracts were combined and washed with brine (3X 10mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel: # 100-. ¹H NMR(400MHz,CDCl₃:δ(ppm):7.89(2H,J＝6.4Hz d)7.72(2H,J＝8.8Hz,d),7.35(1H,J＝1.6Hz d),7.30(1H,J＝1.2Hz,d),3.24-3.17(1H,m),1.32-1.31(6H,d)；LCMS 93％347.15[M+2H]。

Step 2: 2- (tert-butyl) -4- (5- (4- (isopropylsulfonyl) phenyl) thiophen-3-yl) pyridine. The product of step 1 (0.080g,0.2316mmol), 2-tert-butylpyridine 4-boronic acid pinacol ester (0.079g, 0.2779mmol) and K₃PO₄A solution of (0.148g, 0.6948mmol, 2 equiv.) in tetrahydrofuran (THF; 1.6mL) was charged into a 10mL glass sealed tube and purged with nitrogen for 10 minutes. After addition of xantphos (0.013g,0.0231mmol) and palladium tetrakis (0.027g, 0.0231mmol), it was again purged with nitrogen for 10 minutes, then the tube was sealed and heated to 80 ℃ for 16 hours. Upon completion, the reaction mass was cooled, the solvent was evaporated, 10mL water was added, and the product was extracted into EtOAc (3 × 20 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (silica gel: #100-Yl) -4- (5- (4- (isopropylsulfonyl) phenyl) thiophen-3-yl) pyridine (0.060g, 65.21%).¹H NMR(400MHz,CDCl₃):δ(ppm):8.62-8.60(1H,J＝0.8Hz,dd),7.92(2H,J＝1.6Hz,dd),7.84(2H,J＝2Hz,dd),7.74(1H,J＝1.6Hz,d)7.68(1H,J＝1.6Hz,d),7.54-7.53(1H,J＝0.8Hz,dd),7.32-7.30(1H,J＝1.6Hz,dd),3.26-3.19(1H,m),1.43(9H,s),1.34-1.32(6H,d),LCMS 99.56％(m/z 400.1[M+H])。

Synthesis example 2: 2- (tert-butyl) -4- (5- (4- (methylsulfonyl) phenyl) thiophen-3-yl) pyridine (Compound I-8723)

This compound was prepared following a procedure analogous to that in example 1.¹H NMR(400MHz,DMSO):δ8.55(d.J＝5.2Hz,1H),8.38(d,J＝1.2Hz,1H),8.355(s,1H),8.057(d.J＝8.8Hz,2H),7.98(d.J＝8.4Hz,2H),7.806(s,1H),7.61–7.603(m,1H),3.26(s,3H),1.38(s,9H)；LCMS:96.08％(m/z＝372.20[M+H])。

Synthesis example 3: 2- (tert-butyl) -4- (5- (4- ((cyclopentylmethyl) sulfonyl) phenyl) thiophen-3-yl) pyridine (Compound I-8729)

Step 1: 4-bromo-2- (4- ((cyclopentylmethyl) sulfonyl) phenyl) thiophene. To a stirred solution of 1-bromo-4- ((cyclopentylmethyl) sulfonyl) benzene (0.5g, 1.64mmol) in dioxane, water (4:1mL) in a glass tube under a nitrogen atmosphere at room temperature was added K₂CO₃(0.56g, 4.1mmol) followed by the addition of (4-bromothien-2-yl) boronic acid (0.48g, 1.97 mmol). The reaction mass was purged with nitrogen for 15 minutes, then PdCl was added₂(dppf) Dichloromethane (DCM) (0.13g, 0.164mmol) and purged again with nitrogen for 10 minutes. The reaction tube was sealed and stirred at 90 ℃ for 16 hours. The reaction mixture was cooled to 25 ℃, water (50mL) was added and the product was extracted into ethyl acetate; the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 4-bromo-2- (4- ((cyclopentylmethyl) sulfonyl) benzeneYl) thiophene (80mg, 13%).¹H NMR(400MHz,CDCl3):δ7.93–7.91(m,2H),7.81–7.61(m,2H),7.43(d,J＝1.2Hz,1H),7.35(d,J＝1.2Hz,1H),3.18–3.12(m,2H),2.28–2.24(m,1H),1.92–1.88(m,2H),1.64–1.51(m,4H),1.28–1.20(m,2H)；LCMS:45.91％(m/z＝387.21[M+2])。

Step 2: 2- (tert-butyl) -4- (5- (4- ((cyclopentylmethyl) sulfonyl) phenyl) thiophen-3-yl) pyridine. 4-bromo-2- (4- ((cyclopentylmethyl) sulfonyl) phenyl) thiophene (0.075g, 0.19mmol) in dioxane/H in a glass tube at room temperature under a nitrogen atmosphere ₂To a stirred solution of O (0.8:0.2mL) were added (2- (tert-butyl) pyridin-4-yl) boronic acid (0.039g, 0.21mmol), K₂CO₃(0.08g, 0.58 mmol). The reaction mass was purged with nitrogen for 15 minutes, then palladium tetrakis (0.023g, 0.019mmol) was added and purged again with nitrogen for 10 minutes. The reaction vessel was sealed and stirred at 90 ℃ for 16 hours. The reaction mixture was cooled to 25 ℃, water (50mL) was added and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (preparative HPLC) to give 2- (tert-butyl) -4- (5- (4- ((cyclopentylmethyl) sulfonyl) phenyl) thiophen-3-yl) pyridine (10 mg; 12%).¹H NMR(400MHz,DMSO):δ8.55(d,J＝5.2Hz,1H),8.39(d,J＝1.6Hz,1H),8.35(d,J＝1.2Hz,1H),8.05(d,J＝8.4Hz,2H),7.98(d,J＝8.8Hz,2H),7.80(bs,1H),c7.62–7.60(m,1H),3.39(d,J＝6.8Hz,2H),2.11–2.07(m,1H),1.76–1.71(m,2H),1.57–1.53(m,2H),1.51-1.38(m,11H),1.23-1.22(m,2H)；LCMS:97.59％(m/z＝440.77[M+H])。

Synthesis example 4: 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3-isopropylurea (Compound I-8731)

Step 1: 4- (4-bromothiophen-2-yl) -3-chloroaniline. A solution of 2, 4-dibromothiophene (0.800g, 3.307mmol, 1.0 equiv.), 3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) aniline (0.923g, 3.637mmol, 1.1 equiv.), potassium carbonate (1.14g, 8.267mmol, 2.5 equiv.) in water (2mL) and dioxane (10mL) was charged to a glass sealed tube and purged with nitrogen for 15 minutes. After addition of tetrakistriphenylphosphine palladium (0.382g, 0.330mmol, 0.1 eq.), the tube was again purged with nitrogen for 10 minutes, and then the reaction tube was sealed and heated to 100 ℃ for 16 hours. Upon completion, dioxane was removed under reduced pressure and the residue was dissolved in water (10mL) and extracted with EtOAc (3 × 15 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (silica gel 60-120 mesh) eluting with 10% EtOAc in petroleum (pet) ether. The collected fractions were concentrated under reduced pressure to give 4- (4-bromothiophen-2-yl) -3-chloroaniline as a pale yellow liquid, which was used as such in the next step.

Step 2: 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline. To a stirred solution of 4- (4-bromothien-2-yl) -3-chloroaniline (0.550g, 1.906mmol, 1.0 equiv.) in THF (10mL) in a glass tube at room temperature under a nitrogen atmosphere was added 2- (tert-butyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.409g, 2.287mmol, 1.2 equiv.), K₃PO₄(1.010g, 4.766mmol, 2.5 equiv.). The reaction mass was purged with nitrogen for 15 minutes. Tetratriphenylphosphine palladium (0.220g, 0.190mmol, 0.1 equiv.) and xantphos (0.111g, 0.190mmol, 0.1 equiv.) were then added and the tube was again purged with nitrogen for 10 minutes. The reaction tube was sealed and stirred at 80 ℃ for 16 hours. Upon completion, the residue was dissolved in water (10mL) and extracted with EtOAc (3X 15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography eluting with 15% EtOAc in petroleum ether. The product fractions were concentrated under reduced pressure to give 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline as a pale yellow liquid (0.220g, 35%).¹H NMR(400MHz,DMSO:δ(ppm):8.51-8.50(dd,J＝0.4Hz,J＝0.4Hz,1H),8.13(d,J＝1.2Hz,1H),7.74-7.70(dd,J＝1.6Hz,J＝0.8Hz,2H),7.53-7.51(dd,J＝1.6Hz,J＝1.6Hz,1H),7.38(d,J＝8.4Hz,1H),6.72(d,J＝2.0Hz,1H),6.61-6.58(dd,J＝2.4Hz,J＝2.4Hz,1H),5.67(s,2H),1.36(s,9H)。

