Benzothiophene estrogen receptor modulators for the treatment of medical disorders

文档序号：589425 发布日期：2021-05-25 浏览：18次中文

阅读说明：本技术 用于治疗医学疾病的苯并噻吩雌激素受体调节剂 (Benzothiophene estrogen receptor modulators for the treatment of medical disorders ) 是由 J·C·斯特鲁姆于 2019-08-16 设计创作，主要内容包括：本发明是苯并噻吩雌激素受体调节剂或其药学上可接受的盐,N-氧化物,同位素衍生物或其前药或其药学上可接受的组合物,用以治疗雌激素相关医学疾病。如本文中更详细描述的,本发明还包括其与另一种活性剂的组合,用以治疗由雌激素受体介导的疾病,所述另一种活性剂例如CDK抑制剂,包括CDK4/6抑制剂。(The present invention is a benzothiophene estrogen receptor modulator, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, or a pharmaceutically acceptable composition thereof, for the treatment of estrogen-related medical conditions. As described in more detail herein, the present invention also includes combinations thereof with another active agent, such as CDK inhibitors, including CDK4/6 inhibitors, for the treatment of estrogen receptor-mediated disorders.)

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof;

wherein

A is as follows:

y is:

z is:

m is 1,2 or 3;

n is 0,1, 2,3 or 4;

o is 0,1, 2,3,4 or 5;

each Q is independently selected from-CHR⁵-and-CH₂-；

Z¹is-O-, -C (R)³)₂-or-S-;

Z²is a bond, -O-, -C (R)³)₂-or-S-;

Z³is-O-or-S-;

each R¹Is independently selected fromC₁-C₅Alkyl, halogen and C₁-C₃A haloalkyl group;

R²selected from hydroxy, alkoxy, -NH- (CH)₂)_n1-NR⁶R⁷，-NR⁶R⁷4-10 membered monocyclic heterocyclic ring and 6-12 membered bicyclic heterocyclic ring; wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Substituted with a group of (1);

n1 is 2,3,4, 5 or 6;

each R³Independently selected from hydrogen, halogen, C₁-C₃Alkyl and C₁-C₃A haloalkyl group;

each R⁴And R⁵Independently selected from hydrogen, halogen, C₁-C₅Alkyl radical, C₁-C₅Haloalkyl, -COOH, -COOC₁-C₅Alkyl, -CONH₂-CON (H) alkyl and-CON (alkyl)₂；

Or two R on the same carbon atom⁴The substituents optionally being taken together with the carbon to which they are attached to formA group wherein n3 is 1,2,3,4 or 5;

R⁶and R⁷Independently at each occurrence, selected from hydrogen, C₁-C₁₂Alkyl and C₂-C₁₂A haloalkyl group;

R⁸selected from the group consisting of-C (O) R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂；

R⁹Selected from hydrogen, C₁-C₅Alkyl, -OR⁶and-NR⁶R⁷；

Each R¹⁰Independently selected from hydrogen, C₁-C₅Alkyl and-C (O) C₁-C₅An alkyl group;

R¹¹is a 4-10 membered monocyclic heterocycle or a 6-12 membered bicyclic heterocycle; wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Substituted with the substituent(s);

R¹²is a 4-10 membered monocyclic heterocycle or a 6-12 membered bicyclic heterocycle; wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴And wherein the heterocyclic ring is attached through a carbon atom;

R¹³selected from hydroxy, -C (O) R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂；

R¹⁴，R¹⁵And R¹⁶Independently selected from hydrogen, C₁-C₅Alkyl, halogen and C₁-C₃A haloalkyl group; wherein R is¹⁴，R¹⁵And R¹⁶At least one of them is C₁-C₅Alkyl, halogen or C₁-C₃A haloalkyl group.

2. The compound of claim 1, wherein two R on the same carbon atom⁴The substituents being bound together with the carbon to which they are attached to formA group wherein n3 is 1,2,3,4 or 5.

3. The compound of claim 1, wherein no R⁴The substituents are bound together with the carbon to which they are attached.

4. The compound of any one of claims 1-3, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, wherein A is

6. The compound of claim 4, wherein A is

7. The compound of claim 4, wherein A is

8. The compound of any one of claims 1-7, wherein R⁸is-C (O) R⁹。

9. The compound of any one of claims 1-7, wherein R⁸is-OC (O) R⁹。

10. The compound of any one of claims 1-7, wherein R⁸is-OP (O) (OR)¹⁰)₂。

11. The compound of any one of claims 1-3, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, wherein Y is

13. In the application ofThe compound of claim 11 wherein Y is

14. The compound of any one of claims 1-3, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein Z is

16. The compound of claim 14, wherein Z is

17. The compound of claim 14, wherein Z is

18. The compound of claim 14, wherein Z is

19. The compound of claim 14, wherein Z is

20. The compound of any one of claims 11-19, wherein R¹³Is a hydroxyl group.

21. The compound of any one of claims 11-19, wherein R¹³is-C (O) R⁹。

22. The compound of any one of claims 11-19, wherein R¹³is-OC (O) R⁹。

23. The compound of any one of claims 11-19, wherein R¹³is-OP (O) (OR)¹⁰)₂。

24. The compound of any one of claims 1-23, wherein Z is¹，Z²And Z³At least one of which is-O-.

25. The compound of any one of claims 1-23, wherein Z is¹，Z²And Z³is-O-.

26. The compound of any one of claims 1-25, wherein n is 0.

27. The compound of any one of claims 1-25, wherein n is 1.

28. The compound of any one of claims 1-25, wherein n is 2.

29. The compound of any one of claims 1-25, wherein n is 3.

30. The compound of any one of claims 1-25, wherein n is 4.

31. The compound of any one of claims 1-30, wherein m is 0.

32. The compound of any one of claims 1-30, wherein m is 1.

33. The compound of any one of claims 1-30, wherein m is 2.

34. The compound of any one of claims 1-30, wherein m is 3.

35. The compound of any one of claims 1-30, wherein m is 4.

36. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

37. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

38. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

39. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

41. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

42. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

43. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

44. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

46. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

47. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

48. The compound of claim 36, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

49. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

50. A compound of formula VI:

or a pharmaceutically acceptable salt thereof;

wherein

Z is:

Z¹is-O-, -C (R)³)₂-or-S-;

Z²is a bond, -O-, -C (R)³)₂-or-S-;

Z³is-O-, -C (R)³)₂-or-S-;

q is independently selected from-CHR⁵-and-CH₂-；

R¹Independently selected from C₁-C₅Alkyl, halogen and C₁-C₃A haloalkyl group;

R²selected from hydroxy, alkoxy, -NH- (CH)₂)_n1-NR⁶R⁷，-NR⁶R⁷4-10 membered monocyclic heterocycle and 6-12 membered bicyclic heterocycle, wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Substituted with a group of (1);

R³independently selected from hydrogen, halogen, C₁-C₃Alkyl and C₁-C₃A haloalkyl group;

R⁴and R⁵Independently selected from hydrogen, halogen, C₁-C₅Alkyl radical, C₁-C₅Haloalkyl, -COOH, -COOC₁-C₅Alkyl, -CONH₂-CON (H) alkyl and-CON (alkyl)₂；

Or two R on the same carbon atom⁴The substituents optionally being taken together with the carbon to which they are attached to formA group wherein n3 is 1,2,3,4 or 5;

R⁶and R⁷Independently at each occurrence, selected from hydrogen, C₁-C₁₂Alkyl and C₂-C₁₂A haloalkyl group;

R⁹selected from hydrogen, C₁-C₅Alkyl, -OR⁶and-NR⁶R⁷；

R¹¹Is a 4-10 membered monocyclic heterocycle or a 6-12 membered bicyclic heterocycle; wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Substituted with the substituent(s);

R¹⁷is selected from-S-C₁-C₅Alkyl, -SH, -S (O) R⁹and-S (O)₂R⁹；

m is 1,2 or 3;

n is 0,1, 2,3 or 4;

o is 0,1, 2,3,4 or 5; and is

n1 is 2,3,4, 5 or 6.

51. The compound of claim 50, wherein Z is

52. The compound of any one of claims 50-51, wherein R¹²Is a 4-10 membered monocyclic heterocycle.

53. The compound of any one of claims 50-52, wherein R¹⁷is-S (O)₂R⁹。

54. The compound of claim 53, wherein R⁹is-NR⁶R⁷，R⁶And R⁷Is hydrogen.

55. The compound of claim 50, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

57. A method of treating an estrogen-related disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-55 or a pharmaceutical composition thereof, or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the estrogen-related disorder is cancer.

59. The method of claim 57, wherein the cancer is breast cancer.

60. The method of claim 57, wherein the cancer is uterine cancer.

61. The method of claim 57, wherein the cancer is ovarian cancer.

62. The method of claim 57, wherein the cancer is endometrial cancer.

63. The method of any one of claims 57-62, wherein an additional therapeutic agent is administered.

64. The method of claim 63, wherein the additional therapeutic agent is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

65. The method of claim 63, wherein the additional therapeutic agent is:

or a pharmaceutically acceptable salt thereof.

66. The method of claim 64 or 65, wherein the two therapeutic agents are administered together in the same dosage form.

67. The method of claim 66, wherein the dosage form is a solid dosage form.

68. The method of claim 64 or 65, wherein the two therapeutic agents are administered in separate dosage forms.

69. The method of any one of claims 57-68, wherein the subject is a human.

Technical Field

The present invention relates to benzothiophene compounds and compositions thereof useful for the treatment of estrogen-related disorders.

Background

Estrogens regulate a range of metabolic processes in humans, particularly reproduction, cardiovascular health, skeletal integrity, cognition and behavior. Estrogens also play a key role in a wide variety of human diseases, including various types of cancer (e.g., breast, ovarian, colorectal, prostate, renal, and endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates the disease through estrogen receptors. Deroo, et al, Estrogen Receptors and Human Disease, j.clin.invest.2006 March 1, 116 (3): 561-570.

Estrogen receptors coordinate transcriptional and non-genomic functions in response to estrogens. These pleiotropic and tissue-specific effects are thought to occur due to the differential expression of the different subtypes of estrogen receptors (ER α and ER β) and their co-regulatory factors. Moggs, et al, estogen receivers: (ii) the orchelators of pleiotropic cellular responseS, EMBO Report, 2001 Sept 15; 2(9): 775-781. ER-mediated transcription kinetics are complex (supra). Furthermore, in some cases, estrogen receptors also appear to have a direct effect on cytoplasmic signaling (supra).

A great deal of pharmaceutical research has been devoted to identifying compounds that block estrogen receptors and shut down the adverse effects of the receptors, sometimes in an attempt to maintain the beneficial effects of the receptors. Other efforts have been made to attempt to completely shut off the activity of all estrogen receptors to treat potentially life-threatening diseases where blocking all activity is more important than retaining some beneficial effect.

For many years, the gift Company (Eli Lilly and Company) disclosed in U.S. patent No.4,075,227 certain benzothiophene compounds and pharmaceutical compositions thereof for use as antifertility agents. For the treatment of postmenopausal syndrome and related estrogen-mediated disorders, including cancer, see also U.S. patent No.6,403,614. Other disclosures of salsa include U.S. patent nos. 4,400,543, 4,230,862, 4,075,223, 4,400,543, 4,133,814 and 4,323,707.

In 6.2011, Aragon Pharmaceuticals disclosed benzopyran derivatives with basic side chains and apolbifene analogs for the treatment of tamoxifen (tamoxifen) resistant breast cancer (see WO2011/156518, U.S. patent nos. 8,455,534 and 8,299,112). Aragon, in 2013, became serragon, filed a number of patent applications in the SERD field, including U.S. patent nos. 9,078,871, 8,853,423, and 8,703,810. Seragon was purchased by Genentech in 2014.

Genentech continues the study of basic SERDs and discloses a series of tetrahydropyrido [3,4-b ] indol-1-yl compounds with estrogen receptor modulating activity in US2016/0175289 and US 2015/0258080. Genentech is now developing GDC-9545 for the treatment of estrogen receptor positive breast cancer. Genentech gmbh also discloses in US 2016/0304450 a series of compounds having a moiety described as a SERMF (selective estrogen receptor modulator fragment) for use in the treatment of ER-related diseases.

In US 2016/0347742 Genentech discloses chromene-based compounds, thiochromene-based compounds, dihydroquinoline-based compounds, and naphthalene-based compounds, and pharmaceutical compositions thereof, for the treatment of estrogen-mediated diseases, including but not limited to breast, uterine, and endometrial cancers. Genentech describes chromene-based compounds with azetidine functionality in US 2016/0090377 and US 2016/0367526, which claim WO2014/205136 priority. These compounds having a fluorine substituent on the azetidine ring are active in breast, ovarian and uterine cancer cell lines. Other compounds having a fluorine substituted azetidine moiety on the chromene ring are disclosed in Genentech in US 2016/0090378 and US 2016/0175284. Genentech in US 2017/0320871 describes tetrahydroisoquinoline based compounds with azetidine functionality.

Also disclosed in WO 2014/130310 by Novartis International AG is a benzothiophene derivative that is a SERD (selective estrogen receptor degrader) useful for the treatment of diseases indicated by estrogen dysfunction.

Fulvestrant is an estrogen receptor full antagonist with no agonist activity and is disclosed by Imperial Chemical Industries, ICI in us patent No.4,659,516 and sold by Astra Zeneca under the name Faslodex. It is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. Fulvestrant has limited water solubility and requires monthly Intramuscular (IM) injections. The water-insolubility of fulvestrant presents challenges to achieving and maintaining effective serum concentrations.

An example of a Selective Estrogen Receptor Modulator (SERM) that acts as an antagonist or agonist in a gene-and tissue-specific manner is tamoxifen, which was originally sold by AstraZeneca under the trade name Nolvadex. ICI also discloses tamoxifen in us patent No.4,659,516 (see also us patent nos. 6,774,122 and 7,456,160). AstraZeneca is currently developing AZD9496, a novel oral selective estrogen receptor down-regulator for estrogen receptor positive breast cancer patients (WO 2014/191726).

Aromatase inhibitors which prevent estrogen production and thus ER dependent growth include letrozole, anastrozole and exemestane.

A number of SERDs, SERMs and aromatase inhibitors have been disclosed. In 1981, the Li Lai company disclosed SERM raloxifene (U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763 and 5,457,117) for the prevention of breast cancer and the treatment of osteoporosis.

Other examples of SERD and SERM compounds include those disclosed in WO 2014/066692, WO 2014/066695, US 2017/0166551, US 2017/0166550 and WO 2018/081168, each of which disclose technology developed by Thatcher et al and assigned to the University of Illinois. WO 2018/129387, commonly owned by G1 Therapeutics inc. and university of illinois, discloses combinations of various SERDs with CDK4/6 inhibitors.

