JIANG WANLONG (US)
ABRAHAM SUNNY (US)
BUNKER KEVIN (US)
HUANG PETER (US)
WO2020093011A1 | 2020-05-07 | |||
WO2019143730A1 | 2019-07-25 | |||
WO2018013867A1 | 2018-01-18 | |||
WO2006038001A1 | 2006-04-13 | |||
WO2004089913A1 | 2004-10-21 |
WHAT IS CLAIMED IS: 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR5a, or NR5aR5b; R3 is substituted or unsubstituted C3-C8 cycloalkyl or C3-C8 heterocyclyl, wherein the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR5a, NR5aR5b, or OR6; R4 is halogen, CN, alkyl, cycloalkyl, -NR7R8, OR6, -CO2R6, or -C(O)-NR7R8; each R5a, R5b, and R6 is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; R7 and R8 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; wherein the substituted alkyl or substituted cycloalkyl is substituted by 1-3 independently selected from halogen, OR6, CN, alkyl, NHR5a, or NR5aR5b; or R7 and R8, along with the N to which they are connected, are taken together to form an unsubstituted or substituted C3-C8 heterocyclyl wherein the substituted C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR5a, NR5aR5b, or OR6; X is N or CR9; Q1 is C or N; Q2 is CH or N; Q3 is CH, N, or NH; provided that when Q1 is N, then Q3 is N; R9 is hydrogen, each R10 is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; Y and Z are independently N or CH, and each n is independently 0, 1, 2, 3, or 4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is hydrogen. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is halogen. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is CN. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is alkyl. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is alkoxy. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is haloalkyl. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is cycloalkyl. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is NHR5a. 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is NR5aR5b. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or trifluoromethyl. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3 is substituted C3-C8 cycloalkyl. 13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted C3-C8 cycloalkyl. 14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3 is substituted C3-C8 heterocyclyl. 15. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted C3-C8 heterocyclyl. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R3 is piperidinyl, methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, pyrrolidinyl, (N-ethylamino)cyclobutyl, (N-ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxaazaspirodecyl. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is halogen. 18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is CN. 19. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is alkyl. 20. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is cycloalkyl. 21. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is -NR7R8. 22. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is OR6. 23. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is -CO2R6. 24. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4 is -C(O)-NR7R8. 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R4 is CN, N,N-dimethylamido, N,N-diethylamido, , . 26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R5a, R5b, and R6 is hydrogen. 27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R5a, R5b, and R6 is alkyl. 28. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R5a, R5b, and R6 is haloalkyl. 29. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R5a, R5b, and R6 is cycloalkyl. 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R7 and R8 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. 31. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R7 and R8 is hydrogen. 32. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R7 and R8 is substituted alkyl. 33. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R7 and R8 is unsubstituted alkyl. 34. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R7 and R8 is substituted cycloalkyl. 35. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R7 and R8 is unsubstituted cycloalkyl. 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X is N. 37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X is CR9. 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Q1 is C. 39. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Q1 is N and Q3 is N. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q2 is CH. 41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q2 is N. 42. The compound of any one of claims 1 to 38, 40 or 40, or a pharmaceutically acceptable salt thereof, wherein Q3 is CH. 43. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Q3 is N. 44. The compound of any one of claims 1 to 38, 40 or 40, or a pharmaceutically acceptable salt thereof, wherein Q3 is NH. 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R9 is hydrogen. 46. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein 47. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein 48. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein . 50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein at least one of Y and Z is N. 51. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein at least one of Y and Z is CH. 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, with the proviso that, when each R10 is independently methyl or ethyl, Formula (I) i 53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected is selected from , , , , , , 54. A pharmaceutical composition comprising a compound of any one of claims 1 to 53, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. 55. A method for treating a cancer or a tumor comprising administering an effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically active salt thereof, or a pharmaceutical composition of claim 54, to a subject having the cancer or the tumor. 56. The method of claim 55, wherein the cancer or the tumor is selected from urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas. 57. Use of an effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically active salt thereof, or a pharmaceutical composition of claim 54, in the manufacture of a medicament for treating a cancer or a tumor. 58. The use of claim 57, wherein the cancer or the tumor is selected from urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas. |