And step 3: synthesis of 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3-isopropylurea. To a stirred solution of 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline (0.100g, 0.292mmol, 1.0 eq) in dichloromethane (DCM; 5mL) was added TEA (0.061mL, 0.438mmol, 1.5 eq) and isopropyl isocyanate (0.037g, 0.438mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the solvent was evaporated, and the residue was dissolved in water (10mL) and extracted with DCM (3 × 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC. The product fractions were concentrated under reduced pressure to give 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3-isopropylurea. (0.035g, 28%) was a white solid. ¹H NMR(400MHz,DMSO:δ(ppm):8.83(s,1H),8.52-8.51(dd,J＝0.4Hz,J＝0.4Hz,1H),8.23(d,J＝1.6Hz,1H),7.88(d,J＝1.6Hz,1H),7.81(d,J＝2.4Hz,1H),7.73(d,J＝0.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.55-7.54(dd,J＝0.8Hz,J＝1.6Hz,1H),7.31-7.29(dd,J＝2.0Hz,J＝2.4Hz,1H),6.32(d,J＝7.6Hz,1H),3.79-3.74(q,1H),1.36(s,9H),1.10(d,J＝6.4Hz,6H)；LCMS:(428.38[M+H]。

Synthesis example 5: n- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -4-hydroxypiperidine-1-carboxamide (Compound I-8736)

To a stirred solution of 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline (0.060g, 0.093mmol, 1.0 equiv.) in DCM (2mL) was added triethylamine (TEA; 0.061mL, 0.186mmol, 2.0 equiv.) and CDI (0.056g, 0.093mmol, 1.0 equiv.). After 30 min, 4-hydroxypiperidine (0.035g, 0.186mmol, 2.0 equiv.) is added. The reaction mixture was stirred at room temperature for 16 hours and the progress was monitored by Thin Layer Chromatography (TLC). After completion, the residue was dissolved in water (10mL) and extracted with DCM (3X 10mL), and the extracts were combined and washed with anhydrous sodium sulfateDried and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC. The product fractions were concentrated under reduced pressure to give N- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -4-hydroxypiperidine-1-carboxamide as an off-white solid (0.025g, 30%).¹H NMR(400MHz,DMSO:δ(ppm):8.80(s,1H),8.52-8.51(dd,J＝0.4Hz,J＝0.4Hz,1H),8.24(d,J＝1.6Hz,1H),7.91(d,J＝1.6Hz,1H),7.82(d,J＝2.0Hz,1H),7.74(d,J＝0.8Hz,1H),7.64(d,J＝8.4Hz,1H),7.56-7.51(m,2H),4.72(d,J＝4.4Hz,1H),3.85-3.80(m,2H),3.70-3.66(q,1H),3.12-3.06(m,2H),1.77-1.73(m,2H),1.36(s,11H)；LCMS:(470.42[M+H]。

Synthesis example 6: 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3- (4-hydroxycyclohexyl) urea (Compound I-8742)

To a stirred solution of 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline (0.080g, 0.233mmol, 1.0 eq) in DCM (3mL) was added triphosgene (0.068g, 0.233mmol, 1.0 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 3 hours. 4-aminocyclohexan-1-ol (0.053g, 0.46mmol, 2.0 equiv.) was then added. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the solvent was evaporated, and the residue was dissolved in water (10mL) and extracted with DCM (3 × 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by preparative HPLC. The product fractions were concentrated under reduced pressure to give 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3- (4-hydroxycyclohexyl) urea as a white solid (0.011g, 10%). ¹HNMR(400MHz,DMSO:δ(ppm):8.68(s,1H),8.52-8.51(dd,J＝0.8Hz,J＝0.8Hz,1H),8.23(d,J＝1.6Hz,1H),7.88(d,J＝1.2Hz,1H),7.79(d,J＝2.4Hz,1H),7.73(d,J＝0.8Hz,1H),7.61(d,J＝8.4Hz,1H),7.55-7.54(dd,J＝1.6Hz,J＝1.6Hz,1H),7.30-7.27(dd,J＝2.0Hz,J＝2.4Hz,1H),6.18(d,J＝7.6Hz,1H),4.53(d,J＝4.4Hz,1H),3.41-3.39(m,2H),1.85-1.79(m,4H),1.36(s,9H),1.24-1.22(m,4H)；LCMS:(484.47[M+H]。

Synthesis example 7: 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3- (piperidin-4-yl) urea (Compound I-8755)

Step 1: synthesis of phenyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate. To a stirred solution of 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline (0.100g, 0.292mmol, 1.0 eq) in THF (5mL) at 0 deg.C was added Et₃N (0.059g, 0.584mmol, 1.2 equivalents) and then phenyl chloroformate (0.053g, 0.350mmol, 1.2 equivalents) was added. The reaction mixture was stirred for 4 hours. Upon completion, ice-cold water (10mL) was the product and extracted into EtOAc (3X 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude phenyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate (0.135g) as a pale yellow gummy solid, which was used in the next step without purification.

Step 2: synthesis of tert-butyl 4- (3- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) ureido) piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (0.084g, 0.421mmol, 1.5 equiv.) in THF (5mL) at 0 deg.C was added NaH (0.020g, 0.421mmol, 1.5 equiv.). After 10 min, (0.135g, 0.281mmol, 1.5 eq) phenyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate was added at 0 ℃ and stirred at room temperature for 4 h. Upon completion, the residue was dissolved in water (10mL) and extracted with EtOAc (3X 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give tert-butyl 4- (3- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) ureido) piperidine-1-carboxylate (0.073g) as a pale yellow gummy solid.

And step 3: 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) And (3) -piperidine-4-yl urea. A solution of HCl in dioxane (4M) (2.5mL) was added to tert-butyl 4- (3- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) ureido) piperidine-1-carboxylate (0.062g, 0.108mmol, 1.0 equiv) at 0 ℃. The reaction mixture was stirred at room temperature for 16 hours. After completion, dioxane was removed under reduced pressure to give a residue, which was washed with NaHCO₃The residue was basified with solution and extracted with 10% MeOH in DCM (4 × 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by preparative HPLC. The product fractions were concentrated under reduced pressure to give 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3- (piperidin-4-yl) urea as an off-white solid (0.027g, 52%).¹H NMR(400MHz,DMSO:δ(ppm):8.74(s,1H),8.52(d,J＝5.2Hz,1H),8.24(d,J＝1.6Hz,1H),7.89(d,J＝1.6Hz,1H),7.81(d,J＝2.4Hz,1H),7.74(d,J＝0.8Hz,1H),7.61(d,J＝8.4Hz,1H),7.56-7.54(dd,J＝1.6Hz,J＝1.6Hz,1H),7.31-7.28(dd,J＝2.0Hz,J＝2.4Hz,1H),6.32(d,J＝7.2Hz,1H),3.53-3.48(m,1H),2.91-2.88(m,2H),2.50-2.49(m,2H),1.77-1.74(m,2H),1.36(s,9H),1.28-1.23(m,2H)；LCMS:(469.2[M+H]。

Synthesis example 8: 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3- (2- (pyrrolidin-1-yl) ethyl) urea (Compound I-8761)

To a stirred solution of phenyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate (0.052g, 0.454mmol, 1.5 equiv) in THF (5mL) at 0 deg.C was added NaH (0.021g, 0.454mmol, 1.5 equiv). After 10 min, 2- (pyrrolidin-1-yl) ethan-1-amine (0.140g, 0.303mmol, 1.5 equiv.) was added at 0 ℃. The reaction mixture was stirred for 4 hours. Upon completion, water (10mL) was added and the product was extracted into EtOAc (3X 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by preparative HPLC. Concentrating under reduced pressure to give Fractions were collected to give 1- (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) -3- (2- (pyrrolidin-1-yl) ethyl) urea as an off-white solid (0.038g, 26%).¹H NMR(400MHz,DMSO:δ(ppm):9.02(s,1H),8.52-8.51(dd,J＝0.4Hz,J＝0.8Hz,1H),8.24(d,J＝1.6Hz,1H),7.88(d,J＝1.2Hz,1H),7.81(d,J＝2.4Hz,1H),7.73(d,J＝0.8Hz,1H),7.61(d,J＝8.0Hz,1H),7.55-7.54(dd,J＝1.6Hz,J＝1.6Hz,1H),7.31-7.28(dd,J＝2.4Hz,J＝2.0Hz,1H),6.26-6.24(t,J＝5.2Hz,1H),3.23-3.19(q,2H),2.49-2.47(m,6H),1.72-1.69(m,4H),1.36(s,9H)；LCMS:(483.2[M+H]。

Synthesis example 9: (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamic acid isopropyl ester (Compound I-8741)