Xiong et al also published other Estrogen Receptor inhibitors in the Novel Selective Estrogen Receptor receptors (SERDs) Developed acquired approach Treatment-Resistant Breast Cancer (J.Med.chem., Jan.24,2017, network). Examples of such selective Estrogen receptor down-modulators and their biological activity are provided by Lauren m.gutgesell et al in a poster display entitled "Estrogen receptor ligands and the air responses in de novo and tamoxifen reactive cell models" at the american cancer research association (AARC) conference on day 4, month 16, 2016. Other examples of SERD series were verbalized and PPT demonstrated by doctor Thatcher at the 252 th ACS national conference held in philadelphia, pennsylvania, at 2016, 8, 21. Yunlong Lu presented a poster entitled "Design and Synthesis of Basic Amino Selective evolution Reception developers gradients (BA-SERDs) for Treatment Resistant Breast Cancer" at the 2018AACR conference.

Cyanophenanthrene in U.S. Pat. No.9,714,221 discloses dihydro-5H-benzo [7] cyclorene compounds having a basic side chain. U.S. Pat. No.7,713,963 discloses acylated indanyl amines having basic side chains.

Further antiestrogenic compounds are disclosed in WO 2012/084711, WO 2002/013802, WO 2002/004418, WO 2002/003992, WO 2002/003991, WO 2002/003990, WO 2002/003989, WO 2002/003988, WO 2002/003986, WO 2002/003977, WO 2002/003976, WO 2002/003975, WO 2006/078834, US 6821989, US 2002/0128276, US 6777424, US 2002/0016340, US 6326392, US 6756401, US 2002/0013327, US 6512002, US 6632834, US 2001/0056099, US 6583170, US 6479535, WO 1999/024027, US 6005102, EP 0802184, US 5998402, US 5780497 and US 5880137.

Despite this progress, in view of the important role estrogen plays in a range of serious diseases including breast tumors and breast cancer, there remains a need to identify new agents useful in the treatment of estrogen receptor-mediated diseases.

Disclosure of Invention

It has been found that a compound of formula I, formula II, formula III or formula VI, or a pharmaceutically acceptable salt thereof, is useful in the treatment of estrogen-related disorders when administered in an effective amount to treat a host, typically a human, optionally in a pharmaceutically acceptable carrier.

Accordingly, in one aspect of the present invention, there is provided a compound of formula I:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein

A is as follows:

m is 1,2 or 3;

n is 0,1, 2,3 or 4;

o is 0,1, 2,3,4 or 5;

each Q is independently selected from-CHR⁵-and-CH₂-；

Z¹is-O-, -C (R)³)₂-or-S-;

Z²is a bond, -O-, -C (R)³)₂-or-S-;

each R¹Independently selected from C₁-C₅Alkyl (including but not limited to C)₁-C₃Alkyl, e.g. methyl), halogen (including but not limited to F) and C₁-C₃A haloalkyl group;

R²selected from hydroxy, alkoxy, -NH- (CH)₂)_n1-NR⁶R⁷，-NR⁶R⁷4-10 membered monocyclic heterocyclic ring and 6-12 membered bicyclic heterocyclic ring (including, but not limited to, for example, 4,5,6 or 7 membered monocyclic heterocyclic ring or 7,8, 9,10,11 or 12 membered bicyclic heterocyclic ring); wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Substituted with a group of (1);

n1 is 2,3,4, 5 or 6;

each R³Independently selected from hydrogen, halogen, C₁-C₃Alkyl and C₁-C₃A haloalkyl group;

each R⁴And R⁵Independently selected from hydrogen, halogen (e.g. F), C₁-C₅Alkyl radical, C₁-C₅Haloalkyl, -COOH, -COOC₁-C₅Alkyl, -CONH₂-CON (H) alkyl and-CON (alkyl)₂；

Or two R on the same carbon atom⁴The substituents may optionally be taken together with the carbon atom to which they are attached to formA group wherein n3 is 1,2,3,4 or 5;

R⁶and R⁷Independently at each occurrence, selected from hydrogen, C₁-C₁₂Alkyl and C₂-C₁₂A haloalkyl group;

R⁸selected from the group consisting of-C (O) R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂；

R⁹Selected from hydrogen, C₁-C₅Alkyl, -OR⁶and-NR⁶R⁷；

Each R¹⁰Independently selected from hydrogen, C₁-C₅Alkyl and-C (O) C₁-C₅Alkyl (including C)₃-C₅Cycloalkyl groups);

in one embodiment, one R is¹⁰Is hydrogen; and is

R¹¹Is a 4-10 membered monocyclic heterocycle or a 6-12 membered bicyclic heterocycle (including, but not limited to, for example, a4, 5,6, or 7 membered monocyclic heterocycle or a 7,8, 9,10,11, or 12 membered bicyclic heterocycle); wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Is substituted with the substituent(s).

In another aspect of the invention, there is provided a compound of formula II:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein:

y is:

Z³is-O-, -C (R)³)₂-or-S-;

R¹²is a 4-10 membered monocyclic heterocycle or a 6-12 membered bicyclic heterocycle (including, but not limited to, for example, a4, 5,6, or 7 membered monocyclic heterocycle or a 7,8, 9,10,11, or 12 membered bicyclic heterocycle); wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴And wherein the heterocyclic ring is attached through a carbon atom;

R¹³selected from hydroxy, -C (O) R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂(ii) a Or R¹³Selected from hydroxy, -S (O) R⁹，-S(O)₂R⁹，-C(O)R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂；

The remaining variables are as defined above.

In one embodiment, the compound of formula II is:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof.

In one embodiment, the compound of formula II is:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof.

In another embodiment of the invention, the compound of formula III is:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein Z is:

R¹⁴，R¹⁵and R¹⁶Independently selected from hydrogen, C₁-C₅Alkyl, halogen and C₁-C₃A haloalkyl group; wherein R is¹⁴，R¹⁵And R¹⁶At least one of them is C₁-C₅Alkyl, halogen or C₁-C₃A haloalkyl group;

the remaining variables are as defined above.

In another aspect, the compound of formula IV is:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein

X is:

the remaining variables are as defined above.

In one embodiment, the compound of formula IV is selected from:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof.

In an alternative embodiment, the compound of formula IV is selected from:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof.

In another aspect of the invention, there is provided a compound of formula VI:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein R is¹⁷Is selected from-S-C₁-C₅Alkyl, -SH, -S (O) R⁹and-S (O)₂R⁹；

The remaining variables are as defined above.

In certain embodiments, the estrogen-related disorder (e.g., tumor or cancer) is selected from breast cancer, ovarian cancer, endometrial cancer, kidney cancer, uterine cancer, esophageal cancer, urothelial cancer, bladder cancer, genitourinary tract cancer, fallopian tube cancer, and peritoneal cavity cancer. In another embodiment, the disease is metastatic endocrine therapy resistant breast cancer. In some embodiments, the compounds are used after chemotherapy or radiation therapy to avoid relapse, or as a primary therapy instead of chemotherapy or radiation therapy.

In one aspect, a compound of formula I, II, III, IV or VI, or a pharmaceutically acceptable salt or prodrug thereof, is useful for treating estrogen receptor (ER +) positive breast cancer. In one embodiment, the ER + breast cancer is human epidermal growth factor receptor 2 negative (HER 2-). In one embodiment, the ER + breast cancer is HER2 positive. In one embodiment, ER + breast cancer is progesterone receptor positive (PR +). In one embodiment, ER + breast cancer is PR-. In one embodiment, ER + breast cancer is PR + and HER 2-. In one embodiment, ER + breast cancer is PR + and HER2 +. In one embodiment, ER + breast cancer is PR-and HER 2-. In one embodiment, the ER + breast cancer is PR-and HER2 +. In one embodiment, ER + breast cancer is retinoblastoma protein positive (Rb +). In one embodiment, ER + breast cancer is KI67 positive (KI67 +). In one embodiment, the ER + breast cancer is KI67 negative (KI 67-). In one embodiment, the ER + breast cancer is ER + advanced metastatic breast cancer. In one embodiment, the ER + breast cancer is ER + luminal a breast cancer. In one embodiment, the ER + breast cancer is ER + luminal B breast cancer. In one embodiment, the ER + breast cancer is ER + male breast cancer. In one embodiment, the ER + breast cancer is ER + lobular breast cancer. In one embodiment, the ER + breast cancer is ER + ductal breast cancer. In one embodiment, the ER + breast cancer is invasive breast cancer. In one embodiment, the ER + breast cancer is ER + refractory advanced breast cancer.

In one aspect, a compound of formula I, II, III, IV or VI, or a pharmaceutically acceptable salt or prodrug thereof, is useful for treating a hormone-related cancer or tumor that has metastasized to the brain, bone or other organ. In one embodiment of this aspect, the hormone-related cancer is estrogen-mediated. In another embodiment, the estrogen-mediated cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, and endometrial cancer. In other embodiments, the compounds of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, are useful for preventing hormone-related cancers or tumor metastasis to the brain, bone or other organs, including hormone-related cancers mediated by estrogens, such as breast, uterine, ovarian or endometrial cancers.

In another aspect, a compound of formula I, formula II, formula III, formula IV or formula VI is administered in combination with a compound of formula V. The compound of formula V is selected from:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein:

each Q' is independently CH or N;

each R²¹Independently is aryl, alkyl or cycloalkyl, wherein two R on adjacent ring atoms or on the same ring atom²¹The groups together with one or more of the ring atoms to which they are attached optionally form a 3-8 membered ring;

y1 is 0,1, 2 or 3;

R²²is- (alkylene)_m1-heterocycle, - (alkylene)_m1-heteroaryl, - (alkylene)_m1-NR²³R²⁴- (alkylene)_m1-C(O)-NR²³R²⁴- (alkylene)_m1-C (O) -O-alkyl, - (alkylene)_m1-O-R²⁵- (alkylene)_m1-S(O)_n2-R²⁵Or- (alkylene)_m1-S(O)_n2-NR²³R²⁴Any of which may optionally be independently substituted by one or more R, as valency permits^xSubstituted by groups;

m1 is 0 or 1;

n2 is 0,1 or 2;

R²³and R²⁴Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, alkyl-heterocycle, alkyl-aryl, and alkyl-heteroaryl;

or R²³And R²⁴Together with the nitrogen atom to which they are attached may be joined together to form a heterocyclic ring.

R²⁵Is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, alkyl-heterocycle, alkyl-aryl or alkyl-heteroaryl; and is

R^xIndependently selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, cycloalkylalkyl, and alkyl-heterocycle.

In one embodiment, the compound of formula V is selected from:

the above compounds of formula V, as well as other compounds, are disclosed in U.S. patent 8,598,197, U.S. patent 8,598,186, U.S. patent 8,691,830, U.S. patent 8,829,012, U.S. patent 8,822,683, U.S. patent 9,102,682, U.S. patent 9,499,564, U.S. patent 9,527,857, and U.S. patent 9,481,691.

The invention therefore comprises at least the following features:

(a) a compound of formula I, II, III, IV or VI as described herein, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof;

(b) a method of treating or preventing an estrogen-related disorder, including but not limited to a tumor or cancer, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(c) a method of treating or preventing breast cancer, kidney cancer, uterine cancer, ovarian cancer or endometrial cancer, the method comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound selected from the group consisting of formula I, II, III, IV or VI, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(d) a method of treating or preventing hormone receptor positive metastatic breast cancer, the method comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(e) a method of treating or preventing bone loss, including osteoporosis, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(f) a pharmaceutical formulation comprising a therapeutically or prophylactically effective amount of a compound of formula I, II, III, IV or VI as described herein, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

(g) a compound of formula I, II, III, IV or VI as described herein, or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, as a mixture of enantiomers or diastereomers (e.g., related), including as a racemate;

(h) a compound of formula I, II, III, IV or VI of the invention as described herein, in enantiomerically or diastereomerically (e.g. related) enriched form, including as an isolated enantiomer or diastereomer (i.e. greater than 85%, 90%, 95%, 97% or 99% pure);

(i) a compound of formula I, II, III, IV or VI as described herein, comprising at least one deuterium atom;

(j) isotopic derivatives of compounds of formula I, II, III, IV or VI as described herein;

(k) a pharmaceutically acceptable composition as described herein, comprising a compound of formula I, II, III, IV or VI or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, and a compound of formula V or a pharmaceutically acceptable salt or prodrug thereof,

(l) A method of treating or preventing an estrogen-related disorder including, but not limited to, a tumor or cancer, comprising administering to a subject (including a human) in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof and a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(m) a method of treatment or prophylaxis of breast, kidney, uterus, ovary or endometrial cancer, said method comprising administering to a subject, including a human, in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof and a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(N) a method of treating or preventing hormone receptor positive metastatic breast cancer, the method comprising administering to a subject (including a human) in need thereof, a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof and a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier;

(o) a method of treating or preventing ER + breast cancer, said method comprising administering to a subject (including a human) in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof and a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier; and

(p) a method of treatment or prevention of bone loss including osteoporosis, said method comprising administering to a subject (including a human) in need thereof a therapeutically effective amount of a compound selected from formula I, II, III, IV or VI or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof and a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier.

Detailed Description

Definition of

The compounds are described using standard terminology. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The compounds of formulae I, II, III, IV, V and VI as described herein may be provided in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers (e.g., rotamers), as if each form were specifically described, unless otherwise stated or as is clear from the context herein.

The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are inclusive of the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "C₁-C₃Alkyl "independently refers to methyl, ethyl, propyl, isopropyl, and cyclopropyl, as if each were independently described.

The term "C₁-C₅Alkyl "independently refers to methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, butyl, pentyl, isobutyl, isopentyl, sec-butyl, sec-pentyl, tert-butyl, tert-pentyl, neopentyl, 3-pentyl and active pentyl groups, as if each is independently described.

The term "C₁-C₃Haloalkyl "is C₁-C₃Alkyl, wherein any hydrogen may be independently replaced by fluorine, chlorine or bromine. The term "C₁-C₃Haloalkyl "includes-CH₂F，-CHF₂，-CF₃，-CH₂CH₂F，-CH₂CHF₂，-CH₂CF₃，-CHFCF₃，-CF₂CF₃，-CH₂CH₂CH₂F，-CH₂CH₂CHF₂，-CH₂CH₂CF₃，-CH₂CHFCF₃，-CH₂CF₂CF₃，-CHFCF₂CF₃，-CF₂CF₂CF₃，CHFCH₂F，-CHFCHF₂，-CHFCF₃，-CHFCH₂CH₂F，-CHFCH₂CHF₂，-CHFCH₂CF₃，-CHFCHFCF₃，-CHFCF₂CF₃，-CF₂CH₂CH₂F，-CF₂CH₂CHF₂，-CF₂CH₂CF₃，-CF₂CHFCF₃，-CH₂CF₂CHF₂，-CH₂CF₂CH₂F，-CHFCHFCHF₂and-CHFCHFCH₂F as if each were described independently. It will be apparent to those skilled in the art that many of these embodiments have chiral carbons and thus may exist as enantiomers or diastereomers. The present invention encompasses all possible stereoisomers, whether in a mixture or enantiomerically enriched form (e.g., at least 80%, 85%, 90%, 95%, or 98% free of other isomers).