[0076] R 1 and R 2 in Formula (I) can each independently be hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR 5a , or NR 5a R 5b . In an embodiment, at least one of R 1 and R 2 is hydrogen. In another embodiment, at least one of R 1 and R 2 is halogen. In another embodiment, at least one of R 1 and R 2 is CN. In another embodiment, at least one of R 1 and R 2 is alkyl, e.g., C 1-3 alkyl. In another embodiment, at least one of R 1 and R 2 is alkoxy, e.g., C1-3 alkoxy. In another embodiment, at least one of R 1 and R 2 is haloalkyl, e.g., C1-3 haloalkyl. In another embodiment, at least one of R 1 and R 2 is hydroxyalkyl, e.g., C1-3 hydroxyalkyl. In another embodiment, at least one of R 1 and R 2 is cycloalkyl, e.g., C 3-6 cycloalkyl. In another embodiment, at least one of R 1 and R 2 is NHR 5a . In another embodiment, at least one of R 1 and R 2 is NR 5a R 5b . In another embodiment, at least one of R 1 and R 2 is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or trifluoromethyl. [0077] R 3 in Formula (I) can be a substituted or unsubstituted C 3 -C 8 cycloalkyl or C3-C8 heterocyclyl. In various embodiments, the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 . In an embodiment, R 3 is substituted C3-C8 cycloalkyl. In an embodiment, R 3 is unsubstituted C3-C8 cycloalkyl. In an embodiment, R 3 is substituted C3-C8 heterocyclyl. In an embodiment, R 3 is unsubstituted C3- C 8 heterocyclyl. In an embodiment, R 3 is piperidinyl, methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, pyrrolidinyl, (N-ethylamino)cyclobutyl, (N-ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxaazaspirodecyl. [0078] R 4 in Formula (I) can be halogen, CN, alkyl, cycloalkyl, -NR 7 R 8 , OR 6 , - CO 2 R 6 , or -C(O)-NR 7 R 8 . In an embodiment, R 4 is halogen. In an embodiment, R 4 is CN. In an embodiment, R 4 is alkyl, e.g., C1-3 alkyl. In an embodiment, R 4 is cycloalkyl, e.g., C1-3 cycloalkyl. In an embodiment, R 4 is -NR 7 R 8 . In an embodiment, R 4 is OR 6 . In an embodiment, R 4 is -CO2R 6 . In an embodiment, R 4 is -C(O)-NR 7 R 8 . In various embodiments, R 7 and R 8 of R 4 are each independently unsubstituted alkyl, e.g., C1-3 alkyl. In other embodiments, the R 7 and R 8 of R 4 , along with the N to which they are connected, are taken together to form an unsubstituted or substituted C3-C8 heterocyclyl. In various embodiments, R 4 is CN, N,N- dimethylamido, N,N-diethylamido, [0079] Each R 5a , R 5b , and R 6 in Formula (I) can independently be hydrogen, alkyl, haloalkyl, or cycloalkyl. In an embodiment, at least one of R 5a , R 5b , and R 6 is hydrogen. In an embodiment, at least one of R 5a , R 5b , and R 6 is alkyl, e.g., C1-3 alkyl. In an embodiment, at least one of R 5a , R 5b , and R 6 is haloalkyl, e.g., C1-3 haloalkyl. In an embodiment, at least one of R 5a , R 5b , and R 6 is cycloalkyl, e.g., C 3-6 cycloalkyl. [0080] R 7 and R 8 in Formula (I) can each independently be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In various embodiments, the substituted alkyl or substituted cycloalkyl is substituted by 1-3 independently selected from halogen, OR 6 , CN, alkyl, NHR 5a , or NR 5a R 5b . In alternative embodiments, R 7 and R 8 in Formula (I), along with the N to which they are connected, are taken together to form an unsubstituted or substituted C 3 -C 8 heterocyclyl. In an embodiment, the substituted C 3 -C 8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl (e.g., C1-3 alkyl), alkoxy (e.g., C1-3 alkoxy), haloalkyl (e.g., C1-3 haloalkyl), cycloalkyl (e.g., C3-6 cycloalkyl), heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 . In an embodiment, at least one of R 7 and R 8 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C 1-3 alkyl), or substituted or unsubstituted cycloalkyl (e.g., C3-6 cycloalkyl). In an embodiment, at least one of R 7 and R 8 is hydrogen. In an embodiment, at least one of R 7 and R 8 is substituted alkyl. In an embodiment, at least one of R 7 and R 8 is unsubstituted alkyl (e.g., C 1-3 alkyl). In an embodiment, at least one of R 7 and R 8 is substituted cycloalkyl (e.g., substituted C3-6 cycloalkyl). In an embodiment, at least one of R 7 and R 8 is unsubstituted cycloalkyl (e.g., C3-6 cycloalkyl). In an embodiment, R 7 and R 8 in Formula (I), along with the N to which they are connected, are taken together to form an unsubstituted C3-C8 heterocyclyl. In an embodiment, R 7 and R 8 in Formula (I), along with the N to which they are connected, are taken together to form a substituted C 3 -C 8 heterocyclyl. [0081] X in Formula (I) can be N or CR 9 ; Q1 can be C or N; Q2 can be CH or N; and Q3 can be CH, N, or NH. In an embodiment, when Q1 is N, then Q3 is N. In an embodiment, X is N. In another embodiment, X is CR 9 . In an embodiment, Q 1 is C. In another embodiment, Q1 is N and Q3 is N. In an embodiment, Q2 is CH. In another embodiment, Q2 is N. In an embodiment, Q3 is CH. In another embodiment, Q3 is N. In another embodiment, Q3 is NH. [0082] R 9 in Formula (I) can be hydrogen , , or . In an embodiment, R 9 is hydrogen. In an embodiment, R 9 is . I 9 n an embodiment, R is In an embodim 9 9 ent, R is . In an embodiment, R is Each n in Formula (I) can independently be 0, 1, 2, 3, or 4. In an embodiment, n in R 9 is 1. In another embodiment, n in R 9 is 2. [0083] Each R 10 in Formula (I) can independently be hydrogen, alkyl (e.g., C1-3 alkyl), haloalkyl (e.g., C 1-3 haloalkyl), or cycloalkyl (e.g., C 3-6 cycloalkyl). In an embodiment,
each R 10 is C 1-3 alkyl. In various embodiments of Formula (I), when each R 10 is independently methyl or ethyl, Formula (I) is not . [0084] Y and Z in Formula (I) can each independently be N or CH. In an embodiment, at least one of Y and Z is N. In an embodiment, at least one of Y and Z is CH. [0085] In various embodiments, the compound of Formula (I) has a chemical structure as described in any one of Tables 2-6 and/or the examples below. Synthesis [0086] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein, including the Examples provided below. For example, in an embodiment, compounds of the Formula (I) are prepared in accordance with the general scheme illustrated in FIG 1. Compounds of the Formulae A and B can undergo an AlCl3 induced heteroarylation reaction or metal-catalyzed coupling reaction followed by installation of R 9 on X or full decoration of R 4 . In FIG. 1, L represents a suitable leaving group which is replaced by R 3 amine via aromatic nucleophilic substitution or Buchwald amination. Removal of the protecting group via a hydrogenolysis reaction or acidic hydrolysis provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Any preliminary reaction steps required to form starting compounds or other precursors, can be carried out by those skilled in the art. In FIG. 1 and the illustrated formulae, the variables R 1 , R 2 , R 3 R 4 , R 5a , R 5b , R 6 R 7 , R 8 , R 9 , R 10 , X , Y, Z, Q 1, Q 2 , Q 3 and n can be as described elsewhere herein, taking