To a stirred solution of 4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chloroaniline (0.250g, 0.730mmol, 1.0 eq) in DCM (5mL) was added triphosgene (0.216g, 0.730mmol, 1.0 eq) at 0 ℃. After 1 hour, IPA (0.065g, 1.096mmol, 1.5 equiv.) was added at 0 deg.C. The reaction mixture was then stirred at room temperature for 16 hours. Upon completion, the solvent was evaporated from the reaction mixture, ice-cold water (10mL) was added and the product was extracted into DCM (3 × 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by preparative HPLC. The product fractions were concentrated under reduced pressure to give isopropyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate as a white solid (0.176g, 56%).¹H NMR(400MHz,DMSO-d₆):δ(ppm):9.94(s,1H),8.53-8.51(dd,J＝0.4Hz,J＝0.4Hz,1H),8.26(d,J＝0.8Hz,1H),7.91(d,J＝1.2Hz,1H),7.76(d,J＝2.0Hz,1H),7.73(d,J＝0.8Hz,1H),7.68(d,J＝8.4Hz,1H),7.56-7.54(dd,J＝1.6Hz,J＝1.6Hz,1H),7.50-7.48(dd,J＝2.4Hz,J＝2.0Hz,1H),4.95-4.89(m,1H),1.36(s,9H),1.27(d,J＝6.0Hz,6H)；LCMS:(429.53[M+H])。

Synthesis example 10: (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamic acid ethyl ester (Compound I-8735)

This compound was prepared following a procedure similar to example 9 above.¹H NMR(400MHz,DMSO:δ(ppm):10.0(s,1H),8.53-8.51(dd,J＝0.8Hz,J＝0.8Hz,1H),8.26(d,J＝1.2Hz,1H),7.91(d,J＝1.2Hz,1H),7.76-7.73(dd,J＝2.0Hz,J＝0.8Hz,2H),7.69(d,J＝8.8Hz,1H),7.56-7.54(dd,J＝1.6Hz,J＝1.6Hz,1H),7.51-7.48(m,1H),4.19-4.13(q,2H),1.36(s,9H),1.28-1.24(t,J＝7.2Hz,3H)；LCMS:(415.45[M+H]。

Synthesis example 11: 2- (pyrrolidin-1-yl) ethyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate (Compound I-8762)

To a stirred solution of 2- (pyrrolidin-1-yl) ethyl-1-ol (0.056g, 0.486mmol, 1.5 equiv.) in THF (5mL) at 0 deg.C was added NaH (60% moisture) (0.023g, 0.486mmol, 1.5 equiv.). After 10 min, phenyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate (0.150g, 0.324mmol, 1.5 equiv.) was added at 0 ℃. The reaction mixture was then stirred at room temperature for 4 hours. Upon completion, water (10mL) was added and the product was extracted into EtOAc (3X 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by preparative HPLC. The product fractions were concentrated under reduced pressure to give 2- (pyrrolidin-1-yl) ethyl (4- (4- (2- (tert-butyl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) carbamate as a white solid (0.019g, 16%).¹H NMR(400MHz,DMSO:δ(ppm):10.07(s,1H),8.52(d,J＝4.8Hz,1H),8.26(d,J＝1.6Hz,1H),7.91(d,J＝0.3Hz,1H),7.77-7.68(m,3H),7.56-7.49(m,2H),4.22-4.19(t,J＝1.6Hz,2H),2.70(bs,2H),2.51-2.50(m,4H),1.69(bs,4H),1.36(s,9H)；LCMS:(484.42[M+H]。

Synthesis example 12: preparation of reagents 2- (4-bromopyridin-2-yl) -2-methylpropan-1-ol and 2-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propan-1-ol

Step 1: ethyl 2- (4-bromopyridin-2-yl) acetate to a stirred solution of 4-bromo-2-methylpyridine (1.2g, 4.93mmol, 1.0 eq) in THF (15mL) was added diethyl carbonate (0.698mL, 5.92mmol, 1.2 eq) and the mixture was stirred at-78 ℃ under a nitrogen atmosphere. LDA (2M) (2.96mL, 5.92mmol) was added dropwise over 15 min, and the reaction was stirred at-78 deg.C for 2 h. The reaction was then quenched with saturated sodium chloride solution and the product was extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by column chromatography to give ethyl 2- (4-bromopyridin-2-yl) acetate (0.500g, 30%) as a pale yellow liquid.

Step 2: ethyl 2- (4-bromopyridin-2-yl) -2-methylpropionate to a stirred solution of ethyl 2- (4-bromopyridin-2-yl) acetate (0.5g, 2.05mmol, 1.0 eq) in DMF (5mL) at 0 ℃ under a nitrogen atmosphere was added NaH (60%) (0.246g, 6.10mmol, 3 eq). The reaction mass was stirred at room temperature for 30 minutes, then cooled to 0 ℃, followed by the addition of methyl iodide (1.486g, 10.25mmol, 5.0 equiv.) under a nitrogen atmosphere and stirring at room temperature for 16 hours. DMF was removed under reduced pressure, water (10mL) was added and the product was extracted into EtOAc (3X 15 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give ethyl 2- (4-bromopyridin-2-yl) -2-methylpropionate as a pale yellow liquid (0.140g, 25%).

And step 3: 2- (4-Bromopyridin-2-yl) -2-methylpropan-1-ol to a stirred solution of ethyl 2- (4-bromopyridin-2-yl) -2-methylpropionate (600mg, 2.2mmol, 1 eq) in THF (10mL) at 0 deg.C under a nitrogen atmosphere was added 1MBH dropwise₃THF (3.3mL, 3.31 mmol). The mixture was stirred at room temperature for 16 h, then quenched with methanol (10mL) and concentrated under reduced pressure to give the crude product, which was diluted with water and extracted into ethyl acetateIn (1). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to give 2- (4-bromopyridin-2-yl) -2-methylpropan-1-ol (280mg) as a pale yellow liquid.

And 4, step 4: 2-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propan-1-ol a stirred solution of 2- (4-bromopyridin-2-yl) -2-methylpropan-1-ol (200mg, 0.8733mmol), bis (pinacolato) diboron (243.95mg, 0.9606mmol) and potassium acetate (257.14mg, 2.6199) in a 14mL glass sealed tube was purged with nitrogen for 15 minutes. Addition of PdCl₂(dppf.) DCM adduct (71mg, 0.0873mmol), the reaction tube was again purged with nitrogen for 20 minutes, then sealed and heated at 80 ℃ for 16 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and passed And (4) bed filtration. The bed was washed with ethyl acetate (10mL) and the combined organic solutions were concentrated under reduced pressure to give the crude product (300 mg). The crude compound was co-distilled with methanol (3 × 10mL) and stirred with 5% ethyl acetate in petroleum ether. The suspension was filtered and the filtrate was evaporated completely to yield the desired borate salt as a brown gum, which was used without further purification.

Synthesis example 13: n- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide (Compound I-8909)

Step 1: n- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) methanesulfonamide. To a stirred solution of 4- (4-bromothiophen-2-yl) -3-chloroaniline (0.1g, 0.34mmol) in pyridine was added methanesulfonyl chloride (0.08g, 0.696mmol) at room temperature. The reaction mass was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the residue was dissolved in water (10mL) and the product was extracted into EtOAc (3 × 15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (neutral silica gel) eluting with 15EtOAc in petroleum ether to give N- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) methanesulfonamide as a white solid (0.1g, 79%).

Step 2: n- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide. To a stirred solution of N- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) methanesulfonamide (0.10g, 0.273mmol) in dioxane/water (5:1, 12mL) in a glass tube was added K₂CO₃(0.113g, 0.819mmol) and 2-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propan-1-ol (0.076g, 0.273 mmol); the reaction mixture was purged with nitrogen for 5 minutes, and then Pd (PPh) was added₃)₄And purged again with nitrogen for 5 minutes. The tube was sealed and heated at 80 ℃ for 16 hours. After completion (monitored by TLC), the solvent was evaporated and the residue was diluted with ethyl acetate and washed with water (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by preparative HPLC to yield N- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide as an off-white solid (0.19g, 40%).¹H NMR(400MHz,DMSO-d6):δ10.187(s,1H),8.53(d,J＝5.20Hz,1H),8.27(d,J＝1.20Hz,1H),7.91(d,J＝1.60Hz,1H),7.74(d,J＝8.40Hz,1H),7.70(s,1H),7.55(dd,J＝1.60,5.20Hz,1H),7.38(d,J＝2.40Hz,1H),7.26(dd,J＝2.40,8.40Hz,1H),4.67(t,J＝5.60Hz,1H),3.60(d,J＝5.20Hz,2H),3.10(s,3H),1.30(s,6H)；LCMS:98.46％(437.32[M+H])。

The following compounds were prepared in a similar manner:

synthesis example 14: n- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) -4-hydroxypiperidine-1-carboxamide (Compound I-8926)

Step 1: n- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) -4-oxopiperidine-1-carboxamide. To a solution of 4- (4-bromothien-2-yl) -3-chloroaniline (0.2g, 0.696mmol), 4-piperidone (0.141g, 1.04mmol) and TEA (0.21g, 2.088mmol) in DCM at 0 deg.C was added COCl₂And (3) solution. The reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was washed with saturated NaHCO₃Quench and extract product into DCM. The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by neutral alumina column chromatography to yield N- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) -4-oxopiperidine-1-carboxamide as a pale yellow solid.

