Macrocyclic compounds as ROS1 kinase inhibitors

文档序号：1509440 发布日期：2020-02-07 浏览：19次中文

阅读说明：本技术 作为ros1激酶抑制剂的大环化合物 (Macrocyclic compounds as ROS1 kinase inhibitors ) 是由 S.W.安德鲁斯 J.F.布莱克 J.哈斯 G.R.科拉科夫斯基于 2018-03-16 设计创作，主要内容包括：用式I的化合物和其药学上可接受的盐抑制ROS1激酶的方法,其中环A、环B、W、m、D、R2、R2a、R3、R3a和Z如本文定义。本文提供的化合物和方法可用于治疗癌症(例如,如本文定义的ROS1相关癌症)。<Image he="175" wi="230" file="344296DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A method of inhibiting ROS1 kinase with a compound of formula I, and pharmaceutically acceptable salts thereof, wherein Ring A, Ring B, W, m, D, R 2 、R 2a 、R 3 、R 3a And Z is as defined herein. The compounds and methods provided herein are useful for treating cancer (e.g., ROS 1-related cancer, as defined herein).)

1. A method for treating cancer in a patient in need thereof, the method comprising:

(a) detecting that the patient's cancer is associated with dysregulation of the expression or activity or level of ROS1 gene, ROS1 kinase, or any of them; and

(b) administering to the patient a therapeutically effective amount of a ROS1 inhibitor, wherein the ROS1 inhibitor is a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

R^4bis H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C) alkyl, dihydroxy (2-6C) alkyl, (1-6C) alkyl, (O) cycloalkyl, (3-6C cycloalkyl) C (O), Ar¹C(O)-、HOCH₂C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, Ar²(SO₂)-、HO₂CCH₂-or (1-6C alkyl) NH (CO) -;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

2. The method of claim 1, wherein the method further comprises administering a second ROS1 inhibitor.

3. The method of claim 2, wherein the second ROS1 inhibitor is administered before the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

4. The method of claim 2, wherein the second ROS1 inhibitor is administered after the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

5. The method of claim 2, wherein the second ROS1 inhibitor is administered with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

6. The method of claim 5, wherein the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and the second ROS1 inhibitor are administered simultaneously as separate doses.

7. The method of any one of claims 1-6, wherein the method further comprises administering an ALK inhibitor.

8. The method of claim 7, wherein the ALK inhibitor is administered prior to the compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

9. The method of claim 7, wherein the ALK inhibitor is administered after the compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

10. The method of claim 7, wherein the ALK inhibitor is administered with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

11. The method of claim 10, wherein the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and the ALK inhibitor are administered simultaneously as separate doses.

12. The method of any one of claims 1-11, wherein the method further comprises administering a TRK inhibitor.

13. The method of claim 12, wherein the TRK inhibitor is administered prior to the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

14. The method of claim 12, wherein the TRK inhibitor is administered after the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

15. The method of claim 12, wherein the TRK inhibitor is administered with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

16. The method of claim 12, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and the TRK inhibitor are administered simultaneously as separate doses.

17. A method of treating cancer in a patient in need thereof, the method comprising administering to a patient identified or diagnosed as having a ROS 1-associated cancer a therapeutically effective amount of a ROS1 inhibitor, wherein the ROS1 inhibitor is a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

18. A method of treating cancer in a patient in need thereof, the method comprising:

(a) detecting that the cancer in the patient is a ROS 1-associated cancer; and

(b) administering a therapeutically effective amount of a ROS1 inhibitor to a patient determined to have a ROS 1-associated cancer, wherein the ROS1 inhibitor is a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C)) Alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

19. A method of treating a subject having cancer, wherein the method comprises:

(a) administering to the subject a first ROS1 inhibitor;

(b) determining whether cancer cells in a sample obtained from the subject have one or more ROS1 inhibitor resistance mutations after (a); and

(c) administering a second ROS1 inhibitor to the subject as monotherapy or in combination with another anti-cancer agent if the subject has cancer cells containing one or more ROS1 inhibitor resistance mutations, wherein the second ROS1 inhibitor is a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl; or

(d) Administering to the subject an additional dose of the first ROS1 inhibitor of step (a) if the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations.