into consideration the synthetic conversions involved as understood by those of skill in the art. Pharmaceutical Compositions [0087] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0088] The term “pharmaceutical composition” refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. [0089] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended. [0090] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. [0091] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood. [0092] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and/or a metal- chelating agent. A “diluent” is a type of excipient. [0093] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. [0094] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. [0095] Multiple techniques of administering a compound, salt and/or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally. [0096] One may also administer the compound, salt and/or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable. [0097] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for treatment of an indicated condition. Uses and Methods of Treatment [0098] Some embodiments described herein relate to a method for treating a cancer or a tumor described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer or tumor described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or a tumor described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer or a tumor described herein. [0099] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor described herein that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor described herein. In some embodiments, the use can include contacting the growth or the tumor with the medicament. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor described herein. [0100] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. In some embodiments, the use can include contacting the malignant growth or a tumor described herein with the medicament. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for contacting a malignant growth or a tumor described herein, wherein the malignant growth or tumor is due to a cancer described herein. [0101] Examples of suitable malignant growths, cancers and tumors include, but are not limited to: urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas. [0102] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and/or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult. [0103] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance. [0104] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. [0105] For example, an effective amount of a compound is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as non- small cell lung cancer), a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain. As another example, an effective amount, or a therapeutically effective amount of a CDK7 inhibitor is the amount which results in the reduction in CDK7 protein activity. Methods for measuring reductions in CDK7 activity are known to those skilled in the art and can be determined by the analysis of CDK7 binding, e.g., as illustrated in the Examples below. [0106] The amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions. [0107] In general, however, a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between. The compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form. [0108] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. [0109] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine) [0110] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. [0111] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine. [0112] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime. EXAMPLES [0113] FIG. 1 illustrates a synthetic scheme for making compounds of the Formula (I). Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. Intermediate 1 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-in dole-6-carbonitrile 1 [0114] Intermediate 1 was synthesized according to a published procedure (WO 2020/093006). Intermediate 2 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indole-6- carbonitrile (FIG. 2) 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1H-indole-6-carbo nitrile [0115] In a sealed tube, to a stirred solution of 2,4-dichloro-5-nitropyrimidine ( 2.56 g, 13.6 mmol) in 1,2-DCE (15 mL) was added AlCl3 (1.81 g, 20.3 mmol) at RT and stirred at 80 °C for 30 min. Then was added 7-bromo-1H-indole-6-carbonitrile (1.000 g, 4.524 mmol) portion wise at 80 °C and stirred at 80 °C for 12 h. After completion of reaction by TLC, the reaction mixture was cooled to 0 °C and quenched with ice water (30 mL), extracted with 10% tetrahydrofuran in ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and evaporated to get crude compound. The crude compound was triturated with ethyl acetate (100 mL) and dried under vacuum to afford 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1H-indole-6- carbonitrile (1.100 g, 2.906 mmol, 64% yield). MS-(LCMS) m/z: calcd for C13H5BrClN5O2 [M+H] + = 377.93/379.93, observed = 378.07/380.08. LCMS purity: 94%; 1 H NMR (400 MHz, DMSO-d6) 13.13 (s, 1H), 9.32 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H). 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1-((2-(trimethyls ilyl)ethoxy)methyl)-1H-indole- 6-carbonitrile [0116] To a stirred solution of 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1H- indole-6-carbonitrile (2.80 g, 7.40 mmol) in DMF (30 mL) was added NaH (60% in mineral oil, 355 mg, 8.88 mmol) at 0 °C , stirred for 10 min and added SEM-Cl (1.48 g, 8.88 mmol) at 0 °C . The reaction mixture was stirred at 0 °C for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na 2 SO 4 and evaporated. The crude material was purified by silica-gel (100-200) column chromatography using 30-40% EtOAc in pet-ether as an eluent to afford 7-bromo-3-(2-chloro-5-nitropyrimidin- 4-yl)-1-((2 (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (2.50 g, 4.91 mmol, 66% yield). MS-(LCMS) m/z: calcd for C19H19BrClN5O3Si [M+H] + = 508.01/510.01, observed = 508.23/510.25. LCMS purity: 93.28%; 1 H NMR (400 MHz, CDCl3) 8.99 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.99 (t, J =8.0 Hz, 2H), 0.002 (s, 9H). 