Step 2: n- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) -4-hydroxypiperidine-1-carboxamide. To a stirred solution of N- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) -4-oxopiperidine-1-carboxamide (0.25g, 0.606mmol) in THF at 0 deg.C was added NaBH₄(0.046, 1.21 mmol). The reaction mass was stirred at room temperature for 16 hours. After completion (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was dissolved in water (10mL) and extracted with EtOAc (3 × 15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was produced and purified by column chromatography (neutral alumina) to give N- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) -4-hydroxypiperidine-1-carboxamide (0.25g) as a pale yellow solid.

And step 3: n- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophene-2-yl) phenyl) -4-hydroxypiperidine-1-carboxamide. To a stirred solution of N- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) -4-hydroxypiperidine-1-carboxamide (0.250g, 0.603mmol) in dioxane/water (5:1, 12mL) in a glass tube was added K₂CO3(0.250g, 1.809mmol) and 2-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propan-1-ol (0.167g, 0.603mmol), and the reaction mixture was purged with nitrogen for 5 minutes. Addition of Pd (PPh)₃)₄(0.069g, 0.06mmol) and purged again with nitrogen for 5 minutes. The reaction tube was sealed and heated at 80 ℃ for 16 hours. After completion (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (30mL) and washed with water (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give N- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) -4-hydroxypiperidine-1-carboxamide as an off-white solid (41 mg).¹H NMR(400MHz,DMSO-d6):δ8.81(s,1H),8.52(d,J＝5.20Hz,1H),8.23(d,J＝1.60Hz,1H),7.89(d,J＝1.60Hz,1H),7.83(d,J＝2.40Hz,1H),7.70(s,1H),7.64(d,J＝8.4Hz,1H),7.56-7.52(m,2H),4.73(d,J＝4.40Hz,1H),4.67(t,J＝5.20Hz,1H),3.86-3.81(m,2H),3.70-3.67(m,1H),3.60(d,J＝5.20Hz,2H),3.13-3.06(m,2H),1.80-1.70(m,2H),1.45-1.25(m,8H):LCMS:97.78％(486[M+H])。

Synthesis example 15: 3- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) oxazolidin-2-one (compound I-8939)

Step 1: 2-chloroethyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) carbamate. To a stirred solution of 4- (4-bromothiophen-2-yl) -3-chloroaniline (0.5g, 1.74mmol) in pyridine was added chloroethyl chloroformate (0.374g, 2.61mmol) at room temperature. The reaction mass was stirred at room temperature for 16 hours. Upon completion (monitored by TLC), the reaction mixture was diluted with water (10mL) and extracted with EtOAc (3 × 15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (neutral silica gel) eluting with 20% EtOAc in petroleum ether afforded 2-chloroethyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) carbamate (0.5g) as a yellow solid.

Step 2: 3- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) oxazolidin-2-one. To a stirred solution of 2-chloroethyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) carbamate (0.5g, 1.265mmol) in toluene at 0 deg.C was added NaH (0.091g, 3.79 mmol). The reaction mass was stirred at room temperature for 2 hours. Upon completion (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3 × 15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (neutral silica gel) eluting with 30% EtOAc in petroleum ether to give 3- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) oxazolidin-2-one (0.2g) as a yellow solid.

And step 3: 3- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) oxazolidin-2-one. To a stirred solution of 3- (4- (4-bromothiophen-2-yl) -3-chlorophenyl) oxazolidin-2-one (0.300g, 0.83mmol) in dioxane/water (5:1, 14mL) in a glass tube was added K₂CO₃(0.344g, 2.49mmol) and 2-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propan-1-ol (0.164g, 0.83 mmol). The reaction mixture was purged with nitrogen for 15 minutes and Pd (PPh) was added₃)₄(0.096g, 0.083mmol) and the mixture is again purged with nitrogen for 15 minutes. The tube was sealed and heated at 80 ℃ for 16 hours. After completion, the solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with DCM (3 × 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give 3- (3-chloro-4- (4- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) oxazolidin-2-one as an off-white solid (94 mg).¹H NMR:400MHz,DMSO-d6:δ8.55(d,J＝5.20Hz,1H),8.34(br s,1H),7.99(s,1H),7.87(d,J＝2.00Hz,1H),7.82-7.76(m,2H),7.64-7.58(m,2H),4.70(s,1H),4.49(t,J＝8.40Hz,2H),4.12(t,J＝8.40Hz,2H),3.61(s,2H),1.32(s,6H)；LCMS:98.81％(429.31[M+H])。

Synthesis example 16: compound I-8941

Step 1: 2- (4- (5- (4-amino-2-chlorophenyl) thiophen-3-yl) pyridin-2-yl) -2-acetic acid methylpropyl ester. To a stirred solution of 4- (4-bromothien-2-yl) -3-chloroaniline (0.200g, 0.734mmol) in dioxane/water (5:1, 14mL) in a glass tube was added K ₂CO₃(0.304g, 2.2mmol) and propyl 2-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) acetate (0.247g, 0.734 mmol). After purging the reaction mixture with nitrogen for 15 minutes, Pd (PPh) was added₃)₄(0.085g, 0.073mmol) and the reaction was again purged with nitrogen for 15 minutes. The tube was sealed and heated at 80 ℃ for 16 hours. After completion (monitored by TLC), the solvent was evaporated under reduced pressure, the residue was quenched with saturated sodium bicarbonate solution, and the product was extracted into DCM (3 × 10 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (100-200 silica gel) to give 2- (4- (5- (4-amino-2-chlorophenyl) thiophen-3-yl) pyridin-2-yl) -2-acetic acid methylpropyl ester (25g, 90%) as a brown liquid.

Step 2: to a stirred solution of 2- (4- (5- (4-amino-2-chlorophenyl) thiophen-3-yl) pyridin-2-yl) -2-acetic acid methylpropyl ester (0.230g, 0.57mmol) in THF at 0 deg.C was added NaH (0.041g, 1.71 mmol). After 30 min at 0 deg.C, isopropylaminosulfonyl chloride (0.109g, 0.68mmol) was added and the reaction was stirred at 0 deg.C for an additional 2 h. The reaction was quenched with ice-cold water, the reaction mixture was stirred at room temperature for 10 minutes, and the product was extracted into ethyl acetate (3 × 10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by preparative HPLC to give compound I-8941 as an off-white solid (0.2g, 66%). ¹H NMR(400MHz,DMSO-d6):10.09(s,1H),δ8.52(d,J＝5.20Hz,1H),8.25(s,1H),7.90(s,1H),7.75-7.65(m,3H),7.55(dd,J＝1.20,5.20Hz,1H),7.35(d,J＝2.00Hz,1H),7.17(dd,J＝2.00,8.40Hz,1H),4.67(t,J＝5.20Hz,1H),3.60(d,J＝5.20Hz,2H),3.35(m,1H),1.30(s,6H),1.03(d,J＝6.4Hz,6H)；LCMS:98.27％(480.0[M+H])。

The following compounds were prepared in a similar manner:

synthesis example 17: (3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) phenyl) carbamic acid isopropyl ester (Compound I-8966)

Step 1: 3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) aniline. A stirred solution of 4-bromo-2-cyclopropylpyridine (150mg, 0.75mmol), 3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) aniline (380mg, 1.13mmol), and potassium carbonate (314mg, 2.27mmol) in 1, 4-dioxane (5.6mL) and water (1.4mL) was purged with nitrogen for 15 minutes. After adding palladium Pd (PPh)₃)₄After (87mg, 0.07mmol) and purging with nitrogen again, the reaction mass was heated at 80 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (neutral alumina) to give 3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) aniline as a pale yellow gum (0.15g, 60%).

Step 2: (3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) phenyl) carbamic acid isopropyl ester. To a stirred solution of 3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) aniline (150mg, 0.46mmol) and DIPEA (0.2mL) in DCM (5mL) was added isopropyl carbonate (78mg, 0.64mmol) dropwise at 0 ℃. The reaction mass was slowly brought to room temperature and stirred for 16 hours. After completion of the reaction (monitored by TLC), the reaction was quenched with water (10mL) and the product was extracted into DCM (3 × 10mL) and combined And the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give isopropyl (3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) phenyl) carbamate (17mg) as an off-white solid.¹H-NMR(400MHz,DMSO-d6):δ0.94(s,1H),8.40(d,J＝4.80Hz,1H),8.24(d,J＝1.20Hz,1H),7.90(d,J＝1.60Hz,1H),7.77(d,J＝2.40Hz,1H),7.68-7.66(m,2H),7.50-7.48(m,2H),4.95-4.87(m,1H),2.16-2.10(m,1H),1.28(d,J＝6.00Hz,6H),0.96(d,J＝6.00Hz,4H)；LCMS:98.95％(413.26[M+H]⁺。

Synthesis example 18: (3-chloro-4- (4- (2- (1- (hydroxymethyl) cyclopropyl) pyridin-4-yl) thiophen-2-yl) phenyl) carbamic acid isopropyl ester (Compound I-8980)

Step 1: (3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) phenyl) carbamic acid isopropyl ester. Mixing isopropyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) carbamate (250mg, 0.67mmol), B₂Pin₂A stirred solution of (254mg, 1.00mmol) and potassium acetate (197mg, 2.00mmol) in 1, 4-dioxane (5mL) was purged with nitrogen for 15 minutes. Adding palladium Pd (dppf) Cl₄(48mg, 0.067mmol) the reaction mass was heated at 80 ℃ for 16 h. After completion of the reaction (monitored by TLC), the reaction was monitored byThe reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude isopropyl (3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) phenyl) carbamate (370mg) as a brown gum which was used in the next step without purification.