The term "alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains from 1 to about 8 carbon atoms. In certain embodiments, alkyl is C₁-C₂，C₁-C₃，C₁-C₄，C₁-C₅Or C₁-C₆. As used herein, specifying a range means that the alkyl group having each member of the range is described as an independent species. For example, the term C as used herein₁-C₆Alkyl represents a straight or branched chain alkyl group having 1,2,3,4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as an independent species. For example, as used hereinLanguage C₁-C₄Alkyl represents straight or branched chain alkyl groups having 1,2,3 or 4 carbon atoms and is intended to represent that each of them is described as an independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2, 2-dimethylbutane, and 2, 3-dimethylbutane. In an alternative embodiment, alkyl is optionally substituted.

The term "alkyl" also encompasses cycloalkyl. For example, when a term is used that includes "alkyl," then "cycloalkyl" or "carbocyclic" may be considered part of the definition unless the context clearly excludes it. For example, and without limitation, the terms "alkyl," "alkoxy," "haloalkyl," and the like can all be considered to include cyclic forms of alkyl groups unless the context clearly excludes them.

"halo" or "halogen" refers to-Cl, -Br, -I or-F (typically F). In certain embodiments, "halo" or "halogen" may independently refer to-Cl or-F.

"haloalkyl" is a branched or straight-chain alkyl group substituted with 1 or more (up to the maximum allowed number of halogen atoms) halogen atoms, typically F. In certain embodiments, haloalkyl is C₁-C₂，C₁-C₃，C₁-C₄，C₁-C₅Or C₁-C₆. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., sharing 6, 10, or 14 pi electrons in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms ("C") provided in the aromatic ring system_6-14Aryl radicals "). In some embodiments, an aryl group has 6 ring carbon atoms ("C)₆Aryl "; for example, phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C)₁₀Aryl "; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C)₁₄Aryl "; for example, an anthracene group). "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclyl groups, with the linking group or point on the aryl ring, and in which case the number of carbon atoms continues to designate the number of carbon atoms in the aromatic ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4 to 7 membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

The term "heteroaryl" denotes a stable aromatic ring system containing one or more heteroatoms selected from O, N and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Examples include, but are not limited to, unsaturated 5-to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2, 4-triazolyl, IH-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl); unsaturated 5 to 6-membered heterocyclic monocyclic groups containing an oxygen atom such as pyranyl, 2-furyl, 3-furyl and the like; unsaturated 5-to 6-membered heteromonocyclic group containing a sulfur atom, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl); unsaturated 5-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl). In one embodiment, a "heteroaryl" group is an 8-, 9-or 10-membered bicyclic ring system. 8. Examples of 9-or 10-membered bicyclic heteroaryl groups include benzofurocorr, benzothiophene, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl.

The term "heterocycle" refers to saturated and partially saturated heteroatom-containing cyclic groups in which the heteroatoms may be selected from N, S and O. The term "heterocycle" includes monocyclic 3-12 membered ring as well as bicyclic 5-16 membered ring systems (which may include fused, bridged or spiro bicyclic ring systems). It does not include rings containing-O-, -O-S-or-S-moieties. Examples of saturated heterocyclic groups include saturated 4-to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl); saturated 4-to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2, 3-dihydro-benzo [1,4] dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1, 2-dihydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, 2,3,4,4a,9,9 a-hexahydro-1H-3-aza-fluorenyl, 5,6, 7-trihydro-1, 2, 4-triazolo [3,4-a ] isoquinolinyl, 3, 4-dihydro-2H-benzo [1,4] oxazinyl, benzo [1,4] dioxanyl, 2, 3-dihydro-1H-1 λ' -benzo [ d ] isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. "bicyclic heterocycle" includes groups in which a heterocyclyl is fused to an aryl, where the point of attachment is at the heterocycle. "bicyclic heterocycle" also includes heterocyclyl fused to a carbocyclic group. For example, partially unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline, isoindoline, partially unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated fused heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

Non-limiting examples of bicyclic heterocycles include:

unless otherwise indicated or clear from the context, the term "bicyclic heterocycle" includes both cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include:

an "alkyl-aryl" group is an aryl group as defined herein, linked through an alkyl group. Non-limiting examples of alkyl-aryl groups include:

an "alkyl-heteroaryl" is a heteroaryl group as defined herein attached through an alkyl group. Non-limiting examples of alkyl-heteroaryl groups include:

as used herein, "prodrug" refers to a compound that is convertible to the parent drug when administered to a host in vivo. As used herein, the term "parent drug" refers to any of the presently described compounds described herein. Prodrugs can be used to achieve any desired effect, including enhancing the properties of the parent drug or improving the pharmacological or pharmacokinetic properties of the parent. There are prodrug strategies that provide options to modulate the in vivo production conditions of the parent drug, all of which are considered to be included herein. Non-limiting examples of prodrug strategies include covalent attachment of a removable group or removable group moiety, such as but not limited to, acylation, phosphorylation, phosphoramidation, amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfoxy (sulfoxy) or sulfone derivatives, carbonylation or anhydride, and the like.

The invention includes compounds of formulas I, II, III, IV and VI having at least one desired isotopic substitution of atoms in an amount higher than (i.e., enriched in) the natural abundance of the isotope. Isotopes are atoms of the same atomic number but different mass numbers, i.e. of the same proton number but different neutron numbers.

The invention also includes combination therapies and pharmaceutical compositions comprising at least one desired isotopically substituted compound of formula V having an atom in an amount higher than the natural abundance of the isotope (i.e., enriched).

Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，¹⁸F，³⁵S，³⁶And (4) Cl. In one non-limiting embodiment, isotopically labeled compounds are useful for metabolic studies: (¹⁴C) (ii) a Reaction kinetics studies (e.g. for²H or³H) (ii) a Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays; or for radiotherapy of a patient. In particular, for PET or SPECT studies,¹⁸f-labelled compounds may be particularly desirable. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or examples below and preparations by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

As a general non-limiting example, isotopes of hydrogen can be used anywhere in the structures described to achieve the desired results, such as deuterium (g) ((ii))²H) And tritium (f)³H) In that respect Alternatively or additionally, isotopes of carbon may be used, for example¹³C and¹⁴C。

isotopic substitution, for example deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched by 90%, 95%, or 99% or more at any target location. In one non-limiting embodiment, deuterium is enriched to 90, 95, or 99% at the desired position.

In one non-limiting embodiment, a hydrogen atom may be substituted for a deuterium atom in a compound of formula I, II, III, IV, V or VI. In one non-limiting embodiment, the replacement of the hydrogen atom by the deuterium atom occurs at a position selected from the group consisting of X, Y, A, Z, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，R¹¹，R¹²，R¹³，R¹⁴，R¹⁵，R¹⁶，R¹⁷，R²¹，R²²，R²³，R²⁴，R²⁵And R^xWithin the group of any one of (a). For example, when any group is or comprises (e.g., by substitution) a methyl, ethyl or methoxy group, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH₂，CD₂H，CD₃，CH₂CD₃，CD₂CD₃，CHDCH₂D，CH₂CD₃，CHDCHD₂，OCDH₂，OCD₂H or OCD₃Etc.). In certain other embodiments, when two substituents are joined to form a ring, the unsubstituted carbon atom may be deuterated.

Compound (I)

The present invention provides a compound selected from the group consisting of:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein

A is as follows:

x is:

y is:

z is:

m is 1,2, or 3;

n is 0,1, 2,3, or 4;

o is 0,1, 2,3,4, or 5;

each Q is independently selected from-CHR⁵-and-CH₂-；

Z¹is-O-, -C (R)³)₂-or-S-;

Z²is a bond, -O-, -C (R)³)₂-or-S-;

Z³is-O-, -C (R)³)₂-or-S-;

each R¹Independently selected from C₁-C₅Alkyl (e.g. methyl), halogen (e.g. F) and C₁-C₃A haloalkyl group;

R²selected from hydroxy, alkoxy, -NH- (CH)₂)_n1-NR⁶R⁷，-NR⁶R⁷4-10 membered monocyclic heterocyclic ring and 6-12 membered bicyclic heterocyclic ring (including, but not limited to, for example, 4,5,6 or 7 membered monocyclic heterocyclic ring or 7,8, 9,10,11 or 12 membered bicyclic heterocyclic ring); wherein each heterocycle is optionally substituted by one, two or threeIndependently selected from R⁴Substituted with a group of (1);

n1 is 2,3,4, 5 or 6;

each R³Independently selected from hydrogen, halogen, C₁-C₃Alkyl and C₁-C₃A haloalkyl group;

each R⁴And R⁵Independently selected from hydrogen, halogen (e.g. F), C₁-C₅Alkyl radical, C₁-C₅Haloalkyl, -COOH, -COOC₁-C₅Alkyl, -CONH₂-CON (H) alkyl and-CON (alkyl)₂；

Or two R on the same carbon atom⁴The substituents optionally being taken together with the carbon to which they are attached to formA group wherein n3 is 1,2,3,4 or 5;

R⁶and R⁷Independently at each occurrence, selected from hydrogen, C₁-C₁₂Alkyl and C₂-C₁₂A haloalkyl group;

R⁸selected from the group consisting of-C (O) R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂；

R⁹Selected from hydrogen, C₁-C₅Alkyl, -OR⁶and-NR⁶R⁷；

Each R¹⁰Independently selected from hydrogen, C₁-C₅Alkyl and-C (O) C₁-C₅Alkyl (including C)₃-C₅Cycloalkyl groups);

in one embodiment, one R is¹⁰Is hydrogen;

R¹¹is a 4-10 membered monocyclic heterocycle or a 6-12 membered bicyclic heterocycle (including, but not limited to, for example, a4, 5,6, or 7 membered monocyclic heterocycle or a 7,8, 9,10,11, or 12 membered bicyclic heterocycle); wherein each heterocycle is optionally substituted with one, two or three independently selected from R⁴Is substituted with the substituent(s).

R¹²Is a 4-to 10-membered monocyclic heterocycleOr 6-12 membered bicyclic heterocycle (including, but not limited to, for example, a4, 5,6 or 7 membered monocyclic heterocycle or a 7,8, 9,10,11 or 12 membered bicyclic heterocycle), each of which is optionally substituted with one, two or three independently selected from R⁴Wherein the heterocycle is attached through a carbon atom;

R¹³selected from hydroxy, -C (O) R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂；

Or R¹³Selected from hydroxy, -S (O) R⁹，-S(O)₂R⁹-C(O)R⁹，-OC(O)R⁹，-OP(O)(OR¹⁰)₂and-P (O) (OR)¹⁰)₂(ii) a And is

embodiments of formula I, formula II, formula III, formula IV and formula VI

a. In one embodiment, the compounds of the present invention are selected from formula I.

b. In one embodiment, the compound is embodiment a wherein R is⁸is-C (O) R⁹。

c. In one embodiment, the compound is embodiment a wherein R is⁸is-OC (O) R⁹。

d. In one embodiment, the compound is embodiment b or c, wherein R is⁹Is C₁-C₃An alkyl group.

e. In one embodiment, the compound is embodiment b or c, wherein R is⁹is-OR⁶。

f. In one embodiment, the compound is embodiment a wherein R is⁸is-OP (O) (OR)¹⁰)₂。

g. In one embodiment, the compound is embodiment a wherein R is⁸is-P (O) (OR)¹⁰)₂。

h. In one embodiment, the compound is embodiment f or g, wherein at least one R is¹⁰Is hydrogen.

i. In one embodiment, the compound is embodiment f or g, wherein two R are¹⁰The radicals are all hydrogen.

j. In one embodiment, the compounds of the present invention are selected from formula IV.

k. In one embodiment, the compound is embodiment j wherein R is¹³Is a hydroxyl group.

In one embodiment, the compound is embodiment j, wherein R is¹³is-OP (O) (OR)¹⁰)₂，

In one embodiment, the compound is embodiment i, wherein R is¹³is-P (O) (OR)¹⁰)₂。

In one embodiment, the compound is embodiment j, wherein R¹³is-C (O) R⁹。

In one embodiment, the compound is embodiment i wherein R is¹³is-OC (O) R⁹。

In one embodiment, the compound is any one of embodiments a-o, wherein Z is²Is O.

In one embodiment, the compound is any one of embodiments a-o, wherein Z is²Is a bond.

In one embodiment, the compound is any one of embodiments a-q, wherein m is 1.

In one embodiment, the compound is any one of embodiments a-q, wherein m is 2.

In one embodiment, the compound is any one of embodiments a-q wherein m is 3.

In one embodiment, the compounds of the present invention are selected from formula II.

In one embodiment, the compound is embodiment u, wherein R¹²Is composed of

In one embodiment, the compound is embodiment u, wherein R¹²Is selected from

In one embodiment, the compounds of the present invention are selected from formula III.

y. in one embodiment, the compound is embodiment x wherein R is¹⁴Is C₁-C₃Alkyl, halogen and C₁-C₃A haloalkyl group.

z. in one embodiment, the compound is embodiment x wherein R is¹⁴Is halogen.

In one embodiment, the compound is embodiment x, wherein R is¹⁴Is C₁-C₃A haloalkyl group.

In one embodiment, the compound is any one of embodiments x-aa, wherein m is 1.

cc. in one embodiment, the compound is any one of embodiments x-aa, wherein m is 2.

dd. in one embodiment, the compound is any one of embodiments x-aa, wherein m is 3.

ee. in one embodiment, the compound is any one of embodiments a-dd wherein n is 1.

ff. in one embodiment, the compound is any one of embodiments a-dd wherein n is 2.

gg. in one embodiment, the compound is any one of embodiments a-dd wherein n is 3.

hh. in one embodiment, the compound is any one of embodiments a-dd wherein n is 4.

in one embodiment, the compound is any one of embodiments a-hh, wherein o is 1.

jj. in one embodiment, the compound is any one of embodiments a-hh wherein o is 2.

kk. in one embodiment, the compound is any one of embodiments a-hh wherein o is 3.

ll. in one embodiment, the compound is any one of embodiments a-hh wherein o is 4.

In one embodiment, the compound is any one of embodiments a-hh, wherein o is 5.

nn. in one embodiment, the compound is any one of embodiments a-mm, wherein Z is¹is-O-.

oo. in one embodiment, the compound is any one of embodiments a-nn wherein at least one R is¹Is C₁-C₃An alkyl group.

pp. in one embodiment, the compound is any one of embodiments a-nn wherein at least one R is¹Is halogen.

qq. in one embodiment, the compound is any one of embodiments a-nn wherein at least one R is¹Is C₁-C₃A haloalkyl group.

rr. in one embodiment, the compound is any one of embodiments a-nn wherein n is 0.

ss. in one embodiment, the compound is any one of embodiments a-nn wherein o is 0.

tt. in one embodiment, the compound is embodiment rr or ss where at least one R is¹Is C₁-C₃An alkyl group.

uu. in one embodiment, the compound is embodiment rr or ss where at least one R is¹Is halogen.

vv. in one embodiment, the compound is embodiment rr or ss where at least one R is¹Is C₁-C₃A haloalkyl group.

ww. in one embodiment, the compound is any one of embodiments a-vv, wherein at least one R is⁴Is F.

xx. in one embodiment, the compound is any of embodiments a-wwA, wherein R is⁶Is hydrogen.

yy. in one embodiment, the compound is any one of embodiments a-xx, wherein R⁷Is hydrogen.