20. A method of treating a subject having cancer, wherein the method comprises:

(a) administering to the subject a first ALK inhibitor;

(b) determining whether cancer cells in a sample obtained from the subject have one or more ROS1 inhibitor resistance mutations after (a); and

(c) administering to a subject a compound of formula I as monotherapy or in combination with another anti-cancer agent if the subject has cancer cells containing one or more ROS1 inhibitor-resistant mutations

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkaneA group, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl; or

(d) Administering to the subject an additional dose of the first ALK inhibitor of step (a) if the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations.

21. A method of treating a subject having cancer, wherein the method comprises:

(a) administering to the subject a first TRK inhibitor;

(b) determining whether cancer cells in a sample obtained from the subject have one or more ROS1 inhibitor resistance mutations after (a); and

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

R^4bis H, (1-6C) alkyl, fluoro (1-6C) alkyl,Difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl), dihydroxy (2-6C alkyl), (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar¹C(O)-、HOCH₂C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, Ar²(SO₂)-、HO₂CCH₂-or (1-6C alkyl) NH (CO) -;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl; or

(d) Administering to the subject an additional dose of the first TRK inhibitor of step (a) if the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations.

22. A method of treating a subject having cancer, wherein the method comprises:

(a) determining whether cancer cells in a sample obtained from a subject having cancer and a previously administered first ROS1 inhibitor have one or more ROS1 inhibitor resistance mutations that increase the resistance of the cancer cell or tumor to treatment with the previously administered first ROS1 inhibitor to the subject; and

(b) administering to a subject a compound of formula I as monotherapy or in combination with another anti-cancer agent if the subject has a cancer cell containing one or more ROS1 inhibitor resistance mutations that increase the resistance of the cancer cell or tumor to treatment with a first ROS1 inhibitor previously administered to the subject

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

R^4bis H, (1-6C) alkyl, fluoro (1-6C) alkyl, diFluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl), dihydroxy (2-6C alkyl), (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar¹C(O)-、HOCH₂C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, Ar²(SO₂)-、HO₂CCH₂-or (1-6C alkyl) NH (CO) -;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl; or

(c) If the subject has a cancer cell that does not contain one or more ROS1 inhibitor resistance mutations that increase the resistance of the cancer cell or tumor to treatment with the first ROS1 inhibitor previously administered to the subject, the subject is administered an additional dose of the first ROS1 inhibitor.

23. A method of treating a subject having cancer, wherein the method comprises:

(a) determining whether cancer cells in a sample obtained from a subject having cancer and previously administered a first ALK inhibitor have one or more ROS1 inhibitor resistance mutations; and

(b) administering to a subject a compound of formula I as monotherapy or in combination with another anti-cancer agent if the subject has cancer cells containing one or more ROS1 inhibitor-resistant mutations

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

R^4bis H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C) alkyl, dihydroxy (2-6C) alkyl, (1-6C) alkyl, (O) -, (3-6C cycloalkyl) C(O)-、Ar¹C(O)-、HOCH₂C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, Ar²(SO₂)-、HO₂CCH₂-or (1-6C alkyl) NH (CO) -;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl; or

(c) If the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations, the subject is administered additional doses of the first ALK inhibitor.

24. A method of treating a subject having cancer, wherein the method comprises:

(a) determining whether cancer cells in a sample obtained from a subject having cancer and previously administered a first TRK inhibitor have one or more ROS1 inhibitor resistance mutations; and

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl; or

(c) If the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations, the subject is administered an additional dose of a first TRK inhibitor.