Step 2: (3-chloro-4- (4- (2- (1- (hydroxymethyl) cyclopropyl) pyridin-4-yl) thiophen-2-yl) phenyl) carbamic acid isopropyl ester. The isopropyl (3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) phenyl) carbamate (370mg, 0.88mmol), (1- (4-bromopiridol)Pyridin-2-yl) cyclopropyl) methanol (200mg, 0.88mmol) and potassium carbonate (366mg, 2.65mmol) in a stirred solution of 1, 4-dioxane (8mL) and water (2mL) was purged with nitrogen for 15 minutes. Addition of Palladium Pd (PPh)₃)₄(102mg, 0.088mmol), the reaction mixture was again purged with nitrogen and then heated at 80 ℃ for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was passed throughFiltration and concentration of the filtrate under reduced pressure gave the crude compound which was purified by preparative HPLC to give isopropyl (3-chloro-4- (4- (2- (1- (hydroxymethyl) cyclopropyl) pyridin-4-yl) thiophen-2-yl) phenyl) carbamate as an off-white solid (22mg, 17%). 1H NMR (400MHz, DMSO-d6): δ 9.94(s,1H),8.44(dd, J ═ 0.40,5.20Hz,1H),8.22(d, J ═ 1.60Hz,1H),7.88(d, J ═ 1.60Hz,1H),7.77-7.74(m,2H),7.67(d, J ═ 8.80Hz,1H),7.51-7.48(m,2H),4.95-4.85(m,1H),4.80(t, J ═ 5.60Hz,1H),3.83(d, J ═ 5.60Hz,1H),1.28(d, J ═ 6.00Hz,6H),1.15-1.14(m,2H),0.91-0.90(m, 2H); LCMS: 99.67% ((M + H) 443.29).

Synthesis example 19: 3-chloro-4- (4- (2- ((tetrahydro-2H-pyran-3-yl) oxy) pyridin-4-yl) thiophen-2-yl) aniline (Compound I-9107)

Step 1: n- (3-chloro-4- (4- (2-fluoropyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide. To 4-bromo-2-fluoropyrrolidine (1.5g, 0.008mol) in 1, 4-dioxane H₂O (30mL) stirred solution N- (3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) phenyl) methanesulfonamide (5.28g, 0.0012mol) and K₂CO₃(3.312g, 0.024 mmol). The reaction mixture is treated with N₂Purge, addition of Pd (PPh)₃)₄(0.924g, 0.0008mmol), and then heated at 80 ℃ while stirring for 16 hours. After completion of the reaction (TLC and LCMS), the mixture was cooled to room temperature, filtered through celite bed and concentrated under reduced pressure to give crude product, which was passed through columnThe crude product was purified by chromatography to give N- (3-chloro-4- (4- (2-fluoropyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide as a brown solid (1.3g, 60%); LCMS 70% (M/z 383.20[ M + H ]]⁺)。

Step 2: 3-chloro-4- (4- (2- ((tetrahydro-2H-pyran-3-yl) oxy) pyridin-4-yl) thiophen-2-yl) aniline. A solution of the product of step 1 (300mg, 0.783mmol) and tetrahydro-2H-pyran-3-ol (0.32g, 3.1mmol) in DMF (5mL) was cooled to 0-5 ℃. NaH (75.16mg, 3.132mmol) was added slowly and the reaction mass was stirred at room temperature for 16 h. After completion of the reaction (TLC and LCMS), the mixture was quenched with ice and the product was extracted into DCM. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 3-chloro-4- (4- (2- ((tetrahydro-2H-pyran-3-yl) oxy) pyridin-4-yl) thiophen-2-yl) aniline as an off-white solid (20mg, 8%). ¹H NMR(400MHz,DMSO):δ10.19(s,1H),8.31(d,J＝1.6Hz,1H),8.17(d,J＝5.6Hz,1H),7.93(d,J＝1.6Hz,1H),7.74(d,J＝8.4Hz,1H),7.38-7.36(m,2H),7.26-7.24(m,1H),7.21(d,J＝0.8Hz,1H),5.05-5.02(m,1H),3.89-3.85(m,1H),3.66-3.62(m,1H),3.56-3.49(m,2H),3.10(s,3H),2.07-2.03(m,1H),1.81-1.75(m,2H),1.57-1.54(m,1H)；LCMS:98.25％(m/z＝465.25[M+H]⁺)。

The following compounds were prepared in a similar manner:

synthesis example 20: (R) -1- (2- (4- (5- (2-chloro-4- ((N-isopropylaminosulfonyl) amino) phenyl) thiophen-3-yl) pyridin-2-yl) -2-methylpropoxy) -3-methyl-1-oxobutyl-2-ammonium chloride (I-9094)

Step 1: 2- (4- (5- (2-chloro-4- ((N-isopropylaminosulfonyl) amino) phenyl) thiophen-3-yl) pyridin-2-yl) -2-methylpropyl (tert-butoxycarbonyl) -L-valine ester. DMAP (6mg, 0.05mmol) was added to a solution of a mixture of I-8941(250mg, 0.52mmol), (tert-butoxycarbonyl) -L-valine (169mg, 0.78mmol) and DCC (161mg, 0.78mmol) in DMF (5 mL). The reaction was stirred at room temperature for 16 h, and then diluted with ethyl acetate (30mL) and washed with cold water (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by reverse phase column chromatography to give 2- (4- (5- (2-chloro-4- ((N-isopropylaminosulfonyl) amino) phenyl) thiophen-3-yl) pyridin-2-yl) -2-methylpropyl (tert-butoxycarbonyl) -L-valine ester as an off-white solid (200 mg; 57%). LCMS 80.57% (M/z 678.1[ M-H ]])⁺

Step 2: (R) -1- (2- (4- (5- (2-chloro-4- ((N-isopropylaminosulfonyl) amino) phenyl) thiophen-3-yl) pyridin-2-yl) -2-methylpropoxy) -3-methyl-1-oxobutan-2-ium chloride. To the product of step 1 (200mg, 0.29mmol) in EtOH was added dropwise a 4M HCl in EtOH (4mL) solution at 0 ℃. The reaction was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (0.01M% HCL in water and ACN) to give (R) -1- (2- (4- (5- (2-chloro-4- ((N-isopropylaminosulfonyl) amino) phenyl) thiophen-3-yl) pyridin-2-yl) -2-methylpropoxy) -3-methyl-1-oxobutan-2-ium chloride as an off-white solid (50 mg; 28%). ¹HNMR(401MHz,DMSO)δ10.13(s,1H),8.62(d,J＝4.8Hz,1H),8.46-8.35(m,4H),8.01-7.82(m,3H),7.74(d,J＝7.6Hz,1H),7.68(d,J＝8.4Hz,1H)7.36(d,J＝2.4Hz,1H),7.17(m,J＝20.4Hz,1H),4.62(d,J＝10.6Hz,1H),4.39(d,J＝10.6Hz,1H),3.85(t,J＝4.8Hz,1H),3.41-3.32(m,1H),2.01(m,J＝4.6Hz,1H),1.50-1.46(m,6H),1.03(d,J＝6.8Hz,6H),0.76(t,J＝6.4Hz,6H)；LCMS:99.85％(579.43[M+H]⁺Ions are present.