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2-(trimethyls ilyl)ethoxy)methyl)-1H- indole-6-carbonitrile [0117] To a stirred solution of 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1-((2 (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (2.00 g, 3.93 mmol) in THF (20 mL) and AcOH (5 mL) was added Fe powder (2.195 g, 39.31 mmol) and stirred at rt for 16 h. After consumption of starting material by TLC, the reaction mixture was filtered through celite bed and washed with ethyl acetate (50 mL), evaporated under reduced pressure obtained crude was diluted with water (30 mL) and extracted with ethyl acetate (2 x 750 mL). Organic layer was separated, dried over Na 2 SO 4 , filtered and evaporated. Crude was triturated with diethyl ether (25 mL) to afford 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (1.69 g, 3.54 mmol, 90% yield). MS- (LCMS) m/z: calcd for C19H21BrClN5OSi [M+H] + = 478.04/480.04, observed = 478.25/480.22. LCMS purity: 92.79%; 1 H NMR (400 MHz, CDCl3) 8.38 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 3.88 (s, 2H, NH 2 ), 3.61 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8 Hz, 2H), 0.02 (s, 9H). 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl )ethoxy)methyl)- -indole-6- carbonitrile [0118] To a stirred solution of 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (three batches, 3 x 1.00 g, 3 x 2.09 mmol) in ACN (20 mL) were added isoamyl nitrite (3 x 489 mg, 3 x 4.18 mmol) and Cu(I)Cl (414 mg, 4.18 mmol) at rt and stirred at rt for 30 min. After consumption of starting material by TLC, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (2 x 70 mL). The combined organic layer was separated, dried over Na2SO4 and evaporated. The crude material was purified by silica-gel (100-200) column chromatography using 20-30% EtOAc in pet-ether as a eluent to afford 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile, Intermediate 2 (1.40 g, 2.82 mmol, 45% yield). MS-(LCMS) m/z: calcd for C 19 H 19 BrCl 2 N 4 OSi [M+H] + = 496.99/498.99/500.98 (60%/100%/47%), observed = 497.21/499.23/501.20 (60%/100%/47%). LCMS purity: 96.23%; 1 H NMR (400 MHz, CDCl3) 8.76 (d, J = 8.4 Hz, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 5.99 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8.0 Hz, 2H), -0.03 (s, 9H). Intermediate 3 7-bromo-3-(6-halo-2-(methylsulfonyl)-5-(trifluoromethyl)pyri midin-4-yl)-1H-indole-6- carbonitrile [0119] Intermediate 3 was synthesized similarly to Intermediate 1 with starting pyrimidine analogs as (3,5-dichloro-4-(trifluoromethyl)phenyl)(methyl)sulfane and (3-chloro- 5-fluoro-4-(trifluoromethyl)phenyl)(methyl)sulfane (see WO 2005/047279, CN 112739689 and J Fluorine Chemistry, 1987, 35, 275-285) followed by oxidation to sulfone. Intermediate 4 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrr olo[2,3-b]pyridine-6-carboxylic [0120] To a stirred solution of 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4- yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitr ile (Reference: WO 2019/143719) ( 0.900 g, 1.89 mmol) in EtOH (15 mL) were added 5 M aq. NaOH (10 mL) at 0 °C and stirred at 70°C for 16 h. After completion of the reaction, the solvent was evaporated and slowly acidified with 2N HCl to PH = ~4 and the precipitate was filtered and dried under vacuum to afford 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrr olo[2,3- b]pyridine-6-carboxylic acid, Intermediate 4 (0.800 g, crude used for next step without purification). MS-(LCMS) m/z: calcd for C 14 H 9 F 3 N 4 O 2 S [M+H] + = 355.04, observed = 355.14. Intermediate 5 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxid oisothiazolidin-2-yl)-1H-indole- 6-carbonitrile (FIG. 3)
7-amino-1H-indole-6-carbonitrile [0121] In sealed tube, to a stirred solution of 7-bromo-1H-indole-6-carbonitrile (Reference WO 2018/013867, three batches, 3 x 3.000 g, 3 x 13.57 mmol) in NMP (30 mL) and water (10 mL) were added NaN 3 (3 x 3.529 g, 3 x 54.28 mmol), sodium ascorbate (5.377 g, 27.14 mmol,) and degassed with Argon for 10 min. Then was added CuI (3 x 517 mg, 3 x 2.71 mmol) and (S,S’)-N,N’-dimethyl-1,2-cyclohexanediamine (3 x 642 µL,3 x 4.07 mmol,) degassed again for 10 min. The reaction mixture was heated at 100 °C for 2 h. After completion of the reaction, the reaction was cooled to room temperature and solvent was evaporated under reduced pressure. The brown residue diluted with EtOAc (100 mL), passed through Celite pad and washed with EtOAc (100 mL). The filtrate was evaporated under reduced pressure and the crude was purified by silica gel column chromatography using 20-30% EtOAc and Pet. ether to afford 7-amino-1H-indole-6-carbonitrile (3.62 g , 23.0 mmol, 57%). MS-(LCMS) m/z: calcd for C9H7N3 [M+H] + = 158.06, observed = 158.26. 1 H NMR (400 MHz, CDCl3) δ 8.43 (br s, 1H, NH), 7.32 (dd, J = 3.0, 3.0 Hz, 1H), 7.11 (s, 2H), 6.57 (dd, J = 2.2, 3.0 Hz, 1H), 4.45 (br s, 2H, NH 2 ). 3-chloro-N-(6-cyano-1H-indol-7-yl)propane-1-sulfonamide [0122] To a stirred solution of 7-amino-1H-indole-6-carbonitrile (2.80 g, 17.8 mmol) in DCM (20 mL) were added pyridine (2.87 mL, 35.6 mmol), DMAP (1.74 g, 14.3 mmol) and 3-chloropropane-1-sulfonyl chloride (10.8 mL, 89.1 mmol) (portion wise) at 0°C and stirred at rt for 16h. After consumption of starting material by TLC, the reaction mixture was quenched with cold-water (50 mL), extracted with DCM (2 x 75 mL). The combined organic layer was separated, dried over Na 2 SO 4 and evaporated. The resultant crude material was purified by silica gel (100-200) column chromatography using 20% - 30% EtOAc in pet ether to afford 3-chloro-N-(6-cyano-1H-indol-7-yl)propane-1-sulfonamide (3.51 g, 11.8 mmol, 66% yield). MS-(LCMS) m/z: calcd for C 12 H 12 ClN 3 O 2 S [M+H] + = 298.03, observed = 298.24. 7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile [0123] To a stirred solution of 3-chloro-N-(6-cyano-1H-indol-7-yl)propane-1- sulfonamide (3.50 g, 11.8 mmol) in DMF (35 mL) was added DBU (5.27 mL, 35.3 mmol) at 0°C stirred at rt for 16h. After consumption of starting material by TLC, the reaction mixture was quenched with cold-water (100 mL), extracted with ethyl acetate (2 x 150 mL). The combined organic layer was separated, dried over Na2SO4 and evaporated. The resultant crude material was purified by silica gel (100-200) column chromatography using 20% - 30% EtOAc in pet ether to afford 7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (2.61 g, 9.962 mmol, 85% yield). MS-(LCMS) m/z: calcd for C 11 H 11 N 3 O 2 S [M+H] + = 262.06, observed = 262.30. 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H, NH), 7.76 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 2.8, 2.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 2.0, 2.8 Hz, 1H), 3.86 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.63-2.56 (m, 2H). 