Further embodiments of the invention

In one embodiment, n1 is 2.

In one embodiment, n1 is 3.

In one embodiment, n1 is 4.

In one embodiment, n1 is 5.

In one embodiment, n1 is 6.

In one embodiment, the compound of formula I is

In one embodiment, the compound of formula II is

In one embodiment, the compound of formula II is:

in one embodiment, the compound of formula II is:

in one embodiment, the compound of formula III is

In one embodiment, the compound of formula III is

At one isIn embodiments, the compound of formula III is

In one embodiment, the compound of formula III is

In one embodiment, the compound of formula IV is

In one embodiment, the compound of formula I is:

in another embodiment, the compound of formula II is:

in one embodiment, the compounds of the invention are selected from:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition thereof;

wherein the variables are as defined herein.

In another embodiment, the compounds of the invention are selected from:

in another embodiment, the compounds of the invention are:

in one embodiment, the compound of formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula V is:or a pharmaceutically acceptable salt thereof.

R¹Embodiments of (1)

In one embodiment, R¹Is fluorine.

In one embodiment, R¹Is chlorine.

In one embodiment, R¹Is bromine.

In one embodiment, R¹Is trifluoromethane.

In one embodiment, R¹Is difluoromethane.

In one embodiment, R¹Is monofluoromethane.

In one embodiment, R¹Is methyl.

In one embodiment, R¹Is ethyl.

In one embodiment, R¹Is propyl.

In one embodiment, R¹Is cyclopropyl.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is fluorine.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is chlorine.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is bromine.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is trifluoromethane.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is methyl.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is ethyl.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is propyl.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is cyclopropyl.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is difluoromethane.

In each independent embodiment, there are 2,3,4 or 5R¹And at least one R¹Is monofluoromethane.

In certain embodiments, Z³is-O-or-S-.

Embodiments of "alkyl group

In one embodiment, "alkyl" is C₁-C₁₀Alkyl radical, C₁-C₉Alkyl radical, C₁-C₈Alkyl radical, C₁-C₇Alkyl radical, C₁-C₆Alkyl radical, C₁-C₅Alkyl radical, C₁-C₄Alkyl radical, C₁-C₃Alkyl or C₁-C₂An alkyl group.

In one embodiment, "alkyl" has one carbon.

In one embodiment, an "alkyl" group has two carbons.

In one embodiment, an "alkyl" group has three carbons.

In one embodiment, an "alkyl" group has four carbons.

In one embodiment, an "alkyl" group has five carbons.

In one embodiment, an "alkyl" group has six carbons.

Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl and hexyl.

Additional non-limiting examples of "alkyl" include: isopropyl, isobutyl, isoamyl and isohexyl.

Additional non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl and sec-hexyl.

Additional non-limiting examples of "alkyl" include: tert-butyl, tert-amyl and tert-hexyl

Additional non-limiting examples of "alkyl" include: neopentyl, 3-pentyl and active pentyl.

Embodiments of "haloalkyl

In one embodiment, "haloalkyl" is C₁-C₁₀Haloalkyl, C₁-C₉Haloalkyl, C₁-C₈Haloalkyl, C₁-C₇Haloalkyl, C₁-C₆Haloalkyl, C₁-C₅Haloalkyl, C₁-C₄Haloalkyl, C₁-C₃Haloalkyl and C₁-C₂A haloalkyl group.

In one embodiment, "haloalkyl" has one carbon.

In one embodiment, "haloalkyl" has one carbon and one halogen, e.g., -CH₂F。

In one embodiment, "haloalkyl" has one carbon and two independent halogens, e.g., -CHF₂。

In one embodiment, "haloalkyl" has one carbon and three independent halogens, e.g., -CHF₃。

In one embodiment, a "haloalkyl" has two carbons.

In one embodiment, "haloalkyl" has three carbons.

In one embodiment, a "haloalkyl" has four carbons.

In one embodiment, a "haloalkyl" has five carbons.

In one embodiment, "haloalkyl" has six carbons.

Non-limiting examples of "haloalkyl" include:

additional non-limiting examples of "haloalkyl" include

Additional non-limiting examples of "haloalkyl" include:

additional non-limiting examples of "haloalkyl" include

Embodiments of "aryl group

In one embodiment, "aryl" is a 6 carbon aromatic group (phenyl).

In one embodiment, "aryl" is a 10 carbon aromatic group (naphthyl).

In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is an aromatic ring. Non-limiting examples of "aryl" groups include indolines, tetrahydroquinolines, tetrahydroisoquinolines, and dihydrobenzofurans, where the point of attachment of each group is on an aromatic ring.

For example,is an "aryl" group.

However, it is possible to use a single-layer,is a "heterocyclic" group.

In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is an aromatic ring. Non-limiting examples of "aryl" groups include indanes and tetralins, where the point of attachment for each group is on an aromatic ring.

For example,is an "aryl" group.

However, it is possible to use a single-layer,is a "cycloalkyl" group.

Embodiments of "heteroaryl

In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1,2,3, or 4 nitrogen atoms.

Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

Additional non-limiting examples of 5-membered "heteroaryl" groups include:

in one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1,2, or 3 nitrogen atoms (i.e., pyridyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

in one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole and benzothiazole.

Additional non-limiting examples of bicyclic "heteroaryl" groups include:

additional non-limiting examples of bicyclic "heteroaryl" groups include:

in one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and naphthyridine.

Additional non-limiting examples of bicyclic "heteroaryl" groups include:

embodiments of "cycloalkyl" groups

In one embodiment, "cycloalkyl" is C₃-C₈Cycloalkyl radical, C₃-C₇Cycloalkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₅Cycloalkyl radical, C₃-C₄Cycloalkyl radical, C₄-C₈Cycloalkyl radical, C₅-C₈Cycloalkyl or C₆-C₈A cycloalkyl group.

In one embodiment, a "cycloalkyl" has three carbons.

In one embodiment, a "cycloalkyl" has four carbons.

In one embodiment, a "cycloalkyl" has five carbons.

In one embodiment, a "cycloalkyl" has six carbons.

In one embodiment, a "cycloalkyl" has seven carbons.

In one embodiment, a "cycloalkyl" has eight carbons.

In one embodiment, a "cycloalkyl" has nine carbons.

In one embodiment, a "cycloalkyl" has ten carbons.

Non-limiting examples of "cycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.

Additional non-limiting examples of "cycloalkyl" groups include indanes and tetrahydronaphthalenes, in which the point of attachment of each group is on the cycloalkyl ring.

For example,is a "cycloalkyl" group.

However, it is possible to use a single-layer,is an "aryl" group.

Embodiments of "heterocyclic" rings

In one embodiment, "heterocycle" refers to a ring having 1 nitrogen and 3,4,5,6, 7, or 8 carbon atoms.

In one embodiment, "heterocycle" refers to a ring having 1 nitrogen and 1 oxygen and 3,4,5,6, 7, or 8 carbon atoms.

In one embodiment, "heterocycle" refers to a ring having 2 nitrogens and 3,4,5,6, 7, or 8 carbon atoms.

In one embodiment, "heterocycle" refers to a ring having 1 oxygen and 3,4,5,6, 7, or 8 carbon atoms.

In one embodiment, "heterocycle" refers to a ring having 1 sulfur and 3,4,5,6, 7, or 8 carbon atoms.

Non-limiting examples of "heterocycle" include aziridine, ethylene oxide, epithiirane, azetidine, 1, 3-diazetidine, oxetane and cyclopropane sulfide (thietane).

Additional non-limiting examples of "heterocycles" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of "heterocycles" include tetrahydrofuran, 1, 3-dioxolane, tetrahydrothiophene, 1, 2-oxathiolane, and 1, 3-oxathiolane.

Additional non-limiting examples of "heterocycles" include piperidine, piperazine, tetrahydropyran, 1, 4-dioxane, thiacyclopentane, 1, 3-dithiolane, 1, 4-dithiolane, morpholine, and thiomorpholine.

Additional non-limiting examples of "heterocyclic" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the heterocyclic ring.

For example,is a "heterocyclic" group.

However, it is possible to use a single-layer,is an "aryl" group.

Embodiments of "alkyl-aryl

In one embodiment, "alkyl-aryl" refers to a 1-carbon alkyl group substituted with an aryl group.

Non-limiting examples of "alkyl-aryl" include:

in one embodiment, "alkyl-aryl" is

In one embodiment, "alkyl-aryl" refers to a 2 carbon alkyl group substituted with an aryl group.

Non-limiting examples of "alkyl-aryl" include:

in one embodiment, "alkyl-aryl" refers to a3 carbon alkyl group substituted with an aryl group.

R²Embodiments of (1)

In one embodiment, R²Is optionally substituted by one, two or three groups selected from R⁴A 4-6 membered heterocyclic ring substituted with the group of (1).

In one embodiment, R²is-NH₂。

In one embodiment, R²is-NH alkyl.

In one embodiment, R²is-NHCH₃。

In one embodiment, R²is-NHCH₂CH₃。

In one embodiment, R²is-N (alkyl)₂。

In one embodiment, R²is-N (CH)₃)₂。

In one embodiment, R²is-N (CH)₂CH₃)₂。

In one embodiment, R²is-OH.

In one embodiment, R²Is composed of

In various independent embodiments, R²Is composed of

R¹²Embodiments of (1)

In various independent embodiments, R¹²Is composed of

R²²Embodiments of (1)

In one embodiment, R²²Selected from:

in one embodiment, R²²Is composed of

In one embodiment, R²²Is composed of

Embodiments of Z

In certain embodiments, Z is:

in certain embodiments, Z is:

pharmaceutical compositions and dosage forms

In some aspects, the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II, III, IV or VI as described herein, and one or more pharmaceutically acceptable carriers, such as diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, gels or solidified materials. Such excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. Depending on the therapeutic purpose, the compounds may be provided as desired, for example, in the form of solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled-release systems, and the like.

The term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the present disclosure is administered. The term "effective amount" or "pharmaceutically effective amount" refers to an amount of an agent sufficient to provide a desired biological result. The result can be a reduction and/or alleviation of the signs, symptoms or causes of the target disease mediated by the estrogen receptor. The healthcare provider can determine the appropriate "effective" amount in any individual (e.g., human) case based on the needs of the patient. "pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's pharmaceutical sciences, 18 th edition (1990, McCand publishing Co., Iston, Pa.). For example, sterile saline at physiological pH and phosphate buffered saline may be used. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical compositions. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives (supra, 1449). In addition, antioxidants and suspending agents (supra) may be used.

Suitable excipients for non-liquid formulations are also known to those skilled in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is provided in Remington's pharmaceutical sciences, 18 th edition (1990, McCand publishing Co., Iston, Pa.).

In addition, auxiliary substances such as wetting or emulsifying agents, biological buffering substances, surfactants and the like may be present in such carriers. The biological buffer may be any pharmacologically acceptable solution and may provide the desired pH, i.e., a pH within a physiologically acceptable range, for the formulation. Examples of the buffer solution include saline, phosphate buffered saline, Tris buffered saline, Hank's buffered saline, and the like.

Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions and the like, preferably in unit dosage forms suitable for single administration of precise dosages. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may include other agents, adjuvants, diluents, buffers, and the like.

In general, the compositions of the present invention will be administered in a therapeutically effective amount by any acceptable means of administration. The appropriate dosage range will depend upon a number of factors, such as the severity of the condition to be treated, the age and relative health of the subject, the potency of the compound employed, the route and form of administration, the indication for which administration is intended, and the preference and experience of the relevant physician. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation, a therapeutically effective amount of a composition of the invention for a given disease by virtue of personal knowledge and the disclosure of this application.

Thus, the compositions of the present invention may be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. Typical modes of administration are oral, topical or intravenous administration using a convenient daily dosage regimen which may be adjusted according to the degree of illness.

For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically acceptable compositions can be prepared, for example, by dissolving the active compounds described herein and optional pharmaceutical adjuvants, dispersing in an excipient such as water, saline, aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art. For example, see Remington's pharmaceutical sciences, mentioned above.

In yet another embodiment, there is provided the use of a permeation enhancer excipient comprising a polymer, such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, polyacrylic acid); thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

For oral administration, the compositions will generally take the form of tablets, capsules, soft capsules, or may be in the form of aqueous or non-aqueous solutions, suspensions or syrups. Tablets and capsules are typical forms of oral administration. Tablets and capsules for oral administration may include one or more conventional carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. In general, the compositions of the present invention may be used in combination with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, calcium hydrogen phosphate, calcium sulfate, mannitol, sorbitol and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are employed, the active agent may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and the like, as well as emulsifying and suspending agents. Flavoring, coloring and/or sweetening agents may also be added if desired. Other optional ingredients for incorporation into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations may be prepared in conventional forms, whether liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to injection, or emulsion forms. Sterile injectable suspensions are generally formulated according to the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in an acceptable non-toxic parenterally-acceptable diluent or solvent. Acceptable carriers and solvents that may be employed include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters, or polyols are conventionally employed as a solvent or suspending medium. In addition, parenteral administration may involve the use of sustained release or sustained release systems to maintain a constant dosage level.

Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via some parenteral route may involve introducing the formulation of the invention into the patient through a needle or catheter pushed by a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided herein can be administered using a syringe, pump, or any other device recognized in the art for parenteral administration.

Formulations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil and corn oil), gelatin, and injectable organic esters (e.g., ethyl oleate). Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria retaining filter, by incorporating sterilizing agents into the composition, by irradiating the composition, or by heating the composition. They may also be prepared immediately prior to use in sterile water or some other sterile injectable vehicle.

Sterile injectable solutions are prepared by incorporating the compound(s) of the invention in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a base dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the typical methods of preparation are vacuum drying and the freeze-drying technique which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, parenteral compositions suitable for injectable administration are prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol and water. The solution was isotonic with sodium chloride and sterilized.

Alternatively, the pharmaceutical compositions of the present invention may be in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.