The following compounds were prepared in a similar manner:

synthesis example 21: n- (4- (4- (2- (1-amino-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) methanesulfonamide (I-9049)

Nickel (II) chloride hexahydrate (172mg, 0.7218mmol) was added to a stirred solution of N- (3-chloro-4- (4- (2- (2-cyanoprop-2-yl) pyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide (260mg, 0.6015mmol) in methanol at 0-5 ℃. Sodium borohydride (68.27mg, 1.8045mmol) was added portionwise over 40 min and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was then filtered through a celite bed and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give N- (4- (4- (2- (1-amino-2-methylpropan-2-yl) pyridin-4-yl) thiophen-2-yl) -3-chlorophenyl) methanesulfonamide as an off-white solid (25mg, 13.5%).¹H NMR 400MHz,DMSO-d6:δ8.53(d,J＝5.20Hz,1H),8.19(d,J＝1.60Hz,1H),7.82(d,J＝1.60Hz,1H),7.71(s,1H),7.57(dd,J＝1.60,5.20Hz,1H),7.49(d,J＝8.40Hz,1H),7.14(d,J＝2.40Hz,1H),6.96(dd,J＝2.40,8.60Hz,1H),4.92(br s,2H),2.90(s,2H),2.81(s,3H),1.32(s,6H)；LCMS:96.31％(m/z＝436.00[M+H])。

Synthesis example 22: cyclopropyl (3-chloro-4- (4- (2- (1- (hydroxymethyl) cyclopropyl) pyridin-4-yl) thiophen-2-yl) phenyl) (methyl) carbamate (I-9042)

Step 1: cyclopropyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) (methyl) carbamate. To a stirred solution of cyclopropyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) carbamate (300mg, 0.80mmol) in THF (10mL) at 0 deg.C was added NaH (64mg, 1.61mmol) and stirring continued for 15 min. MeI (171mg, 1.21mmol) was added dropwise to the reaction and stirred at room temperature for 3 hours. The reaction was quenched with ice-cold water (30mL) and the product was extracted into EtOAc (3X 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give cyclopropyl (4- (4-bromothiophen-2-yl) -3-chlorophenyl) (methyl) carbamate (300mg crude) which was used in the next step without purification.

Step 2: cyclopropyl (3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) phenyl) (methyl) carbamate. A stirred solution of the product of step 1 (300mg, 0.77mmol), bis (pinacolato diboron) (296mg, 1.16mmol) and potassium acetate (230mg, 2.33mmol) in 1, 4-dioxane (6mL) was purged with nitrogen for 5 minutes. Addition of PdCl₂(dppf) (57mg, 0.07mmol), then the reaction was heated to 80 ℃ for 16 hours. The reaction mixture was cooled to room temperature, filtered through a celite bed and concentrated under reduced pressure to give cyclopropyl (3-chloro-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) phenyl) (methyl) carbamate (800mg crude) which was used in the next step without purification.

And step 3: cyclopropyl (3-chloro-4- (4- (2- (1- (hydroxymethyl) cyclopropyl) pyridin-4-yl) thiophen-2-yl) phenyl) (methyl) carbamate. The product of step 2 (150mg, 0.66mmol), (1- (4-bromopyridin-2-yl) cyclopropyl) methanol (343mg, 0.79mmol), K₂CO₃A solution of (273mg, 1.98mmol) 1, 4-dioxane: water (8mL:2mL) was purged with nitrogen for 5 minutes. Tetrapalladium (76mg, 0.06mmol) was then added and the reaction mixture was stirred at 80 ℃ for 16 h. The mixture was filtered through a celite bed and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give cyclopropyl (3-chloro-4- (4- (2- (1- (hydroxymethyl) cyclopropyl) pyridin-4-yl) thiophen-2-yl) phenyl) (methyl) carbamate as an off-white solid (0.045 g; 15%). ¹H NMR 400MHz,DMSO-d6:δ8.45(d,J＝5.20Hz,1H),8.28(d,J＝1.60Hz,1H),7.96(d,J＝1.60Hz,1H),7.75-7.72(m,2H),7.61(d,J＝2.00Hz,1H),7.51(dd,J＝1.60,5.20Hz,1H),7.40(dd,J＝2.40,8.40Hz,1H),4.80(t,J＝5.60Hz,1H),4.07-4.04(m,1H),3.83(d,J＝5.60Hz,2H),3.24(s,3H),1.16-1.13(m,2H),0.92-0.90(m,2H),0.68-0.66(m,4H)；LCMS:99.77％(m/z＝455.34[M+H])。

Synthesis example 23: n- (3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) phenyl) -N-methylmethanesulfonamide (I-9037)

To a stirred solution of N- (3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) phenyl) methanesulfonamide (200mg, 0.49mmol) in THF (5mL) at 0 deg.C was added NaH (40mg, 0.99 mmol). MeI (104mg, 0.74mmol) was then added dropwise and stirring continued at room temperature for 24 h. The reaction was cooled to 0 ℃ and quenched by the addition of ice water, and the product was extracted into EtOAc (3 × 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give N- (3-chloro-4- (4- (2-cyclopropylpyridin-4-yl) thiophen-2-yl) phenyl) -N-methylmethanesulfonamide as an off-white solid (0.085 mg; 41%).¹H NMR 400MHz,DMSO-d6:δ8.41(d,J＝4.80Hz,1H),8.32(d,J＝1.20Hz,1H),8.00(d,J＝1.60Hz,1H),7.80(d,J＝8.40Hz,1H),7.68-7.66(m,2H),7.51-7.48(m,2H),3.32(s,3H),3.04(s,3H),2.16-2.07(m,1H),0.97-0.96(m,4H)；LCMS:99.84％(419.17[M+H]⁺Ions are present.

The following compounds were prepared in a similar manner:

synthesis example 24: cyclopropyl (3-chloro-4- (5- (2- (1-hydroxy-2-methylprop-2-yl) pyridin-4-yl) thiophen-3-yl) phenyl) carbamate (I-9161)

Step 1: cyclopropyl (3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate. To a stirred solution of 3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (0.600g, 2.37mmol) and cyclopropanol (0.45mL, 7.1146mmol) in DCM cooled to 0-5 deg.C was added Et ₃N (0.71g, 7.1146 mmol). After 15 minutes, COCl was added dropwise₂(25% toluene solution) (1.408g, 2.817mmol), and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with sodium bicarbonate and the product was extracted into ethyl acetate. The organic layer was concentrated to give the crude product as a brown gum (0.670g), which was purified by column chromatography to give cyclopropyl (3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate as a yellow liquid (0.3 g; 38%).

Step 2: cyclopropyl (3-chloro-4- (5- (2- (1-hydroxy-2-methylprop-2-yl) pyridin-4-yl) thiophen-3-yl) phenyl) carbamate (I-9161). To the product of step 1 (0.3g, 0.8902mmol) in 1, 4-dioxane H₂O (7mL) stirred solution was added 2- (4- (4-bromothien-2-yl) pyridin-2-yl) -2-methylpropan-1-ol (0.304g, 0.9792mmol) and K₂CO₃(0.368g, 2.6706 mmol). The reaction mixture is treated with N₂Purge, addition of Pd (PPh)₃)₄(0.061g, 0.0534mmol) and the reaction mixture was heated to 80 ℃ while stirring for 16 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give a crude product which was purified by preparative HPLC to give cyclopropyl (3-chloro-4- (5- (2- (1-hydroxy-2-methylpropan-2-yl) pyridin-4-yl) thiophen-3-yl) phenyl) carbamate as a white solid (0.1 g; 25%). 1HNMR 400MHz, DMSO-d6:δ9.98(s,1H),8.53(d, J ═ 4.80Hz,1H),7.97(d, J ═ 1.20Hz,1H),7.81(d, J ═ 1.60Hz,1H),7.73(d, J ═ 1.60Hz,1H),7.62(d, J ═ 0.80Hz,1H),7.55(s,1H),7.47-7.45(m,2H),4.68(t, J ═ 5.20Hz,1H),4.09-4.08(m,1H),3.59(d, J ═ 5.60Hz,2H),1.29(s,6H),0.71-0.70(m, 4H); LCMS: 99.43% (M + H443.48.

Synthesis example 25: 2- (4- (4- (2-chloro-4- (((isopropylamino) thio) amino) phenyl) thiophen-2-yl) pyridin-2-yl) -2-methylpropan-1-ol, S, S-dioxide (I-9162)

Step 1: n- (3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -S- (isopropylamino) thiohydroxylamine S, S-dioxide. A solution of 3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (500mg, 1.97mmol) in pyridine was cooled to 0-5 deg.C and isopropylaminosulfonyl chloride (341mg, 2.17mmol) was added dropwise. After stirring at room temperature for 4 hours, the reaction was quenched with water and the product was extracted into DCM. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give crude N- (3-chloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -S- (isopropylamino) thiohydroxylamine S, S-dioxide as a yellow gum (360 mg; 49%).