25. A method of treating a subject having cancer, wherein the method comprises:

(b) administering a second ROS1 inhibitor to the subject as monotherapy or in combination with another anti-cancer agent if the subject has a cancer cell containing one or more ROS1 inhibitor resistance mutations that increase the resistance of the cancer cell or tumor to treatment with the first ROS1 inhibitor previously administered to the subject; or

(c) If the subject has a cancer cell that does not contain one or more ROS1 inhibitor resistance mutations that increase the resistance of the cancer cell or tumor to treatment with a first ROS1 inhibitor previously administered to the subject, then an additional dose of the first ROS1 inhibitor previously administered to the subject is administered.

26. A method of treating a subject having cancer, wherein the method comprises:

(a) determining whether cancer cells in a sample obtained from a subject having cancer and a previously administered ALK inhibitor have one or more ROS1 inhibitor resistance mutations; and

(b) administering a ROS1 inhibitor to the subject as monotherapy or in combination with another anti-cancer agent if the subject has cancer cells that contain one or more ROS1 inhibitor resistance mutations; or

(c) If the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations, additional doses of the ALK inhibitor previously administered to the subject are administered.

27. A method of treating a subject having cancer, wherein the method comprises:

(a) determining whether cancer cells in a sample obtained from a subject having cancer and a previously administered TRK inhibitor have one or more ROS1 inhibitor resistance mutations; and

(c) If the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations, an additional dose of a TRK inhibitor previously administered to the subject is administered.

28. A method of treating a patient comprising administering to a patient having a clinical record indicating that the patient has a dysregulation of ROS1 gene, ROS1 kinase, or the expression or activity or level of any of them a therapeutically effective amount of a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

29. A method of selecting a treatment for a patient, the method comprising selecting a treatment for a patient identified or diagnosed as having an ROS 1-associated cancer, the treatment comprising administering a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

30. A method of selecting a treatment for a patient having cancer, the method comprising:

(a) determining whether the cancer of the patient is a ROS 1-associated cancer; and

(b) selecting a treatment for a patient determined to have an ROS 1-associated cancer, the treatment comprising administering a therapeutically effective amount of a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl group having 1-2 ring heteroatomsA ring;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

31. A method of selecting a patient for treatment comprising administering a therapeutically effective amount of a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl,

the method comprises the following steps:

(d) the patient is selected for treatment comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

32. A method of selecting a patient having cancer for treatment comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising:

(a) determining whether the cancer of the patient is a ROS 1-associated cancer; and

(b) selecting a patient determined to have a ROS 1-associated cancer for treatment comprising administering a therapeutically effective amount of a compound of formula I

Or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of connection of ring a to ring B and wavy line indicia 2 indicates the point of connection of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

ring B is selected from rings B-1 and B-2 having the following structures:

wherein wavy line indicia 3 indicates the point of attachment to ring A and wavy line indicia 4 indicates the point of attachment to the pyrazolo [1,5-a ] pyrimidine ring of formula I;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

d is carbon, R²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently is H, (1-3C) alkyl or hydroxy (1-3C) alkyl, or

D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

33. The method of any one of claims 1, 18, and 30-32, wherein the step of detecting that the cancer in the patient is an ROS 1-related cancer or determining whether the cancer in the patient is an ROS 1-related cancer comprises performing an assay in a sample from the patient to detect a dysregulation in the expression or activity or level of an ROS1 gene, an ROS1 kinase protein, or any of them.

34. The method of claim 33, further comprising obtaining a sample from the patient.

35. The method of claim 34, wherein the sample is a biopsy sample.

36. The method of any one of claims 33-35, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and Fluorescence In Situ Hybridization (FISH).

37. The method of claim 36, wherein said assay is split FISH.

38. The method of claim 36, wherein the assay is double fusion FISH.

39. The method of claim 36, wherein the sequencing is pyrosequencing or next generation sequencing.

40. The method of any one of claims 33-39, wherein the deregulated expression or activity or level of ROS1 gene, ROS1 kinase protein, or any of them, is one or more point mutations of ROS1 gene.