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxid oisothiazolidin-2-yl)-1H-indole- 6-carbonitrile [0124] In a sealed tube, to a stirred solution of 2,4-dichloro-5- (trifluoromethyl)pyrimidine (3.737 g, 17.22 mmol) in 1,2-DCE (15 mL) was added AlCl3 (1.378 g, 10.33 mmol) at RT and stirred at 80 °C for 30 min. Then was added 7-(1,1- dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (900 mg, 3.44 mmol) at 80°C and stirred at 80 °C for 16 h. After completion of reaction by TLC, the reaction mixture was cooled to 0 °C and quenched with ice water (30 mL), extracted with 2-Methyl tetrahydrofuran (2 x 150 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to get crude compound. The crude compound was purified by silica gel column chromatography using 20%-30% EtOAc in pet-ether as a mobile phase to afford partially pure compound of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxid oisothiazolidin-2- yl)-1H-indole-6-carbonitrile, Intermediate 5, which was purified by prep-HPLC to afford Intermediate 5 (590 mg, 1.34 mmol, 39% yield). MS-(LCMS) m/z: calcd for C17H11ClF3N5O2S [M+H] + = 442.03, observed = 442.35. 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H, NH), 9.16 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.67-2.60 (m, 2H). Intermediate 6 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxid o-1,2-thiazinan-2-yl)-1H-indole- 6-carbonitrile [0125] Intermediate 6 was synthesized similarly to Intermediate 5. MS-(LCMS) m/z: calcd for C18H13ClF3N5O2S [M+H] + = 456.04, observed = 456.37. 1 H NMR and 19F- HOESY] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (brs, 1H, NH), 9.14 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.76 – 3.73 (m, 1H), 3.48 – 3.32 (m, 1H), 2.40 – 2.23 (m, 2H), 2.01 – 1.83 (m, 2H). Intermediate 7 [0126] A solution of 1,4-dibromobutane (2.000 g, 9.263 mmol) in THF (5 mL) was added to activated magnesium (0.474 g, 19.5 mmol) in THF (5 mL) at 0°C and stirred at 0°C for 1.5 h. Then a solution of diethylphosphite (0.61 mL, 4.8 mmol) in THF (2 mL) was added to the reaction mixture at 0°C and stirred at RT for 16 h. After consumption of the starting material by monitoring TLC, the reaction mixture was quenched with aq. NH4Cl solution (20 mL) and filtered through a celite bed, washed with DCM (10 mL). The separated organic layer was dried over Na 2 SO 4 , filtered and evaporated at 35°C to afford phospholane 1-oxide, Intermediate 1 (0.300 g, 2.88 mmol, crude) as a pale-yellow gummy liquid and which was used as such for next step without further purification and analysis. (Reference: J. Molecular Catalysis A: Chemical, 2000, 160 (2), 249) Intermediate 8 Phosphinane 1-oxide [0127] Intermediate 8 was synthesized similarly to Intermediate 7. Example 1 3-(2-(((3S,6S)-6-Methylpiperidin-3-yl)amino)-5-(trifluoromet hyl)pyrimidin-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile (FIG. 4) [0128] To a stirred solution of 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-indole-6-carbonitrile (Intermediate 1, WO 2020/093006) (590 mg, 1.47 mmol) in NMP (6 mL) were added DIPEA (1.28 mL, 7.35 mmol) and benzyl (2S,5S)-5-amino-2- methylpiperidine-1-carboxylate HCl salt (420 mg, 1.47 mmol) and stirred at 140 °C for 16 h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude was purified by silica gel (100-200) column chromatography using 20-30% EtOAc in pet-ether to afford Benzyl (2S,5S)- 5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyr imidin-2-yl)amino)-2- methylpiperidine-1-carboxylate (750 mg, 1.22 mmol, 83% yield). MS-(LCMS) m/z: calcd for C28H24BrF3N6O2 [M+H] + = 613.11/615.11, observed = 613.16/615.14. [0129] In a microwave vial, to an argon degassed solution of Benzyl (2S,5S)-5-((4- (7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin -2-yl)amino)-2- methylpiperidine-1-carboxylate (three batches, 3 x 100 mg, 0.163 mmol) in DMF (1 mL) were added phospholane 1-oxide, Intermediate 7 (3 x 339 mg, 3 x 3.26 mmol), K3PO4 (3 x 38 mg, 3 x 0.18 mmol), xanthphos (3 x 9.3 mg, 3 x 0.016 mmol) and Pd(OAc) 2 (3 x 3.6 mg, 3 x 0.016 mmol). The reaction mixture was heated at 150 °C in a microwave for 1h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The crude compound was purified by silica gel (100-200) column chromatography using 50-60% EtOAc as a mobile phase in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-cyano-7-(1-oxidophospholan-1-yl)-1H-indol-3 -yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-methyl-piperidine-1 -carboxylate (85 mg, for 3 batches, 0.13 mmol, 27% yield) as a pale-yellow sticky liquid. MS (LCMS) m/z: calcd for C32H32F3N6O3P [M+H] + = 637.22, observed = 637.42. [0130] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-cyano-7-(1- oxidophospholan-1-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyri midin-2-yl)amino)-2-methyl- piperidine-1-carboxylate (150 mg, 0.236 mmol) in ethyl acetate (2 mL) was added 10% palladium on carbon (50% moisture) (70 mg) and stirred under hydrogen balloon atmosphere at room temperature for 3 days. After completion of reaction by monitoring TLC, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was concentrated to get crude material, which was purified by prep HPLC to afford3-(2-(((3S,6S)- 6-Methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-7-(1-oxidophospholan-1- yl)-1H-indole-6-carbonitrile, Example 1 (36.8 mg, 0.0732 mmol, 31%). [0131] Prep. HPLC method: Column/dimensions: X–bridge PHENYL (19*250*5µm); Mobile phase A: 10mm Ammonium bicarbonate in water; Mobile phase B: Acetonitrile Gradient (Time/%B): 0.01/30, 1/30, 10/55, 14/59, 14.1/100, 17/100, 20/30, 20.1/30. Flow rate: 18 ml/min solubility: Acetonitrile + THF+WATER. [0132] MS-(LCMS) m/z: calcd for C24H26F3N6OP [M+H] + = 503.19, observed = 503.52. 1 H NMR (400 MHz, , 90 °C VT, DMSO-d6) δ 8.57 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.61 (dd, J = 3.0, 8.4 Hz 1H), 7.43 (d, J = 8.4 Hz, 1H, NH), 3.92 – 3.78 (m, 1H), 3.20 – 3.13 (m, 1H), 2.50 – 2.58 (m, 1H), 2.45 – 2.35 (m, 3H), 2.30 – 2.07 (m, 6H), 2.07 – 1.95 (m, 1H), 1.71 – 1.64 (m, 1H), 1.55 – 1.39 (m, 1H), 1.18 – 1.06 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H). LCMS purity: 98.47%; HPLC purity: 99.36%. [0133] The examples in Table 2 were prepared using methods similar to those described for the synthesis of Example 1. Table 2