Step 2: 2- (4- (4- (2-chloro-4- (((isopropylamino) thio) amino) phenyl) thiophen-2-yl) pyridin-2-yl) -2-methylpropan-1-ol, S-dioxide (I-9162). A stirred solution of the product of step 1 (360mg, 0.96mmol), 2- (4- (4-bromothiophen-2-yl) pyridin-2-yl) -2-methylpropan-1-ol (250mg, 0.80mmol), potassium carbonate (332mg, 2.41mmol) in 1, 4-dioxane (8mL) and water (2mL) was purged with nitrogen for 5 minutes. Addition of Palladium Pd (PPh) ₃)₄(55mg, 0.04mmol) the reaction mass was heated to 80 ℃ for 16 h. The reaction mixture was cooled to 25-30 ℃, filtered through a celite bed and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 2- (4- (4- (2-chloro-4- (((isopropylamino) thio) amino) phenyl) thiophen-2-yl) pyridin-2-yl) -2-methylpropan-1-ol, S-dioxide (42 mg; 11%) as an off-white solid. 1HNMR 400MHz, DMSO-d6:δ9.82(br s,1H),8.52(d, J ═ 5.20Hz,1H),7.97(d, J ═ 1.60Hz,1H),7.79(d, J ═ 1.20Hz,1H),7.63(d, J ═ 0.80Hz,1H),7.47-7.48(m,3H),7.31(d, J ═ 2.40Hz,1H),7.13(dd, J ═ 2.00,8.40Hz,1H),4.68(t, J ═ 5.20Hz,1H),3.59(d, J ═ 5.60Hz,2H),3.41(s,1H),1.29(s,6H),1.03(d, J ═ 6.40Hz, 6H); LCMS: 99.68% ((M + H) 480.20).

Biological example 1: gene expression, reporter assay and liver microsomes

Gene expression: the effect of selected compounds on gene expression of HepG2 cells was evaluated. HepG2 cells (P2) were seeded in 24-well plates (80,000 cells/well) for RNA extraction and 96-well plates (10,000 cells/well) for Cell Titer Glow (CTG). The medium used was DMEM and contained 10% FBS. Each compound was evaluated at 500Mm for 48 hours. RNA was evaluated for two biological replicates for each experimental group. For gene analysis, RNA was collected using RNEasy kit and cDNA was synthesized using 20-100ng of random primers. Quantitative PCR was performed on 1pg to 100ng cDNA of the following genes: ACACA, ACLY, FASN, LSS, PNPLA 3. Gene expression was normalized to baseline relative to housekeeping genes, β -actin and relative expression levels determined using a Δ Δ CT method comparing treated cells to sham or vector treated cells. "Total" gene expression refers to the average of the values of the 5 genes listed above. The results are presented in table 1 below.

Reporter selection assay: this assay was used to assess the effect of selected compounds using the SRE-luciferase reporter construct on transcriptionally active SREBP. On day 1, 10,000 cells were seeded in 96-well (white) plates according to plate maps in growth medium without antibiotics. Cells were incubated at 37 ℃ for 8 hours. After 8 hours, the cells were washed with DPBS to completely remove FBS. DPBS was completely removed and growth medium was replaced with phenol-free treatment medium (90 μ Ι) at different FBS concentrations. The cells were then incubated with different doses (0.01uM to 10uM) of the compound for 24 hours at 37 ℃. Luciferase assays were then performed.

Reagents for performing luciferase assays were stored at-20 ℃. To a tube of lyophilized assay substrate, 1mL of substrate solvent was added and mixed well. The reconstituted substrate tube was covered with aluminum foil to protect it from light. The assay buffer was thawed to room temperature. To 20mL of assay buffer, 200 μ L of reconstituted 100x substrate was added and mixed well. The reconstituted substrate and assay solution (buffer + substrate) were protected from light by covering with aluminum foil throughout the procedure. Using a multichannel pipettor, 100. mu.L of assay solution (buffer + substrate) was added directly to each sample well of plate 1, which was incubated for 30 minutes (plate covered with aluminum foil). After 30 minutes incubation, the total luminescence of the plate was read. Each well was read in a plate luminometer for 2 seconds. (microplate reader Envision microplate reader from Perkin Elmer). Precautions are taken to incubate the plates for exactly 30 minutes before reading on the plate reader. The results are presented in table 1 below.

Reporter assay materials: SREBPv1 reporter cell line: HepG2- # 32251. Production medium: MEM (Corning, Inc. (Corning)10-010), 10% FBS, 1% GlutaMax (Invitrogen, Inc.) catalog #35050061), μ g/ml puromycin (Invitrogen catalog # A1113803), and 1% penicillin-streptomycin (Pen-Strep). Treating the culture medium: phenol-free MEM (Invitrogen Cat # 51200-. Luciferase assay: LightSwitch luciferase assay kit (catalog # 32032). LDH determination: pierce LDH cytotoxicity assay kit (catalog # SD 249616).

Half-life human microsomes: compounds were evaluated for stability in human liver microsomes. Stock solutions of 10mM of the compound to be evaluated were prepared in DMSO and diluted with water acetonitrile (1:1) to a concentration of 1 mM. The working concentration of 100. mu.M was prepared by further dilution with water acetonitrile (1: 1). To prepare the preincubation mixture, 2.5. mu.L of the diluted compound was combined with 75. mu.L of 3.33mg/mL human liver microsomes and 85. mu.L of 100mM potassium phosphate buffer, and the mixture was preincubated at 37 ℃ for 10 minutes. To prepare a 60 min mixture without cofactor, 32.5. mu.L of the preincubation mixture were combined with 17.5. mu.L of 100mM potassium phosphate buffer and incubated at 37 ℃ for 60 min. To prepare a 0 minute sample with cofactor (NADPH), 16.25. mu.L of the preincubation mix was combined with 200. mu.L of acetonitrile containing an internal standard and 8.75. mu.L of cofactor (NADPH). To prepare the incubation mixture, 62. mu.L of cofactor (2.85mM) were combined with the remaining incubation mixture and incubated at 37 ℃ for 60 minutes. To prepare the sample mixture to be evaluated, 25 μ L of the incubation mixture was combined with 200 μ L of acetonitrile containing the internal standard and vortexed at 1200rpm for 5 minutes, then centrifuged at 4000rpm for 10 minutes. The supernatant was diluted 2-fold with water and injected onto LC-MS/MS. The sample mixture was evaluated by LC-MS/MS using 10mM ammonium acetate and 0.1% FA as aqueous mobile phase and methanol as organic mobile phase.

Half-life mouse microsomes: compounds were evaluated in mouse liver microsomes following a procedure similar to that described above for human liver microsomes. Similar procedures can be used to evaluate compounds in rat liver microsomes. The results are presented in table 1 below.

Table 1. data for selected compounds. Items A-F are the effect of compounds on gene expression in HepG2 cells. A: ACACA; b: ACLY; c: FASN; d: LSS: e: PNPLA 3; f: and (4) totalizing. For gene expression at the tested doses, 0-0.309 ═ + + +, 0.31-0.7509 ═ + +, >0.751 ═ q +. Entries G and H are the half-life of the liver microsomes (percent rem at 60 min; G is human, H is mouse), where 0-30 ═ c; 30.1-60 ++; more than or equal to 60.1 ++. Entry I was used in a reporter screening assay (Ave EC50(nM)), where 0-249 ═ + + +, 250-.

Biological example 2: dynamic solubility

Kinetic solubility program: a 10mM stock solution of the compound was prepared in DMSO, then 4 μ Ι _ of the stock solution was added to a deep well plate containing 396 μ Ι _ of pH 7.4 buffer. The sample plate was vortexed at 800rpm on a hot mixer for 24 hours at room temperature. During incubation, the plates were well sealed. The content of dimethyl sulfoxide (DMSO) in the sample was 1.0%. The concentration of the evaluation compound in the final incubation was 100. mu.M. At the end of the incubation period, the sample plates were centrifuged at 4000rpm for 10 minutes and analyzed in LC-UV against a Calibration Curve (CC).

Biological example 3: SREBP treated Western blot

The effect of selected compounds on SREBP treatment and activation was assessed by western blotting in HepG2 cells. The cells were washed with 8e⁶Was inoculated in 150mm plates in DMEM (Dulbecco's modified eagle's medium) supplemented with 10% (V/V) heat-inactivated FBS (fetal bovine serum), penicillin G (100 units/ml) and gentamicin (0.2 mg/ml). After overnight incubation, it was washed twice in PBS, and then DMEM medium containing 0% FBS and 500nM compound was added to the plate. Cells were incubated at 37 ℃. After 48 hours, cells were washed and lysed to obtain cytoplasmic and nuclear extracts for western blotting to measure SREBP expression as well as topoisomerase I as loading controls.

Biological example 4: adipocyte differentiation and oil red-O staining

The effect of selected compounds on adipocyte differentiation of human preadipocytes and 3T3-L1 cells was evaluated.

Human preadipocyte differentiation: in preadipocyte Medium (ZenBio) according to the manufacturer's instructionsAt 40,625 cells/cm²Thawing and seeding the cells. The cells were allowed to reach confluence for 48 hours and the medium was changed to adipocyte differentiation medium (ZenBio corporation) for 7 days. The medium was then changed to adipocyte maintenance medium (ZenBio corporation) for another 7 days. The compounds to be evaluated are added to the cells on days 1-7 during differentiation or on days 7-14 during maturation. The cells were then stained with oil red-O, as described below.