41. The method of claim 40, wherein the one or more point mutations in the ROS1 gene result in translation of the ROS1 protein having one or more amino acid substitutions at one or more of the following amino acid positions: 15. 118, 1025, 1735, 1948, or 2072.

42. The method of claim 41, wherein the one or more point mutations in the ROS1 gene result in translation of the ROS1 protein with one or more of the following amino acid substitutions: a15G, R118N, G1025R, T1735M, R1948H, or R2072N.

43. The method of claim 40, wherein the one or more point mutations in the ROS1 gene result in translation of the ROS1 protein having one or more amino acid substitutions at one or more of the following amino acid positions: 1935. 1945, 1946, 1947, 1948, 1951, 1958, 1959, 1961, 1962, 1971, 1974, 1981, 1982, 1986, 1990, 1993, 1994, 2000, 2002, 2004, 2008, 2009, 2010, 2011, 2016, 2019, 2020, 2022, 2026, 2028, 2029, 2030, 2032, 2033, 2035, 2036, 2039, 2040, 2052, 2059, 2060, 2075, 2077, 2078, 2087, 2081, 2092, 2094, 2098, 2099, 2100, 2101, 2106, 2107, 2182, 2113, 2116, 2125, 2127, 2128, 2131, 2134, 2139, 2141, 2142, 2148, 2151, 2154, 2155, 2160, 2165, 2201, 2204, 2202, 2205, 2187, 2183, 2203, 2204, 2184, 2187, 2184, 2183 or 2204.

44. The method of claim 43, wherein the one or more point mutations in the ROS1 gene result in translation of the ROS1 protein with one or more of the following amino acid substitutions: e1935, L1945, T1946, L1947, R1948, L1951, E1958, V1959, E1961, G1962, G1971, E1974, T1981, L1982, S1986, E1990, E1993, F1994, L2000, S2002, F2004, N2008, I2009, L2010, K2011, C2016, N2019, E2020, Q2022, L2026, L2028, M2029, E2030, G2032, D3, D2033, L2035, T2036, R2039, K2040, T2222, L2059, C2050, F2055, F2155, T2156, R2039, R2220, K2040, T2222, L2059, F2050, F2055, F2158, V2152, V2201, V2202, V2204, V2202, V2204, V2202, V2204, V2134, V2202, V2204, V2202, V2134, V2.

45. The method of any one of claims 33-39, wherein the dysregulation of the expression or activity or level of ROS1 gene, ROS1 kinase protein, or any of them is a ROS1 gene fusion.

46. The method of claim 45, wherein the ROS1 gene fusion is selected from the group consisting of: CD74, SLC34A2, TPM3, SDC4, EZR, LRIG3, KDELR2, CCDC6, FIG, GOPC, PIST, TPD52L1, CEP85L, ZCCHC8, CCDC30, TFG, TMEM106B, YWHAE, MSN, PWWP2A, FYN, MKX, PPFIBP1, ERCl, MY05A, CLIP1, HLA-A, KIAA1598, CLTC, LIMA1, NFkB2 and NCOR 2.

47. The method of any one of claims 1, 18, and 30-46, wherein the ROS 1-associated cancer is selected from the group consisting of: lung cancer, colorectal cancer, gastric cancer, adenocarcinoma, small intestine adenocarcinoma, bile duct cancer, glioblastoma, ovarian cancer, vascular cancer, congenital glioblastoma multiforme, papillary thyroid carcinoma, inflammatory myofibroblast tumors, spitzoid neoplasms, anaplastic large cell lymphoma, diffuse large B cell lymphoma, and B cell acute lymphoblastic leukemia.

48. The method of any one of claims 1-47, wherein the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

49. The method of any one of claims 1-48, further comprising administering to the patient an additional therapy or therapeutic agent.