Example 8 3-(5-Chloro-2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimid in-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile (FIG. 5) [0134] To a stirred solution of benzyl (2S,5S)-5-amino-2-methylpiperidine-1- carboxylate HCl salt (0.689 g, 2.42 mmol) in 1,4-dioxane (12 mL) was added DIPEA (2.10 mL, 12.1 mmol), followed by adding Intermediate 2 (1.21 g, 2.42 mmol) and stirred at 120 °C for 16 h. After consumption of starting material, the reaction mixture was evaporated under reduced pressure to obtain crude compound. Crude was purified by silica gel (100-200) column chromatography using 20-30% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(7-bromo- 6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)- 5-chloropyrimidin-2-yl)amino)- 2-methyl-piperidine-1-carboxylate (0.8 g, 1.13 mmol, 47% yield). MS (LCMS) m/z: calcd for C 33 H 38 BrClN 6 O 3 Si [M+H] + = 709.16/711.16/712.17 (75%/100%/36%), observed = 709.53/711.54/712.56 (71%/100%/36%). LCMS purity: 93.35%; 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 – 7.25 (bs, 5H), 5.99 (s, 2H), 5.54 (d, J = 7.6 Hz, 1H), 5.18-5.09 (m, 2H), 4.64 – 4.54 (m, 1H), 4.32 (d, J = 14.0 Hz, 1H), 4.25-4.13 (m, 1H), 3.63 (t, J = 8.0 Hz, 2H), 3.26 (dd, J = 2.4, 14 Hz, 1H), 2.10 – 1.90 (m, 2H), 1.53 – 1.44 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 0.98 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H). [0135] To a stirred solution of Benzyl (2S,5S)-5-((4-(7-bromo-6-cyano-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-chloropyrimi din-2-yl)amino)-2-methyl- piperidine-1-carboxylate (two batches, 2 x 0.400 g, 0.563 mmol) in THF (4 mL) was added ethylene diamine (2 x 0.11 mL, 2 x 1.69 mmol) and TBAF (2 x 3.38 mL, 2 x 3.38 mmol). The reaction mixture was stirred at 70 °C for 1 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was separated, dried over Na 2 SO 4 , filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 40-50% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-chloropyrimi din- 2-yl)amino)-2-methylpiperidine-1-carboxylate (0.570 g, 0.983 mmol, 87% yield). MS- (LCMS) m/z: calcd for C27H24BrClN6O2 [M+H] + = 579.08/581.08/582.08 (77%/100%/31%), observed = 579.19/581.21/583.20 (77%/100%/30%). LCMS purity: 98.85%; 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H, NH), 8.49 (d, J =8.4 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.34 – 7.20 (bs, 5H), 5.48 (d, J = 7.2 Hz, 1H, NH), 5.15 – 5.07 (m, 2H), 4.62 – 4.56 (m, 1H), 4.32 (d, J = 14.0 Hz, 1H), 4.23 – 4.14 (m, 1H), 3.24 (dd, J = 2.4, 14.0 Hz, 1H), 2.06 – 1.91 (m, 2H), 1.50 – 1.42 (m, 1H), 1.24 (d, J =6.8 Hz, 3H). [0136] In a microwave vial, to an argon degassed solution of Benzyl (2S,5S)-5-((4- (7-bromo-6-cyano-1H-indol-3-yl)-5-chloropyrimidin-2-yl)amino )-2-methylpiperidine-1- carboxylate (five batches, 5 x 100 mg, 5 x 0.172 mmol) in DMF (1 mL) were added phospholane 1-oxide, Intermediate 7 (5 x 359 mg, 5 x 3.45 mmol), K 3 PO 4 (5 x 40 mg, 5 x 0.19 mmol), xantphos (5 x 10 mg, 5 x 0.017 mmol) and Pd(OAc)2 (3.9 mg, 5 x 0.017 mmol), stirred at 150 °C in a microwave reactor for 1 h. After consumption of starting material, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was dried over Na 2 SO 4 and evaporated to get crude material. The crude compound was purified by silica gel column chromatography using 90-100% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((5-chloro-4-(6-cyano-7-(1-oxidophospholan-1-yl)- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-methylpiperidine-1-car boxylate, Intermediate 9 (180 mg, 0.298 mmol, 35% yield). MS-(LCMS) m/z: calcd for C 31 H 32 ClN 6 O 3 P [M+H] + = 603.20, observed = 603.55. LCMS purity: 94.25%; 1 H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H, NH), 8.74 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 7.58 (dd, J =3.2, 8.0 Hz, 1H), 7.34 –7.20 (bs, 5H), 5.47 (d, J = 7.2 Hz, 1H), 5.16 – 5.05 (m, 2H), 4.62 – 4.52 (m, 1H), 4.31 (d, J = 14.0 Hz, 1H), 4.25 – 4.17 (m, 1H), 3.23 (dd, J = 2.4, 14.0 Hz, 1H), 2.50 – 2.17 (m, 8H), 2.10 – 1.87 (m, 2H), 1.50 – 1.40 (m, 1H), 1.24 (d, J =6.8 Hz, 3H). [0137] To a stirred degassed solution of Intermediate 9 (two batches, 2 x 40 mg, 0.066 mmol) in DCM (0.4 mL), Et 3 N (2 x 4 µL, 2 x 0.03 mmol), Et 3 SiH (2 x 53 µL, 2 x 39 mg, 2 x 0.33 mmol), Pd(OAc) 2 (2 x 3.0 mg, 2 x 0.013 mmol) was added and stirred at RT for 1.5 h. After consumption of starting material, reaction mixture was evaporated under reduced pressure. The crude compound was purified by prep-HPLC to afford 3-(5-Chloro-2-(((3S,6S)- 6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophosp holan-1-yl)-1H-indole-6- carbonitrile, Example 8 (18 mg, 0.038 mmol, 29% yield). [0138] Prep. HPLC purification conditions: Column/dimensions: YMC C18(19*250*5µm); Mobile Phase A :10 mM ABC in water; Mobile phase B: Acetonitrile Gradient (Time/%B): 0.01/15, 1/15, 10/45, 14.5/45, 14.6/100, 18/100, 18.1/15, 21/15. Flow rate: 18 ml/min. Solubility: THF+ACN. [0139] MS-(LCMS) m/z: calcd for C 23 H 26 ClN 6 OP [M-H]- = 467.16, observed = 467.38. LCMS purity: 98.87%; HPLC purity: 97.05%; 1 H NMR (400 MHz, DMSO-d 6 ) (D 2 O Exchange-VT at 90 °C) δ 8.88 (dd, J = 1.6, 8.4 Hz, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J = 3.2, 8.4 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.34 – 3.16 (m, 1H), 2.61 – 2.52 (m, 1H), 2.44 – 2.34 (m, 3H), 2.30 – 2.21 (m, 6H), 2.10 – 2.03 (m, 1H), 1.75 – 1.66 (m, 1H), 1.48 – 1.37 (m, 1H), 1.26 – 1.16 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). Example 13 3-(5-Methyl-2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimid in-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile
[0140] In a microwave vial, to an argon degassed solution of Intermediate 9 (two batches, 2 x 40 mg, 2 x 0.066 mmol) in 1,4-dioxane/H2O (1.0 mL) were added methylboronic acid (2 x 40 mg, 2 x 0.33 mmol), Cs2CO3 (2 x 65 mg, 2 x 0.20 mmol), Catacxium (2 x 24 mg, 2 x 0.066 mmol) and Pd(OAc) 2 (2 x 7.4 mg, 2 x 0.033 mmol) at rt. The reaction mixture was stirred at 100 °C in a microwave reactor for 2 h. After consumption of starting material, the reaction mixture was diluted with ethyl acetate (10 mL), filtered through celite pad, filtrate concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography using 2-3% methanol in DCM to afford Benzyl (2S,5S)-5-((4-(6-cyano-7-(1-oxidophospholan-1-yl)-1H-indol-3 -yl)-5-methylpyrimidin-2- yl)amino)-2-methylpiperidine-1-carboxylate (60 mg, 0.10 mmol, 78% yield). MS-(LCMS) m/z: calcd for C 32 H 35 N 6 O 3 P [M+H] + = 583.25, observed = 583.55. LCMS purity: 88.50%. [0141] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-cyano-7-(1- oxidophospholan-1-yl)-1H-indol-3-yl)-5-methylpyrimidin-2-yl) amino)-2-methylpiperidine- 1-carboxylate (two batches, 2 x 30 mg, 2 x 0.051 mmol) in DCM (0.4 mL) were added Et 3 N (2 x 2.9 µL, 2 x 0.021 mmol), Et3SiH (2 x 41 µL, 2 x 30 mg, 2 x 0.26 mmol) and Pd(OAc)2 (2 x 2.3 mg, 2 x 0.010 mmol) at rt. The reaction mixture was stirred at 45 °C for 1.5 h. After consumption of starting material by TLC, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford3-(5-Methyl-2-(((3S,6S)- 6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophosp holan-1-yl)-1H-indole-6- carbonitrile, Example 13 (7.0 mg, 0.015 mmol, 15% yield). [0142] MS-(LCMS) m/z: calcd for C 24 H 29 N 6 OP [M+H] + = 449.21, observed = 449.57. LCMS purity: 97.42%; HPLC purity: 98.66%; Chiral purity: 98.84; 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1H, NH), 8.91 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 6.53 (br s, 1H, NH), 3.81 – 3.69 (m, 1H), 3.20 – 3.11 (m, 1H), 2.50 – 2.30 (m, 4H), 2.28 (s, 3H), 2.30 – 1.96 (m, 7H), 1.70 – 1.60 (m, 1H), 1.43 – 1.30 (m, 1H), 1.19 – 1.06 (m, 1H), 1.04 (d, J = 6.2 Hz, 3H). [0143] The examples in Table 3 were prepared using methods similar to those described for the syntheses of Examples 8 and 13. Table 3