Typical formulations for topical drug delivery are ointments and creams. Ointments are semisolid preparations, usually based on petrolatum or other petroleum derivatives. As is known in the art, creams containing selected active agents are oil-in-water or water-in-oil, viscous liquid or semisolid emulsions. Cream bases are water-washable and comprise an oil phase, an emulsifier and an aqueous phase. The oil phase, sometimes also referred to as the "internal" phase, is typically composed of petrolatum and a fatty alcohol (e.g., cetyl or stearyl alcohol). The aqueous phase typically, although not necessarily, exceeds the oil phase in volume and typically contains a humectant. The emulsifier in the cream is typically a nonionic surfactant, an anionic surfactant, a cationic surfactant or an amphoteric surfactant. As will be appreciated by those skilled in the art, the particular ointment or cream base to be used will provide optimal drug delivery. As with the other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration may be performed using transmucosal delivery systems known to those skilled in the art. The compounds of the present invention may also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches" in which the agent is typically contained in a laminate structure that is used as a drug delivery device to be secured to a body surface. In such a configuration, the pharmaceutical composition is typically contained in a layer or "reservoir" beneath the upper backing layer. The laminating apparatus may comprise one container or a plurality of containers. In one embodiment, the reservoir comprises a polymer matrix of a pharmaceutically acceptable contact adhesive material, which is used to secure the system to the skin during drug delivery. Examples of suitable skin-contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and the skin contact adhesive are present as separate, distinct layers, with the adhesive underlying the reservoir, in which case the reservoir may be a polymer matrix as described above, or may be a liquid or gel reservoir or may take other forms. The support layer in these laminates, which serves as the upper surface of the device, can function as the primary structural element of the laminate structure and provide great flexibility to the device. The material selected for the support layer should be substantially impermeable to the active agent as well as any other materials present.

The compositions of the present invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds may generally have a small particle size, for example, on the order of 5 microns or less. Such particle sizes may be obtained by methods known in the art, for example by micronisation. The active ingredient is provided in pressurized packs with a suitable propellant, e.g., a chlorofluorocarbon (CFC), e.g., dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently comprise a surfactant, for example lecithin. The dosage of the medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in gelatin or blister pack capsules or cartridges, from which the powder may be administered by means of an inhaler.

A pharmaceutically effective amount or a therapeutically effective amount of the composition will be delivered to the subject. The exact effective amount will vary from individual to individual, depending on the species, age, size and health of the individual, the nature and extent of the disease being treated, the recommendations of the treating physician, and the choice of the therapy or combination of therapies to be administered. An effective amount in a given case can be determined by routine experimentation. For the purposes of the present invention, a therapeutic amount may be, for example, in the range of about 0.01mg/kg body weight to about 250mg/kg body weight, more typically in the range of about 0.1mg/kg body weight to about 10mg/kg body weight in at least one dose. If desired, many doses may be administered to an individual to reduce and/or alleviate the signs, symptoms or causes of the disease in question, or to cause any other desired alteration of a biological system. When desired, the formulations can be prepared with an enteric coating suitable for sustained or controlled release administration of the active ingredient.

A therapeutically effective dose of any of the active compounds described herein will be determined by the healthcare practitioner based on the condition, size and age of the patient and the route of delivery. In one non-limiting embodiment, a dosage of about 0.1 to about 200mg/kg has therapeutic efficacy, all weights being calculated based on the weight of the active compound, including the case where a salt is used.

In certain embodiments, the pharmaceutical composition is a dosage form comprising the following amounts of active compound and optionally additional active agent in a unit dosage form: from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg or from about 200mg to about 600mg of active compound; and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg or from about 200mg to about 600mg of additional active agent. Examples are dosage forms having at least 5, 10, 15, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 850, 900, 950 or 1000mg of active compound, alone or calculated as a salt thereof. The pharmaceutical compositions may also comprise a molar ratio of the active compound and the additional active agent in a proportion that achieves the desired result.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Likewise, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these in packaged form.

Method of treatment

The compounds and compositions of the present invention may be used in methods of treating or preventing estrogen-related medical conditions, such as cancer. For example, the cancer may be breast cancer, ovarian cancer, endometrial cancer, kidney cancer, uterine cancer, esophageal cancer, urothelial cancer, bladder cancer, genitourinary tract cancer, fallopian tube cancer and peritoneal cavity cancer. In another embodiment, the disease is metastatic endocrine therapy resistant breast cancer. In some embodiments, the compound is used after chemotherapy or radiation therapy to avoid relapse, or as a primary treatment instead of chemotherapy or radiation.

In one embodiment, "cancer" refers to abnormal growth of cells that tend to proliferate in an uncontrolled manner and in some cases tend to metastasize (spread). Types of cancer include, but are not limited to, those in solid tumors (e.g., bladder, intestine, brain, breast, endometrium, heart, kidney, lung, uterus, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma) or hematologic tumors (e.g., leukemia and lymphoma) at any stage of the disease, with or without metastasis.

In one embodiment, the cancer or tumor is estrogen-mediated. In an alternative embodiment, the cancer or tumor is not estrogen-mediated. In various embodiments, the cancer or tumor is not hormone-mediated. Non-limiting examples of cancer include acute lymphocytic leukemia, acuteMyeloid leukemia, adrenocortical carcinoma, anal carcinoma, appendiceal carcinoma, astrocytoma, atypical teratocarcinoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, bone carcinoma (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumors, breast cancer, bronchial tumor, burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonic tumor, endometrial cancer, ependymoma, esophageal cancer, ewing's sarcoma family tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans 'cell histiocytosis, laryngeal cancer, leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, lung cancer, non-small cell lung cancer, Burkitt's lymphoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myelogenous leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignancy potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, intermediately differentiated pineal parenchymal tumor, pineal somatic tumor and supratentorial primary neuroectodermal tumor, pituitary tumor, plasmacytoma/multiple myeloma, pleuropneumoniumblastomaPrimary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, ewing 'S sarcoma family tumor, sarcoma, kaposi' S disease, szary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, urinary tract cancer, uterine sarcoma, vaginal cancer, vulval cancer,macroglobulinemia, Wilms' tumor.

The treatment method can prevent or reduce the risk of cancer. The treatment method can cause partial or complete regression of the cancer in the individual.

The treatment method can cause partial or complete regression of tamoxifen resistant cancers or tumors. The treatment method can cause partial or complete regression of triple negative breast cancer.

In some embodiments, the compounds of the present invention are useful for treating or preventing cancer or tumors in a mammal, such as a human. In some embodiments, the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a hormone-dependent cancer. In some embodiments, the cancer is an estrogen receptor dependent cancer. In some embodiments, the cancer is an estrogen sensitive cancer. In some embodiments, the cancer is resistant to anti-hormone therapy. In some embodiments, the cancer is an estrogen sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormone therapy. In some embodiments, the cancer is a hormone sensitive cancer or hormone receptor dependent cancer that is resistant to anti-hormone therapy. In some embodiments, the anti-hormone therapy comprises treatment with at least one drug selected from tamoxifen, fulvestrant, a steroid aromatase inhibitor and a non-steroid aromatase inhibitor.

In one aspect, a compound of formula I, II, III, IV or VI, or a pharmaceutically acceptable salt or prodrug thereof, is useful for treating estrogen receptor (ER +) positive breast cancer. In one embodiment, the ER + breast cancer is human epidermal growth factor receptor 2 negative (HER 2-). In one embodiment, the ER + breast cancer is HER2 positive. In one embodiment, ER + breast cancer is progesterone receptor positive (PR +). In one embodiment, ER + breast cancer is PR-. In one embodiment, ER + breast cancer is PR + and HER 2-. In one embodiment, the ER + breast cancer is PR + and HER2 +. In one embodiment, ER + breast cancer is PR-and HER 2-. In one embodiment, the ER + breast cancer is PR-and HER2 +. In one embodiment, ER + breast cancer is retinoblastoma protein positive (Rb +). In one embodiment, ER + breast cancer is KI67 positive (KI67 +). In one embodiment, the ER + breast cancer is KI67 negative (KI 67-). In one embodiment, the ER + breast cancer is ER + advanced metastatic breast cancer. In one embodiment, the ER + breast cancer is ER + luminal a breast cancer. In one embodiment, the ER + breast cancer is ER + luminal b breast cancer. In one embodiment, the ER + breast cancer is ER + male breast cancer. In one embodiment, the ER + breast cancer is ER + lobular breast cancer. In one embodiment, the ER + breast cancer is ER + ductal breast cancer. In one embodiment, the ER + breast cancer is invasive breast cancer. In one embodiment, the ER + breast cancer is ER + refractory advanced breast cancer.

In one aspect, a compound of formula I, II, III, IV or VI, or a pharmaceutically acceptable salt or prodrug thereof, is useful for treating an estrogen receptor (ER +) positive cancer selected from: esophageal cancer, bladder cancer, uterine cancer, cervical cancer, ovarian cancer, urinary cancer, fallopian tube cancer, primary peritoneal cavity cancer and non-small cell lung cancer.

In some embodiments, the compounds disclosed herein are used to treat hormone receptor positive, metastatic breast cancer in postmenopausal women with disease progression after anti-estrogen therapy.

In some embodiments, the compounds disclosed herein are used to treat a hormone-dependent, benign or malignant disorder of the mammary or reproductive tract of a mammal. In some embodiments, the benign or malignant disease is breast cancer.

In one embodiment, the compounds of the invention are used in hormonal therapy.

The foregoing may be better understood by reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the invention.

In one aspect, the compounds of the invention, or pharmaceutically acceptable salts or prodrugs thereof, are useful for treating hormone-related cancers or tumors that have metastasized to the brain, bone or other organs. In one embodiment of this aspect, the hormone-related cancer is estrogen-mediated. In another embodiment, the estrogen-mediated cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, and endometrial cancer. In other embodiments, the compounds of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, are useful for preventing the metastasis of hormone-related cancers or tumors (including estrogen-mediated, hormone-related cancers such as breast, uterine, ovarian, or endometrial cancers) to the brain, bone, or other organs.

Combination therapy

In one aspect, the compounds of formula I, formula II, formula III, formula IV or formula VI of the present invention are administered in combination with a selected CDK inhibitor, including but not limited to CDK2, CDK4, CDK6 or CDK8 inhibitors, which may be selective inhibitors or may have inhibitory activity against more than one kinase as long as there is no unacceptable toxicity. Examples of CDK4/6 inhibitors are palbociclib, abeciclib and rebociclib. In one aspect, selected compounds of formula I, formula II, formula III, formula IV or formula VI of the present invention are administered in combination with a CDK4/6 inhibitor of formula V.

In one main aspect, selected compounds of formula I, formula II, formula III, formula IV or formula VI are provided in combination with a compound of formula V having the structure:

for example, the selected drugs used in combination may be provided in a single fixed dosage form once, twice or three times daily, which may be beneficial for treatment compliance. In another embodiment, the medicament may be formulated in two or more dosage forms and may be taken simultaneously or during the day, e.g., once, twice or three times a day, as specified by the healthcare provider. In yet another embodiment, the drugs are provided in separate dosage forms and are administered at about the same time during the day or at different times during the day, so long as they have a combined effect on the patient (e.g., human). In one embodiment, when the drugs are provided in separate dosage forms, they are provided in effective amounts of both drugs (C)_trough) While present in the body.

In one aspect, there is provided a method for treating an abnormal cell proliferation disease in a host (e.g., a human), the method comprising administering an effective amount of one or more active compounds described herein in combination or alternation with another active compound.

In one aspect of this embodiment, the additional active compound is an immunomodulator, including but not limited to a checkpoint inhibitor. Checkpoint inhibitors for use in the methods described herein include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, and V-domain Ig inhibitors of T cell activation, or combinations thereof.

In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, thereby inhibiting immunosuppression. In one embodiment, the checkpoint inhibitor is a PD-1 checkpoint inhibitor selected from the group consisting of: nivolumab, pembrolizumab, pidilizumab, AMP-224(AstraZeneca and MedImmune), PF-06801591(Pfizer), MEDI0680(AstraZeneca), PDR001(Novartis), REGN2810(Regeneron), SHR-12-1 (Jiangsu Henry pharmaceuticals and Inc Corporation), TSR-042(Tesaro) and PD-L1/VISTA inhibitor CA-170(Curis Inc.).

In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor and thereby inhibits immunosuppression. PD-L1 inhibitors include, but are not limited to, Avermectin, Attributab, Devolumab, KN035 and BMS-936559(Bristol-Myers Squibb).

In one aspect of this embodiment, the checkpoint inhibitor is a CTLA-4 checkpoint inhibitor that binds to CTLA-4 and inhibits immune suppression. CTLA-4 inhibitors include, but are not limited to, ipilimumab, texumumab (AstraZeneca and MedImmune), age 1884, and age 2041 (Agenus).

In another embodiment, the checkpoint inhibitor is a LAG-3 checkpoint inhibitor. Examples of LAG-3 checkpoint inhibitors include, but are not limited to BMS-986016(Bristol-Myers Squibb), GSK2831781(GlaxoSmithKline), IMP321(Prima BioMed), LAG525(Novartis), and the PD-1 and LAG-3 dual inhibitors MGD013 (MacroGenics). In another aspect of this embodiment, the checkpoint inhibitor is a TIM-3 checkpoint inhibitor. Specific TIM-3 inhibitors include, but are not limited to TSR-022 (Tesaro).

In yet another embodiment, an effective amount of one of the active compounds described herein is administered in combination or alternation with an effective amount of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor down-regulator), a complete estrogen receptor down-regulator or another form of a partial or complete estrogen antagonist, to treat abnormal tissue of the female reproductive system, such as breast, ovarian, renal, endometrial or uterine cancer. Some antiestrogens such as raloxifene and tamoxifen retain some estrogenic-like effects, including estrogenic-like stimulation of uterine growth, and in some cases, tumor growth during breast cancer progression. In contrast, fulvestrant is a complete antiestrogen, has no estrogenic-like effect on the uterus, and is effective against tamoxifen resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO2014/19176 assigned to AstraZeneca. Additional non-limiting examples of anti-estrogenic compounds include: SERMS such as norgestimate, bazedoxifene, bronarestrol, clorenyl, clomiphene citrate, cyclofenib, lasofoxifene, oxymetaxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane and letrozole; and gonadotrophins, such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, trimegestone acetate, dydrogestone, medroxyprogesterone acetate, megestrol acetate, nomegestone acetate, norethindrone acetate, progesterone and spironolactone.

In another embodiment, an effective amount of one of the active compounds described herein is administered in combination or alternation with an effective amount of an androgen (e.g., testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor down-regulator and/or degrader, a complete androgen receptor degrader or another form of a partial or complete androgen antagonist, to treat abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In one embodiment, the prostate cancer or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogen compounds are provided in WO2011/156518 and U.S. Pat. Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide (apalcutamide), cyproterone acetate, chlormadinone acetate, spironolactone, epididymolactone, drospirenone, ketoconazole, topiramide (topilutamide), abiraterone acetate and cimetidine.

In one aspect, a therapeutic regimen is provided that includes administering a compound of the invention in combination with at least one additional chemotherapeutic agent. The combinations disclosed herein may be administered to produce a beneficial, additive or synergistic effect in the treatment of an abnormal cell proliferative disease.

In particular embodiments, the treatment regimen comprises administering a compound of the invention in combination with at least one kinase inhibitor. In one embodiment, the at least one kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's Tyrosine Kinase (BTK) inhibitor or a spleen tyrosine kinase (Syk) inhibitor or a combination thereof.