NIH 3T3-L1 cell differentiation: cells were thawed into preadipocyte medium (ZenBio) and grown to 80-85% confluence. Cells were seeded at 50,000 cells/well into 96-wp in preadipocyte medium (ZenBio Inc.) and allowed to reach confluence for 48-72 hours. It was grown for another 48 hours after reaching confluence, and then the medium was changed to a differentiation medium (ZenBio corporation) and incubated for 72 hours. The medium was changed to adipocyte differentiation medium (ZenBio corporation) using 150 microliters/well in 96-wp for 72 hours, and then the medium was removed and replaced with 150 microliters of adipocyte maintenance medium for another 8-14 days, feeding the cells every 2-3 days. The compounds to be evaluated are added to the cells on days 3-6 during differentiation or on days 7-14 during maturation. The cells were then stained with oil red-O, as described below.

Oil red-O staining: after maturation of the cells, they were washed and then fixed in 10% formalin for 30-60 minutes. Formalin was removed, cells were washed twice in water, and then cells were incubated in 60% isopropanol for 5 minutes. The isopropanol was removed and the oil red-O solution was added for 20 minutes while gently swirling the plate. Stain was removed, cells were washed twice with water, and hematoxylin was added for 1 minute. The cells were washed twice with water and air-dried, and then images were obtained.

Biological example 5: log D of Compounds

Log D of selected compounds was assessed by octanol/aqueous buffer partitioning. 500 μ L of the organic phase (1-octanol) was added to each well of a 2mL deep well plate followed by 500 μ L of buffer and 15 μ L of DMSO (0.15mM) solution of the test compound. Plates were vortexed for 10 seconds and incubated at 200rpm for 1 hour at room temperature on a plate shaker. After incubation, the samples were allowed to equilibrate for 20 minutes and then centrifuged at 4000rpm for 30 minutes to achieve complete phase separation. Distribution of the test compound in the buffer and octanol phases was analyzed by HPLC-UV. Log D ═ Log (octanol area/buffer area).

Biological example 6: in vivo Activity assay

The ob/ob mouse model can be used to assess the in vivo effects of selected compounds. Ob/Ob mice are a well characterized model of obesity, fatty liver and diabetes caused by mutations in the Ob gene encoding leptin.

The compounds were administered once or twice daily for 4 weeks in male ob/ob mice by the oral route. Body weight and food and water intake were assessed daily and improvement in glycemic control was assessed by plasma glucose and insulin measurements. After the end of the test period, terminal blood samples were taken and analyzed for triglyceride, cholesterol (total, HDL-C and LDL-C), Blood Urea Nitrogen (BUN), alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) levels. Liver and fat pad weights were determined and liver tissues were processed for histological determination of NASH activity scores (NAS: ballooning, inflammation, steatosis and fibrosis). Liver levels of triglycerides, cholesterol and non-esterified fatty acids (NEFA) were also determined.

Biological example 7: evaluation of in vivo pharmacokinetic Properties of Compounds

The in vivo pharmacokinetic properties of compounds administered intravenously and orally were evaluated in male Sprague Dawley rats or C57BL/6J mice.

Animals were housed in cages with clean bedding. Providing a certified rodent diet. Water is available ad libitum. Environmental control of the animal house was set to maintain a temperature of 22 ℃ to 25 ℃, humidity of 40-70% RH and 12 hour light/12 hour dark cycle. Normal healthy animals, certified by the attending veterinarian, were selected and acclimatized for at least three days prior to the start of the study.

Rat jugular vein cannulation surgery: rats were anesthetized by a single intraperitoneal injection of 50mg/kg ketamine plus 6mg/kg xylazine. The right jugular vein was exposed, a loose ligature placed caudally, and the cranial end of the vein was ligated. A small incision was made between the ligatures inserted in a catheter (polyethylene 50 tubing with an inner diameter of 0.58mm and an outer diameter of 0.96 mm). The catheter is secured in place by tying a loose ligature around the vessel in which it is inserted. A small incision was made in the scapular region to serve as the exit site for the catheter. The catheter is tunneled and externalized subcutaneously through a scapula incision. The abutment sutures were placed in the scapular region. Patency was tested and the catheter was filled with a blocking solution (heparinized saline) and sealed with a stainless steel plug. The incision is then sutured with sterile suture material. The suture sites were coated with an antimicrobial solution and the animals were returned to their home cages.

To evaluate the pharmacokinetic properties of intravenous delivery, male slogregator dorey rats were administered 2.00mg of compound per kg of animal body weight via the tail vein. Concentrations of compounds in animal plasma were assessed at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours by taking blood samples from the cannulated jugular vein.

To assess the pharmacokinetic profile of oral delivery, 10mg of compound per kg of animal body weight was orally administered to rats (male slogregator dore rats) or mice (C5 Bl/6J). Compound concentrations in animal plasma were assessed at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours by taking blood samples from the cannulated jugular vein (rat) or by capillary vessels leading in the retroorbital plexus (mouse).

Biological example 8: evaluation of the Effect of Compounds on mouse liver Gene expression

The pharmacodynamic profile of the selected compounds was evaluated in mice. Animals were housed in cages with clean bedding and their health status was maintained and monitored according to the SOP of the test facility and the judgment of the laboratory animal veterinarian. Providing a certified rodent diet. Food and water are available ad libitum. Environmental control of the animal house was set to maintain a temperature of 22 ℃ to 25 ℃, humidity of 40-70% RH and 12 hour light/12 hour dark cycle. Normal healthy animals, certified by the attending veterinarian, were selected and acclimatized for at least three days prior to the start of the study. Animals are identified with body markers.

An aliquot of the compound being evaluated was weighed and ground to the appropriate dosage concentration with 0.5% methylcellulose (5% N-methylpyrrolidone added when removal of lumps is required). Information on study number, test item, concentration and preparation date was attached to the vial. A description of the appearance of the formulation (e.g., color, turbidity, etc.) is recorded. The composition of the formulation vehicle was recorded. Aliquots of each dosage solution were taken before the start of administration and after the end of administration and stored at a temperature of about-20 ℃ or less for subsequent analysis. Animals were dosed orally by oral gavage and the time of dosing was recorded.

After dosing, mice were anesthetized using gaseous anesthesia. Blood samples were collected at 6 hours or 24 hours via capillary vessels leading in the retroorbital plexus. Approximately 100uL of blood was collected from each mouse and placed in a pre-labeled tube. The collected blood was stored on ice prior to centrifugation. Blood samples were then centrifuged to separate plasma within 1 hour after collection. Centrifugation was carried out at 2500 x g for 15 minutes at 4 ℃. The plasma was separated and transferred to pre-labeled microcentrifuge tubes and rapidly frozen at-80 ± 10 ℃ until bioanalysis.

Liver was collected at 6 or 24 hours: liver tissue was collected immediately after blood draw for pharmacokinetic assessment (6 or 24 hours) without perfusion. In CO₂The animals were euthanized with carbon dioxide gas in the chamber. Whole blood was removed by cutting the bilateral jugular vein and the abdominal aorta. The liver was isolated. All liver samples were divided into two parts. The first fraction (approximately 200mg) was snap frozen as soon as possible using liquid nitrogen. These samples were immediately transferred to-80 ℃ for storage. The remaining portion was weighed and used for biological analysis.

RNA treatment and gene expression analysis: liver tissue RNA was collected using RNEasy kit and cDNA was synthesized using 20-100ng of random primers according to the manufacturer's protocol. Quantitative PCR was performed on 1pg to 100ng cDNA of the following genes: ACACA, ACLY, FASN, LSS, PNPLA 3. Gene expression levels were determined using the Δ Δ CT method, which compares the treated samples to the vector treated samples as baseline and calculates fold changes. The mean of all 5 genes above was averaged and referred to as the total fold change.

Biological example 9: evaluation of the Effect of Compounds on growth inhibition of cancer cells

Selected compounds were evaluated for their ability to inhibit cell growth in various cancer cell lines. Treatment of cells with a dose of compound ranging from 10uM to 1pM to generate an IC for growth inhibition of cell lines ₅₀Curve line. The cell lines shown in table 2 show at least a 50% reduction in growth at 10uM or less after 72 hours of treatment in growth medium. Cell lines shown in Table 3 are IC₅₀Growth was reduced by at least 50% at >10 uM.

Six 10-fold dilutions of the compound (e.g., 10mM, 1mM, 100uM, 10uM, 1uM, and 0.1uM) were prepared in DMSO. A single data point was obtained for each concentration. The final concentration of DMSO was 0.1%. The duration of the treatment was 72 hours. Growth inhibition was measured in a protein staining assay using sulforhodamine B. The activity of the agent is determined by evaluating the following parameters: IC (integrated circuit)₅₀、GI₅₀、IC₁₀、TGI、LC₅₀、IC₉₀And GI₉₀(these values can be calculated).

Table 2: responsive cell line with IC50<10uM

Table 3: IC50>10uM or unidentified non-responsive cell lines

131页详细技术资料下载

上一篇：一种医用注射器针头装配设备

下一篇：使用KDM1A抑制剂如化合物伐菲德司他治疗注意缺陷多动症的方法

SREBP inhibitors comprising a thiophene central ring

相关技术

网友询问留言