Example 18 N-(3,5-dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperid in-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6 -carboxamide (FIG. 6)
[0144] To a stirred solution of Intermediate 4 (800 mg, crude) in DMF (10 mL) were added DIPEA (2.21 mL, 12.7 mmol), HOBt (512 mg, 3.79 mmol) and EDC-HCl (720 mg, 3.76 mmol) at 0 °C. The reaction mixture was stirred for 10 min and then was added 3,5- dimethylisoxazol-4-amine (420 mg, 3.75 mmol) at room temperature. The reaction mixture was stirred for 16h at room temperature. After consumption of starting materials by TLC, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over Na2SO4 and evaporated to get crude compound. The crude compound was purified by silica gel (100-200) column chromatography using 70-80% EtOAc in pet-ether as an eluent to afford N-(3,5-dimethylisoxazol-4-yl)-3-(2- (methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2 ,3-b]pyridine-6-carboxamide (300 mg , 0.669 mmol, 35% over 2 steps). MS-(LCMS) m/z: calcd for C 19 H 15 F 3 N 6 O 2 S [M+H] + = 449.09, observed = 449.24. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.72 (br s, 1H, NH), 9.98 (s, 1H), 8.99 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 2.67 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H). [0145] To a stirred solution of N-(3,5-dimethylisoxazol-4-yl)-3-(2-(methylthio)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6 -carboxamide (300 mg, 0.669 mmol) in 1,2-DME (8 mL) was added m-CPBA (~70%, 412 mg, 1.67 mmol) at- 40 °C and stirred at -40 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4 and evaporated to afford N-(3,5-dimethylisoxazol-4-yl)-3-(2- (methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrro lo[2,3-b]pyridine-6- carboxamide (400 mg, crude used for next step without purification). MS-(LCMS) m/z: calcd for C19H15F3N6O4S [M+H] + = 481.08, observed = 481.26. [0146] To a stirred solution of N-(3,5-dimethylisoxazol-4-yl)-3-(2- (methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrro lo[2,3-b]pyridine-6- carboxamide (400 mg, crude) in THF (5 mL) were added DIPEA (0.76 mL, 4.4 mmol), benzyl (2S,5S)-5-amino-2-methylpiperidine-1-carboxylate HCl salt (191 mg, 0.669 mmol) and stirred at rt for 1h. After consumption of starting material by TLC, the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 50 mL). The organic layer was separated, dried over Na 2 SO 4 , filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 40-50% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-((3,5- dimethylisoxazol-4-yl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-methylpiperidine-1- carboxylate (60 mg, 0.092 mmol, 14% yield over two steps). MS-(LCMS) m/z: calcd for C 32 H 31 F 3 N 8 O 4 [M+H] + = 649.24, observed = 649.57. [0147] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-((3,5-dimethylisoxazol-4- yl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromet hyl)pyrimidin-2-yl)amino)-2- methylpiperidine-1-carboxylate (60 mg, 0.092 mmol) in DCM (1 mL) was added BBr3 (1M in DCM (0.5 mL) at 0 °C and stirred at 0 °C for 30 min. The reaction mixture was quenched with ice water (1 mL) and evaporated. Crude was purified by prep HPLC to afford N-(3,5- dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6 -carboxamide, Example 18 (7.0 mg, 0.014 mmol, 15% yield). [0148] Prep-HPLC method: Column/dimensions: X BRIDGE PHENYL (19*250*5um); Mobile phase A: 10 MM ABC in water (aq); Mobile phase B: Acetonitrile (org); Gradient (Time/%B): 0/25,1/25,09/55,11.8. /55,11.9/100,14.8/100,14.9/25,17/25. Flow rate: 19 mL/min; Solubility: Acetonitrile+ THF+WATER. [0149] MS-(LCMS) m/z: calcd for C 24 H 25 F 3 N 8 O 2 [M-H]- = 513.21, observed = 513.32. 1 H NMR (400 MHz, DMSO-d6) VT at 90 °C δ 12.72 (br s, 1H, NH), 9.61 (s, 1H, NH), 8.81 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H, NH), 3.92 – 3.83 (m, 1H), 3.22 – 3.15 (m, 1H), 2.60 – 2.47 (m, 2H), 2.33 (s, 3H), 2.16 (s, 3H), 2.07 – 2.00 (m, 1H), 1.72 – 1.64 (m, 1H), 1.55 – 1.41 (m, 1H), 1.20 – 1.10 (m, 1H), 1.00 (d, J = 6.0 Hz, 3H). LCMS purity: 98.68%, UPLC purity 97.62%. [0150] The examples in Table 4 were prepared using methods similar to those described for the synthesis of Example 18. Table 4
Example 28 N-(3,5-dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperid in-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxamide (FIG. 7) [0151] To a stirred solution of 1H-indole-6-carboxylic acid (two batches, 2 x 5.00 g, 2 x 31.0 mmol) in DMF (60 mL) were added DIPEA (2 x 16.2 mL, 93.0 mmol) and HATU (2 x 14.1 g, 37.2 mmol). The reaction mixture was stirred for 10 min, then added 3,5- dimethylisoxazol-4-amine (2 x 3.48 g, 31.0 mmol). The reaction mixture was stirred at rt for 16 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (250 mL) and extracted with ethyl acetate (2x 100 mL), solvent was evaporated to get crude compound. The combined crude compound was purified by silica gel (100-200) column chromatography using 70-80% EtOAc in pet-ether to afford N-(3,5-dimethylisoxazol- 4-yl)-1H-indole-6-carboxamide (10.0 g, 39.2 mmol, 63% yield). MS-(LCMS) m/z: calcd for C14H13N3O2 [M+H] + = 256.10, observed = 256.22. [0152] In a sealed tube, to a stirred solution of 2,4-dichloro-5- (trifluoromethyl)pyrimidine (15.176 g, 69.95 mmol) in DCE (60 mL) was added AlCl 3 (4.694 g, 35.21 mmol) at room temperature and stirred at 80 °C for 30 min. Then was added N-(3,5- dimethylisoxazol-4-yl)-1H-indole-6-carboxamide (6.000 g, 23.50 mmol) to the above reaction mixture at 80 °C and stirred for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with ice cold water (60 mL), extracted with 10% THF in ethyl acetate (2 x 300 mL). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered and evaporated to get semi pure compound. The crude compound was purified by silica gel column chromatography using 30% EtOAc in pet-ether to afford partially pure 3-(2-chloro-5- (trifluoromethyl) pyrimidin-4-yl)-N-(3,5-dimethylisoxazol-4-yl)-1H-indole-6-ca rboxamide which was purified by prep-HPLC to afford pure desired product (700 mg, 1.61 mmol, 7% yield). Structure was further confirmed by 19 F HOESY. MS-(LCMS) m/z: calcd for C 19 H 13 ClF 3 N 5 O 2 [M+H] + = 436.06, observed = 436.34. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.56 (s, 1H), 9.83 (s, 1H), 9.08 (s, 1H), 8.43 (d, J = 8.80 Hz, 1H)), 8.25 (s, 1H)), 8.20 (s, 1H), 7.88 (d, J = 8.80 Hz, 1H)), 2.34 (s, 3H), 2.16 (s, 3H). [0153] Prep-HPLC method: Column/dimensions: X-BRIDGE-C18 (19*250*5um); Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: CAN; Gradient (Time/%B): 0/35, 3/35, 15/75, 18/75, 18.1/100, 20/100, 20.1/35, 22/35; Flow rate: 17ml/min. Solubility: WATER+THF+ACN. [0154] To a stirred solution of 3-(2-chloro-5-(trifluoromethyl) pyrimidin-4-yl)-N- (3,5-dimethylisoxazol-4-yl)-1H-indole-6-carboxamide (700 mg, 1.61 mmol) in NMP (10 mL) were added DIPEA (1.40 mL, 8.05 mmol), benzyl (2S,5S)-5-amino-2-methylpiperidine-1- carboxylate hydrochloride (458 mg, 1.61 mmol) and stirred at 120 °C for 16h. After consumption of starting material, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 20-30% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-((3,5- dimethylisoxazol-4-yl)carbamoyl)-1H-indol-3-yl)-5-(trifluoro methyl)pyrimidin-2-yl)amino)- 2-methylpiperidine-1-carboxylate (500 mg, 0.772 mmol, 48% yield). MS-(LCMS) m/z: calcd for C 33 H 32 F 3 N 7 O 4 [M+H] + = 648.25, observed = 648.54. [0155] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-((3,5-dimethylisoxazol-4- yl)carbamoyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-2-methylpiperidine- 1-carboxylate (500 mg, 0.772 mmol) in DCM (5 mL) was added BBr 3 (1M in DCM, 3.9 mL, 3.9 mmol) and stirred at room temperature for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated to get crude material, which was purified by prep-HPLC to afford N-(3,5- dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxamide, Example 28 (200 mg, 0.389 mmol, 50%). [0156] Prep-HPLC Method: Column/dimensions: X –bridge PHENYL ((19*250*5µm); Mobile phase A: 10mM ABC in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0.01/20, 1/20, 10/40, 17/40, 17.1/100, 21/100, 21.1/20, 23/20; Flow rate: 18 ml/min; Solubility: Acetonitrile + THF+WATER. [0157] MS-(LCMS) m/z: calcd for C25H26F3N7O2 [M+H] + = 514.21, observed = 514.29. 1 H NMR (400 MHz, DMSO-d6) VT at 90 °C; δ 11.81 (br s, 1H, NH), 9.47 (s, 1H, NH), 8.53 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.40 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H, NH), 3.96 – 3.83 (m, 1H), 3.21 – 3.15 (m, 1H), 2.60 – 2.48 (m, 2H), 2.13 (s, 3H), 2.15 (s, 3H), 2.10 – 2.00 (m, 1H), 1.72 – 1.66 (m, 1H), 1.52 – 1.42 (m, 1H), 1.20 – 1.07 (m, 1H), 1.00 (d, J = 6.00 Hz, 3H). LC-MS purity: 97.11%; HPLC purity: 98.63%. [0158] The examples in Table 5 were prepared using methods similar to those described for the synthesis of Example 28. Table 5
Example 32 (S)-7-(1,1-dioxidoisothiazolidin-2-yl)-3-(2-(piperidin-3-yla mino)-5-(trifluoromethyl) pyrimidin-4-yl)-1H-indole-6-carbonitrile [0159] To a stirred solution of Intermediate 5 (120 mg, 0.272 mmol) in NMP (1.21 mL) were added DIPEA (237 µL, 1.36 mmol), tert-butyl (S)-3-aminopiperidine-1-carboxylate (54.4 mg, 0.272 mmol) and stirred at 140 °C for 16 h. After consumption of starting material, reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 15 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 50-70% EtOAc in pet-ether to afford tert-butyl (S)-3-((4-(6-cyano-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-ind ol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxyla te (113 mg, 0.186 mmol, 69% yield). MS-(LC-MS) m/z: calcd for C27H30F7N7O4S [M+H] + = 606.20, observed = 606.58. [0160] To a stirred solution of tert-butyl (S)-3-((4-(6-cyano-7-(1,1- dioxidoisothiazolidin-2-yl)-1H-indol-3-yl)-5-(trifluoromethy l)pyrimidin-2- yl)amino)piperidine-1-carboxylate (120 mg, 0.198 mmol) in DCM (3 mL) was added TFA (76 µL, 0.99 mmol) at 0 °C and stirred at 0 °C for 30 min. After consumption of starting material by TLC, the reaction mixture was concentrated under vac. The obtained crude material was purified by combi-flash (C-18) using 0.1% ABC buffer to afford (S)-7-(1,1- dioxidoisothiazolidin-2-yl)-3-(2-(piperidin-3-ylamino)-5-(tr ifluoromethyl) pyrimidin-4-yl)- 1H-indole-6-carbonitrile, Example 32 ( 22 mg , 0.044 mmol, 22% yield). [0161] MS-(LCMS) m/z: calcd for C 22 H 22 F 3 N 7 O 2 S [M-H]- = 504.15, observed = 504.25. LCMS purity: 98.78%; UPLC purity: 98.60%; 1 H NMR (400 MHz, DMSO-d6, D2O Exchange-VT at 90 °C) δ 8.58 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 3.95 (d, J = 6.6 Hz, 2H), 3.98 – 3.89 (m, 1H), 3.56 (d, J = 7.4 Hz, 2H), 3.10 (dd, J = 3.2, 12.0 Hz, 1H), 2.86 – 2.77 (m, 1H), 2.74 – 2.63 (m, 2H), 2.60 – 2.50 (m, 2H), 2.02 – 1.94 (m, 1H), 1.74 – 1.64 (m, 1H), 1.62 – 1.42 (m, 2H). [0162] The examples in Table 6 were prepared using methods similar to those described for the synthesis of Example 32. Table 6
Example A [0163] CDK7 enzymatic inhibition activity was evaluated at Reaction Biology Corporation using the “HotSpot” assay platform as published in the literature (Anastassiadis T. et al., Nat Biotechnol. 2011, 29(11):1039-45). The data is provided in Table 7. [0164] The effect of the CDK7 inhibitor to inhibit the growth of MCF7 and OVCAR3 cells was evaluated through the 6 day-time period of viability assay (Table 7). Briefly, the candidate cell lines were plated in 96 well plate at the following density of cells respectively, 3000-3500 cells/well for MCF7, 3000 cells/well for OVCAR-3. After 24 hours, the cells were treated with various concentrations of the compound (diluting the compound 1:3 in DMSO for 10 points). DMSO solvent without compound served as a control. After 6 days of incubation at 37 °C, 5% CO2 incubator, cells were analyzed for the viability using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat# G7570). All viability assays were performed in duplicate, and Luminescence was read using an Envision (Perkin Elmer, USA). Nonliner regression and sigmoidal dose-response curves are used to calculate EC50 with Graphpad Prism software. [0165] The results of these assays are shown in Table 7 where “A” represents a measured CDK7/cyclin H IC50 of less than 10 nM or OVCAR3 CGT EC50 of less than 100 nM or MCF7 CGT EC 50 of less than 100 nM; “B” represents a measured CDK7/cyclin H IC 50 of between 10 nM and less than 100 nM or OVCAR3 CGT EC50 of between 100 nM and less than 1 μΜ or MCF7 CGT EC50 of between 100 nM and less than 1 μΜ; “C” represents a measured CDK7/cyclin H IC 50 of greater than or equal to 100 nM or OVCAR3 CGT EC 50 of greater than or equal to 1 μΜ or MCF CGT EC 50 of greater than or equal to 1 μΜ, and “NT” represents that the specified compound was not tested in the specified assay. Table 7
[0166] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.