PI3k inhibitors useful in the present invention are well known. Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, desmethoxychloromycetin, perifosine, erigerol, piculisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, GDC-0032(2- [4- [2- (2-isopropyl-5-methyl-1, 2, 4-triazol-3-yl) -5, 6-dihydroimidazo [1,2-d ] -2][1,4]Benzoxazepines-9-yl]Pyrazol-1-yl]-2-methylpropionamide), MLN-1117((2R) -1-phenoxy-2-butylhydro (S) -methylphosphonate; or methyl (oxo) { [ (2R) -1-phenoxy-2-butyl]Oxy } phosphorus)), BYL-719((2S) -N1- [ 4-methyl-5- [2- (2,2, 2-trifluoro-1, 1-dimethylethyl) -4-pyridinyl]-2-thiazolyl]-1, 2-pyrrolidinedicarboxamide), GSK2126458(2, 4-difluoro-N- {2- (methoxy) -5- [4- (4-pyridazinyl) -6-quinolinyl]-3-pyridyl } benzenesulfonamide), TGX-221(±) -7-methyl-2- (morpholin-4-yl) -9- (1-phenylaminoethyl) -pyrido [1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1- (2-methyl-3- (trifluoromethyl) benzyl) -6-morpholino-1H-benzo [ d [)]Imidazole-4-carboxylic acid dihydrochloride), KIN-193((R) -2- ((1- (7-methyl-2-morpholino-4-oxo-4H-pyrido [1, 2-a)]Pyrimidin-9-yl) ethyl) amino) benzoic acid), TGR-1202/RP5264, GS-9820((S) -1- (4- ((2- (2-aminopyrimidin-5-yl) -7-methyl-4-hydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2- ([ S)]-1- [ 9H-purin-6-ylamino group]-propyl) -3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR 24409 (N- (4- (N- (3- ((3, 5-dimethoxyphenyl) amino) quinoxalin-2-yl) sulfamoyl) phenyl) -3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N- (7-methoxy-8- (3-morpholinopropoxy) -2, 3-dihydroimidazo [1, 2-c)]Quinazoline), AS 252424(5- [ l- [5- (4-fluoro-2-hydroxy-phenyl) -furan-2-yl)]-methyl- (Z) -ylidene]Thiazolidine-2, 4-dione), CZ 24832(5- (2-amino-8-fluoro- [ l,2, 4-d)]Triazolo [1,5-a]Pyridin-6-yl) -N-tert-butylpyridine-3-sulfonamide), buparlisib (5- [2, 6-bis (4-morpholinyl) -4-pyrimidinyl)]-4- (trifluoromethyl) -2-pyridylamine)GDC-0941(2- (1H-indazol-4-yl) -6- [ [4- (methylsulfonyl) -1-piperazinyl]Methyl radical]-4- (4-morpholinyl) thieno [3,2-d]Pyrimidine), GDC-0980((S) -1- (4- ((2- (2-aminopyrimidin-5-yl) -7-methyl-4-morpholino thieno [3, 2-d)]Pyrimidin-6 yl) methyl) piperazin-1-yl) -2-hydroxypropan-1-one (also known as RG7422)), SF1126((8S,14S,17S) -14- (carboxymethyl) -8- (3-guanidinopropyl) -17- (hydroxymethyl) -3,6,9,12, 15-pentaoxo-1- (4- (4-oxo-8-phenyl-4H-chromen-2-yl) morpholin-4-ium) -2-oxa-7, 10,13, 16-tetraazaoctadeca-18-oic acid ester), PF-05212384(N- [4- [ [4- (dimethylamino) -1-piperidinyl-18-oate)]Carbonyl radical]Phenyl radical]-N' - [4- (4, 6-di-4-morpholinyl-1, 3, 5-triazin-2-yl) phenyl]Urea), LY3023414, BEZ235 (2-methyl-2- {4- [ 3-methyl-2-oxo-8- (quinolin-3-yl) -2, 3-dihydro-1H-imidazo [4, 5-c)]Quinolin-1-yl]Phenyl } propionitrile), XL-765(N- (3- (N- (3- (3, 5-dimethoxyphenylamino) quinoxalin-2-yl) sulfamoyl) phenyl) -3-methoxy-4-methylbenzamide) and GSK1059615(5- [ [4- (4-pyridyl) -6-quinolyl-l-)]Methylene group]-2, 4-thiazolidinedione), PX886([ (3aR,6E,9S,9aR,10R,11aS) -6- [ [ bis (prop-2-enyl) amino group]Methylene radical]-5-hydroxy-9- (methoxymethyl) -9a,11 a-dimethyl-1, 4, 7-trioxo-2, 3,3a,9,10, 11-hexahydroindeno [4,5h]Heterochromen-10-yl radical]Acetate (also known as sonolisib).

In one embodiment, the compounds of the present invention are combined with PIk3 inhibitors in a single dosage form.

BTK inhibitors useful in the present invention are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (ibruvica)^TM) (1- [ (3R) -3- [ 4-amino-3- (4-phenoxy-phenyl) pyrazolo [3,4-d]Pyrimidin-1-yl]Piperidin-1-yl radical]Prop-2-en-1-one), dianilinopyrimidine-based inhibitors, such as AVL-101 and AVL-291/292(N- (3- ((5-fluoro-2- ((4- (2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide) (Avila Therapeutics) (see U.S. patent publication No.2011/0117073, which is incorporated herein in its entirety), dasatinib ([ N- (2-chloro-6-methylphenyl) -2- (6- (4- (2-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide)]LFM-A13(α -cyano- β -hydroxy- β -methyl-N- (2, 5-dibromophenyl) acrylamide), GDC-0834([ R-N- (3- (6- (4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenylamino)) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b]Thiophene-2-carboxamides]CGI-5604- (tert-butyl) -N- (3- (8- (phenylamino) imidazo [1, 2-a)]Pyrazin-6-yl) phenyl) benzamide, CGI-1746(4- (tert-butyl) -N- (2-methyl-3- (4-methyl-6- ((4- (morpholine-4-carbonyl) phenyl) amino) -5-oxo-4, 5-dihydropyrazin-2-yl) phenyl) benzamide), CNX-774(4- (4- ((4- ((3-acrylamidophenyl) amino) -5-fluoropyrimidin-2-ylamino) phenoxy) -N-methylpyridinecarboxamide), CTA056 (7-benzyl-1- (3- (piperidin-1-yl) propyl) -2- (4- (pyridin-4-yl) phenyl) -1H-imidazo [4,5-g]Quinoxalin-6 (5H) -one), GDC-0834((R) -N- (3- (6- ((4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenyl) amino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b]Thiophene-2-carboxamide), GDC-0837((R) -N- (3- (6- ((4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenyl) amino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b ] a]Thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059(Ono Pharmaceuticals), PRT062607(4- ((3- (2H-1,2, 3-triazol-2-yl) phenyl) amino) -2- ((((1R,2S) -2-aminocyclohexyl) amino) pyrimidine-5-carboxamide hydrochloride), QL-47(1- (1-acryloylindolin-6-yl) -9- (1-methyl-1H-pyrazol-4-yl) benzo [ H ] e][1,6]Naphthyridin-2 (1H) -one) and RN486 (6-cyclopropyl-8-fluoro-2- (2-hydroxymethyl-3- { 1-methyl-5- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino)]-6-oxo-1, 6-dihydro-pyridin-3-yl } -phenyl) -2H-isoquinolin-1-one) and other molecules capable of inhibiting BTK activity, as disclosed for example in akinley et ah, Journal of Hematology&Those BTK inhibitors disclosed in Oncology,2013,6:59, which are incorporated herein by reference in their entirety. In one embodiment, the compounds of the present invention are combined with a BTK inhibitor in a single dosage form.

Syk inhibitors useful in the present invention are well known and include, for example, cerdulatinib (4- (cyclopropylamino) -2- (((4- (4- (ethylsulfonyl) piperazin-1-yl) phenyl) amino) pyrimidine-5-carboxamide), entospletinib (6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine), fosfatinib ([6- ({ 5-fluoro-2- [ (3,4, 5-trimethoxyphenyl) amino ] -4-pyrimidinyl } amino) -2, 2-dimethyl-3-oxo-2, 3-dihydro-4H-pyridinyl [3,2-b ] [1,4] oxazin-4-yl ] methyl dihydrogen phosphate), fostertine disodium salt ((6- ((5-fluoro-2- ((3,4, 5-trimethoxyphenyl) amino) pyrimidin-4-yl) amino) -2, 2-dimethyl-3-oxo-2H-pyrido [3,2-b ] [1,4] oxazin-4 (3H) -yl) sodium methyl phosphate), BAY 61-3606(2- (7- (3, 4-dimethoxyphenyl) -imidazo [1,2-c ] pyrimidin-5-ylamino) -nicotinamide hydrochloride), RO9021(6- [ (1R,2S) -2-amino-cyclohexylamine ] -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid amide), imatinib (Gleevec; 4- [ (4-methylpiperazin-1-yl) methyl ] -N- (4-methyl-3- { [4- (pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl) benzamide), staurosporine, GSK143(2- ((((3R,4R) -3-aminotetrahydro-2H-pyran-4-yl) amino) -4- (p-toluidino) pyrimidine-5-carboxamide), PP2(1- (tert-butyl) -3- (4-chlorophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine), PRT-060318(2- ((((1R,2S) -2-aminocyclohexyl) amino) -4- (m-tolylamino) pyrimidine-5- Formamide), PRT-062607(4- ((3- (2H-1,2, 3-triazol-2-yl) phenyl) amino) -2- ((((1R,2S) -2-aminocyclohexyl) amino) pyrimidine-5-carboxamide hydrochloride), R112(3,3' - ((5-fluoropyrimidine-2, 4-diyl) bis (azanediyl)) diphenol), R348 (3-ethyl-4-methylpyridine), R406(6- ((5-fluoro-2- ((3,4, 5-trimethoxyphenyl) amino) pyrimidin-4-yl) amino) -2, 2-dimethyl-2H-pyrido [3,2-b ] [1,4] oxazin-3 (4H) -one), YM193306 (see Singh et al, discovery and Development of spread type Kinase (SYK) Inhibitors, J.Med.chem.2012,55, 3614-D. -), 7-azaindole, piceatannol, ER-27319 (see Singh et al, discovery and Development of spread type Kinase (SYK) Inhibitors, J.Med.chem.2012,55, 3614-D3643, which is incorporated herein in its entirety), compound D (see Singh et al, discovery and Development of spread type Kinase (SYK) Inhibitors, J.chem.2012, 55, 3614-D3643, which is incorporated herein in its entirety), PRT 193318 (see Singh et al, Development and Development of spread type Kinase (SYK) Inhibitors, J.3655, 3614-d.3643, which is incorporated herein, J.J.0609, J.S. Pat. 3643, which is incorporated herein, J.S.7-n.7, J.7-n.7-a, and J.7-n.7-a, a. a blend of a mixture of a plant type 3614, med. chem.2012,55, 3614-. In one embodiment, the compounds of the present invention are combined with Syk inhibitors in a single dosage form.

In one embodiment, the at least one additional chemotherapeutic agent is a B-cell lymphoma 2(Bcl-2) protein inhibitor. BCL-2 inhibitors are known in the art and include, for example, ABT-199(4- [4- [ [2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl ] methyl ] piperazin-1-yl ] -N- [ [ 3-nitro-4- [ [ (tetrahydro-2H-pyran-4-yl) methyl ] amino ] phenyl ] sulfonyl ] -2- [ (1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy ] benzamide), ABT-737(4- [4- [ [ [2- (4-chlorophenyl) phenyl ] methyl ] piperazin-1-yl ] -N- [4- [ [ (2R) -4- (dimethylamino) -1- Phenylsulfanylbut-2-yl ] amino ] -3-nitrophenyl ] sulfonylbenzamide), ABT-263((R) -4- (4- (((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4-morpholino-1- ((phenylthio) but-2-yl) amino) -3 ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide), GX15-070(obatoclax methanesulfonate, (2Z) -2- [ (5Z) -5- [ (3, 5-dimethyl-1H-pyrrol-2-yl) methylidene ] -4-methoxypyrazine Pyrrol-2-ylidene ] indole; methanesulfonic acid))), 2-methoxy-antimycin a3, YC137(4- (4, 9-dioxo-4, 9-dihydronaphtho [2,3-d ] thiazol-2-ylamino) -phenyl ester), Pogosin, 2-amino-6-bromo-4- (1-cyano-2-ethoxy-2-oxoethyl) -4H-chromene-3-carboxylic acid ethyl ester, nilotinib-d 3, TW-37(N- [4- [ [2- (1, 1-dimethylethyl) phenyl ] sulfonyl ] phenyl ] -2,3, 4-trihydroxy-5- [ [2- (1-methylethyl) phenyl ] methyl ] benzamide), apogossypolone (ApoG2) or G3139 (Obllisers en). In one embodiment, the compounds of the present invention are combined with at least one BCL-2 inhibitor in a single dosage form.

The compounds of the present invention or pharmaceutically active salts thereof may be combined with immunotherapy. As discussed in more detail below, the compounds of the invention may be conjugated to antibodies, radioactive agents or other targeting agents that direct the compounds to diseased or abnormally proliferating cells.

In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some mabs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these mabs can "coat" the surface of cancer cells, triggering their destruction by the immune system. For example, bevacizumab targets Vascular Endothelial Growth Factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment, which promotes the development of tumor vessels. When bound to bevacizumab, VEGF is unable to interact with its cellular receptors, thereby preventing signaling leading to new blood vessel growth. Similarly, cetuximab and panitumumab target Epidermal Growth Factor Receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). Mabs that bind to cell surface growth factor receptors can prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

In some embodiments, the combination may be further administered to the individual in combination with other chemotherapeutic agents. If convenient, the combination described herein may be administered simultaneously with an additional chemotherapeutic agent to simplify the treatment regimen. In some embodiments, the combination and the other chemotherapeutic agent may be provided in a single formulation. In one embodiment, the use of a compound described herein is combined with other agents in a therapeutic regimen. Such drugs may include, but are not limited to, tamoxifen, midazolam, letrozole, bortezomib, anastrozole, goserelin, mTOR inhibitors, PI3 kinase inhibitors, dual mTOR-PI3K inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (e.g., HSP70 and HSP90 inhibitors, or a combination thereof), BCL-2 inhibitors, apoptotic compounds, AKT inhibitors, including, but not limited to, MK-2206, GSK690693, piperacillin (KRX 0401), GDC-0068, triciribine, AZD5363, magnolol, PF-04691502, and miltefosine; PD-1 inhibitors, including but not limited to nivolumab, CT-011, MK-3475, BMS 936558; and AMP-514 or FLT-3 inhibitors, including, but not limited to, P406, dolivitinib, quinzatinib (AC220), Amuvatinib (MP-470), Tandudinib (MLN518), ENMD-2076 and KW-2449 or combinations thereof. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, descrolimus (Deforolimus), and sirolimus. Examples of MEK inhibitors include, but are not limited to, trametinib/GSK 1120212(N- (3- { 3-cyclopropyl-5- [ (2-fluoro-4-iodophenyl) amino ] -6, 8-dimethyl-2, 4, 7-trioxo-3, 4,6, 7-tetrahydropyrido [4,3-d ] pyrimidin-1 (2H-yl } phenyl) acetamide), semetinib (6- (4-bromo-2-chloroaniline) -7-fluoro-N- (2-hydroxyethoxy) -3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC1935369((S) -N- (2, 3-dihydroxypropyl) -3- ((2-fluoro-4-iodophenyl) amino) isonicotinamide), XL-518/GDC-0973(1- ({3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] phenyl } carbonyl) -3- [ (2S) -piperidin-2-yl ] azetidin-3-ol), refametinib/BAY869766/RDEAl19(N- (3, 4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide), PD-0325901(N- [ (2R) -2, 3-dihydroxypropoxy ] -3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -benzamide), TAK733((R) -3- (2, 3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3d ] pyrimidine-4, 7(3H,8H) -dione), MEK162/ARRY438162(5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3- [ [ 3-fluoro-2- (methylsulfamoylamino) -4-pyridyl ] methyl ] -4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655(3, 4-difluoro-2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -5- ((3-oxo-1, 2-oxazin-2 yl) methyl) benzamide) or AZD8330(2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -1, 5-dimethyl-6-oxo-1, 6-dihydropyridine-3-carboxamide). Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER. Examples of ALK inhibitors include, but are not limited to, crizotinib, AP26113, and LDK 378. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol. In a particular embodiment, the compounds described herein are administered in combination with letrozole and/or tamoxifen. Other chemotherapeutic agents that may be used in combination with the compounds described herein include, but are not limited to, chemotherapeutic agents whose antitumor effect does not require cell cycle activity.