50. The method of claim 49, wherein the additional therapy or therapeutic agent is selected from the group consisting of radiation therapy, cytotoxic chemotherapeutic agents, kinase-targeted therapeutic agents, apoptosis modulators, signal transduction inhibitors, immune-targeted therapy, and angiogenesis-targeted therapy.

51. The method of claim 50, wherein the additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents.

52. The method of any one of claims 49-51, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are administered simultaneously as separate doses.

53. The method of any one of claims 49-51, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are administered sequentially, in any order, as separate doses.

54. The method of any one of claims 1-60, wherein the compound of formula I is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from rings A-1, A-2 and A-3 having the following structures:

wherein wavy line indicia 1 indicates the point of attachment of ring a to the pyrrolidine ring of formula I, and wavy line indicia 2 indicates the point of attachment of ring a to W;

x is N or CH;

y is H or F;

R¹is H, (1-3C) alkoxy or halogen;

w is O, NH or CH₂Wherein when ring A is A-2, then W is CH₂；

m is 0, 1 or 2;

R²and R^2aIndependently H, F or OH, provided that R²And R^2aNot all are OH;

R³is H, (1-3C) alkyl or hydroxy (1-3C) alkyl;

z is-NR^4aC(=O)-、*-ONHC(=O)-、*-NR^4bCH₂-or-OC (= O) -, where the asterisks indicate Z and the ring with R³The point of attachment of carbon (b);

R^4ais H, (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl);

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and

R⁵and R⁶Independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.

55. The method of any one of claims 1-54, wherein Ring A is Ring A-1 having the structure:

56. the method of any one of claims 1-55, wherein X is CH.

57. The method of any one of claims 1-55, wherein X is N.

58. The method of any one of claims 1-54, wherein Ring A is Ring A-3 having the structure:

59. the method of any one of claims 1-58, wherein W is O.

60. The method of any one of claims 1-58, wherein W is NH.

61. The method of any one of claims 1-58, wherein W is CH₂。

62. The method of any one of claims 1-54, wherein Ring A is Ring A-2 having the structure:

63. the method of any one of claims 1-62, wherein Y is F.

64. The method of any one of claims 1-62, wherein Y is H.

65. The method of any one of claims 1-64, wherein R¹Is H.

66. The method of any one of claims 1-64, wherein R¹Is (1-3C) alkyl or (1-3C) alkoxy.

67The method of claim 66, wherein R¹Is methyl or methoxy.

68. The method of any one of claims 1-64, wherein R¹Is a halogen.

69. The method of claim 68, wherein R¹Is fluorinated.

70. The method of any one of claims 1-69, wherein Z is-NR^4aC(=O)-。

71. The method of claim 70, wherein R^4aIs hydrogen.

72. The method of claim 70, wherein R^4aIs (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl, trifluoro (1-6C) alkyl, hydroxy (1-6C alkyl) or dihydroxy (2-6C alkyl).

73. The method of claim 72, wherein R^4aIs (1-6C) alkyl.

74. The method of any one of claims 1-69, wherein Z is-ONHC (= O) -.

75. The method of any one of claims 1-69, wherein Z is-NR^4bCH₂-。

76. The method of claim 75, wherein R^4bIs H.

77. The method of claim 75, wherein R^4bSelected from the group consisting of (1-6C) alkyl, fluoro (1-6C) alkyl, difluoro (1-6C) alkyl and trifluoro (1-6C) alkyl.

78. The method of claim 77, wherein R^4bIs (1-6C) alkyl.

79. In the application ofThe method of claim 77, wherein R^4bSelected from (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar¹C (O) -and HOCH₂C(O)-。

80. The method of claim 79, wherein R^4bIs (1-6C alkyl) C (O) -.

81. The method of claim 75, wherein R^4bSelected from (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl and Ar²(SO₂)-。

82. The method of claim 81, wherein R^4bIs a (1-6C alkyl) sulfonyl group.

83. The method of claim 75, wherein R^4bIs HO₂CCH₂-。

84. The method of claim 75, wherein R^4bIs (1-6C alkyl) NH (CO) -.

85. The method of any one of claims 1-60, wherein D is carbon and R is²And R^2aIndependently H, F, (1-3C) alkyl or OH (provided that R²And R^2aNot all OH), and R³And R^3aIndependently H, (1-3C) alkyl or hydroxy (1-3C) alkyl.