In one embodiment, the compounds of the invention described herein may be combined with chemotherapeutic agents selected from, but not limited to: imatinib mesylateDasatinibNilotinibBosutinibTrastuzumabPertuzumab (Perjeta TM), lapatinibGefitinibErlotinibCetuximabPanitumumabVandetanibVemurafenibVorinostatRomidepsinBexaroteneAliviroc acidRetinoic acidCarfilzomib (Kyprolis TM), PralatrexateBevacizumabAbiracy (Ziv-aflibercept)SorafenibSunitinibPazopanibRegorafenibAnd cabozantinib (Cometriq TM).

In certain aspects, the additional therapeutic agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressive agent.

Suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents, which include any agent detrimental to the viability of a cell), agents, and liposomes or other vesicles containing chemotherapeutic compounds. Typical anticancer drugs include: vincristineOr liposomal vincristineDaunorubicin (daunomycin or daunorubicin)) Or doxorubicinCytarabine (arabinosyl cytosine, ara-C or) L-asparaginaseOr PEG-L-asparaginase (pemetrexed or pemetrexed)) Etoposide (VP-16), teniposide6-mercaptopurine (6-MP or) Methotrexate, cyclophosphamidePrednisone, dexamethasone (Decadron), imatinibDasatinibNilotinibBosutinibAnd pinatinib (Iucig)^TM). Examples of other suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, alkylating agents, allopurinol sodium, hexamethamine, amifostine, anastrozole, Anthracycline (AMC)), antimitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diaminoplatinum, anthracycline antibiotics, antimetabolites, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium folinate, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cladribine, colchicine, conjugated estrogens, cisplatin, cyclophosphamide, cytarabine, cytochalasin B, cyclophosphamide, dacarbazine, actinomycin D (formerly actinomycin), daunorubicin hydrochloride, daunorubicin citrate, dinierein, dexrazoxane, dibrommannitol, dihydroxyanthrax dione, docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, E.coli L-asparaginase, etidine, epoetin-alpha, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustineStatin sodium phosphate, ethidium bromide, ethinyl estradiol, etidronic acid, etoposide folinic acid factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine hydrochloride, glucocorticoids, goserelin acetate, gramicidin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon alpha-2 b, irinotecan hydrochloride, letrozole, calcium folinate, leuprolide acetate, levamisole hydrochloride, lidocaine, lomustine, maytansine, mechlorethamine hydrochloride, medroxyprogesterone acetate, megestrol acetate, melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nimidoxuridine acetate, emsidanone hydrochloride, paclitaxel, disodium pamidronate, pentostatin, pilocarpine hydrochloride, plicamycin, polifeprosan 20 (with carmustine implant), porfillin sodium, procaine, procarbazine hydrochloride, propranolol, sargrastim, streptozotocin, tamoxifen, paclitaxel, teniposide, testosterone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that may be administered in combination with the compounds disclosed herein may include 2-methoxyestradiol or 2ME2, finasteride, vatalanib, vorozimab, etalizumab (MEDI-522), cilengitide, dovitinib, phentermine monocrotaxane, atacept, rituximab, alemtuzumab, aldesleukin, alemtuzumab, tositumumab, lucitumumab, daclizumab, HLL1, huN901-DM1, atimod, natalizumab, bortezomib, malizomib, tanespidromycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belief, panobitat, mapatuzumab, lexatuzumab, lam, ritamin, ritylid, P-00, tiprinone, 276, tiprinil, lenalimine, doxamide, fapidotimod, P-00, nekininavir, 276, tipiranib, 276Lidocaine, pomalidomide, simvastatin, and celecoxib. In one aspect of the invention, the compounds described herein may be combined with at least one immunosuppressive agent. In one embodiment, the immunosuppressant is selected from calcineurin inhibitors, e.g. cyclosporine or ascomycin, e.g. cyclosporine aFK506 (tacrolimus), pimecrolimus; mTOR inhibitors such as rapamycin or derivatives thereof, e.g. sirolimusEverolimusTemsirolimus, zotarolimus, biolimus-7, biolimus-9; rapalog, such as, for example, phospholimus, azathioprine, campath 1H; S1P receptor modulators, e.g. fingolimod or an analogue thereof, anti-IL-8 antibodies, mycophenolic acid or a salt thereof such as the sodium salt or a prodrug thereof, e.g. Mycophenolate MofetilOKT3At least one of prednisone and prednisone,brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, aspergirolimus, Lefiunosideanti-CD 25, anti-IL 2R, basiliximabDalizumabMizoribine, methotrexateDexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus,) CTLA4lg, abaccept, Belacian, LFA3lg, etanercept (by ImmuneXcite)Sale), adalimumabInfliximabanti-LFA-1 antibody, natalizumabThe pharmaceutical composition comprises one or more of an emomumab, gavilimomab, golimumab, antithymocyte immunoglobulin, sibira mab, Alefacept, efavirenz, Pentasa, mesalazine, amsaceae, codeine phosphate, benorilate, fenbufen, naproxen, diclofenac, etodolac, indomethacin, aspirin, and ibuprofen.

In yet another embodiment, the selected compounds of the invention can be used in combination with CAR-T therapy or non-engineered T cell therapy.

In certain embodiments, a compound described herein is administered to an individual prior to treatment with another chemotherapeutic agent, during treatment with another chemotherapeutic agent, after administration of another chemotherapeutic agent (or a combination thereof).

Synthesis method

The compounds described herein may be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared using the described protocols.

Certain compounds described herein may have chiral centers, and the compounds may exist in isomeric or diastereomeric forms. When multiple chiral variables are present on a formula of the invention, the formula also encompasses each of the possible diastereomers, unless otherwise indicated or clearly evident from the text. For example, (R, R), (S, R), (S, S) and (R, S) of a molecule having two chiral centers. One skilled in the art will recognize that pure enantiomers, diastereomers and cis/trans isomers can be prepared by methods known in the art. Examples of the method of obtaining the optically active material include at least the following.

i) Physical separation of crystals-a technique in which macroscopic crystals of individual enantiomers are separated by hand. This technique can be used if crystals of the individual enantiomers are present, i.e. the material is an aggregate (conglomerate) and the crystals are visually different.

ii) simultaneous crystallization-a technique in which the enantiomers are crystallized separately from the racemic solution, only possible if the racemate is a solid aggregate;

iii) enzymatic resolution-a technique in which racemates are partially or completely separated by the different reaction rates of the enantiomers with the enzyme;

iv) enzymatic asymmetric synthesis-a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

v) chemical asymmetric synthesis-a synthetic technique in which the desired enantiomer is synthesized from an achiral precursor under conditions that result in asymmetry (i.e., chirality) in the product, which may be achieved using a chiral catalyst or chiral auxiliary;

vi) diastereoisomeric separation-a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) which converts the individual enantiomer into the diastereomer. The now more pronounced structural differences are then exploited to separate the diastereomers by chromatography or crystallization, followed by removal of the chiral auxiliary to give the desired enantiomers.

vii) first and second order asymmetric transformations-a technique in which the diastereoisomers from the racemate are balanced to give advantage in the solution of the diastereoisomers from the desired enantiomer, or preferential crystallization of the diastereoisomers from the desired enantiomer disturbs the balance so that ultimately in principle all the material is converted from the desired enantiomer to the crystalline diastereoisomer. Then releasing the desired enantiomer from the diastereomer;

viii) kinetic resolution-this technique refers to the partial or complete resolution of the racemate (or the further resolution of the partially resolved compound) by virtue of unequal reaction rates of the enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions;

ix) enantiomer-specific synthesis from non-racemic precursors-a synthetic technique in which the desired enantiomer is obtained from achiral starting materials, the stereochemical integrity is not compromised or only minimally compromised during the synthesis;

x) chiral liquid chromatography-a technique in which enantiomers of a racemate are separated in a liquid mobile phase (including by chiral HPLC) by virtue of their different interactions with a stationary phase. The stationary phase may be made of chiral material, or the mobile phase may contain additional chiral material to initiate different interactions;

xi) chiral gas chromatography-a technique in which the racemate is volatilized and the enantiomers are separated by virtue of different interactions in a gaseous mobile phase with a column containing a fixed, non-racemic chiral adsorbent phase;

xii) extraction with a chiral solvent-a technique in which enantiomers are separated by preferential dissolution of one enantiomer into a particular chiral solvent; and

xiii) transport through chiral membranes-a technique in which the racemate is brought into contact with a thin membrane barrier. Barriers typically separate two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. The separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

xiv) in one embodiment simulated moving bed chromatography is used. A variety of chiral stationary phases are commercially available.

General synthetic route

Scheme 1

To a commercially available solution of 3-chloro-6-methoxybenzo [ b ] thiophene-2-carbonyl chloride (compound 1) was added Weinreb amine and a base to give Weinreb amide 2. Weinreb amide 2 is then treated with an appropriate grignard reagent to provide compound 3. Compound 3 undergoes nucleophilic attack by intermediate 4 to give compound 5. Compound 5 is then demethylated to afford compound 6. Compound 6 can be further functionalized by nucleophilic attack by an appropriate electrophile to give compound 7 or compound 8.

Scheme 2

To a solution of commercially available methyl 3-chloro-6-methoxy-benzo [ b ] thiophene-2-carboxylate (compound 9) was added butyllithium and optionally substituted benzene bromide to give compound 10. Compound 10 is then demethylated and then nucleophilic addition of benzyl bromide affords compound 11. Compound 11 undergoes nucleophilic attack by intermediate 4 to give compound 12. Compound 12 is then deprotected to afford compound 6. Compound 6 can be further functionalized by nucleophilic attack by an appropriate electrophile to give compound 7 or compound 8.

Scheme 3

Weinreb amine and a base were added to a solution of a commercially available solution of 3-chloro-6-methoxybenzo [ b ] thiophene-2-carbonyl chloride (compound 1) to give Weinreb amide 2. Weinreb amide 2 is then treated with an appropriate grignard reagent to provide compound 3. Compound 3 undergoes nucleophilic attack by intermediate 16 to give compound 17. Compound 17 is then demethylated to afford compound 18.

Scheme 4

In step 1, commercially available primary alcohols of compound 22 are converted to compound 23 by methods known in the art. In step 2, compound 23 is substituted with R²The group undergoes nucleophilic attack to give intermediate 4, which intermediate 4 is used in scheme 1.

Scheme 5

Scheme 8 is a non-limiting example of the method described in scheme 4. In step 1, a commercially available primary alcohol of 4- (2-hydroxyethyl) phenol 24 was treated with concentrated hydrochloric acid in a microwave to give compound 25. In step 2, compound 25 is mixed with azetidine under nucleophilic conditions to provide compound 26, which compound 26 can be used in scheme 1.

Scheme 6

In step 1, the chlorine group of commercially available compound 27 is passed through R²The group undergoes nucleophilic attack to provide intermediate 28. In step 2, compound 28 was converted to a grignard reagent known in the art to provide intermediate 16 used in scheme 3.

Scheme 7

Scheme 7 is a non-limiting example of the method described in scheme 6. In step 1, the chloro group of commercially available 1-bromo-4- (2-chloroethoxy) benzene 29 is treated with diethylamine under nucleophilic conditions to provide compound 30. In step 2, compound 30 is mixed with magnesium to give compound 31, and compound 31 can be used in scheme 4.

Example 1: representative Compounds of the invention

Table 1 provides non-limiting examples of compounds of the invention that may be prepared according to the methods described above or in example 2. One of ordinary skill in the art will be able to use these methods, or conventional variations thereof, to prepare the compounds described herein.

Table 1.

Table 1B.

Table 2 provides representative examples of compounds of formula I:

TABLE 2 non-limiting examples of Compounds of formula I

Table 3 provides representative examples of compounds of formula II:

TABLE 3 non-limiting examples of Compounds of formula II

Table 4 provides representative examples of compounds of formula III:

TABLE 4 non-limiting examples of Compounds of formula III

Table 5 below provides representative examples of compounds of formula IV:

TABLE 5 non-limiting examples of compounds of formula IV

TABLE 6 representative embodiments of variables in formula I

Representative compounds of formula I may be selected from A, R provided in Table 6 above⁸Andany combination of (a).

TABLE 7 representative embodiments of variables of formula II

Representative compounds of formula II may be selected from Y, R provided in Table 7 above¹³Andany combination of (a).

TABLE 8 representative embodiments of variables of formula III

Representative compounds of formula III may be selected from Z, R provided in table 8 above¹³，R¹⁴，R¹⁵，R¹⁶Andwith the proviso that R is¹⁴，R¹⁵And R¹⁶Is not hydrogen.

TABLE 9 representative embodiments of variables of formula IV

Representative compounds of formula IV may be selected from X, R provided in table 9 above¹³Andany combination of (a).

TABLE 10 additional representative embodiments of the variables of formulas IVe-IVj

Representative compounds of formula IVe may be selected from R of Table 10¹，R²Any combination of Q, m and o.

Representative compounds of formula IVf can be selected from R of Table 10¹，R²And any combination of Q and o.

Representative compounds of formula IVg may be selected from R of Table 10¹，R²And any combination of Q and o.

Representative compounds of formula IVh may be selected from R of Table 10¹，R²And o in any combination.

Representative compounds of formula IVi can be selected from R of Table 10¹，R⁴And o in any combination.

Representative compounds of formula IVj may be selected from R of Table 10¹And o in any combination.