86. The method of any one of claims 1-85, wherein R²And R^2aEach is hydrogen.

87. The method of any one of claims 1-85, wherein R²And R^2aEach is fluoro.

88. The method of any one of claims 1-85, wherein R²Is hydrogen and R^2aIs fluorinated.

89. The method of any one of claims 1-85, whereinR²Is hydrogen and R^2aIs OH.

90. The method of any one of claims 1-85, wherein R²Is H and R^2aIs methyl, or R²And R^2aAre both methyl groups.

91. The method of any one of claims 1-60, wherein:

R³and R^3aIs H; or

R^3aIs methyl and R³Is H; or

R³And R^3aAre both methyl groups.

92. The method of any one of claims 1-60, wherein D is carbon or nitrogen, R²And R³Is absent, and R^2aAnd R^3aTogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.

93. The method of any one of claims 1-60, wherein ring B is ring B-1:

R⁵and R⁶Independently H, F, OH, methyl, ethyl, HOCH₂-or HOCH₂CH₂-。

94. The method of any one of claims 1-93, wherein R⁵Is hydrogen and R⁶Is H, F, OH, methyl, ethyl, HOCH₂-or HOCH₂CH₂-。

95. The method of any one of claims 1-93, wherein R⁶Is H.

96. The method of any one of claims 1-60, wherein ring B is ring B-2:

97. the method of any one of claims 1-96, wherein m is 0.

98. The method of any one of claims 1-96, wherein m is 1.

99. The method of any one of claims 1-96, wherein m is 2.

100. The method of any one of claims 1-60, wherein the compound has the absolute configuration of formula 1-a:

101. the method of any one of claims 1-60, wherein the compound has the absolute configuration of formula 1-b:

102. the method of any one of claims 1-60, wherein the compound is selected from the group consisting of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

103. The method of any one of claims 1-60, wherein the compound is selected from example nos. 2, 3, 7, 9, 14, 19, 20, 22, 33-A, 33-B, 35, 36, and 45, or a pharmaceutically acceptable salt or solvate thereof.

Technical Field

Provided herein are compounds and pharmaceutical compositions comprising the compounds as well as the use of the compounds in therapy. More specifically, provided herein are certain macrocyclic compounds that exhibit ROS1 protein kinase inhibition and are useful for the treatment of cancer.

Background

ROS1 is a receptor tyrosine kinase closely related to ALK and, like ALK, it undergoes genomic rearrangements to produce fusion proteins in various cancers (Davies KD and Doebele RC (2013) Clin Cancer Res 19: 4040-4045). It is well established that these fusion proteins function as oncogenic propellents and that ROS1 inhibition is antiproliferative in cells expressing ROS1 fusions (Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL et al (2012) Clin Cancer Res 18: 4570-. Thus, it appears likely that ROS 1-targeted therapy will soon be the standard of care for this patient population. However, based on experience with other kinase inhibitors in various cancers, it is fully expected that resistance will be acquired to ROS1 inhibition, and this will ultimately limit the treatment options for the patient.

Brief description of the drawings

It has now been found that macrocyclic compounds are inhibitors of ROS1 kinase and are useful in the treatment of various cancers. Compounds that are inhibitors of ROS1 are useful for the treatment of various types of cancer, including cancers that exhibit resistance to ROS1 inhibition.