Additional compounds of the invention include:

additional compounds of the invention also include:

example 2 representative Synthesis methods

Synthesis of compound 100: ((S) - (4-fluoro-2, 6-dimethylphenyl) (3- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenoxy) -6-hydroxybenzo [ b ] thiophen-2-yl) methanone)

Scheme 8

In step 1, 100 g of compound 32 are dissolved in thionyl chloride and pyridine. Methanol was added to the solution to give compound 33. Compound 33 was recrystallized to yield 50 g of pure product. H-NMR was clean. In step 2, 25 grams of compound 33 are subjected to 1.3 equivalents of n-butyllithium and compound 34. After column purification, 9.8 g of pure compound 35 were isolated. H-NMR was clean. In step 3, 50 g of compound 35 are reacted with BBr₃Reaction, work-up and purification gave 48 g of compound 36. H-NMR was clean. In step 4, 43.8 g of compound 36 are reacted with sodium hydride and benzyl bromide to give 61.6 g of compound 37. In step 5, compound 37 is then mixed with compound 38 and cesium carbonate in DMSO to give compound 39. In step 6, the compound is removed by hydrogenation39 to yield compound 100.

Synthesis of compound 104: (S) -diethyl (2- (4-fluoro-2, 6-dimethylbenzoyl) -3- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenoxy) benzo [ b ] thiophen-6-yl) phosphate

Scheme 9

In step 1, 280 mg of compound 100 was mixed with triethylamine and diethyl chlorophosphate in DCM for 12 hours to give 90mg of compound 104.

Synthesis of compound 105: (S) -2- (4-fluoro-2, 6-dimethylbenzoyl) -3- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenoxy) benzo [ b ] thiophen-6-yl dihydrogenphosphate

Scheme 10

In step 1, 45 mg of compound 104 was mixed with bromotrimethylsilane in DCM for 12 hours to give compound 105. After purification, 24.4 mg of compound 105 were obtained.

Synthesis of compound 38: (S) -4- ((1- (3- (fluoropropyl) pyrrolidin-3-yl) oxy) phenol

Scheme 11

In step 1, 1g of Compound 40 is combined with 3 equivalents of 4- (benzyloxy) phenol and DEAD/PPh₃And (4) mixing. After work-up and column purification, 4g of impure compound 1 are obtained. LCMS analysis showed 40% of the desired compound 41 and 60% excess of 4- (benzyloxy) phenol. Phenol and compound 41 are very similar in polarity and cannot be separated by column chromatography. In step 2, 4g of crude compound 40 from the previous step are subjected to trifluoroacetic acidAnd (4) deprotection. After work-up and column purification, 1.36 g of pure compound 42 are obtained. In step 3, 1.36 g of compound 42 is mixed with potassium carbonate in DMF. After work-up and column purification, 0.8 g of compound 43 are obtained. H-NMR was clean. Compound 43 is then hydrogenated in step 4 to provide compound 38.

Synthesis of compound 106: 3- (4- (2- (ethylamino) ethyl) benzyl) -2- (4-fluoro-2, 6-dimethylbenzoyl) benzo [ b ] thiophene-6-carboxylic acid

Scheme 12

In step 1, compound 44(1.0g) was dissolved in THF and reacted with (Boc) in the presence of TEA₂And (4) reacting. The reaction was stirred at room temperature for 1 hour and purified to give compound 45(1.2 g). In step 2, 600mg of Compound 45 is combined with Tf₂O was reacted in TEA/DCM at 0 ℃ for 1.5 h. After purification, compound 46(420mg) was obtained. In step 3, compound 46(360mg) is reacted with Zn (CN) in DMF₂(1.5 equiv.), tris (dibenzylidene-acetone) dipalladium (0.3 equiv.) and 1,1' -bis (diphenylphosphino) ferrocene (0.1 eq.). The reaction was heated to 80 ℃ and stirred overnight. Compound 47 was observed by LC-MS and, after purification, compound 47(250mg) was obtained. LC-MS and¹HNMR indicates the product. In step 4, compound 47(20mg) was exposed to aqueous NaOH (10%/2 mL) in EtOH (1.0mL) for 3 hours at 80 ℃. Compound 48 was observed by LC-MS. In step 5, compound 48(35mg) was used in Et₂O (1mL)/DCM (1.0mL step) step 5 in HCl. The reaction was stirred at room temperature overnight and then purified to give compound 106 as the HCl salt (21 mg).¹HNMR, HPLC and LC-MS indicated the product.

Synthesis of compound 107: 3- (4- (2- (ethylamino) ethyl) phenoxy) -2- (4-fluoro-2, 6-dimethylbenzoyl) benzo [ b ] thiophen-6-yl dihydrogenphosphate

Scheme 13

In step 1, compound 49(500mg) was reacted with Boc₂O and Na₂CO₃In THF/H₂O at 5 ℃ for 1 hour. Purification gave 480mg of Compound 50. In step 2, compound 50(200mg) was mixed with compound 51 and trimethylamine in THF at 20 ℃ for 12 hours. LC-MS indicated product. After purification, compound 52(180mg) was obtained. In step 3, compound 52(180mg) was mixed with bromotrimethylsilane in DCM at 20 ℃. After stirring for 12 hours, compound 107 was observed by LC-MS. Purification yielded 22.0mg of compound 107. The performance of the HPLC is improved by carrying out the HPLC,¹HNMR and LC-MS indicated compound 107.

Synthesis of compound 108: (S) - (4-fluoro-2, 6-dimethylphenyl) (3- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6-hydroxybenzo [ b ] thiophen-2-yl) methanone

Scheme 14

In step 1, PPh was used in THF₃And DEAD Compound 54(1g) is reacted with Compound 55. The reaction was cooled to 0 ℃ and allowed to warm to room temperature while stirring overnight. After purification, compound 56(1.76g) was obtained. In step 2, compound 56(1.7g) was subjected to deprotection conditions using TFA in DCM. The reaction was stirred at room temperature for 2 hours and purified to give compound 57(1.25 g). In step 3, compound 57(200mg, 1eq) is dissolved in DMF and taken up at K₂CO₃(3 equivalents) with 1-fluoro-3-iodopropane (1.2 equivalents). The reaction was heated to 110 ℃ and stirred overnight. Purification afforded compound 58(70 mg). Pd (PPh) was then used in dioxane₃)₄And K₂CO₃Compound 58(70mg, 1 equivalent) was combined with compound 59And (3) coupling. The reaction was heated to 110 ℃ and stirred overnight. After purification, 95mg of compound 60 was obtained.¹HNMR indicates the product. In step 5, compound 60 is subjected to hydrogenolysis. Dissolve Compound 60(90mg) in CH₃COOH and MeOH, and Ph (OH)₂. After hydrogenolysis at 60 ℃ for 2 hours and purification, compound 108(14.8mg) was obtained.¹HNMR, LC-MS and HPLC indicated Compound 108.

Synthesis of compound 109: (4-fluoro-2, 6-dimethylphenyl) (6-hydroxy-3- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) benzo [ b ] thiophen-2-yl) methanone

Scheme 15

In step 1, compound 61(2.1g) was reacted in PPh₃And DEAD with compound 54. The reaction was cooled to 0 ℃ and allowed to warm to room temperature over 2 hours. Purification gave 1.3g of compound 62. In step 2, Pd (PPh) dissolved in dioxane was used₃)₄And K₂CO₃Compound 62(200mg) was coupled to compound 59. The reaction was heated to 110 ℃ overnight. LC-MS and TLC indicated product. Purification gave compound 63(300 mg). In step 3, compound 63 is subjected to hydrogenolysis. Compound 63(85mg) was dissolved in CH₃COOH and MeOH, and Ph (OH)₂. After hydrogenolysis at 60 ℃ for 2h and purification, compound 109(23mg) was obtained.¹HNMR, LC-MS and HPLC indicated compound 109.

Synthesis of compound 110: (R) - (4-fluoro-2, 6-dimethylphenyl) (3- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6-hydroxybenzo [ b ] thiophen-2-yl) methanone

Scheme 16

In step 1, in PPh in THF₃And DEAD, compound 54(50mg) was reacted with compound 64. The reaction was heated to 65 ℃ and stirred overnight. LC-MS and TLC indicated product. In step 2, compound 65(2g) was dissolved in DCM and TFA was added. The reaction was stirred at room temperature for 2 hours and purified to give compound 66(1.24 g). In step 3, at K₂CO₃(3 equiv.) Compound 66(200mg, 1 equiv.) is reacted with 1-fluoro-3-iodopropane (1.2 equiv.). The reagents were dissolved in DMF and the reaction was heated to 110 ℃ while stirring overnight. Purification gave compound 67(50 mg).¹HNMR indicates the product. In step 4, Pd (PPh) was used in dioxane₃)₄And K₂CO₃Compound 67(50mg) was coupled to compound 59. The reaction was heated to 110 ℃ and stirred overnight. After purification, compound 68(50mg) was obtained.¹HNMR indicates the product. In step 5, compound 68 is subjected to hydrogenolysis. Compound 68(50mg) was dissolved in CH₃COOH and MeOH, and Ph (OH)₂. After hydrogenolysis at 60 ℃ for 2 hours and purification, compound 110(20mg) was obtained.¹HNMR, LC-MS and HPLC indicated Compound 110.

Synthesis of compound 112: (S) - (4-fluoro-2, 6-dimethylphenyl) (7-fluoro-3- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenoxy) -6-hydroxybenzo [ b ] thiophen-2-yl) methanone

Scheme 17

In step 2, compound 78(10g) was converted to compound 79 using methyl 2-mercaptoacetate in piperidine/pyridine at 100 ℃. The reaction was stirred for 4 hours, then purified to give compound 79(11.7 g). In the step ofIn 3, SOCl is used₂Compound 79(2g) was converted to benzothiophene compound 72 in xylene/pyridine. The reaction was heated to 120 ℃ and stirred overnight. In step 4, compound 72 is subjected to n-butyllithium and 2-bromo-5-fluoro-1, 3-dimethylbenzene to give compound 73. In step 5, BBr is used₃Demethylation of compound 73 affords compound 74. In step 6, compound 74 is reacted with sodium hydride and benzyl bromide to provide compound 75. In step 7, compound 75 was mixed with compound 38 and cesium carbonate in DMSO to give compound 76. In step 8, the benzyl protecting group of compound 76 is removed by hydrogenation. Compound 112 is obtained.

Example 3 human ER α reporter Gene assay

All reagents used in this assay were provided by Indigo Biosciences # IB00401 in the human ER α reporter assay. To screen for Selective Estrogen Receptor Degraders (SERDs), the human era reporter assay provided by Indigo Biosciences was used to quantify antagonist functional activity against human estrogen receptors. Reporter cells were thawed at 37 ℃ and then added to Cell Recovery Medium (CRM) pre-warmed to 37 ℃. Stock concentrations of 17 β -estradiol were serially diluted in CRM. Diluted 17 β -estradiol was added to CRM containing reporter cells to give a working concentration of 1.6nM (2 ×). Cells and 17 β -estradiol were dispersed in white-walled 96-well plates provided in the kit. The concentrated stock solutions of test compounds were diluted to 2 × working concentration in Cell Screening Medium (CSM). 2 x concentrated compounds were added to the plated cells in a dose dependent manner with a final concentration ranging from 1E-11 to 1E-5M and a final 17 β -estradiol concentration of 8E-10M. The assay plates were incubated in a humidified 37 ℃ incubator for 24 hours. The medium was removed from the assay plate by inversion. The assay substrate and buffer are warmed to room temperature, mixed well, and then added immediately to the assay plate. The assay plates were incubated for 15 minutes at room temperature in the dark. Luminescence was measured in a Synergy HTX luminescence plate reader. Data were processed using GraphPad Prism 7 by plotting the relative light units measured at each compound concentration.

Example 4 Estrogen Receptor (ER) degradation assay

Screening strategies were carried out using an intracellular Western assay to measure their ability to degrade estrogen receptors in vitro. Estrogen receptor positive MCF7 cells were plated at a cell density of 3.5E-05 cells/mL into black-walled clear-bottom 96-well plates. Cells were incubated in Dulbecco's Modified Eagle Media (DMEM) without phenol red and supplemented with 8% charcoal-treated fetal bovine serum for 24 hours at 37 ℃ in a humidified incubator. The concentrated stock compound was diluted 10 x in complete medium. The compounds were added to the plated cells in a dose-dependent manner at 1E-12 to 1E-05M and incubated at 37 ℃ for an additional 24 hours. The medium was removed from the plate by gentle inversion. Cells were fixed in 4% paraformaldehyde in calcium magnesium free 1 x phosphate buffered saline (PBS-CMF) for 15 min at room temperature and washed 3 times for 5 min each in 1 x PBS-CMF. Cells were permeabilized in Immunofluorescence (IF) blocking buffer (Cell Signaling #12411) containing 0.3% Triton X100. Cells were washed 3 times in 1 × PBS-CMF for 5 minutes each and incubated in the following solutions: in IF antibody dilution buffer (Cell Signaling #12378) at 1: 300 dilution of estrogen receptor alpha (D6R2W) rabbit primary antibody (Cell Signaling # 13258). Cells were washed 3 times for 5 minutes each in 1 x PBS-CMF and diluted with IF antibody in 1: goat anti-rabbit (Biotium # CF770) secondary antibody diluted 2000 and a 1: CellTag 700 at 500 dilutions was stained with normalized stain (Licor # 926-. ER protein expression was assessed by the Licor Odyssey CLx imaging system using Image Studio v 5.2. Data was processed using GraphPad Prism 7 as follows: background from vehicle was subtracted, vehicle was set to 100% ER activity, and treated samples were then compared to vehicle.

Example 5 data from human ER α reporter assay and Estrogen Receptor (ER) degradation assay

The methods in example 3 and example 4 were used to generate the data provided in table 3 below. In the estrogen receptor degradation assay and the human era reporter assay in the following table:

denotes<1μM；IC₅₀；

Denotes <50 μ M IC 50; and

denotes>51μM IC₅₀。

In the following table, for estrogen receptors,% remaining:

represents 0-40% of estrogen receptors remaining.

Indicates 41-70% of estrogen receptors remaining.

Indicates that 71-90% of estrogen receptors remain.

Indicates that 91-100% of estrogen receptors remain.

Table 11.

The scope of the materials and methods of the appended claims is not limited to the specific materials and methods described herein, which are intended to be illustrative of several aspects of the claims, and any materials and methods that are functionally equivalent are within the scope of this disclosure. Various modifications of the materials and methods, in addition to those shown and described herein, are intended to fall within the scope of the appended claims. Moreover, while only certain representative materials, methods, and aspects of such materials and methods have been specifically described, other materials and methods, and combinations of various features of such materials and methods, are intended to fall within the scope of the appended claims, even if not specifically described. Thus, combinations of steps, elements, components or ingredients may be specifically mentioned herein; however, the invention includes all other combinations of steps, elements, components and ingredients, even if not explicitly stated.

143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：SARM1抑制剂

Benzothiophene estrogen receptor modulators for the treatment of medical disorders

相关技术

网友询问留言