Thus, in one aspect of the disclosure, provided are methods comprising administering a ROS1 inhibitor, wherein the ROS1 inhibitor is a compound of formula I

Or a pharmaceutical thereofA pharmaceutically acceptable salt or solvate thereof, wherein ring A, ring B, W, m, D, R²、R^2a、R³、R^3aAnd Z is as defined herein.

In some embodiments, the compounds of formula I have the general formula (la):

or a pharmaceutically acceptable salt or solvate thereof, wherein ring A, W, m, R²、R^2a、R³And Z is as defined herein.

In some embodiments, the compound of formula I is selected from the compounds of table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula I is selected from example nos. 2,3, 7,9, 14, 19,20, 22, 33-a, 33-B, 35, 36, and 45, or a pharmaceutically acceptable salt or solvate thereof.

Provided herein is a method of treating cancer in a patient in need thereof, the method comprising:

(a) determining whether the cancer is associated with a dysregulation of the expression or activity or level of ROS1 gene, ROS1 kinase, or any of them; and

(b) administering to the patient a therapeutically effective amount of a ROS1 inhibitor if the cancer is determined to be associated with a dysregulation of the expression or activity or level of ROS1 gene, ROS1 kinase, or any one thereof, wherein the ROS1 inhibitor is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

Provided herein is a method of treating cancer in a patient in need thereof, the method comprising:

(a) detecting that the cancer is associated with a dysregulation of the expression or activity or level of ROS1 gene, ROS1 kinase, or any of them; and

(b) administering to the patient a therapeutically effective amount of a ROS1 inhibitor, wherein the ROS1 inhibitor is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a method of treating cancer in a patient in need thereof, the method comprising administering to a patient identified or diagnosed as having a ROS 1-associated cancer a therapeutically effective amount of a ROS1 inhibitor, wherein the ROS1 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments of the present disclosure, a method of treating cancer in a patient in need thereof is provided. The method comprises the following steps:

(a) determining whether the cancer of the patient is a ROS 1-associated cancer; and

(b) administering a therapeutically effective amount of a ROS1 inhibitor to a patient determined to have a ROS 1-associated cancer, wherein the ROS1 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments of the present disclosure, a method of treating cancer in a patient in need thereof is provided. The method comprises the following steps:

(a) detecting that the cancer in the patient is a ROS 1-associated cancer; and

Further provided herein is a method of treating a subject having cancer, wherein the method comprises:

(a) administering to the subject a first ROS1 inhibitor;

(b) determining whether cancer cells in a sample obtained from the subject have one or more ROS1 inhibitor resistance mutations after (a); and

(c) administering a second ROS1 inhibitor to the subject as monotherapy or in combination with another anti-cancer agent, if the subject has a cancer cell that contains one or more ROS1 inhibitor resistance mutations, wherein the second ROS1 inhibitor is a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof; or

(d) Administering to the subject an additional dose of the first ROS1 inhibitor of step (a) if the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations.

Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

(a) administering to the subject a first ALK inhibitor;

(b) determining whether cancer cells in a sample obtained from the subject have one or more ROS1 inhibitor resistance mutations after (a); and

(c) administering to the subject a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anti-cancer agent, if the subject has cancer cells that contain one or more ROS1 inhibitor resistant mutations; or

(d) Administering to the subject an additional dose of the first ALK inhibitor of step (a) if the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations.

In some embodiments, provided herein is a method of treating a subject having cancer, wherein the method comprises:

(a) administering to the subject a first TRK inhibitor;

(b) determining whether cancer cells in a sample obtained from the subject have one or more ROS1 inhibitor resistance mutations after (a); and

(d) Administering to the subject an additional dose of the first TRK inhibitor of step (a) if the subject has cancer cells that do not contain one or more ROS1 inhibitor resistance mutations.

Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

(b) administering to the subject a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anti-cancer agent, if the subject has a cancer cell that contains one or more ROS1 inhibitor resistance mutations that increase the resistance of the cancer cell or tumor to treatment with the first ROS1 inhibitor previously administered to the subject; or